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 of related applications This application is an international application claiming the benefits of U.S. Provisional Application No. 63 / 203,761 filed on 30 July 2021, which is incorporated herein by reference in its entirety.

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

[0003] Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder of the brain characterized by symptoms of involuntary movements, cognitive impairment, and mental decline. Death is typically caused by pneumonia or coronary artery disease and usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is 3 to 7 per 100,000 people in the Western population. 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 the elongation of a series of trinucleotide CAG repeats in the "mutated" huntingtin (Htt) gene, which leads to the production of HTT (Htt protein), which exhibits an elongation of the polyglutamine (PolyQ) stretch, also known as the "CAG repeat" sequence. Current small molecule therapies do not target the underlying cause of the disease, and the high need for drugs that can be used to treat or induce remission of HD remains unmet. As a result, there remains a need to identify and provide small molecule compounds for treating or relieving HD. All other documents referenced herein are incorporated by reference as fully specified herein. [Overview of the project]

[0004] The embodiments described herein relate to compounds of the following formula (I): [ka] Or relating to its form, in the formula, R A , R A1 , R A2 , X 1 , X 2 , R B1 , and R B2 This is as defined herein. Aspects of this specification also relate to methods of using a compound of formula (I), a form thereof, or a composition thereof to treat or induce remission of HD in a subject requiring treatment or remission of HD, the method comprising administering an effective amount of the compound, a form thereof, or a composition thereof to the subject. Aspects of this specification further relate to the use of a compound of formula (I) or a form thereof for treating or relieving HD in a subject requiring treatment or remission of HD, the use of which includes administering an effective amount of the compound or a form thereof to the subject. Aspects of this specification further relate to the use of a compound of formula (I) or a form thereof for preparing a medicament useful for treating or relieving HD in a subject requiring treatment or remission of HD, the use of which includes administering an effective amount of the medicament to the subject. Aspects of this specification further relate to the use of a compound of formula (I) or a form thereof useful for treating or relieving HD in combination with other agents in subjects requiring treatment or remission of HD, the use of which includes administering an effective amount of the combination product to the subject for treating or relieving HD. [Modes for carrying out the invention]

[0005] Embodiments of this specification relate to compounds of the following formula (I): [ka] Or, in relation to its form, in the formula: RA is represented by the following formula:

Chemical Formula

[0006] Specification One aspect of this specification relates to a compound of the following formula (I): [ka] Or, in relation to its form, in the formula: R A The formula is as follows: [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 selected from the group consisting of hydrogen, hydroxyl, and C 1‐4 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 selected from the group consisting of 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 bonded form a saturated 3- to 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 bonded form a saturated 5- to 10-membered ring system; or R 2 and R 7 together with the atoms to which they are bonded form a saturated 5- to 10-membered ring system; or R 4 and R 5 together with the atoms to which they are bonded form a saturated 3- to 6-membered ring incorporating 0 or 1 heteroatom ring member selected from N, O, and S; R A1 and R A2each independently selected from the group consisting of 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)2amino, amino-C 1‐4 alkyl, and hydroxy-C 1‐4 selected from the group consisting of alkyl; and R B1 and R B2 each independently selected from the group consisting of 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 form of said compound is selected from the group consisting of salts, racemates, enantiomers, diastereomers, stereoisomers, and tautomers thereof.

[0007] One embodiment comprises a compound of formula (I), wherein R A is of the following formula:

Chemical Formula

[0008] One embodiment comprises a compound of formula (I), wherein R A is of the following formula:

Chemical Formula

[0009] One embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] And, In the equation, p is 0 and q is 1.

[0010] One embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] And, In the equation, p is 1 and q is 0.

[0011] One embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] And, In the equation, p and q are 1.

[0012] Another embodiment includes a compound of formula (I), where R A This group consists of the following: [ka] and any of these stereoisomers are selected.

[0013] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0014] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0015] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0016] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0017] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0018] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] and any stereoisomer thereof.

[0019] Another embodiment includes a compound of formula (I), where R A -2 is given by the following formula: [ka] or any further stereoisomers thereof.

[0020] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0021] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0022] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0023] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0024] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0025] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0026] Another embodiment includes a compound of formula (I), where R A -2-c is the following formula: [ka] That is the case.

[0027] Another embodiment includes a compound of formula (I), where R A -2-d is given by the following formula: [ka] That is the case.

[0028] Another embodiment includes a compound of formula (I), where R A -5 is given by the following formula: [ka] or any further stereoisomers thereof.

[0029] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0030] Another embodiment includes a compound of formula (I), where R A The formula is as follows: [ka] That is the case.

[0031] Another embodiment includes a compound of formula (I), where R A -7 is given by the following formula: [ka] or any further stereoisomers thereof.

[0032] Another aspect comprises a compound of formula (I), wherein R A is of the following formula:

Chemical Formula

[0033] Another aspect comprises a compound of formula (I), wherein R A is of the following formula:

Chemical Formula

[0034] Another aspect comprises a compound of formula (I), wherein R A -7 is of the following formula:

Chemical Formula

[0035] Another aspect comprises a compound of formula (I), wherein R A -7-b is of the following formula:

Chemical Formula

[0036] Another aspect comprises a compound of formula (I), wherein R A -8 is of the following formula:

Chemical Formula

[0037] Another aspect comprises a compound of formula (I), wherein R A -10 is of the following formula:

Chemical Formula

[0038] Another aspect includes a compound of formula (I), wherein R A is represented by the following formula:

Chemical Formula

[0039] Another aspect includes a compound of formula (I), wherein R A is represented by the following formula:

Chemical Formula

[0040] Another aspect includes a compound of formula (I), wherein R A -11 is represented by the following formula:

Chemical Formula

[0041] Another aspect includes a compound of formula (I), wherein R A is represented by the following formula:

Chemical Formula

[0042] Another aspect includes a compound of formula (I), wherein R A is represented by the following formula:

Chemical Formula

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

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

[0045] One embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 These are, independently, hydrogen, halogen, hydroxyl, cyano, and 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 Selected from the group consisting of alkoxys. Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 These are, independently, hydrogen, halogen, and C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 Each of them is an independent hydrogen atom. Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 , and R 11 Each of these is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is alkyl. Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 Each of these is independently methyl.

[0046] Another embodiment includes a compound of formula (I), where R 2 and R 3 Each of these is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is alkyl. Another embodiment includes a compound of formula (I), where R 2 It is methyl. Another embodiment includes a compound of formula (I), where R 3 It is methyl. Another embodiment includes a compound of formula (I), where R 2 and R 3 Each of these is methyl. Another embodiment includes a compound of formula (I), where R 4 and R 5 Each of these is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is alkyl. Another embodiment includes a compound of formula (I), where R 4 It is methyl. Another embodiment includes a compound of formula (I), where R 5 It is methyl. Another embodiment includes a compound of formula (I), where R 4and R 5 Each of these is methyl.

[0047] Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 Each of these is an independent halogen selected from the group consisting of bromo, chloro, fluoro, and iodine. Another embodiment includes a compound of formula (I), where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 Each of them is independently fluoro. Another embodiment includes a compound of formula (I), where R 7 , R 8 , R 10 , and R 11 Each of these is an independent halogen selected from the group consisting of bromo, chloro, fluoro, and iodine. Another embodiment includes a compound of formula (I), where R 7 , R 8 , R 10 , and R 11 Each of them is independently fluoro. Another embodiment includes a compound of formula (I), where R 7 It is fluoro. Another embodiment includes a compound of formula (I), where R 8 It is fluoro. Another embodiment includes a compound of formula (I), where R 10 It is fluoro. Another embodiment includes a compound of formula (I), where R 11 It is fluoro.

[0048] One embodiment includes a compound of formula (I), where R 2 and R 3 These, along with the atoms to which they are bonded, form saturated 3- to 6-membered rings incorporating zero or one heteroatom ring member selected from N, O, and S. Another embodiment includes a compound of formula (I), where R 2 and R 3 It forms a cyclopropane ring. Another embodiment includes a compound of formula (I), where R 2 and R 3 It forms a cyclobutane ring. Another embodiment includes a compound of formula (I), where R 2 and R 3 It forms a cyclopentane ring. One embodiment includes a compound of formula (I), where R 2 and R 4 These, together with the atoms to which they are bonded, form a saturated 5-10 membered ring system. One embodiment includes a compound of formula (I), where R 2 and R 7 These, together with the atoms to which they are bonded, form a saturated 5-10 membered ring system.

[0049] One embodiment includes a compound of formula (I), where R 4 and R 5 These, along with the atoms to which they are bonded, form saturated 3- to 6-membered rings incorporating zero or one heteroatom ring member selected from N, O, and S. Another embodiment includes a compound of formula (I), where R 4 and R 5 It forms a cyclopropane ring. Another embodiment includes a compound of formula (I), where R 4 and R 5 It forms a cyclobutane ring. Another embodiment includes a compound of formula (I), where R 4 and R 5 It forms a cyclopentane ring.

[0050] One embodiment includes a compound of formula (I), where R A1and R A2 These are independently hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R A1 and R A2 Each of them independently consists of hydrogen and C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R A1 and R A2 Each of them is an independent hydrogen atom. Another embodiment includes a compound of formula (I), where R A1 and R A2 Each of these is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is alkyl. Another embodiment includes a compound of formula (I), where R A1 and R A2 Each of these is independently methyl. Another embodiment includes a compound of formula (I), where R A1 These are hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 1‐4Alkyl and hydroxy-C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), wherein R A1 These are hydrogen, deuterium, halogens, cyano, and C 1‐4 Alkyl, deuterium-C 1‐4 Alkyl and halo-C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R A1 It is hydrogen. Another embodiment includes a compound of formula (I), where R A2 is hydrogen, deuterium, halogen, hydroxyl, 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 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R A2 is hydrogen and C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R A2 It is hydrogen. Another embodiment includes a compound of formula (I), where R A2 C is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1‐4 It is alkyl. Another embodiment includes a compound of formula (I), where R A2 It is methyl.

[0051] One embodiment includes a compound of formula (I), where R B1 and R B2These are, independently, hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 alkoxys. Another embodiment includes a compound of formula (I), where R B1 and R B2 These are, independently, hydrogen, halogen, and C 1‐4 Selected from the group consisting of alkyl groups. Another embodiment includes a compound of formula (I), where R B1 and R B2 Each of them is independently hydrogen. Another embodiment includes a compound of formula (I), where R B1 It is hydrogen. Another embodiment includes a compound of formula (I), where R B2 It is hydrogen. Another embodiment includes a compound of formula (I), where R B1 and R B2 Each is independently C 1‐4 It is an alkyl group, and in the formula, C 1‐4 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. Another embodiment includes a compound of formula (I), where R B1 and R B2 Each of these is independently methyl. Another embodiment includes a compound of formula (I), where R B1 It is methyl. Another embodiment includes a compound of formula (I), where R B2 It is methyl. Another embodiment includes a compound of formula (I), where R B1 and R B2 Each of these is an independent halogen, and in the formula, the halogen is selected from the group consisting of bromo, chloro, fluoro, and iodine. Another embodiment includes a compound of formula (I), where R B1 and RB2 Each of them is chloroform independently. Another embodiment includes a compound of formula (I), where R B1 It is chloroform.

