Heterocyclic and heteroaryl compounds for treatment of huntington's disease

Abstract

The present invention relates to compounds, forms, and pharmaceutical compositions thereof, and methods of using such compounds, forms, or compositions to treat or ameliorate Huntington's disease. In particular, the present invention relates to substituted bicyclic heterocyclic and heteroaryl compounds of formula (I), forms and pharmaceutical compositions thereof, and methods of using such compounds, forms or compositions thereof to treat or ameliorate Huntington's disease. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is an international application claiming the benefit of U.S. Provisional Patent Application No. 63 / 352,255, filed on June 15, 2022, entitled “Heterocycles and Heterocyclyl Compounds for the Treatment of Huntington’s Disease,” the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] One aspect of the present invention relates to compounds, forms thereof and pharmaceutical compositions, and methods of using such compounds, forms thereof or compositions to treat or improve Huntington's disease. In particular, another aspect of the present specification relates to substituted bicyclic heterocyclic compounds and substituted bicyclic heteroaryl compounds, forms thereof and pharmaceutical compositions, and methods of using such compounds, forms thereof or compositions to treat or improve Huntington's disease. Background Art

[0004] Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disease of the brain with symptoms characterized by involuntary movements, cognitive impairment, and mental decline. Death is usually caused by pneumonia or coronary artery disease, usually occurring 13 to 15 years after the onset of symptoms. The incidence of HD is 3 to 7 per 100,000 people in people of Western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 are at risk of inheriting the disease from an affected parent. The disease is caused by an uninterrupted trinucleotide CAG repeat expansion in the "mutated" huntingtin protein (Htt) gene, resulting in the production of HTT (Htt protein) with an expanded polyglutamine (polyQ) stretch, also known as a "CAG repeat" sequence. There are currently no small molecule therapies targeting the underlying cause of the disease, creating a high unmet need for drugs for treating or improving HD. Therefore, there is still a need to discover and provide small molecule compounds for treating or improving HD.

[0005] All other documents referred to herein are incorporated by reference into the present invention as if fully set forth herein. Summary of the invention

[0006] One aspect of the present disclosure relates to compounds of formula (I):

[0007]

[0008] or its form, where R A , R B , W 1 and W 2 As defined herein.

[0009] One aspect of the specification also relates to a method of using a compound of formula (I) or a form or composition thereof to treat or improve HD in a subject in need thereof, comprising administering an effective amount of the compound or a form or composition thereof to the subject.

[0010] One aspect of the specification further relates to the use of a compound of formula (I) or a form thereof for treating or improving HD in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.

[0011] One aspect of the specification further relates to the use of a compound of formula (I) or a form thereof for the preparation of a medicament useful for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[0012] One aspect of the specification further relates to the use of a compound of formula (I) or a form thereof in combination with other drugs useful for treating or improving HD in a subject in need thereof, comprising administering to the subject an effective amount of a product combination for treating or improving HD. DETAILED DESCRIPTION

[0013] One aspect of the present disclosure relates to compounds of formula (I):

[0014]

[0015] or a form thereof in which:

[0016] R A Represented by the following structure:

[0017]

[0018] R B is represented by a structure selected from the group consisting of:

[0019]

[0020] Where available valences permit, W 1 Selected by CR W1 , C-(R W1 )2 and N;

[0021] Where available valences permit, W 2 Selected by CR W2 , C-(R W2 )2 and N;

[0022] Each R W1 and R W2 independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C1-4 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 Alkylamino, (C 1-4 alkyl)2-amino, amino-C 1-4 Alkyl and hydroxyl C 1-4 A group consisting of alkyl groups;

[0023] R 1 Selected from hydrogen and C 1-4 A group consisting of alkyl groups;

[0024] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and hydroxy-C 1-4 alkyl; or

[0025] R 2 and R 3 Together with the atoms to which it is attached, it forms a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S; or

[0026] R 2 and R 4 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0027] R 2 and R 7 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0028] R 4 and R 5 Together with the atoms to which they are attached, they form a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S;

[0029] X 1 , X 2 , X 3 and X 4 Each independently selected from CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S;

[0030] Each R X are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and C 1-4 A group consisting of alkylthio groups;

[0031] Each R X’ Independently selected from hydrogen, hydroxyl, C 1-4 Alkyl and C 1-4 A group consisting of alkoxy groups;

[0032] R B1 For halogen, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy and halo-C 1-4 Alkoxy;

[0033] n is 0 or 1;

[0034] p is 0 or 1;

[0035] q is 0 or 1; and

[0036] If valence permits, independently represent a single bond or a double bond;

[0037] The form of the compound can be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomers thereof.

[0038] Aspects of the Instructions

[0039] One aspect of the present disclosure includes compounds of formula (I):

[0040]

[0041] or a form thereof in which:

[0042] R A Represented by the following structure:

[0043]

[0044] R B is represented by a structure selected from the group consisting of:

[0045]

[0046] Where available valences permit, W 1 Selected by CR W1 , C-(R W1 )2 and N;

[0047] Where available valences permit, W 2 Selected by CR W2 , C-(R W2 )2 and N;

[0048] Each R W1 and R W2 independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-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 Alkylamino, (C 1-4 alkyl)2-amino, amino-C 1-4 Alkyl and hydroxyl C 1-4 A group consisting of alkyl groups;

[0049] R 1 Selected from hydrogen and C 1-4 A group consisting of alkyl groups;

[0050] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and hydroxy-C 1-4 alkyl; or

[0051] R 2 and R 3 Together with the atoms to which it is attached, it forms a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S; or

[0052] R 2 and R 4 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0053] R 2 and R 7 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0054] R 4 and R 5 Together with the atoms to which they are attached, they form a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S;

[0055] X 1 , X 2 , X 3 and X 4 Each independently selected from CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S;

[0056] Each R X are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and C 1-4 A group consisting of alkylthio groups;

[0057] Each R X’ Independently selected from hydrogen, hydroxyl, C 1-4 Alkyl and C 1-4 A group consisting of alkoxy groups;

[0058] R B1 For halogen, cyano, C 1-4Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy and halo-C 1-4 Alkoxy;

[0059] n is 0 or 1;

[0060] p is 0 or 1;

[0061] q is 0 or 1; and

[0062] If valence permits, independently represent a single bond or a double bond;

[0063] Provided that the compound of formula (I) is not 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol, (3E)-3-(hydroxyimino)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-2,3-dihydro-1H-indene-5-ol, l-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol, 2-Methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1H-benzimidazol-6-ol;

[0064] The form of the compound can be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomers thereof.