[0052] Another embodiment of the compound of formula (I) is the compound of formula (Ia) shown below. [ka]

[0053] Another embodiment of the compound of formula (I) is the compound of formula (Ib) shown below. [ka]

[0054] The compound of formula (I) or its form includes a compound selected from the group consisting of the following, where, # " indicates that the compound is a racemic mixture of enantiomers: [ka] TIFF0007918255000045.tif140156 TIFF0007918255000046.tif135153 In the formula, the form of the compound is selected from the group consisting of its salt, hydrate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms.

[0055] One embodiment of the compound of formula (I) or a form thereof (wherein the compound number (#^) indicates that the salt form has been isolated) includes a compound selected from the group consisting of: [Table 1] TIFF0007918255000048.tif244170 In formula TIFF0007918255000049.tif250165, the form of the compound is selected from the group consisting of its salt, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer.

[0056] The compound of formula (I) or another embodiment thereof is a compound salt selected from the group consisting of: [Table 2] In formula TIFF0007918255000051.tif190170, the form of the compound salt is selected from the group consisting of its racemic, enantiomer, diastereoisomer, stereoisomer, and tautomer forms.

[0057] Aspects of this specification include methods of using a compound of formula (I) or a form thereof to treat or induce remission of HD in a subject requiring treatment or remission of HD, the method comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject. Another aspect of this specification includes a method of using a compound salt of formula (I) or a form thereof to treat or induce remission of HD in a subject requiring treatment or remission of HD, the method comprising administering an effective amount of the compound salt of formula (I) or a form thereof to the subject. Aspects of this specification include the use of a compound of formula (I) or a form thereof for treating or relieving HD in a subject requiring treatment or remission of HD, the use including administering an effective amount of a compound of formula (I) or a form thereof to the subject. Another aspect of this specification involves the use of a compound salt of formula (I) or a form thereof for treating or relieving HD in a subject requiring treatment or remission of HD, the use of which involves administering an effective amount of the compound salt of formula (I) or a form thereof to the subject.

[0058] chemical definition Chemical terms used above and throughout this specification will be understood by those skilled in the art to have the meanings set forth below, unless otherwise defined. The term "C" used in this specification 1‐4 The term "alkyl" generally refers to saturated hydrocarbon radicals having 1 to 4 carbon atoms in a linear or branched chain configuration, and includes, but is 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, etc. In certain embodiments, C 1‐4 Alkyl is C 1‐4 This includes, but is not limited to, alkyl groups. 1‐4 The alkyl radicals are optionally substituted with substituent species described herein, where possible depending on the available valencies.

[0059] The term "C" used in this specification 2‐4 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon radical having 2 to 4 carbon atoms in a linear or branched configuration, and having one or more carbon-carbon double bonds, and includes, but is not limited to, ethenyl (also called vinyl), allyl, propenyl, and butenyl. In certain embodiments, C 2‐4 Alkenil is C 2‐3 Alkenyl and C 2‐4 Includes, but is not limited to, alkenyls. 2‐4 The alkenyl radicals are optionally substituted with substituent species described herein, where possible depending on the available valencies. The term "C" used in this specification 2‐4 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon radical having 2 to 4 carbon atoms in a linear or branched configuration, and having one or more carbon-carbon triple bonds, and includes, but is not limited to, ethynyl, propynyl, and butynyl. In certain embodiments, C 2‐4 Alkinyl is C 2‐3 Alkinyl and C 2‐4 Includes, but is not limited to, alkinyl.2‐4 The alkynyl radical is optionally substituted with the substituent species described herein, where possible depending on the available valency.

[0060] The term "C" used in this specification 1‐4 The term "alkoxy" generally refers to the formula: -O-C 1‐4 This refers to saturated hydrocarbon radicals having 1 to 4 carbon atoms in a linear or branched alkyl chain configuration, and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. In certain embodiments, C 1‐4 Alkoxy is C 1‐4 This includes, but is not limited to, alkoxys. 1‐4 The alkoxy radicals are optionally substituted with substituent species described herein, where possible depending on the available valency. The term "C" used in this specification 3‐10 The term "cycloalkyl" generally refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon radicals, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, and tetrahydro-naphthalenyl. In certain embodiments, C 3‐10 Cycloalkyl is C 3‐8 Cycloalkyl, C 5‐8 Cycloalkyl, C 3‐10 This includes, but is not limited to, cycloalkyl groups. 3‐10 The cycloalkyl radicals are optionally substituted with substituent species described herein, where possible depending on the available valency.

[0061] As used herein, the term “aryl” generally refers to monocyclic, bicyclic, or polycyclic aromatic carbon atom ring radicals, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azlenyl, and phenantrenyl. Aryl radicals are optionally substituted with substituent species listed herein, where possible depending on the available valencies. As used herein, the term “heteroaryl” generally refers to monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radicals in which one or more carbon atom ring members are replaced by one or more heteroatoms, such as O, S, or N atoms, where structural stability allows, including furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, teto Lazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, indazolyl, indolidinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diadinyl, 1,2-diadinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, flo[3,2-b]pyridinyl Dinyl, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrorolo[1,2-a]pyridinyl, pyrorolo[1,2-b]pyridadinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1, This includes, but is 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]pyridadinyl, imidazo[1,2-a]pyradinyl, 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. The heteroaryl radical is optionally substituted on a carbon or nitrogen ring member with the substituent species described herein, where possible depending on the available valency.

[0062] In certain aspects, the nomenclature of heteroaryl radicals may differ, for example in non-limiting cases, such as furanyl also being called furyl, thienyl also being called thiophenyl, pyridinyl also being called pyridyl, benzothienyl also being called benzothiophenyl, and 1,3-benzoxazolyl also being called 1,3-benzoxazolyl. In certain other embodiments, terms relating to heteroaryl radicals may 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.; and the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc. In some cases, the term tetrazolyl may include 1H-tetrazolyl and 2H-tetrazolyl, the term indol may include 1H-indolly, the term indazolyl may include 1H-indazolyl and 2H-indazolyl, the term benzimidazolyl may include 1H-benzimidazolyl, and the term prinyl may include 9H-prinyl. In non-restrictive examples, other positional isomers may also be included.

[0063] As used herein, the term “heterocyclyl” generally refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure radicals in which one or more carbon atom ring members are replaced by heteroatoms, such as O, S, or N atoms, where structural stability allows, including oxyranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, ox Zolinyl, 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-benzodioxynyl, hexahydropyrrolo[3,4-b]pyrrole-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrole-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-(2H)-yl, hexahydropyrrolo[3,4- c]pyrrole-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrole-(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]pyrazine-(1H)-yl, (7R,8aS)-Hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aS)-Hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aR)-Hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aS)-Octahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aR)-Octahydropyrrolo[1,2-a]pyrazine-(1H)-yl, Hexa Hydropyrrolo[1,2-a]pyrazine-(2H)-one, octahydro-2H-pyrido[1,2-a]pyradinyl, 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]octa-2-enyl, (1R,5 S)-8-azabicyclo[3.2.1]octa-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 This includes, but is not limited to, 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, etc. The heterocyclyl radical is optionally substituted on a carbon or nitrogen atom ring member with the substituent species described herein, where possible depending on the available valency.

[0064] In certain embodiments, the nomenclature of heterocyclyl radicals may differ, for example, 1,3-benzodioxolyl may also be called benzo[d][1,3]dioxolyl, and 2,3-dihydro-1,4-benzodioxynyl may also be called 2,3-dihydrobenzo[b][1,4]dioxynyl, in non-limiting examples. The term "deuterium-C" used in this specification1‐4 The term "alkyl" is derived from the formula: -C 1‐4 This refers to alkyl-deuterium radicals, and if possible depending on the available valency, C 1‐4 Alkyl atoms are partially or completely substituted with one or more deuterium atoms. The term "C" used in this specification 1‐4 Alkoxy-C 1‐4 The term "alkyl" is derived from the formula: -C 1‐4 Alkyl-O-C 1‐4 This refers to alkyl radicals. The term "C" used in this specification 1‐4 The term "alkyl-amino" is defined by the formula: -NH-C 1‐4 This refers to alkyl radicals.

[0065] The term "(C)" used in this specification 1‐4 The term "alkyl)2-amino" is derived from the formula: -N(C 1‐4 This refers to the alkyl(2) radical. The term "C" used in this specification 1‐4 The term "alkyl-thio" is derived from the formula: -S-C 1‐4 This refers to alkyl radicals. The term "amino-C" used herein 1‐4 The term "alkyl" is derived from the formula: -C 1‐4 This refers to the alkyl-NH2 radical.

[0066] As used herein, the terms "halo" or "halogen" generally refer to halogen atom radicals, including fluoro, chloro, bromo, and iodine. The term "HALO-C" used herein is used in this specification. 1‐4 The term "alkoxy" is derived from the formula: -O-C 1‐4 This refers to the radical of an alkyl-halo molecule, C 1‐4 Alkyl atoms are partially or completely substituted with one or more halogen atoms, where possible depending on the available valencies.

[0067] The term "HALO-C" used herein is used in this specification. 1‐4 The term "alkyl" is derived from the formula: -C 1‐4This refers to the alkyl-halo radical, C 1‐4 Alkyl atoms are partially or completely substituted with one or more halogen atoms, where possible depending on the available valencies. As used herein, the term "hydroxy" refers to the radical of the formula: -OH.

[0068] The term "hydroxy-C" used herein is used in this specification. 1‐4 The term "alkyl" is derived from the formula: -C 1‐4 This refers to the radical of an alkyl-OH group, C 1‐4 Alkyl groups are partially or completely substituted with one or more hydroxyl radicals, where possible depending on the available valencies. As used herein, the term “substituent” means a positional variable group on an atom of a core molecule that replaces one or more hydrogen atoms on a specified atom, substituted at a specified atomic position, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution results in a stable compound. Combinations of substituents and / or variable groups are permitted only if such combinations result in a stable compound. Those skilled in the art should note that any carbon and heteroatom that appear to have an unfulfilled valence as described or shown herein is presumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In some examples, one or more substituents having a double bond as an attachment site (e.g., “oxo” or “=O”) may be described, shown or enumerated within the substituents herein, and the structure may only show a single bond as an attachment site to the core structure of formula (I). Those skilled in the art will understand that even if only a single bond is shown, a double bond is intended for such substituents.

[0069] With respect to the definitions of chemical terms as used herein, the term “etc.” as used herein means that any deformation of the chemical structure that a person skilled in the art can foresee includes, but is not limited to, all other deformations that result in a stable compound, if possible by the available valencies, including isomers (including chain, branched, or regioisomers), hydration of the ring system (including saturation or partial unsaturation of monocyclic, bicyclic, or polycyclic ring structures). For the purposes of this description, if a compound of formula (I) or one or more substituted variables of the same form encompasses a functional group incorporated into the compound of formula (I), each functional group appearing anywhere in the disclosed compound may be independently selected and may be independently and / or optionally substituted as needed.

[0070] As used herein, the terms “independently selected” or “each selected” refer to the functional variable groups in the list of substituents that can occur more than once on the structure of formula (I), and the substitution pattern in each occurrence is independent of the pattern in any other occurrence. Furthermore, the use of any common substituted variable group in any formula or structure for the compounds described herein includes the substitution of common substituents with substituents of species contained within a particular genus, for example, aryl may be replaced with phenyl or naphthalenyl, and the resulting compound is understood to fall within the range of compounds described herein. As used herein, the terms "each example" or "if present, each example" are, 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 before the phrase "alkyl," each element exists either individually or as a substituent, and is C 3‐14 This term is intended to refer to cycloalkyl, aryl, heteroaryl, and heterocyclyl ring systems. As used herein, the term “may be substituted” means any substitution using a particular substituted variable group, group, radical or part.

[0071] compound form As used herein, the term "form" means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms. In certain embodiments described herein, the compound of formula (I) is in the form of its free acid, free base, or salt. In certain embodiments described herein, the form of the compound of formula (I) is its salt.

[0072] In certain embodiments described herein, the form of the compound of formula (I) is its stereoisomer, racemate, enantiomer, or diastereoisomer. In certain embodiments described herein, the form of the compound of formula (I) is its tautomer. In certain embodiments described herein, the form of the compound of formula (I) is its isotopically substituted form. In certain embodiments described herein, the form of the compound of formula (I) is a pharmaceutically 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” means the physical state of the compound of formula (I) or its form 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, to a purity sufficient to be characterized by standard analytical techniques described herein or well known to those skilled in the art, according to an isolation or purification process or a process described herein or well known to those skilled in the art (e.g., chromatography, recrystallization). As used herein, the term “protected” means that the compound of formula (I) or the functional group in that form is modified to exclude undesirable side reactions at the protected site when the compound is reacted. Suitable protecting groups will be recognized by those skilled in the art and by referring to standard textbooks, e.g., TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino, and carboxylic acids. 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, etc. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl, or arylalkyl esters. In some cases, the protecting group may be a polymer resin, such as Wang resin or 2-chlorotrityl chloride resin. Protecting groups are well known to those skilled in the art and may be added or removed according to the standard techniques described herein. Also, as will be understood to those skilled in the art, such protected derivatives of the compounds described herein may not have pharmacological activity on their own, but may be metabolized in the body after administration to a subject to form pharmacologically active compounds described herein.

[0074] One or more compounds described herein may exist in a non-solvated form as well as in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol, and the description herein is intended to include both solvated and non-solvated forms. As used herein, the term “solvate” refers to the 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 cases, a solvate can be isolated, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, “solvate” encompasses both solution phases and isolateable solvates. Non-limiting examples of suitable solvates include ethanolates, methanelates, and the like. As used herein, the term "hydrate" refers to a solvate in which the solvent molecule is water.

[0075] Compounds of formula (I) may form salts intended to be included within the scope of this specification. References to compounds of formula (I) or forms thereof in this specification are understood to include references to forms of their salts unless otherwise indicated. As used herein, the term “salt” refers to acidic salts formed with inorganic acids and / or organic acids, and basic salts formed with inorganic bases and / or organic bases. Furthermore, if a compound of formula (I) or form thereof contains both a basic moiety, e.g., an amine moiety (but not limited to the following), and an acidic moiety, e.g., a carboxylic acid (but not limited to the following), zwitterions (“intramolecular salts”) may be formed and may be included within the term “salt” as used herein. As used herein, the term “medically acceptable salts” means salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) and possess biological activity for use in mammals, although other salts are also useful. Salts of the compounds of formula (I) may be formed, for example, by reacting the compound of formula (I) or a form thereof with a certain amount, such as an equivalent amount of acid or base, in a medium, such as a medium in which the salt is precipitated or in an aqueous medium, followed by freeze-drying.

[0076] Pharmacovigilant salts include salts of one or more acidic or basic groups present in the compounds described herein. Detailed embodiments of acid addition salts include, but are not limited to, acetates, ascorbic acid salts, benzoates, benzenesulfonates, bisulfates, hydrogen tartrates, borates, bromides, butyrates, chlorides, citrates, camphorates, camphor sulfonates, ethanesulfonates, formates, fumarates, gentisinates, glucons, glucuronates, glutamates, iodides, isonicotinates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, pamoates, pantothenates, phosphates, propionates, sugarates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), trifluoroacetates, and the like. Specific detailed embodiments of the acid addition salt include chlorides, bromides, or dichlorides. Furthermore, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.), Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (on the Food & Drug Administration, Washington, DC website). These disclosures are incorporated herein by reference.

[0077] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts. Both such acidic and basic salts are intended to fall within the range of pharmaceutically acceptable salts as described herein. Furthermore, all such acidic and basic salts are considered, for the purposes of this specification, equivalent to the free form of the corresponding compound.

[0078] The compounds of formula (I) and their forms may also exist in tautomerized forms. All such tautomerized forms are assumed and intended to fall within the range of the compounds of formula (I) or their forms described herein. The compounds of formula (I) or their forms may contain asymmetric or chiral centers and therefore may exist in different stereoisomers. This specification is intended to include all stereoisomers 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 embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions containing substantially only (S) isomers. In another detailed embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions containing substantially only (R) isomers. 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. As used herein, the term “chiral” refers to a carbon atom bonded to four non-identical substituents. The stereochemical definitions and conventions used herein generally follow those of SP. 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. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). Substituents attached to the chiral center under consideration are ranked according to the Cahn-Ingold-Prelogue priority rule (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0080] As used herein, the term “substantially pure” means a compound consisting substantially 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%. In one aspect of this specification, the compound of formula (I) or the form thereof is a substantially pure (S) enantiomer form present in amounts of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%.

[0081] In one aspect of this specification, the compound of formula (I) or the form thereof is a substantially pure (R) enantiomer form present in amounts of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%. As used herein, “racemic compound” is a mixture of any equiaxial form that is not “enantiomerically pure,” and includes, for example, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20, but is not limited to the following. Furthermore, this specification encompasses all geometric and positional isomers. For example, if a compound of formula (I) or its form incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are included within the scope of this specification. Diastereoisomer mixtures can be separated into their individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art, e.g., chromatography and / or fractional crystallization. Enantiomers can be separated by using a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by reaction with a suitable optically active compound (e.g., a chiral additive such as a chiral alcohol or moscheric acid chloride), separation of diastereoisomers, and conversion of an enantiomer mixture into a diastereoisomer mixture by conversion of individual diastereoisomers to their corresponding pure enantiomers (e.g., hydrolysis). In addition, some of the compounds of formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this specification.

[0082] The use of terms such as "salt" and "solvate" is intended to apply equally to the salts, solvates, enantiomers, stereoisomers, or tautomers of this compound. The term "isotope-substituted compound" refers to the isotope-enriched compounds described herein, which are identical to those described herein, but in which one or more atoms are substituted with atoms having an atomic mass, a mass number different from the atomic mass, or a mass number commonly 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, for example, respectively. 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 Examples include Cl, each of which is also within the scope of this specification.

[0083] Use of compounds Aspects of this specification relate to methods of using a compound of formula (I) or a form thereof to treat or induce remission of HD in subjects requiring treatment or remission of HD, the methods comprising administering an effective amount of the compound or a form thereof to the subject. Another aspect of this specification relates to the use of a compound of formula (I) or a form thereof for treating or relieving HD in subjects requiring treatment or remission of HD. Another aspect of this specification relates to the use of a compound of formula (I) or a form thereof that is active against HD. One aspect of this specification relates to the use of a compound of formula (I) or a form thereof in combination therapy to enable the development of a combined product for treating or relieving HD by providing additional or synergistic activity.

[0084] In addition to its use as monotherapy, this compound is useful in combination therapy with current standard drugs and exhibits additive or synergistic activity with one or more known drugs. Combination therapies using the compounds described herein with one or more known drugs may be used to treat HD regardless of whether HD is responsive to known drugs. Certain aspects of this specification include the use of a compound of formula (I) or a form thereof in combination therapy for treating or relieving HD in subjects requiring treatment or remission of HD, the use of which includes administering an effective amount of a compound of formula (I) or a form thereof, and an effective amount of one or more agents. Certain aspects of this specification include the use of a compound of formula (I) or a form thereof in combination therapy for treating or relieving HD in a subject requiring treatment or remission of HD, 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 agents.

[0085] In certain embodiments of the uses or methods provided herein, a compound or form of formula (I) used in combination with one or more additional activators may be administered to a subject or patient, or brought into contact with the cells of the subject or patient, before, simultaneously with, or after, the administration of the compound or form of formula (I) or the additional activators. The compound or form of formula (I) and the additional activators may be administered to a subject or brought into contact with cells in a single composition or in different compositions. In certain embodiments, a compound or form of formula (I) may be used in combination with gene treatment that inhibits HTT expression (e.g., using a viral delivery vector) or administration of another small molecule HTT inhibitor. In other specific embodiments, a compound or form of formula (I) may be used in combination with cell replacement using differentiated non-mutant HTT stem cells. In other specific embodiments, a compound or form of formula (I) may be used in combination with cell replacement using differentiated HTT stem cells. In one embodiment, the use of a compound of formula (I) or a form thereof in combination with supportive standards of care therapy, including palliative care, is provided herein.

[0086] Aspects of this specification include preparing a kit and instructions containing the compound of formula (I) or a form thereof, and using the compound of formula (I) or a form thereof in combination therapy with an effective amount of one or more drugs to treat or induce remission of HD in subjects requiring treatment or remission of HD. Accordingly, this specification relates to the use of compounds of formula (I) or forms thereof for treating or relieving HD. In accordance with the use described herein, compounds useful for selectively treating or relieving HD have been identified, and the use of these compounds for treating or relieving HD is provided. Another aspect of use as described herein relates to the use of a compound of formula (I) or a form thereof for treating or relieving HD in a subject requiring treatment or remission of HD, the use comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject. Another aspect of the use of this specification relates to a method of using a compound of formula (I) or a form thereof to treat or induce remission of HD in a subject that requires treatment or remission of HD, the method comprising administering an effective amount of the compound to the subject.

[0087] Another aspect of the use of this specification relates to a method of using a compound of formula (I) or a form thereof to treat or induce remission of HD in a subject that requires treatment or remission of HD, the method comprising administering an effective amount of the compound to the subject. Another aspect of use of this specification relates to the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or relieving HD in a subject that requires treatment or remission of HD, the use of which includes administering an effective amount of the medicament to the subject. Another aspect of the use described herein relates to the use of the compound of formula (I) or a form thereof in which a kit and instructions are prepared containing the compound of formula (I) or a form thereof, and the compound is administered to a subject who requires treatment or remission of HD in order to treat or remission of HD.

[0088] From one perspective, in each of those embodiments, the subject is untouched. From another perspective, in each of those embodiments, the subject is not untouched. As used herein, the term “to treat” relates to: (i) preventing the development of a disease, disorder, or condition in a subject who may be predisposed to a disease, disorder, or condition but has not yet been diagnosed with such a disease; (ii) inhibiting a disease, disorder, or condition, i.e., halting its progression; and / or (iii) alleviating a disease, disorder, or condition, i.e., relieving a disease, disorder, or condition.