[0065] One aspect of formula (I) includes compounds of formula (Ia):

[0066]

[0067] or its form.

[0068] Another aspect of formula (I) includes compounds of formula (Ia1), formula (Ia2) or formula (Ia3):

[0069]

[0070] or its form.

[0071] One aspect of formula (I) includes compounds of formula (Ib):

[0072]

[0073] or its form.

[0074] Another aspect of formula (I) includes compounds of formula (Ib1) or forms thereof:

[0075]

[0076] or its form.

[0077] One aspect includes compounds of formula (I) wherein R A for

[0078]

[0079] When p and q are both 0, and any stereoisomers thereof.

[0080] One aspect includes compounds of formula (I) wherein R A for

[0081]

[0082] When p is 0 and q is 1, and any stereoisomers thereof. One aspect includes compounds of formula (I), wherein R A for

[0083]

[0084] When p is 1 and q is 0, and any stereoisomers thereof. One aspect includes compounds of formula (I), wherein R A for

[0085]

[0086] When p and q are both 1, and any stereoisomers thereof.

[0087] Another aspect includes compounds of formula (I) wherein R A Selected from:

[0088]

[0089] and any stereoisomers thereof.

[0090] Another aspect includes compounds of formula (I) wherein R A for

[0091]

[0092] and any stereoisomers thereof.

[0093] Another aspect includes compounds of formula (I) wherein R A for

[0094]

[0095] and any stereoisomers thereof.

[0096] Another aspect includes compounds of formula (I) wherein R A for

[0097]

[0098] and any stereoisomers thereof.

[0099] Another aspect includes compounds of formula (I) wherein R A for

[0100]

[0101] and any stereoisomers thereof.

[0102] Another aspect includes compounds of formula (I) wherein R A for

[0103]

[0104] and any stereoisomers thereof.

[0105] Another aspect includes compounds of formula (I) wherein R A -2 Selected from:

[0106]

[0107] and any other stereoisomers thereof.

[0108] Another aspect includes compounds of formula (I) wherein R A -2 means:

[0109]

[0110] Another aspect includes compounds of formula (I) wherein R A -2 means:

[0111]

[0112] Another aspect includes compounds of formula (I) wherein R A -5 selected from:

[0113]

[0114] and any other stereoisomers thereof.

[0115] Another aspect includes compounds of formula (I) wherein R A -5 means:

[0116]

[0117] Another aspect includes compounds of formula (I) wherein R A -5 means:

[0118]

[0119] Another aspect includes compounds of formula (I) wherein R A -7 selected from:

[0120]

[0121]

[0122] and any other stereoisomers thereof.

[0123] Another aspect includes compounds of formula (I) wherein R A -7 means:

[0124]

[0125] Another aspect includes compounds of formula (I) wherein R A -7 means:

[0126]

[0127] Another aspect includes compounds of formula (I) wherein R A -10 selected from:

[0128]

[0129] and any other stereoisomers thereof.

[0130] Another aspect includes compounds of formula (I) wherein R A -10 is:

[0131]

[0132] Another aspect includes compounds of formula (I) wherein R A -10 is:

[0133]

[0134] One aspect includes compounds of formula (I) wherein R B Selected from:

[0135]

[0136] When n is 0.

[0137] One aspect includes compounds of formula (I) wherein R B for:

[0138]

[0139]

[0140] When n is 1.

[0141] Another aspect includes compounds of formula (I) wherein R B Selected from:

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] Another aspect includes compounds of formula (I) wherein R B Selected from:

[0150]

[0151]

[0152] One aspect includes compounds of formula (I), wherein, where available valences permit, W 1 Selected by CR W1 , C-(R W1 )2. A group consisting of and N.

[0153] Another aspect includes compounds of formula (I) wherein W 1 CR W1 .

[0154] Another aspect includes compounds of formula (I) wherein W 1 C-(R W1 )2.

[0155] Another aspect includes compounds of formula (I) wherein W1 is N.

[0156] One aspect includes compounds of formula (I), wherein, where available valences permit, W 2 Selected by CR W2 , C-(R W2 )2 and N.

[0157] Another aspect includes compounds of formula (I) wherein W 2 CR W2 .

[0158] Another aspect includes compounds of formula (I) wherein W 2 C-(R W2 )2.

[0159] Another aspect includes compounds of formula (I) wherein W 2 is N.

[0160] One aspect includes compounds of formula (I) wherein each R W1 and R W2 independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-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 Alkylamino, (C 1-4 alkyl)2-amino, amino-C 1-4 Alkyl and hydroxyl C 1-4 Alkyl group.

[0161] Another aspect includes compounds of formula (I) wherein each R W1 and R W2 are independently hydrogen.

[0162] Another aspect includes compounds of formula (I) wherein W 1 For CH.

[0163] Another aspect includes compounds of formula (I) wherein W 1 For CH2.

[0164] Another aspect includes compounds of formula (I) wherein W 1 is N.

[0165] Another aspect includes compounds of formula (I) wherein W 2 For CH.

[0166] Another aspect includes compounds of formula (I) wherein W 2 For CH2.

[0167] Another aspect includes compounds of formula (I) wherein W 2 is N.

[0168] One aspect includes compounds of formula (I) wherein R 1 Selected from hydrogen and C 1-4 Alkyl group.

[0169] Another aspect includes compounds of formula (I) wherein R 1 For hydrogen.

[0170] Another aspect includes compounds of formula (I) wherein R 1 is a C selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl 1-4 alkyl.

[0171] Another aspect includes compounds of formula (I) wherein R 1 It is methyl.

[0172] One aspect includes compounds of formula (I) wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and hydroxy-C 1-4 alkyl; or

[0173] R 2 and R 3 Together with the atoms to which it is attached, it forms a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S; or

[0174] R 2 and R 4 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0175] R2 and R 7 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or

[0176] R 4 and R 5 Together with the atoms to which it is attached, it forms a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S.

[0177] Another aspect includes compounds of formula (I) wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen and C 1-4 Alkyl group.

[0178] Another aspect includes compounds of formula (I) wherein R 2 is selected from the group consisting of hydrogen and methyl.

[0179] Another aspect includes compounds of formula (I) wherein R 3 is selected from the group consisting of hydrogen and methyl.

[0180] Another aspect includes compounds of formula (I) wherein R 4 is selected from the group consisting of hydrogen and methyl.