[0089] As used herein, the term “subject” refers to an animal or living organism that possesses the capacity for sensation and voluntary movement and requires oxygen and organic food. Non-limiting examples include members of the species of humans, primates, equids, pigs, bovids, mice, rats, canids, and felines. In certain embodiments, the subject is a mammal or a warm-blooded vertebrate. In other embodiments, the subject is a human. As used herein, the term “patient” may be used interchangeably with “subject” and “human.” As used herein, the terms “effective dose” or “treatment effective dose” mean the amount of compound of formula (I), or its form, composition, or pharmaceutical product, that achieves a target plasma concentration effective for the treatment or remission of hemoglobin (HD) as described herein, and that results in the desired treatment, remission, inhibition, or preventive effect in a subject requiring such treatment, remission, inhibition, or prevention. In one embodiment, the effective dose may be the amount required for the treatment of HD in a subject or patient, more specifically in a human.

[0090] In another embodiment, the observed concentration-to-biological effect relationship for the compound of formula (I) or its form refers to target plasma concentrations ranging from approximately 0.001 μg / mL to approximately 50 μg / mL, approximately 0.01 μg / mL to approximately 20 μg / mL, approximately 0.05 μg / mL to approximately 10 μg / mL, or approximately 0.1 μg / mL to approximately 5 μg / mL. To achieve such plasma concentrations, the compounds described herein may be administered in doses ranging, for example, 0.1 ng to 10,000 mg, but not limited to these. In one embodiment, the dose administered to achieve an effective target plasma concentration may be administered based on subject or patient-specific factors, and the dose administered on a weight basis may range from approximately 0.001 mg / kg / day to approximately 3500 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 3000 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 2500 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 2000 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 1500 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 1000 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 500 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 250 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 200 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 150 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 100 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 75 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 50 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 25 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 10 mg / kg / day, or This ranges from approximately 0.001 mg / kg / day to approximately 5 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 1 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 0.5 mg / kg / day, or approximately 0.001 mg / kg / day to approximately 0.1 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 3500 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 3000 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 2500 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 2000 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 1500 mg / kg / day , or approximately 0.01 mg / kg / day to approximately 1000 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 500 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 250 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 200 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 150 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 100 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 75 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 50 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 25 mg / kg / day, or approximately 0.0.1 mg / kg / day to approximately 10 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 5 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 1 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 0.5 mg / kg / day, or approximately 0.01 mg / kg / day to approximately 0.1 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 3500 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 3000 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 2500 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 2000 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 1500 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 1000 mg / kg / day, or approximately 0.1 mg / kg / The dosage may range from approximately 500 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 250 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 200 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 150 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 100 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 75 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 50 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 25 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 10 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 5 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 1 mg / kg / day, or from approximately 0.1 mg / kg / day to approximately 0.5 mg / kg / day.

[0091] The effective dose for a given subject may be determined by routine experimentation within the scope of the skills and judgment of a clinician or person skilled in the art, taking into account factors relevant to the subject. Dosage may be adjusted to provide a sufficient level of activator(s) or to maintain the desired effect. Factors to be considered include genetic screening, severity of disease state, status of disease progression, overall health of the subject, ethnicity, age, weight, sex, diet, time and frequency of administration, combination(s) of drugs, response 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 daily (approximately once every 24 hours, i.e., "qd"), twice daily (approximately once every 12 hours, i.e., "bid" or "q.12h"), three times daily (approximately once every 8 hours, i.e., "tid" or "q.8h"), or four times daily (approximately once every 6 hours, i.e., "qds", "qid", or "q.6h").

[0092] In certain embodiments, the dose administered to achieve an effective target plasma concentration may be administered as a single dose, in divided doses, or in continuous doses to patients or subjects with a body weight in the range of approximately 40 to approximately 200 kg (the dose may be adjusted for patients or subjects above or below this range, particularly children weighing less than 40 kg). A typical adult subject is expected to have a median body weight in the range of approximately 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3, or 4 days, once every week, or once every 2 weeks, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions described herein may be administered to a subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and intrapulmonary routes of administration.

[0093] In another embodiment, the dose administered may be adjusted based on the dosage forms described herein and formulated to be delivered at approximately 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 dose may first be evaluated in a cell culture assay or a relevant animal model, such as a mouse, guinea pig, chimpanzee, marmoset, or tamarin animal model. The relevant animal model may also be used to determine the appropriate concentration range and route of administration. Such information may then be used to determine the useful dose and route of administration in humans. The efficacy and toxicity of the treatment may be determined using standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED. 50 (The dose that is therapeutically effective in 50% of the population) and LD 50 This can be determined by the dose that is lethal in 50% of the population. The dose ratio between the treatment effect and the toxic effect is the treatment index, and the ratio LD50 is the LD50. 50 / ED 50 It can be expressed as follows: In certain embodiments, the effective dose is such that a high treatment index is achieved. In more detailed embodiments, the dose is such that there is little or no toxicity. 50 This is within the range of circulating concentrations. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0094] In one embodiment, a method for regulating the amount of HTT (huntingtin protein) is provided herein, comprising contacting human cells with a compound of formula (I) or a form thereof. In a particular embodiment, a method for regulating the amount of HTT is provided herein, comprising contacting human cells with a compound of formula (I) or a form thereof that modulates HTT expression. Human cells can be contacted with the compound of formula (I) or a form thereof in vitro or in vivo, for example, in a non-human animal or in a human. In a particular embodiment, human cells are derived from or within a human. In another particular embodiment, human cells are derived from or within a human having HD. In another particular embodiment, human cells are derived from or within a human having HD, in which loss of HTT expression and / or function occurs due to a CAG repeat in the Htt gene. In another embodiment, human cells are derived from or within a human having HD. In another embodiment, human cells are derived from or within a human having HD. In one embodiment, the compound is a form of the compound of formula (I). In certain embodiments, a method for improving the inhibition of mutant HTT transcribed from the Htt gene is provided herein, comprising contacting human cells with a compound of formula (I) or a form thereof. Human cells can be contacted with the compound of formula (I) or a form thereof in vitro or in vivo, for example, in a non-human animal or in a human. In certain embodiments, the human cells are derived from or within a human. In another particular embodiment, the human cells are derived from or within a human having HD. In another particular embodiment, the human cells are derived from or within a human having HD, in which loss of wild-type "normal" HTT expression and / or function is caused by a CAG repeat in the Htt gene. In another embodiment, the human cells are derived from or within a human having HD. In another embodiment, the human cells are within a human having HD. In one embodiment, the compound is a form of the compound of formula (I).

[0095] In another embodiment, a method for modulating the inhibition of mutant HTT transcribed from the Htt gene is provided herein, comprising administering a compound of formula (I) or a form thereof to a non-human animal model for HD. In a particular embodiment, a method for modulating the inhibition of mutant HTT transcribed from the Htt gene is provided herein, comprising administering a compound of formula (I) or a form thereof to a non-human animal model for HD. In a particular embodiment, the compound is the form of the compound of formula (I). In another embodiment, a method for reducing the amount of mutant HTT is provided herein, comprising contacting human cells with a compound of formula (I) or a form thereof. In a particular embodiment, a method for reducing the amount of mutant HTT is provided herein, comprising contacting human cells with a compound of formula (I) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another particular embodiment, a method for reducing the amount of HTT is provided herein, comprising contacting human cells with a compound of formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. Human cells 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 in a human. In a particular embodiment, human cells are derived from or within a human. In another particular embodiment, human cells are derived from or within a human having HD. In another particular embodiment, human cells are derived from or within a human having HD, in which loss of HTT expression and / or function occurs due to CAG repeats in the Htt gene. In another embodiment, the human cells are derived from a human having HD. In yet another embodiment, the human cells are from within a human having HD. In one embodiment, the compound is in the form of the compound of formula (I).

[0096] In certain embodiments, treating or relieving HD with a compound of formula (I) or in a form thereof (alone or in combination with additional agonists) has a therapeutic effect and / or beneficial effect. In certain embodiments, treating HD with a compound of formula (I) or in a form thereof (alone or in combination with additional agents) results in one, two or more of the following effects: (i) reducing or relieving the severity of HD; (ii) delaying the onset of HD; (iii) inhibiting the progression of HD; (iv) reducing the length of hospital stay in the subject; (v) reducing the length of hospital stay in the subject; (vi) increasing the survival of the subject; (vii) improving the quality of life of the subject; (viii) reducing the number of HD-related symptoms; (ix) reducing or relieving the severity of HD-related symptoms; (x) reducing the duration of HD-related symptoms; (xi) preventing relapse of HD-related symptoms; (xii) inhibiting the onset or development of HD symptoms; and / or (xiii) inhibiting the progression of HD-related symptoms.

[0097] metabolites The use of in vivo metabolites of the compounds described herein is also included within the scope of this specification. Such products may be obtained primarily by enzymatic processes, such as oxidation, reduction, hydrolysis, amidation, and esterification of the administered compound. Accordingly, this description includes the use of compounds produced by processes involving contact of the compounds described herein with mammalian tissue or mammals for a period of time sufficient to obtain their metabolites.

[0098] Pharmaceutical composition Aspects of this specification include the use of a compound of formula (I) or a form thereof in a pharmaceutical composition for the treatment or remission of HD in subjects requiring treatment or remission of HD, the use of which includes administering an effective amount of a compound of formula (I) or a form thereof mixed with one or more pharmaceutically acceptable excipients. Aspects of this specification include the use of a compound of formula (I) or a pharmaceutical composition in a similar form, in which a kit and instructions are prepared containing a compound of formula (I) or a pharmaceutical composition in a similar form, and the compound is administered to a subject requiring treatment or remission of HD in order to treat or remission of HD. . As used herein, the term “composition” means a product containing specified raw materials in specified amounts, and any product resulting directly or indirectly from a combination of specified raw materials in specified amounts. Pharmaceutical compositions can be formulated to achieve a physiologically compatible pH ranging from approximately pH 3 to approximately pH 11. In certain embodiments, pharmaceutical compositions are formulated to achieve a pH of approximately pH 3 to approximately pH 7. In other embodiments, pharmaceutical compositions are formulated to achieve a pH of approximately pH 5 to approximately pH 8.

[0099] The term "pharmaceutically acceptable excipient" refers to an excipient used to administer a pharmaceutical, such as the compounds described herein. This term refers to any pharmaceutical excipient that can be administered without excessive toxicity. A pharmaceutically acceptable excipient can be determined to some extent by the specific composition being administered, as well as by the specific mode of administration and / or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, and diluents. Therefore, a wide variety of suitable formulations of the compounds of the present invention described herein exist (see, for example, Remington's Pharmaceutical Sciences). Suitable excipients may include carrier molecules containing large, slowly metabolized polymers such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymerized amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), and stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting agents or emulsifiers; and pH buffering agents. Liposomes are also included within the definition of pharmaceutically 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 pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids that can be re-prepared with physiologically suitable solvents before administration. When intended for oral use, for example, tablets, lozenges, aqueous or oily suspensions, non-aqueous liquids, dispersible powders or granules (including fine particles or nanoparticles), emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method of manufacturing pharmaceutical compositions known in the art, and such compositions may contain one or more activators, 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 carbonate or sodium, lactose, calcium phosphate or sodium; 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 coated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby extending their effect for a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or with 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 embodiments, the pharmaceutical compositions described herein may be formulated as suspensions containing the compound of formula (I) or a form thereof mixed with one or more pharmaceutically acceptable excipients suitable for the preparation of suspensions. In yet another embodiment, the pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for the preparation of suspensions by adding one or more excipients. Excipients suitable for use in conjunction with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickeners, such as carbomer, beeswax, solid paraffin, or cetyl alcohol. The suspension may also contain one or more preservatives such as acetic acid, methyl and / or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweeteners 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 peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum; naturally occurring phospholipids such as soy lecithin, fatty acid-derived esters or partial esters; hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain analgesics, preservatives, flavorings, or colorings. Furthermore, the pharmaceutical compositions described herein may be in the form of sterile injectable preparations, such as sterile injectable aqueous emulsions or oily suspensions. Such emulsions or suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspensions mentioned above. Sterile injectable preparations may also be sterile injectable liquids or suspensions in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. Sterile injectable preparations may also be prepared as lyophilized powders. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile fixative oils may be used as solvents or suspension media. For this purpose, any sterile fixative oil containing synthetic mono- or di-glycerides may be used. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectable substances.