[0181] Another aspect includes compounds of formula (I) wherein R 5 is selected from the group consisting of hydrogen and methyl.

[0182] Another aspect includes compounds of formula (I) wherein R 6 Selected from the group consisting of hydrogen and fluorine.

[0183] Another aspect includes compounds of formula (I) wherein R 7 , R 8 , R 9 and R 11 are each independently hydrogen.

[0184] Another aspect includes compounds of formula (I) wherein R 10 Selected from the group consisting of hydrogen and fluorine.

[0185] Another aspect includes compounds of formula (I) wherein R 2 and R 3 Together with the atoms to which they are attached they form a cyclopropyl ring or a cyclobutyl ring.

[0186] Another aspect includes compounds of formula (I) wherein R 4 and R 5 Together with the atoms to which they are attached they form a cyclopropyl ring or a cyclobutyl ring.

[0187] Another aspect includes compounds of formula (I) wherein R 2 and R 4 Together with the atoms to which it is attached, it forms a saturated 5-10 membered ring system.

[0188] One aspect includes compounds of formula (I), wherein X 1 , X 2 , X 3 and X 4 Each independently selected from ring CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S.

[0189] One aspect includes compounds of formula (I), wherein X 1 Selected by CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S.

[0190] Another aspect includes compounds of formula (I) wherein X 1 Selected by CR X 、C=O、C=NR X’ , N, NR X’ , O and S.

[0191] One aspect includes compounds of formula (I), wherein X 2 Selected by CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S.

[0192] Another aspect includes compounds of formula (I) wherein X 2 Selected by CR X , C-(R X )2. C=O、N、NR X’ and S.

[0193] One aspect includes compounds of formula (I), wherein X 3 Selected by CRX , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S.

[0194] Another aspect includes compounds of formula (I) wherein X 3 Selected by CR X , C-(R X )2. C=O、N、NR X’ , O and S.

[0195] One aspect includes compounds of formula (I), wherein X 4 Selected by CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S.

[0196] Another aspect includes compounds of formula (I) wherein X 4 Selected by CR X , a group consisting of C=O, N and O.

[0197] One aspect includes compounds of formula (I) wherein R X are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and C 1-4 A group consisting of alkylthio groups.

[0198] Another aspect includes compounds of formula (I) wherein each R X are independently selected from hydrogen, halogen, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 A group consisting of alkylthio groups.

[0199] Another aspect includes compounds of formula (I) wherein each R X Independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and thiomethyl.

[0200] One aspect includes compounds of formula (I) wherein R X’ Independently selected from hydrogen, hydroxyl, C1-4 Alkyl and C 1-4 A group consisting of alkoxy groups.

[0201] Another aspect includes compounds of formula (I) wherein R X’ independently selected from hydrogen, C 1-4 Alkyl and C 1-4 A group consisting of alkoxy groups.

[0202] Another aspect includes compounds of formula (I) wherein R X’ are independently selected from the group consisting of hydrogen, methyl and methoxy.

[0203] One aspect includes compounds of formula (I) wherein R B1 For halogen, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy and halo-C 1-4 Alkoxy.

[0204] Another aspect includes compounds of formula (I) wherein R B1 It is a halogen.

[0205] Another aspect includes compounds of formula (I) wherein R B1 For fluorine.

[0206] One aspect of the method or use comprises a compound of formula (I) or a form thereof, comprising a compound selected from the group consisting of: ％ " indicates that the compound is a single isomer with the relative configuration shown:

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] wherein the compound is in the form selected from the group consisting of salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomeric forms.

[0216] One aspect of the compound of formula (I) or a form thereof (wherein the compound number (#^) indicates that the salt form was isolated) includes compounds selected from the group consisting of:

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] wherein the compound is in the form selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomeric forms.

[0225] Another aspect of the compound of formula (I) or a form thereof is a salt of the compound selected from the group consisting of:

[0226]

[0227]

[0228]

[0229] Wherein the salt form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomeric forms.

[0230] One aspect of the disclosure includes methods of using a compound of Formula (I) or a form thereof to treat or improve HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

[0231] Another aspect of the disclosure includes a method of using a salt of a compound of formula (I) or a form thereof to treat or improve HD in a subject in need thereof, comprising administering an effective amount of a salt of a compound of formula (I) or a form thereof to the subject.

[0232] One aspect of the disclosure includes the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof to the subject.

[0233] Another aspect of the present specification includes the use of a salt of a compound of formula (I) or a form thereof for treating or improving HD in a subject in need thereof, comprising administering an effective amount of a salt of a compound of formula (I) or a form thereof to the subject.

[0234] Chemical Definition

[0235] Unless expressly defined otherwise, those of ordinary skill in the art would understand the chemical terms used above and throughout the specification herein to have the meanings shown below.

[0236] As used herein, the term “C 1-4 The term "alkyl" generally refers to a saturated hydrocarbon radical having one to four carbon atoms in a straight or branched configuration, including, but not limited to, methyl, ethyl, n-propyl (also known as propyl or propanyl), isopropyl, n-butyl (also known as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, and the like. Where available valences permit, C 1-4 Alkyl groups are optionally substituted with substituent species described herein.

[0237] As used herein, the term “C 2-6 "Alkenyl" generally refers to partially unsaturated hydrocarbon groups having two to six carbon atoms in a straight or branched configuration and having one or more carbon-carbon double bonds therein, including but not limited to ethenyl (also known as vinyl), allyl, propenyl, and the like. In certain aspects, C 2-6 Alkenyl includes but is not limited to C 2-4 Where available valences permit, C 2-6 Alkenyl groups are optionally substituted with substituent species described herein.

[0238] As used herein, the term “C 2-6 "Alkynyl" generally refers to partially unsaturated hydrocarbon groups having two to six carbon atoms in a straight or branched configuration and having one or more carbon-carbon triple bonds, including but not limited to ethynyl, propynyl, butynyl and the like. In certain aspects, C 2-8 Alkynyl groups include, but are not limited to, C 2-4 Alkynyl and the like. Where available valences permit, C 2-6 Alkynyl groups are optionally substituted with substituent species described herein.

[0239] As used herein, the term “C 1-4 "Alkoxy" generally refers to a group having one to four carbon atoms with the chemical formula: -OC 1-4A saturated hydrocarbon group of a straight or branched configuration of an alkyl group, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Where available valences permit, C 1-4 Alkoxy groups are optionally substituted with substituent species as described herein.