[0104] The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically 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. Accordingly, compounds modified by substitution or addition of chemical or biochemical moieties to make the compounds more suitable for delivery (e.g., improved solubility, biological activity, palatability, reduced side effects, etc.) are assumed herein, for example by esterification, glycosylation, or PEGylation. In certain embodiments, the compounds described herein are formulated for oral administration as lipid-based compositions suitable for low-solubility compounds. Lipid-based formulations can generally improve the oral bioavailability of such compounds. Accordingly, the pharmaceutical compositions described herein may contain an effective amount of the compound of formula (I) or a form thereof, together with a medium-chain fatty acid or its propylene glycol ester (e.g., propylene glycol esters of edible fatty acids such as caprylic and caprin fatty acids), and at least one pharmaceutically acceptable excipient selected from polysorbate 20 or 80 (also known as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

[0105] In other embodiments, the bioavailability of low-solubility compounds can be enhanced using particle size optimization techniques, which include preparing nanoparticles or nanosuspensions using techniques known to those skilled in the art. Compound forms present in such preparations include amorphous, partially amorphous, partially crystalline, or crystalline forms. In alternative embodiments, the pharmaceutical composition may further contain one or more water solubility enhancers, such as cyclodextrins. Non-limiting examples of cyclodextrins include hydroxypropyl, hydroxyethyl, glycosyl, maltosyl, and maltotriosyl derivatives of α-, β-, and γ-cyclodextrins, as well as hydroxypropyl-β-cyclodextrin (HPBC). In specific embodiments, the pharmaceutical composition may further contain HPBC in amounts ranging from about 0.1% to about 20%, about 1% to about 15%, or about 2.5% to about 10%. The amount of solubility enhancer used may depend on the amount of the compound in the composition.

[0106] Preparation of compounds General synthesis method As disclosed herein, general methods for preparing the compounds of formula (I) or forms thereof described herein are available by well-known standard synthetic methodologies. Many of the starting materials are commercially available or, if unavailable, can be prepared using techniques known to those skilled in the art, using the routes described below. The synthetic schemes provided herein comprise multiple reaction steps, each reaction step intended to function independently and can be carried out with or without any preceding or succeeding steps. In other words, each of the individual reaction steps of the synthetic schemes presented herein is assumed to have an isolation component.

[0107] The compound of formula (I) can be prepared as described in Scheme 1 below. Scheme 1 [ka] Compound A1 (wherein W1, W2, and W3 are independently bromo, chloro, etc.) is converted to compound A3 by Suzuki coupling with pinacol boronic acid ester (or boronic acid) A2 in a suitable solvent (such as 1,4-dioxane) in the presence of a catalyst (such as Pd(dppf)Cl2) and a base (such as aqueous K2CO3). Compound A3 is converted to compound A3 by Suzuki coupling with a primary amine (R) in a suitable solvent (such as acetonitrile) in the presence of a base (such as N,N-diisopropylethylamine). ABy heating with NH2, it is converted to 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 A7 by Suzuki coupling with bonding partner A6 (wherein Y is a boronic acid or boronic acid ester and P is a suitable protecting group) in a suitable solvent (such as 1,4-dioxane) in the presence of a catalyst (such as Pd(dppf)Cl2) and a base (such as aqueous K2CO3). Alternatively, compound A5 is converted to compound A7 by Still coupling with bonding partner A6 (wherein Y is a stanane) in a suitable solvent (such as 1,4-dioxane) in the presence of a catalyst (such as Pd2(dba)3), a ligand (such as X-Phos), and a base (such as CsF). Alternatively, compound A5 is converted to compound A7 by Negishi coupling with bonding partner A6 (wherein Y is zinc halide) in a suitable solvent (such as THF) in the presence of a catalyst (such as Pd(PPh3)4). Compound A7 is converted to compound A8 by treatment in a suitable solvent (such as dioxane) under conditions suitable for the removal of the protecting group (such as HCl in dioxane in the case of a MOM protecting group).

[0108] Alternatively, the compound of formula (I) may be prepared as described in Scheme 2 below. Scheme 2 [ka] Compound A4 is converted to compound A9 by Suzuki coupling with bonding partner A6 (wherein Y is a boronic acid or boronic acid ester) in a suitable solvent (such as 1,4-dioxane) in the presence of a catalyst (such as Pd(dppf)Cl2) and a base (such as aqueous K2CO3). Alternatively, compound A4 is converted to compound A9 by Still coupling with bonding partner A6 (wherein Y is a stanane) in a suitable solvent (such as 1,4-dioxane) in the presence of a catalyst (such as Pd2(dba)3), a ligand (such as X-Phos), and a base (such as CsF). Alternatively, compound A4 is converted to compound A9 by Negishi coupling with bonding partner A6 (wherein Y is a zinc halide and P is a suitable protecting group) in a suitable solvent (such as THF) in the presence of a catalyst (such as Pd(PPh3)4). 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 by treatment with a suitable solvent (such as dioxane) under conditions suitable for the removal of protecting groups (such as HCl in dioxane in the case of a MOM protecting group).

[0109] Specific synthesis examples To provide a more detailed explanation and aid in understanding, the following non-limiting examples are provided to illustrate the scope of the compounds described herein in more detail and are not intended to be construed as specifically limiting that scope. Such variations of the compounds described herein that may be currently known or subsequently developed within the scope of what a person skilled in the art can ascertain are considered to fall within the scope of the compounds described herein and are claimed below. These examples illustrate the preparation of a certain compound. A person skilled in the art will understand that the techniques described in these examples represent techniques that function correctly in the practice of synthesis and thus constitute a preferred form for that practice, as will be explained by a person skilled in the art. However, it should be recognized that a person skilled in the art will recognize that, building upon this disclosure, many variations can be made in the specific methods disclosed, and that similar or analogous results can be obtained without departing from the spirit and scope of this specification. Except for the following examples of specific compounds, all numbers used herein and in the claims to express quantities of raw materials, reaction conditions, experimental data, etc., are understood to be modified by the term “approximately,” unless otherwise indicated. Thus, all such numbers represent approximations that may vary depending on the desired properties to be obtained as a result of the reaction or various experimental conditions. Accordingly, within the expected range of experimental reproducibility, the term “approximately” with respect to the resulting data refers to a range of data, provided that it may vary according to the standard deviation from the mean. Similarly, with respect to the experimental results obtained, the resulting data may be consistently rounded up or down without loss of significant figures. At a minimum, without intending to limit the application of the equivalence principle to the scope of the claims, each numerical parameter should be interpreted in accordance with the number of significant figures and rounding techniques used by those skilled in the art. While the ranges of numbers and parameter settings used to specify a broad range in this specification are approximations, the numerical values ​​in the examples provided below are reported as accurately as possible. However, every numerical value inherently contains a certain degree of error that inevitably arises from the standard deviation found in each test measurement.

[0110] Compound example As used above, and throughout this specification, the following abbreviations shall be understood to have the following meanings unless otherwise indicated. [Table 3] TIFF0007918255000055.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-methoxybenzene (100 g, 319 mmol) in 100 mL of DCM, BBr3 (1 M in DCM, 600 mL, 600 mmol) was added. The mixture was stirred at rt for 16 hours, then poured onto crushed ice and extracted with DCM (200 mL x 3). The combined organic phase was concentrated and purified by flash column chromatography (PE / siRNA = 10:1) to obtain 2-bromo-5-iodophenol (90 g, yield 94.2%).

[0112] Step 2. To a solution of NaH (60% in mineral oil, 25 g, 625 mmol) in 400 mL of THF at 0°C, 100 mL of THF containing 2-bromo-5-iodophenol (92 g, 308 mmol) was added dropwise. After addition, the mixture was stirred at 0°C for 30 minutes, and then MOMBr (46 g, 368 mmol) was added. The mixture was stirred further at 0°C for 5-10 minutes, then quenched with 5% citric acid and concentrated. The residue was mixed with 500 mL of DCM, washed with water and brine, dried over Na2SO4, and purified by flash column chromatography (PE / Â=20:1) to obtain 1-bromo-4-iodo-2-(methoxymethoxy)benzene (110 g, yield 100%).

[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), Cs2CO3 (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 hours and then cooled to rt. The mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography (PE / Â=2:1) ​​to obtain 1-(4-bromo-3-(methoxymethoxy)phenyl)-1H-1,2,3-triazole (25 g, yield 27.4%).

[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(pinacolate)diborone (38 g, 150 mmol), KOAc (17.5 g, 178 mmol), and Pd(dppf)Cl2 (6.5 g, 8.9 mmol) were added. The reaction mixture was stirred at 100°C for 20 hours under an Ar atmosphere and then concentrated. The residue was purified by flash column chromatography (PE / Â=1.5:1) to obtain 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. Sodium tert-butoxide (0.8 g, 8.2 mmol) was added to a solution of 5-bromo-2-chloro-1-fluoro-3-methoxybenzene (1.0 g, 4.2 mmol), diphenylmethaneimine (1.05 g, 5.79 mmol), tris(dibenzylideneacetone)dipalladium (0.39 g, 0.42 mmol), and RuPhos (0.4 g, 0.84 mmol) in toluene (10 mL) at 25°C under nitrogen protection. The mixture was stirred at 100°C for 16 hours. After the reaction was complete, the mixture was extracted with phenylethylamine and washed with brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (PE:Â=5:1) to obtain N-(4-chloro-3-fluoro-5-methoxyphenyl)-1,1-diphenyl-methanymine (800 mg, 2.35 mmol, yield 56.3%) as a colorless oil. MS m / z 340.3 [M+H] + .

[0116] Step 2. To a solution of N-(4-chloro-3-fluoro-5-methoxyphenyl)-1,1-diphenyl-methanymine (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 hour. After the reaction was complete, Na2CO3 was added to adjust the pH to 9, the mixture was extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by silica gel chromatography (PE:ethyl acetate = 5:1) to obtain 4-chloro-3-fluoro-5-methoxyaniline (300 mg, yield 82.9%) as a pale yellow oil. MS m / z 176.2 [M+H] + .