[0240] As used herein, the term “C 1-4 "Alkylthio" generally refers to a group having one to four carbon atoms with the chemical formula: -SC 1-4 A saturated hydrocarbon group of a straight or branched configuration of an alkyl group, including but not limited to thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thioisobutyl and the like. Where available valences permit, C 1-4 The alkylthio group is optionally substituted with substituent species as described herein. As used herein, the term "C 3-10 "Cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydronaphthyl and the like. In certain aspects, C 3-10 Cycloalkyl includes but is not limited to C 3-8 Cycloalkyl, C 5-8 Cycloalkyl, C 3-10 Cycloalkyl and the like. Where available valences permit, C 3-10 Cycloalkyl groups are optionally substituted with substituent species described herein.

[0241] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group, including but not limited to phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. Where available valence permits, the aryl group may be optionally substituted with substituents described herein.

[0242] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group, in which one or more carbon atom ring members are substituted by one or more heteroatoms (e.g., O, S or N atoms) when structural stability permits, including but not limited to furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-naphthyridinyl, acridinyl, furano[3,2-b]pyridinyl, furano[3,2-c]pyridinyl, furano[2,3-c]pyridinyl yl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a] pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and the like. Heteroaryl groups are optionally substituted on carbon or nitrogen atom ring members with substituent species as described herein, as permitted by available valences.

[0243] In some aspects, the nomenclature of the heteroaryl group may be different, for example, in non-limiting examples, furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl, and 1,3-benzoxazolyl may also be referred to as 1,3-benzooxazolyl.

[0244] In certain other aspects, the term heteroaryl group may also include other positional isomers, for example, in a non-limiting example, the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and the like, the term pyrazolyl may also include 1H-pyrazolyl and the like, the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term indazolyl may also include 1H-indazolyl, 2H-indazolyl and the like, the term benzimidazolyl may also include 1H-benzimidazolyl, and the term purinyl may also include 9H-purinyl and the like.

[0245] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure group, in which one or more carbon atom ring members are replaced by heteroatoms (e.g., O, S or N atoms) when structural stability permits, including but not limited to oxirane, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyran 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-benzodioxanyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3, 4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c] Pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyridinyl Oxazine-(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 yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl cyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl and the like. Carbon or nitrogen atom ring members of the heterocyclyl group are optionally substituted with substituent species as described herein, where permitted by available valences.

[0246] In some aspects, the nomenclature of the heterocyclyl group may be different, for example, in non-limiting example, 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxol and 2,3-dihydro-1,4-benzodioxanyl may also be referred to as 2,3-dihydrobenzo[b][1,4]dioxanyl.

[0247] As used herein, the term "deuterated-C 1-4 "Alkyl" refers to the chemical formula: -C 1-4 Alkyl-deuterated groups in which, where available valences permit, C 1-4 The alkyl group is partially or fully substituted with one or more deuterium atoms.

[0248] As used herein, the term “C 1-4 Alkoxy-C 1-4 "Alkyl" refers to the chemical formula: -C 1-4 Alkyl-OC 1-4 Alkyl group.

[0249] As used herein, the term “C 1-4 "Alkylamino" refers to the chemical formula: -NH-C 1-4 Alkyl group.

[0250] As used herein, the term “ 1-4 "alkyl)2-amino" refers to the chemical formula: -N(C 1-4 alkyl)2 group.

[0251] As used herein, the term "amino-C 1-4"Alkyl" refers to -C 1-4 Alkyl-NH2 group.

[0252] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluorine, chlorine, bromine, and iodine.

[0253] As used herein, the term "halo-C 1-4 "Alkyl" refers to the chemical formula: -C 1-4 Alkyl-halogenated groups in which, where available valences permit, C 1-4 The alkyl group is partially or fully substituted by one or more halogen atoms.

[0254] As used herein, the term "halogenated C 1-4 "Alkoxy" refers to the chemical formula: -OC 1-4 Alkyl-halogenated groups in which, where available valences permit, C 1-4 The alkyl group is partially or fully substituted by one or more halogen atoms.

[0255] As used herein, the term "hydroxyl" refers to a group of the formula: -OH.

[0256] As used herein, the term "hydroxy-C 1-4 "Alkyl" refers to the chemical formula: -C 1-4 An alkyl-OH group in which, where available valences permit, C 1-4 The alkyl group is partially or fully substituted by one or more hydroxy groups.

[0257] As used herein, the term "substituent" refers to a position variable on an atom of a core molecule that is substituted at a specified atomic position, replacing one or more hydrogens on a specified atom, without exceeding the normal valence of the specified atom and under the premise that the substitution produces a stable compound. Combinations of substituents and / or variables are permitted only when such combinations produce stable compounds. It should be noted by those of ordinary skill in the art that any carbon atom and heteroatom that do not appear to conform to the valences described or displayed herein should be assumed to have a sufficient number of hydrogen atoms to conform to the valences described or displayed. In some cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment may be within the substituents described, displayed, or listed herein, where the structure may only show a single bond as a point of attachment to the core structure of formula (I). It will be appreciated by those of ordinary skill in the art that, although only single bonds are shown, double bonds are also used for these substituents.

[0258] As used herein, the term "and the like", with reference to the definitions of chemical terms provided herein, refers to variations of chemical structures that would be expected by one skilled in the art, including but not limited to isomers (including chain, branched or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic or polycyclic structures), and all other variations permitted by available valences that result in stable compounds.

[0259] For the purposes of this specification, when one or more substituent variables of a compound of Formula (I) or a form thereof contain functional groups incorporated into a compound of Formula (I), each functional group occurring at any position in the disclosed compound may be independently selected and appropriately, independently and / or optionally substituted.

[0260] As used herein, the term "independently selected" or "individually selected" refers to a functional group variable in a list of substituents that can appear more than once on a structure of Formula (I), with the substitution pattern of each occurrence being independent of any other occurrence. Further, the use of generic substituent variables on any chemical formula or structure of the compounds described herein should be understood to include replacement of the generic substituent with a substituent of a type contained within the specific genus, for example, an aryl group can be substituted with a phenyl or naphthyl group and the like, and the resulting compounds will be included within the scope of the compounds described herein.

[0261] As used herein, when, for example, in “…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 The term "each instance" or "in each instance, when present" as used before the phrase "alkyl" is intended to refer to each instance of a C 3-14 Cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems.

[0262] As used herein, the term "optionally substituted" refers to optional substitution of a specified substituent variable, group, radical or moiety.