[0117] Step 3. A solution of 4-methylbenzenesulfonhydrazide (284 mg, 1.49 mmol) and 2,2-dimethoxyacetaldehyde (259 mg, 1.49 mmol, 60% by mass in H2O) in methanol (5 mL) was stirred at 25°C for 1 hour. Then, 4-chloro-3-fluoro-5-methoxyaniline (250 mg, 1.42 mmol) and acetic acid (89 mg, 1.42 mmol) were added sequentially. The mixture was stirred at 75°C overnight. After the reaction was complete, the solvent was evaporated and removed. The residue was purified by column chromatography (0-50% ethyl acetate in PE) to obtain the product 1-(4-chloro-3-fluoro-5-methoxyphenyl)triazole (200 mg, yield 61.7%). MS m / z 228.1 [M+H] + .

[0118] Step 4. A solution of 1-(4-chloro-3-fluoro-5-methoxyphenyl)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-dioxaborolan (200 mg, 0.78 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.052 mmol), and tricyclohexylphosphine (29 mg, 0.104 mmol) in 1,4-dioxane (3 mL) was stirred at 70°C for 16 hours under an N2 atmosphere. After the reaction was complete, the solvent was removed under vacuum. The crude residue was purified on silica gel using 30%-35% ammonium sulfate / PE to obtain 1-[3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole (80 mg, yield 47%) 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-fluorophenol (1 g, 4.4 mmol) in tetrahydrofuran (10 mL), mineral oil (230 mg, 5.7 mmol) containing sodium hydride (60 mass%) was added below 0°C. This mixture was stirred at 25°C for 1 hour, after which bromomethyl methyl ether (1.1 g, 8.8 mmol) was added. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was evaporated to dryness under vacuum and purified by flash column chromatography (PE / ethyl acetate = 20:1) to obtain 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene (800 mg, yield 66.9%) as a colorless oil.

[0120] Step 2. Sodium tert-butoxide (0.8 g, 8.2 mmol) was added to a solution of 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene (1 g, 3.7 mmol), diphenylmethaneimine (1.05 g, 5.79 mmol), tris(dibenzylideneacetone)dipalladium (0.39 g, 0.37 mmol), and RuPhos (0.4 g, 0.76 mmol) in toluene (10 mL) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 100 °C for 16 hours. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over Na₂SO₄, concentrated, and purified by silica gel chromatography to obtain N-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]-1,1-diphenylmethaneimine (0.6 g, 2 mmol, yield 40%) 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-methanymine (600 mg, 1.6 mmol) in tetrahydrofuran (5 mL), hydrochloric acid (2 mol / L, 2 mL) was added. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, Na2CO3 was added to adjust the pH to 9, the mixture was extracted with ethyl acetate, dried over Na2SO4, concentrated, and purified by flash chromatography (PE:ethyl acetate = 4:1) to obtain 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. A solution of 4-methylbenzenesulfonhydrazide (194 mg, 0.5 mmol) and H2O (177 mg, 0.5 mmol) containing 2,2-dimethoxyacetaldehyde in methanol (5 mL) was stirred at rt for 1 hour. 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 overnight at 75°C. After the reaction was complete, the solvent was evaporated. The residue was purified by column chromatography (0-60% ethyl acetate in PE) to obtain the product 2-chloro-4-fluoro-5-(triazole-1-yl)phenol (80 mg, yield 77%). MS m / z 214.1 [M+H] + .

[0123] Step 5. To a solution of 2-chloro-4-fluoro-5-(triazole-1-yl)phenol (80 mg, 0.37 mmol) in tetrahydrofuran (2 mL), sodium hydride (60% by mass) (36 mg, 0.45 mmol) in mineral oil was added at 0°C. The mixture was stirred at rt for 0.5 hours. Bromomethyl methyl ether (112 mg, 0.45 mmol) was added, and the reaction was stirred at rt for 2 hours. After the reaction was complete, the mixture was quenched with water and extracted with Â. The combined organic layer was evaporated to dryness under vacuum. The crude residue was purified on silica gel using 15% PE / Â to obtain 1-[4-chloro-2-fluoro-5-(methoxymethoxy)phenyl]triazole (90 mg, yield 93%) 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-dioxaborolan (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 stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was evaporated under vacuum. The crude residue was purified on silica gel using 30%-35% ammonium compound / PE to obtain 1-[2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]triazole (90 mg, yield 83%) 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), 1,1-dimethoxypropan-2-one (350 mg, 2.9 mmol) was added. The reaction mixture was stirred at rt for 10 minutes. This substance was used directly in the next step.

[0126] Step 2. 4-bromo-3-methoxyaniline (586 mg, 2.9 mmol) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) were added to the mixture obtained from Step 1. The reaction mixture was heated to 140°C over 10 minutes, then cooled to rt and stirred at rt for 16 hours. The mixture was fractionated 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 using gradient hexane / Â (0-100% Â) elution to obtain 1-(4-bromo-3-methoxyphenyl)-4-methyltriazole (610 mg, 86% yield). MS m / z 270.0 [M+H] + ; 1 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-methoxyphenyl)-4-methyltriazole (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 mixture was slowly warmed to rt and stirred at rt for 16 hours. The reaction mixture was quenched by dropwise addition of sat.NaHCO3 aq. and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using gradient DCM / MeOH (0-30% MeOH) elution to obtain 2-bromo-5-(4-methyltriazole-1-yl)phenol (305 mg, yield 52.7%). MS m / z 256.0 [M+H] + .

[0128] Step 4. To a solution of 2-bromo-5-(4-methyltriazole-1-yl)phenol (305 mg, 1.20 mmol) in DMF (6.0 mL), N,N-diisopropylethylamine (0.3 mL, 1.80 mmol) was added. The reaction mixture was cooled to 0°C, and chloro(methoxy)methane (0.12 mL, 1.44 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours, and then fractionated between brine and Â. 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 / Â (0-100% Â) to obtain 1-[4-bromo-3-(methoxymethoxy)phenyl]-4-methyltriazole (325 mg, yield 90.8%). MS m / z 299.8 [M+H] + ; 1 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. Add the following to a dry screw-cap vial: 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-dioxaborolan (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). Degass the mixture with argon for 10 minutes, then add dioxane (2 mL) and water (0.5 mL). Heat the reaction mixture at 90°C for 5 hours. Cool the reaction mixture and fractionate it between water and ethyl acetate. Dry the combined organic layers (lauers) over sodium sulfate and concentrate under reduced pressure. The residue was purified by flash column chromatography using a gradient hexane / Â (0-100% Â) to obtain 1-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methyltriazole (275 mg, yield 73.0%). MS m / z 346.1 [M+H] + ; 1 ¹H 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. In a dry screw-cap vial, 4-azido-1-bromo-2-methoxybenzene (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) were added. The vial was purged with Ar, and ethinyl(trimethyl)silane (1.3 g, 13.1 mmol) was added. The resulting mixture was stirred at rt for 3 days. At completion, the reaction product was fractionated between HCl and brine. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / HCl (0-100% HCl) to obtain [1-(4-bromo-3-methoxyphenyl)triazole-4-yl]trimethylsilane (1.3 g, 91% yield). MS m / z 328 [M+H] + .

[0131] Step 2. To a solution of [1-(4-bromo-3-methoxyphenyl)triazole-4-yl]trimethylsilane (800 mg, 2.45 mmol) in ACN (6.0 mL), CsF (547 mg, 3.6 mmol) and N-chlorosuccinimide (100 mg, 7.35 mmol) were added. The mixture was heated to 90°C and stirred for 16 hours. The reaction product was fractionated between  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 /  (0-100% Â) to obtain 1-(4-bromo-3-methoxyphenyl)-4-chlorotriazole (385 mg, yield 54%). MS m / z 290.1,292.1 [M+H] + ; 1 ¹H NMR (chloroform-d) δ: 7.96 (s, 1H), 7.71 (d, J=8.5Hz, 1H), 7.43 (d, J=2.4Hz, 1H), 7.09 (dd, J=8.5, 2.4Hz, 1H), 4.02 (s, 3H).

[0132] Step 3. Add 1-(4-bromo-3-methoxyphenyl)-4-chlorotriazole (385 mg, 1.3 mmol), bis(pinacolate)diborone (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) to a dry screw-cap vial. Degass the mixture with argon for 10 minutes, and add dioxane (2 mL) and water (0.5 mL). Heat the reaction mixture at 90°C for 7 hours. Cool the reaction mixture and fractionate between water and ethyl acetate. Dry the combined organic layers over sodium sulfate and concentrate under reduced pressure. The residue was purified by flash column chromatography eluting with gradient hexane / Ã (0-100% Ã) to obtain a brownish oil (400 mg, yield 89%). The product is not ionized by LC / MS.

[0133] Preparation of (2-(methoxymethoxy)-4-(5-methyl-1H-1,2,3-triazole-1-yl)phenyl)boronic acid [ka] Step 1. To a solution of 4-azido-1-bromo-2-methoxybenzene (3 g, 13.15 mmol) in ACN (6.0 mL), 1,1,3,3-tetramethylguanidine (2.3 g, 19.7 mmol) and 1-dimethoxyphosphorylpropan-2-one (3.3 g, 19.73 mmol) were added. The reaction mixture was heated to 80°C over 2 hours. The reaction mixture was fractionated between HCl and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient DCM / HCl (0-100% HCl) to obtain 1-(4-bromo-3-methoxyphenyl)-5-methyltriazole (1.1 g, 31% yield). MS m / z 268.1,270.1 [M+H] + ; 1¹H NMR (chloroform-d) δ: 7.62 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.01 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.4, 2.0Hz, 1H), 3.87 (s, 3H), 2.30 (s, 3H).

[0134] Step 2. A solution of 1-(4-bromo-3-methoxyphenyl)-5-methyltriazole (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 mixture was slowly heated to rt, stirred at rt for 3 hours, then quenched by adding aq. of sat.NaHCO3 dropwise, and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude 2-bromo-5-(5-methyltriazole-1-yl)phenol, which was used in the next step without further purification.

[0135] Step 3. To a solution of 2-bromo-5-(5-methyltriazole-1-yl)phenol (1.0 g, 3.9 mmol) in DMF (10 mL), N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) was added. The mixture was cooled to -78°C. Chloro(methoxy)methane (378 mg, 4.7 mmol) was added dropwise. The reaction mixture was warmed to 0°C and stirred at this temperature for 2 minutes. The reaction mixture was fractionated between  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 /  (0-100% Â) to obtain 1-[4-bromo-3-(methoxymethoxy)phenyl]-5-methyltriazole (550 mg, yield 47%). MS m / z 298.1,300.1 [M+H] + ; 1 ¹H 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. Add the following to a dry screw-cap vial: 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-dioxaborolan (700 mg, 2.76 mmol), XPhos Pd G3 (68 mg, 0.14 mmol), and potassium acetate (636 mg, 4.6 mmol). Degass the mixture with argon for 10 minutes, and add dioxane (2 mL) and water (0.5 mL). Heat the reaction mixture at 90°C for 5 hours. Cool the reaction mixture and fractionate between water and ethyl acetate. Dry the combined organic layer over sodium sulfate and concentrate under reduced pressure. The residue was purified by flash column chromatography using a gradient hexane / Â (0-100% Â) to obtain [2-(methoxymethoxy)-4-(5-methyltriazole-1-yl)phenyl]boronic acid (240 mg, 49% yield). MS m / z 264 [M+H] + ; 1 ¹H NMR (methanol-d4) 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-dichloropyridazine (26.0 g, 114.1 mmol) in 260 mL of 1,4-dioxane and 65 mL of water, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (18.5 g, 120.1 mmol), K2CO3 (31.5 g, 228.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.25 g, 5.7 mmol) were added. The mixture was stirred at 50°C for 5 hours under an N2 atmosphere and then concentrated. The residue was purified by flash column chromatography (PE / SiO7 = 4:1) to obtain 3,6-dichloro-4-vinylpyridazine (12.5 g, 58.3%) as a white solid. MS m / z 175.1,176.1 [M+H] + .

[0138] Step 2. A mixture of 3,6-dichloro-4-vinylpyridazine (5.0 g, 28.6 mmol), Na2CO3 (3.1 g, 29.2 mmol), and (3S,4S)-3-fluoro-2,2,6,6-tetramethyl-piperidine-4-amine (5.5 g, 31.6 mmol) in 25 mL of acetonitrile was heated at 120 °C for 16 hours under an N2 atmosphere. After the mixture cooled to room temperature, it was concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 20:1) to obtain 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, 6.0 g of 3-chloro-7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethyl-4-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine, 300 mL of anhydrous toluene, 84 g of activated MnO2, and 2.0 g of a 4 Å molecular sieve (immediately after drying at high temperature) were added. The mixture was stirred at 135°C for 16 hours and then cooled to room temperature. Solid matter was removed by filtration, and the filtrate was concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 20:1) to obtain 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. Add the following to a dry screw-cap vial: 3-chloro-7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-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 K2CO3 (66 mg, 0.48 mmol). Degass the mixture with argon for 10 minutes, then add dioxane (2 mL) and water (0.5 mL). Heat the reaction mixture at 90°C for 5 hours. Cool the reaction mixture to rt and fractionate between ethyl acetate and water. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography with elution under a gradient (0-10%) CH2Cl2 / MeOH to obtain 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-3-(2-(methoxymethoxy)-4-(1H-1,2,3-triazole-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (40 mg, 52% yield). MS m / z 480.5 [M+H] + ;1 ¹H NMR (500MHz, methanol-d4) 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, 3H), 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. 2-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(1H-1,2,3-triazole-1-yl)phenol (40 mg, 0.083 mmol) and 2 drops of MeOH were dissolved in CH2Cl2 (1 mL), to which 1,4-dioxane (0.1 mL, 0.4 mmol) containing HCl (4 mol / L) was added. The reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient (0-30%) CH2Cl2 / MeOH (containing 2.5% NH4OH) to obtain 2-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(1H-1,2,3-triazole-1-yl)phenol (25 mg, yield 69%) as a yellowish-brown solid. MS m / z 436.4 [M+H] + ; 1¹H NMR (500MHz, methanol-d4) δ: 8.89 (s, 1H), 8.67 (m, 2H), 7.97 (m, 2H), 7.72 (s, 1H), 7.65 (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 (t, J=13.50Hz, 1H), 2.41 (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] The additional compounds described herein can be prepared using the procedure described in Example 1 above, by substituting appropriate starting materials, suitable reagents, and reaction conditions, to obtain compounds selected from the following: [Table 4] TIFF0007918255000064.tif207157 TIFF0007918255000065.tif212158 TIFF0007918255000066.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, and then a solution of nBuLi (1.6 mol / L in hexane, 0.41 mL, 0.66 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes, then tributyltin chloride (0.20 mL, 0.71 mmol) was slowly added, and the mixture was stirred for a further 30 minutes. The cooling bath was removed, the solution was warmed to rt, and stirred for a further 1 hour at rt. 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-(tributylstanyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate, 2-iodo-3-(methoxymethoxy)-5-(triazole-1-yl)pyridine (100 mg, 0.3 mmol), Pd(dppf)Cl2-DCM complex (25 mg, 0.03 mmol), and CuI (11 mg, 0.058 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to rt, concentrated, and the residue was purified by reverse-phase chromatography using a gradient ACN / H2O / TFA (0-100% ACN (0.1% TFA)) to obtain a mixture of benzyl(R)-7-(3-(3-(methoxymethoxy)-5-(1H-1,2,3-triazole-1-yl)pyridine-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-triazole-1-yl)pyridine-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate (170 mg). This mixture was used in the next step without further purification.

[0145] Step 3. The mixture of benzyl(R)-7-(3-(3-(methoxymethoxy)-5-(1H-1,2,3-triazole-1-yl)pyridine-2-yl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-4-azaspiro[2.5]octane-4-carboxylate obtained in Step 2 and benzyl(R)-7-(3-(3-hydroxy-5-(1H-1,2,3-triazole-1-yl)pyridine-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 hours. The reaction mixture was cooled to rt, concentrated, and purified by reverse-phase chromatography using a gradient ACN / H2O / TFA (0-100% ACN (0.1% TFA)) to obtain 2-[7-[(7S)-4-azaspiro[2.5]octan-7-yl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(triazole-1-yl)pyridin-3-ol;2,2,2-trifluoroacetic acid (14 mg, yield 9%) as a yellowish-brown foam. MS m / z 389.3 [M+H] + ; 1 H NMR (500MHz, methanol-d4) 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=14.0Hz, 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. Add the following to a dry screw-cap vial: 3-chloro-7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-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), and K2CO3 (66 mg, 0.48 mmol). After degassing the mixture with argon for 10 minutes, add dioxane (2 mL) and water (0.5 mL). The reaction mixture was heated at 90°C for 5 hours. The mixture was cooled to rt and fractionated between ethyl acetate and water. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography with a gradient (0-10%) CH2Cl2 / MeOH to obtain 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazole-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. 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazole-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (58 mg, 0.12 mmol), active MnO2 (204 mg, 2.34 mmol), and anhydrous toluene (1.0 mL) were added to a sealed tube. The mixture was stirred at 90°C for 7 hours and then cooled to room temperature. The solid was removed by filtration, and the filtrate was concentrated to obtain crude 7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazole-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (57 mg, 99% yield) as a brown solid. This 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-tetramethylpiperidine-4-yl)-3-(2-(methoxymethoxy)-4-(4-methyl-1H-1,2,3-triazole-1-yl)phenyl)-7H-pyrrolo[2,3-c]pyridazine (57 mg, 0.12 mmol) in TFA (1 mL) was heated to 70°C over 5 minutes. The mixture was concentrated, and the residue was purified by reverse-phase chromatography with elution using a gradient ACN / H2O / formic acid (0-100% ACN) to obtain 2-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(4-methyl-1H-1,2,3-triazole-1-yl)phenol (25 mg, yield 48%) as a yellowish-brown solid. MS m / z 450.5 [M+H] + ; 1¹H NMR (methanol-d4) δ: 8.80 (s, 1H), 8.36 (s, 2H), 8.02 (d, J=8.63Hz, 1H), 7.60 (d, J=2.00Hz, 2H), 7.04 (d, J=3.50Hz, 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] Using the procedure described in Example 3 above, additional compounds described herein may be prepared by substituting appropriate starting materials, suitable reagents, and reaction conditions, to obtain compounds selected from the following: [Table 5] TIFF0007918255000070.tif51156

[0150] Biological examples The following in vitro biological examples demonstrate the usefulness of the compounds herein for the treatment of Huntington's disease. To further illustrate and aid in understanding this specification, the following non-limiting biological examples are provided to better illustrate the scope of the specification and should not be construed as specifically limiting its scope. Similar variations of this specification that may be currently known or subsequently developed, which should be within the scope of those skilled in the art, are considered to be within the scope of this specification and are claimed below. The compound of formula (I) was tested using the Meso Scale Discovery (MSD) assay described in International Application No. PCT / US2016 / 066042, filed on 11 December 2016, claiming priority to U.S. Provisional Application No. US62 / 265,652, filed on 10 December 2015 (the entire contents of these applications are incorporated herein by reference). The endogenous huntingtin protein assay used in Example 1 was developed using the ELISA-based MSD electrochemiluminescence assay platform.

[0151] Example 1: Endogenous huntingtin protein assay Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4°C with MW1 (extended polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 μg / mL in PBS (30 μL per well). The plates were then washed three times with 300 μL of washing buffer (0.05% Tween-20 in PBS), blocked at room temperature for 4-5 hours with rotation and shaking (100 μL of blocking buffer, 5% BSA in PBS), and then washed three times with washing buffer.

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

[0153] As shown in Table 1, the test compounds described herein are as follows IC 50 ICs with a value, and one asterisk (*) indicate ICs with a thickness of >3μM to ≤9μM. 50 The values ​​are shown, and the two asterisks (**) indicate ICs with a thickness of >1μM to ≤3μM. 50 The values ​​are shown, and the three asterisks (***) indicate ICs with a thickness of >0.5μM to ≤1μM. 50 The values ​​are shown, and the four asterisks (****) indicate ICs >0.1μM to ≤0.5μM. 50 The values ​​are shown, and five asterisks (*****) indicate ICs with a minimum thickness of 0.1 μM. 50 Show the value. [Table 6]

[0154] Example 2 Results for comparative compound: Increased titer The comparative compound was reported in International Publication No. 2020 / 005873 as a compound found to be active in an endogenous huntingtin protein assay. The comparative compound lacks various structural features compared to the compound of the present invention encompassed in formula (I). The comparative compound was tested according to the assay described in Example 1, and the results are shown in Table 2. It was observed that the titer changed in various ways due to the structural modification. Compared to Cpd72 of International Publication 2020 / 005873, which has a 3H-[1,2,3]-triazolo[4,5-c]pyridazine core, Cpd1 of the present invention, which has a 7H-pyrrolo[2,3-c]pyridazine core, was observed to have a significantly higher titer of 223 times. In contrast, similar titers were observed for Cpd26 of International Publication 2020 / 005873, which has a 7H-pyrrolo[2,3-c]pyridazine core, and Cpd7 of International Publication 2020 / 005873, which has a 3H-[1,2,3]-triazolo[4,5-c]pyridazine core.