[0263] Compound form

[0264] As used herein, the term "form" refers to a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomeric forms.

[0265] In certain aspects described herein, the compound of Formula (I) is in the form of a free acid, a free base, or a salt thereof.

[0266] In certain aspects described herein, the compound of Formula (I) is in the form of a salt thereof.

[0267] In certain aspects described herein, the compounds of Formula (I) are in the form of isotopic isomers thereof.

[0268] In certain aspects described herein, the compounds of Formula (I) are in the form of stereoisomers, racemates, enantiomers or diastereomers thereof.

[0269] In certain aspects described herein, the compounds of Formula (I) are in the form of tautomers thereof.

[0270] In certain aspects described herein, the compound of Formula (I) is in a pharmaceutically acceptable form.

[0271] In certain aspects described herein, the compound of Formula (I) or a form thereof is used in isolation.

[0272] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof after separation and / or purification from a synthetic process (e.g., from a reaction mixture) or a natural source, or a combination thereof, according to one or more separation or purification methods described herein or well known to those skilled in the art (e.g., chromatography, recrystallization, etc.), to a purity sufficient to be characterized by standard analytical techniques described herein or well known to those skilled in the art.

[0273] As used herein, the term "protected" refers to a functional group in a compound of formula (I) or a form thereof that is modified to prevent undesirable side reactions from occurring at the protected position when the compound reacts. Suitable protecting groups will be known to those of ordinary skill in the art and reference standard textbooks, such as TW Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York. These functional groups include hydroxyl, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxyl or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol and the like. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or aralkyl esters. In some cases, the protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl chloride resin. Protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. It will also be understood by those skilled in the art that, although such protected derivatives of the compounds described herein may not produce such pharmacological activity, they can be administered to a subject and subsequently metabolized in vivo to form pharmacologically active compounds described herein. Therefore, such derivatives can be referred to as "prodrugs". All prodrugs of the compounds described herein are included within the scope of use described herein.

[0274] As used herein, the term "prodrug" refers to a form (e.g., a drug precursor) that is converted in vivo to produce a ready-to-use compound of formula (I) active compound or a form thereof. The conversion can occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), for example, by hydrolysis and / or metabolism in blood, liver and / or other organs and tissues. T. Higuchi and W. Stella provide a discussion of the use of prodrugs in Volume 14 of the ACSSymposium Series, "Pro-drugs as Novel Delivery Systems," and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0275] In one example, when the compound of formula (I) or its form contains a carboxylic acid functional group, the prodrug may include an ester formed by replacing the hydrogen atom of the acid group with a functional group (e.g., alkyl and the like). In another example, when the compound of formula (I) or its form contains a hydroxyl functional group, the prodrug form may be prepared by replacing the hydrogen atom of the hydroxyl with another functional group (e.g., alkyl, alkylcarbonyl, or phosphonate and the like). In another example, when the compound of formula (I) or its form contains an amine functional group, the prodrug form may be prepared by replacing one or more amine hydrogen atoms with a functional group (e.g., alkyl or substituted carbonyl). Pharmaceutically acceptable prodrugs of the compound of formula (I) or its form include compounds substituted with one or more of the following groups: carboxylate, sulfonate, amino acid ester, phosphonate, and mono-, di-, or tri-phosphate or alkyl substituents (if applicable). As described herein, it is understood by those of ordinary skill in the art that one or more such substituents may be used to provide a compound of formula (I) or its form as a prodrug.

[0276] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to encompass both solvated and unsolvated forms.

[0277] As used herein, the term "solvate" refers to a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" includes both solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[0278] As used herein, the term "hydrate" refers to a solvate wherein the solvent molecule is water.

[0279] Formula (I) compounds can form salts, which are intended to be included within the scope of this specification. Unless otherwise indicated, the formula (I) compounds or forms thereof mentioned herein are understood to include reference to their salt forms. The term "salt" as used herein means an acidic salt formed with an inorganic and / or organic acid, and a basic salt formed with an inorganic and / or organic base. In addition, when the formula (I) compound or its form contains a basic group (such as, but not limited to, an amine group) and an acidic group (such as, but not limited to, a carboxylic acid) at the same time, a zwitterion ("inner salt") can be formed, and is included in the term "salt" as used herein.

[0280] The term "pharmaceutically acceptable salt", as used herein, refers to those salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that have biological activity, although other salts are also useful. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with an amount of an acid or base (e.g., an equal amount) in a salt precipitating medium or in an aqueous medium, followed by lyophilization.

[0281] Pharmaceutically acceptable salts include one or more salts of the acidic or basic groups present in the compounds described herein. Specific aspects of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthenate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, sugar acid salt, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate and the like. Certain specific aspects of acid addition salts include chloride, bromide or dichloride.

[0282] In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic drug compounds are discussed, for example, by P. Stahld 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 the Orange Book (Food and Drug Administration, Washington, D.C., on its website). These disclosures are incorporated herein by reference.

[0283] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts.

[0284] All such acid salts and base salts are intended to be included within the scope of the pharmaceutically acceptable salts described herein. In addition, for the purposes of this specification, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds.

[0285] The compounds of formula (I) and forms thereof may further exist in tautomeric forms. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of formula (I) or forms thereof described herein.

[0286] The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. The present specification is intended to include all stereoisomeric forms of the compounds of formula (I) and mixtures thereof, including racemic mixtures.

[0287] The compounds described herein may include one or more chiral centers and thus may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions that substantially contain only (S) isomers. In another particular aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions that substantially contain only (R) isomers. As will be appreciated by those skilled in the art, when 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.

[0288] As used herein, the term "substantially pure" refers to a compound consisting essentially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[0289] In one aspect of the disclosure, the compound of formula (I) or a form thereof is in substantially pure (S) enantiomeric form, present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[0290] In one aspect of the disclosure, the compound of formula (I) or a form thereof is in substantially pure (R) enantiomeric form, which is present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[0291] As used herein, "racemate" refers to any mixture of isomeric forms that is not "enantiomerically pure," including but not limited to, for example, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20.