[0155] A comparison of Cpd7 and Cpd72 in International Publication No. 2020 / 005873 shows that substituting the 1H-pyrazole moiety with the 1H-1,2,3-triazole moiety significantly reduces the potency. In contrast, Cpd1 of the present invention and Cpd26 in International Publication No. 2020 / 005873 showed an improvement in potency of more than eight times with the same structural modification. [Table 7]

[0156] Whether or not any document cited herein is specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference to this application with respect to any and all purposes, just as each individual reference is fully specified herein. As the subject matter of the claims has been adequately described herein, it will be understood by those skilled in the art that it may be carried out within the scope of a broad range of equivalents without affecting the scope of the subject matter or detailed embodiments described herein. The appended claims are intended to be construed to include all such equivalents. The present specification includes the following embodiments. Section 1: Compounds of the following formula (I): [ka] or in that form, in the formula: R A The formula is as follows: [ka] And, In the formula, p and q are independently either 0 or 1; X 1 It is selected from the group consisting of CH, C-halogen, and N; X 2 It is selected from the group consisting of CH and C-halogens; R 1is hydrogen, hydroxyl, and C 1-4 Selected from the group consisting of alkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 These are independently hydrogen, halogen, hydroxyl, cyano, and 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 Selected from the group consisting of alkoxys; or R 2 and R 3 They form saturated 3-6 membered rings incorporating zero or one heteroatom ring member selected from N, O, and S, together with the atoms to which they are bonded; or R 2 and R 4 They form a saturated 5-10 membered ring system together with the atoms to which they are bonded; or R 2 and R 7 They form a saturated 5-10 membered ring system together with the atoms to which they are bonded; or R 4 and R 5 These, together with the atoms to which they are bonded, form saturated 3- to 6-membered rings incorporating zero or one heteroatom ring member selected from N, O, and S; R A1 and R A2 These are independently hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 1-4Alkyl, 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 groups; R B1 and R B2 These are independently hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 alkoxys; Here, the form of the compound is selected from the group consisting of its salt, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms. A compound or its form. Section 2: The aforementioned compound has the following formula (Ia): [ka] It has a structure The compound or form thereof as described in item 1. Section 3: The aforementioned compound is given by the following formula (Ib): [ka] It has a structure The compound or form thereof as described in item 1. Section 4: R A This group consists of the following: [ka] [ka] More selected The compound or form thereof described in any one of items 1 to 3. Section 5: R AThis group consists of the following: [ka] More selected A compound or form thereof as described in any one of items 1 to 4. Item 6: R A The formula is as follows: [ka] That is A compound or form thereof as described in any one of items 1 to 5. Section 7: R A This group consists of the following: [ka] More selected A compound or form thereof as described in any one of items 1 to 5. Section 8: The compound described in any one of items 1 to 7, wherein the form of the compound is a salt. Section 9: The compound described in any one of claims 1 to 8, wherein the form of the compound is a salt selected from the group consisting of hydrochloride, dihydrochloride, formate, diformate, and trifluoroacetate. Section 10: The following group: 2-[7-(2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-[7-(4-azaspiro[2,5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4RS)-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 5-(1H-1,2,3-triazole-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-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-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-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-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7R)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)pyridine-3-ol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(5-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol; 5-(4-chloro-1H-1,2,3-triazol-1-yl)-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-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-triazole-1-yl)phenol; 2-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-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-triazole-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-triazole-1-yl)phenol; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8R,9R)-9-fluoro-5-azaspiro[3,5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8S,9S)-9-fluoro-5-azaspiro[3,5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-[7-(4-Azadispiro[2.1.2 5 .3 3 ]decane-9-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8S,9R)-8-fluoro-6-azaspiro[4.5]decane-9-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8R,9S)-8-fluoro-6-azaspiro[4.5]decane-9-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 4-Fluoro-2-{7-[(3S,4S)-3-Fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(1H-1,2,3-triazole-1-yl)pheno; and 3-Fluoro-2-{7-[(3S,4S)-3-Fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; A more selected compound, The form of the compound is selected from the group consisting of its salt, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms. Section 11: The following group: 2-[7-(2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3S,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-[7-(4-azaspiro[2,5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(4RS)-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 5-(1H-1,2,3-triazole-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}phenol hydrochloride; 2-[7-(4-methyl-4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-[7-(4-azaspiro[2,5]octan-7-yl)-6-methyl-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol diformate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol diformate; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenoltrifluoroacetate; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)pyridine-3-ol trifluoroacetate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol formate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(5-methyl-1H-1,2,3-triazole-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-triazole-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-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}phenol formate; A more selected compound, The compound is one whose form is selected from the group consisting of a racemic mixture, enantiomers, diastereoisomers, stereoisomers, and tautomers. Section 12: A method for treating or achieving remission of hemolytic hypertension (HD) in a subject requiring treatment or remission of HD, comprising administering an effective amount of any one of the compounds described in items 1 to 11 to the subject. Section 13: The method according to item 12, wherein the effective amount of the compound is in the range of about 0.001 mg / kg / day to about 500 mg / kg / day. Section 14: Use of a compound described in any one of paragraphs 1 to 11 for treating or relieving HD in a subject requiring treatment or remission of HD, comprising administering an effective amount of the compound to the subject. Section 15: The effective amount of the compound is in the range of approximately 0.001 mg / kg / day to approximately 500 mg / kg / day, as described in item 14. Section 16: Use of a compound according to any one of paragraphs 1 to 11 in manufacturing a pharmacopoeia for treating or relieving HD in a subject requiring treatment or remission of HD, wherein the treatment or remission comprises administering an effective amount of the pharmacopoeia to the subject. Section 17: The use described in item 16, wherein the effective amount of the compound in the pharmaceutical is in the range of about 0.001 mg / kg / day to about 500 mg / kg / day. Section 18: Use of a compound according to any one of claims 1 to 11, in which the compound is miscible in a pharmaceutical composition with one or more pharmaceutically acceptable excipients for the purpose of treating or relieving HD in a subject requiring treatment or remission of HD, wherein the treatment or remission comprises administering an effective amount of the pharmaceutical composition to the subject. Section 19: The use described in item 18, wherein the effective amount of the compound in the pharmaceutical composition is in the range of about 0.001 mg / kg / day to about 500 mg / kg / day. Section 20: A pharmaceutical composition for use in the treatment or remission of hemoglobin (HD), comprising an effective amount of a compound described in any one of items 1 to 9 and a pharmaceutically acceptable excipient. Section 21: A pharmaceutical composition for use in the treatment or remission of HD, comprising the compound described in item 10 or 11 in an effective amount and a pharmaceutically acceptable excipient.

Claims

1. Compound of the following formula (I): 【Chemistry 1】 or in that form, in the formula: R Ａ The formula is as follows: 【Chemistry 2】 And, In the formula, p and q are independently either 0 or 1; X １ It is selected from the group consisting of CH, C-halogen, and N; X ２ It is selected from the group consisting of CH and C-halogens; R １ is hydrogen, hydroxyl, and C １－４ Selected from the group consisting of alkyl groups; R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C １－４ alkyl, deuterated-C １－４ alkyl, halo-C １－４ alkyl, amino, C １－４ alkyl-amino, di(C １－４ alkyl) ２ -amino, C １－４ alkoxy, and halo-C １－４ alkoxy; or R ２ and R ３ They form saturated 3- to 6-membered rings incorporating zero or one heteroatom ring member selected from N, O, and S, together with the atoms to which they are bonded; or R ２ and R ４ They form a saturated 5-10 membered ring system together with the atoms to which they are bonded; or R ２ and R ７ They form a saturated 5-10 membered ring system together with the atoms to which they are bonded; or R ４ and R ５ These, together with the atoms to which they are bonded, form saturated 3- to 6-membered rings incorporating zero or one heteroatom ring member selected from N, O, and S; R Ａ１ and R Ａ２ These are independently hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 groups; R Ｂ１ and R Ｂ２ These are independently hydrogen, deuterium, halogen, hydroxyl, cyano, and 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 alkoxys; Here, the form of the compound is selected from the group consisting of its salt, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms. A compound or its form.

2. The aforementioned compound has the following formula (Ia): 【Transformation 3】 It has a structure The compound or form thereof according to claim 1.

3. The aforementioned compound is given by the following formula (Ib): 【Chemistry 4】 It has a structure The compound or form thereof according to claim 1.

4. R Ａ The group consists of the following: 【Transformation 5】 【Transformation 6】 More selected The compound or form thereof according to any one of claims 1 to 3.

5. R Ａ The group consists of the following: 【Transformation 7】 More selected The compound or form thereof according to any one of claims 1 to 3.

6. R Ａ The formula is as follows: 【Transformation 8】 That is The compound or form thereof according to any one of claims 1 to 3.

7. R Ａ The group consists of the following: 【Chemistry 9】 More selected The compound or 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 form of the compound is a salt.

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

10. The group consists of the following: 2-[7-(2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-[7-(4-azaspiro[2,5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4RS)-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 5-(1H-1,2,3-triazole-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-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-triazole-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-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7R)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)pyridine-3-ol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(4-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(5-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol; 5-(4-chloro-1H-1,2,3-triazole-1-yl)-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-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-triazole-1-yl)phenol; 2-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-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-triazole-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-triazole-1-yl)phenol; 2-{7-[(8R,9R)-9-fluoro-5-azaspiro[3,5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8S,9S)-9-fluoro-5-azaspiro[3,5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-[7-(4-Azadispiro[2.1.2 5 .3 3 ]decane-9-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8S,9R)-8-fluoro-6-azaspiro[4,5]decane-9-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 2-{7-[(8R,9S)-8-fluoro-6-azaspiro[4.5]decane-9-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; 4-Fluoro-2-{7-[(3S,4S)-3-Fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(1H-1,2,3-triazole-1-yl)pheno; and 3-Fluoro-2-{7-[(3S,4S)-3-Fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol; A more selected compound, The form of the compound is selected from the group consisting of its salt, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomer forms.

11. The group consists of the following: 2-[7-(2,2,6,6-tetramethylpiperidine-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3R,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(3S,4R)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-[7-(4-azaspiro[2,5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol dihydrochloride; 2-{7-[(4RS)-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 5-(1H-1,2,3-triazole-1-yl)-2-{7-[(4RS)-1,2,2-trimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}phenol hydrochloride; 2-[7-(4-methyl-4-azaspiro[2.5]octan-7-yl)-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-[7-(4-azaspiro[2,5]octan-7-yl)-6-methyl-7H-pyrrolo[2,3-c]pyridazine-3-yl]-5-(1H-1,2,3-triazole-1-yl)phenol diformate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-6-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol diformate; 2-{7-[(4S,5R)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-{7-[(4R,5S)-5-fluoro-2,2-dimethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenol hydrochloride; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)phenoltrifluoroacetate; 2-{7-[(7S)-4-azaspiro[2,5]octan-7-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}-5-(1H-1,2,3-triazole-1-yl)pyridine-3-ol trifluoroacetate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(4-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol formate; 2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}5-(5-methyl-1H-1,2,3-triazole-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-triazole-1-yl)phenol formate, and 5-(4-chloro-1H-1,2,3-triazol-1-yl)-2-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine-4-yl]-7H-pyrrolo[2,3-c]pyridazine-3-yl}phenol formate; A more selected compound, The compound is one whose form is selected from the group consisting of a racemic mixture, enantiomers, diastereoisomers, stereoisomers, and tautomers.

12. Use of the compound according to any one of claims 1 to 3 in the manufacture of a pharmaceutical for treating or relieving Huntington's disease in a subject who requires treatment or remission of Huntington's disease, wherein the treatment or remission comprises administering an effective amount of the pharmaceutical to the subject.

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

14. Use of the compound according to any one of claims 1 to 3, in which the compound is mixed with one or more pharmaceutically acceptable excipients in a pharmaceutical composition for the purpose of treating or achieving remission of Huntington's disease in a subject who requires treatment or remission of Huntington's disease, wherein the treatment or remission comprises administering an effective amount of the pharmaceutical composition to the subject.

15. The use according to claim 14, wherein the effective amount of the compound in the pharmaceutical composition is in the range of 0.001 mg / kg / day to 500 mg / kg / day.

16. A pharmaceutical composition for use in the treatment or remission of Huntington's disease, comprising an effective amount of the compound described in any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition for use in the treatment or remission of Huntington's disease, comprising an effective amount of the compound according to claim 10 or 11 and a pharmaceutically acceptable excipient.

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