[0292] In addition, all geometric and positional isomers are encompassed by this specification. For example, if the compound of formula (I) or its form contains a double bond or a fused ring, then the cis and trans forms and mixtures are all included within the scope of this specification. A diastereomeric mixture can be separated into its respective diastereoisomers according to its physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by using chiral HPLC columns or other chromatographic methods known to those skilled in the art. Enantiomers can also be converted into diastereomeric mixtures by reacting with appropriate optically active compounds (e.g., chiral auxiliary agents, such as chiral alcohols or Moshe's acyl chlorides), separating diastereomers and converting (e.g., hydrolyzing) single diastereomers into corresponding pure enantiomers for separation. In addition, some compounds of formula (I) can be atropisomers (e.g., substituted biaryls) and are considered as part of this specification.

[0293] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the invention (including salts, solvates, esters and prodrugs of the compounds, and salts, solvates and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotational isomers, atropisomers and diastereomeric forms, are considered within the scope of the present specification, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture as described above.

[0294] The use of the terms "salt", "solvate", "ester", "prodrug" and the like is intended to apply equally to the enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers or racemates of the compound in question.

[0295] Compound Uses

[0296] One aspect of the disclosure relates to methods of using a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a form thereof.

[0297] Another aspect of the disclosure relates to the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof.

[0298] Another aspect of the present description relates to the use of a compound of formula (I) or a form thereof active against HD.

[0299] One aspect of the present disclosure relates to the use of a compound of formula (I) or a form thereof in combination therapy to provide additive or synergistic activity, thereby enabling the development of a combination product for the treatment or amelioration of HD.

[0300] In addition to monotherapy uses, the instant compounds may also be used in combination therapy with current standard drugs, having additive or synergistic activity with one or more known drugs.

[0301] Combination therapies comprising the compounds described herein in combination with one or more known drugs can be used to treat HD, whether or not HD is responsive to known drugs.

[0302] Certain aspects of the disclosure include the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof in a combination therapy comprising administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more drugs.

[0303] Certain specific aspects of the disclosure include the use of a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof in a combination therapy comprising administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more drugs.

[0304] In one aspect of the uses or methods provided herein, a compound of formula (I) or a form thereof used in combination with one or more additional drugs can be administered to a subject or contacted with subject and patient cells before, simultaneously with, or after administration to a subject or patient or contacting the cells with the additional drugs. The compound of formula (I) or a form thereof and the additional drug can be administered to a subject or contacted with cells in a single composition or in different compositions. In a specific aspect, a compound of formula (I) or a form thereof is used in combination with gene therapy to inhibit HTT expression (e.g., using a viral delivery vector) or administering another small molecule HTT inhibitor. In another specific aspect, a compound of formula (I) or a form thereof is used in combination with cell replacement using differentiated non-mutated HTT stem cells. In another specific aspect, a compound of formula (I) or a form thereof is used in combination with cell replacement using differentiated HTT stem cells.

[0305] In one aspect, provided herein is a compound of Formula (I), or a form thereof, for use in combination with supportive standard of care therapy, including palliative care.

[0306] One aspect of the disclosure includes the use of a compound of formula (I) or a form thereof in the preparation of a kit, comprising a compound of formula (I) or a form thereof, and instructions for administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more drugs in a combination therapy for treating or ameliorating HD in a subject in need thereof.

[0307] Therefore, the present specification relates to the use of the compound of formula (I) or its form for treating or improving HD. According to the use of the present specification, compounds that can be used to selectively treat or improve HD have been found, and the use of these compounds for treating or improving HD is provided.

[0308] Another aspect of the use of the present specification relates to the use of a compound of formula (I) or a form thereof for treating or improving HD in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof to the subject.

[0309] Another aspect of the use of the present specification relates to a method of using a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

[0310] Another aspect of the use of the present specification relates to a method of using a compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

[0311] Another aspect of the use of the present specification relates to the use of a compound of formula (I) or a form thereof in the preparation of a medicament for treating or improving HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[0312] Another aspect of the use of the present disclosure relates to the use of a compound of formula (I) or a form thereof in the preparation of a kit comprising a compound of formula (I) or a form thereof, and instructions for administering the compound to treat or ameliorate HD in a subject in need thereof.

[0313] In one aspect, for each such aspect, the subject is treatment naive. In another aspect, for each such aspect, the subject is not treatment naive.

[0314] As used herein, the term "treating," ...

[0315] As used herein, the term "subject" refers to an animal or any living organism that has the ability of sensation and autonomous movement, and which requires oxygen and organic food. Non-limiting examples include members of human, primate, horse, pig, cow, mouse, rat, dog and cat species. In some aspects, the subject is a mammal or a warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" can be used interchangeably with "subject" and "human".

[0316] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of formula (I) or a form, composition or medicament thereof that achieves a target plasma concentration effective for treating or improving HD as described herein, thereby producing the desired therapeutic, ameliorative, inhibitory or preventive effect in a subject in need thereof. In one aspect, an effective amount may be the amount required to treat HD in a subject or patient (more specifically, in a human).

[0317] On the other hand, the concentration-biological effect relationship observed for the compound of formula (I) or its form indicates that the target plasma concentration ranges from about 0.001 μg / mL to about 50 μg / mL, about 0.01 μg / mL to about 20 μg / mL, or about 0.05 μg / mL to about 10 μg / mL, or about 0.1 μg / mL to about 5 μg / mL. In order to achieve such plasma concentrations, the compounds described herein can be administered in different doses, such as, but not limited to, from 0.1 ng to 10000 mg.

[0318] In one aspect, to achieve an effective target plasma concentration, the dosage administered can be based on subject or patient specific factors, wherein the dosage based on body weight can be from about 0.001 mg / kg / day to about 3500 mg / kg / day, or about 0.001 mg / kg / day to about 3000 mg / kg / day, or about 0.001 mg / kg / day to about 2500 mg / kg / day, or about 0.001 mg / kg / day to about 2000 mg / kg / day, or about 0.001 mg / kg / day to about 1500 mg / kg / day, or about 0.001 mg / kg / day to about 1000 mg / kg / day, or about 0.001 mg / kg / day to about 500 mg / kg / day. g / kg / day, or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or about 0.001 mg / kg / day to about 5 mg / kg / day, or about 0. The present invention relates to an agent that is present in an amount of about 0.01 mg / kg / day to about 1 mg / kg / day, or about 0.001 mg / kg / day to about 0.5 mg / kg / day, or about 0.001 mg / kg / day to about 0.1 mg / kg / day, or from about 0.01 mg / kg / day to about 3500 mg / kg / day, or about 0.01 mg / kg / day to about 3000 mg / kg / day, or about 0.01 mg / kg / day to about 2500 mg / kg / day, or about 0.01 mg / kg / day to about 2000 mg / kg / day, or about 0.01 mg / kg / day to about 1500 mg / kg / day, or about 0.01 mg / kg / day to about 1000 mg / kg / day, or about 0.01 mg / kg / day to about g / day to about 500 mg / kg / day, or about 0.01 mg / kg / day to about 250 mg / kg / day, or about 0.01 mg / kg / day to about 200 mg / kg / day, or about 0.01 mg / kg / day to about 150 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day, or about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 50 mg / kg / day, or about 0.01 mg / kg / day to about 25 mg / kg / day, or about 0.01 mg / kg / day to about 10 mg / kg / day, or about 0.01 mg / kg / day to about 5 mg / kg / day, or about 0.01 mg / kg / day to about 0.The dosage form may be from about 0.01 mg / kg / day to about 1 mg / kg / day, or from about 0.01 mg / kg / day to about 0.5 mg / kg / day, or from about 0.01 mg / kg / day to about 0.1 mg / kg / day, or from about 0.1 mg / kg / day to about 3500 mg / kg / day, or from about 0.1 mg / kg / day to about 3000 mg / kg / day, or from about 0.1 mg / kg / day to about 2500 mg / kg / day, or from about 0.1 mg / kg / day to about 2000 mg / kg / day, or from about 0.1 mg / kg / day to about 1500 mg / kg / day, or from about 0.1 mg / kg / day to about 1000 mg / kg / day, or from about 0.1 mg / kg / day to about 500 mg / kg / day, or from about 0.1 mg / kg / day to about 500 mg / kg / day kg / day to about 250 mg / kg / day, or about 0.1 mg / kg / day to about 200 mg / kg / day, or about 0.1 mg / kg / day to about 150 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day, or about 0.1 mg / kg / day to about 75 mg / kg / day, or about 0.1 mg / kg / day to about 50 mg / kg / day, or about 0.1 mg / kg / day to about 25 mg / kg / day, or about 0.1 mg / kg / day to about 10 mg / kg / day, or about 0.1 mg / kg / day to about 5 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0319] The effective amount for a particular subject can be determined by routine experimentation, which is within the skill and judgment of the clinician or practitioner skilled in the art according to factors related to the subject. The dosage and administration method can be adjusted to provide sufficient levels of active drug or maintain the desired effect. Factors that may be considered include genetic screening, severity of the disease state, disease progression, general health of the subject, race, age, weight, sex, diet, dosing time and frequency, drug combination, reaction sensitivity, experience with other therapies, and tolerance / response to treatment.

[0320] The dosage to achieve an effective target plasma concentration can be administered orally once a day (once within approximately 24 hours; i.e., "qd"), twice (once within approximately 12 hours; i.e., "bid" or "q.12h"), three times (once within approximately 8 hours; i.e., "tid" or "q.8h"), or four times (once within approximately 6 hours; i.e., "qds", "qid" or "q.6h")

[0321] In certain aspects, for patients or subjects with a body weight in the range of about 40 kg to about 200 kg, the dosage administered can also be administered in single, divided or continuous doses to achieve an effective target plasma concentration (for patients or subjects above or below this range, particularly children below 40 kg, the dosage can be adjusted). Typical adult subjects are expected to have a median body weight in the range of about 70 kg. Long-acting pharmaceutical compositions can be administered once every 2, 3 or 4 days, once a week, or once every two weeks, depending on the half-life and clearance rate of a particular formulation.

[0322] The compounds and compositions described herein can be administered to a subject by any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (suppository and infusion), intracerebral and pulmonary routes of administration.

[0323] 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, or 4000 mg / day.

[0324] For any compound, the effective amount can be initially estimated in cell culture assays or relevant animal models (e.g., mouse, guinea pig, chimpanzee, marmoset, or tamarin animal models). The relevant animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine a useful dose and route of administration for humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as ED 50 (therapeutically effective dose for 50% of the population) and LD 50 (lethal dose for 50% of the population). The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, which can be expressed as LD 50 / ED 50 In certain aspects, the effective amount can achieve a large therapeutic index. In further specific aspects, the dose is within a range of circulating concentrations that include ED with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0325] In one aspect, provided herein is a method for regulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of formula (I) or a form thereof. In a specific aspect, provided herein is a method for regulating the amount of HTT, comprising contacting a human cell with a compound of formula (I) or a form thereof that regulates HTT expression. Human cells can be contacted with a compound of formula (I) or a form thereof in vitro or in vivo (e.g., in a non-human animal or in a human body). In a specific aspect, the human cell is from a human or in a human body. In another specific aspect, the human cell is from a human with HD or in a human with HD. In another specific aspect, the human cell is from a human with HD caused by CAG repeats in the Htt gene, resulting in loss of HTT expression and / or function, or in a human with HD caused by CAG repeats in the Htt gene, resulting in loss of HTT expression and / or function. On the other hand, the human cell is from a human with HD. On the other hand, the human cell is in a human with HD. In one aspect, the compound is in the form of a compound of formula (I).

[0326] In one specific aspect, provided herein is a method for enhancing the inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of formula (I) or a form thereof. The human cell can be contacted with a compound of formula (I) or a form thereof in vitro or in vivo (e.g., in a non-human animal or human body). In one specific aspect, the human cell is from a human or in a human body. In another specific aspect, the human cell is from a human with HD or in a human with HD. In another specific aspect, the human cell is from a human with HD caused by CAG repeats in the Htt gene, resulting in loss of wild-type "normal" HTT expression and / or function or in a human with HD caused by CAG repeats in the Htt gene, resulting in loss of wild-type "normal" HTT expression and / or function. On the other hand, the human cell is from a human with HD. On the other hand, the human cell is in a human with HD. In one aspect, the compound is in the form of a compound of formula (I).

[0327] In another aspect, provided herein is a method for regulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering a compound of formula (I) or a form thereof to a non-human HD animal model. In a specific aspect, provided herein is a method for regulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering a compound of formula (I) or a form thereof to a non-human HD animal model. In a specific aspect, the compound is in the form of a compound of formula (I).

[0328] On the other hand, a method for reducing the amount of mutant HTT is provided herein, comprising contacting a human cell with a compound of formula (I) or a form thereof. In one specific aspect, a method for reducing the amount of mutant HTT is provided herein, comprising contacting a human cell with a compound of formula (I) that inhibits mutant HTT (huntingtin protein mRNA) transcribed from the Htt gene. In another specific aspect, a method for reducing the amount of HTT is provided herein, comprising contacting a human cell 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 (e.g., in a non-human animal or human body). In one specific aspect, the human cell is from a human or in a human body. In another specific aspect, the human cell is from a human with HD or in a human with HD. In another specific aspect, the human cell is from a human with HD caused by CAG repeats in the Htt gene, resulting in loss of HTT expression and / or function, or in a human with HD caused by CAG repeats in the Htt gene, resulting in loss of HTT expression and / or function. On the other hand, the human cell is from a human with HD. In another aspect, the human cell is in a human suffering from HD. In one aspect, the compound is in the form of a compound of formula (I).

[0329] In certain aspects, the use of a compound of formula (I) or a form thereof (alone or in combination with an additional drug) to treat or improve HD has a therapeutic effect and / or a beneficial effect. In a specific aspect, the use of a compound of formula (I) or a form thereof (alone or in combination with an additional drug) to treat HD can produce one, two or more of the following effects: (i) reducing or improving the severity of HD; (ii) delaying the onset of HD; (iii) inhibiting the progression of HD; (iv) reducing the subject's hospitalization; (v) reducing the subject's hospitalization time; (vi) improving the subject's survival; (vii) improving the subject's quality of life; (viii) reducing the number of symptoms associated with HD; (ix) reducing or improving the severity of symptoms associated with HD; (x) reducing the duration of symptoms associated with HD; (xi) preventing the recurrence of symptoms associated with HD; (xii) inhibiting the development or onset of HD symptoms; and / or (xiii) inhibiting the development of symptoms associated with HD.

[0330] Metabolites

[0331] The scope of this specification also includes the use of in vivo metabolites of the compounds described herein. These products can be produced primarily due to enzymatic processes, such as oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Thus, this specification includes the use of compounds produced by the following methods: comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to produce its metabolic products.

[0332] Such products are generally prepared by radiolabeling isotopes of the compounds described herein (e.g., 14 C or 3 H), administering a radiolabeled compound to a mammal (e.g., rat, mouse, guinea pig, dog, monkey, or human) at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (generally about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood, or other biological samples for identification. The conversion products are readily isolated because they are isotopically enriched "radiolabeled" (other conversion products are isolated by using antibodies that bind to epitopes present in the metabolites). The structure of the metabolite is determined in a conventional manner, for example, by MS or NMR analysis. In general, analysis of metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products, even if they themselves are not biologically active, can also be used in diagnostic assays for therapeutic dosing of the compounds described herein, as long as they are not otherwise found in vivo.

[0333] Pharmaceutical composition

[0334] Aspects of the disclosure include using a compound of formula (I) or a form thereof in a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

[0335] One aspect of the present disclosure includes the use of a compound of formula (I) or a pharmaceutical composition in a form thereof in the preparation of a kit, comprising a compound of formula (I) or a pharmaceutical composition in a form thereof and instructions for administering the compound to treat or improve HD in a subject in need thereof.

[0336] As used herein, the term "composition" is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0337] The pharmaceutical composition can be formulated to achieve a physiologically compatible pH value ranging from about pH 3 to about pH 11. In certain aspects, the pharmaceutical composition is formulated to achieve a pH value of about pH 3 to about pH 7. In other aspects, the pharmaceutical composition is formulated to achieve a pH value of about pH 5 to about pH 8.

[0338] The term "pharmaceutically acceptable excipient" refers to an excipient used for the administration of a drug (e.g., a compound described herein). The term refers to any pharmaceutical excipient that can be administered without excessive toxicity. Pharmaceutically acceptable excipients may be determined in part by the specific composition administered and by the specific mode and / or dosage form of administration. Non-limiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, and the like. Therefore, there are a variety of suitable formulations for pharmaceutical compositions of ready-to-use compounds described herein (see, e.g., Remington's Pharmaceutical Sciences).

[0339] Suitable excipients can be carrier molecules, including large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose (e.g., hydroxypropyl methyl cellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting agents or emulsifiers; pH buffer substances, etc. Liposomes are also included in the definition of pharmaceutically acceptable excipients.

[0340] The pharmaceutical compositions described herein can be formulated in any form suitable for the intended use described herein. Formulations suitable for oral administration include solids, liquid solutions, emulsions and suspensions, and inhalation formulations suitable for pulmonary administration include liquids and powders. Other formulations include syrups, creams, ointments, tablets and lyophilized solids, which can be compounded with physiologically compatible solvents before administration.

[0341] When used for oral administration, for example, tablets, lozenges, lozenges, water or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized granules or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents and preservatives, to provide a palatable preparation.

[0342] Pharmaceutically acceptable excipients suitable for use with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrants such as cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, corn starch or alginic acid; binders such as polyvinylpyrrolidone, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated with known techniques including microencapsulation technology to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action for a longer period of time. For example, a time-delay material (e.g., glyceryl monostearate and glyceryl distearate) may be used alone or with a wax.

[0343] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., 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 (e.g., glycerol, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil).

[0344] In other aspects, the pharmaceutical compositions described herein can be formulated into suspensions, comprising a mixture of a compound of formula (I) or a form thereof and one or more pharmaceutically acceptable excipients suitable for the preparation of suspensions. In other aspects, the pharmaceutical compositions described herein can be formulated into dispersible powders and granules suitable for the preparation of suspensions by adding one or more excipients.

[0345] Excipients suitable for suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, gum arabic, dispersants or wetting agents such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecaethyleneoxycethanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate); and thickeners such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives such as acetic acid, methyl and / or n-propyl paraben; one or more coloring agents; one or more flavoring agents; one or more sweeteners such as sucrose or saccharin.

[0346] The pharmaceutical compositions described herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers include natural gums such as gum arabic and gum tragacanth; natural phospholipids such as soy lecithin; esters or partial esters derived from fatty acids; hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring, or a coloring agent.

[0347] In addition, the pharmaceutical compositions described herein can be in the form of sterile injectable preparations, such as sterile injectable aqueous emulsions or oily suspensions. Such emulsions or suspensions can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,2-propylene glycol. Sterile injectable preparations can also be prepared as lyophilized powders. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can also be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) can also be used in the preparation of injections.

[0348] The compounds described herein may be substantially insoluble in water, may be sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but are generally soluble in medium chain fatty acids (e.g., caprylic acid and capric acid) or triglycerides and propylene glycol esters of medium chain fatty acids. Thus, the description contemplates compounds modified by substitution or addition of chemical or biochemical groups, such as by esterification, glycosylation, pegylation, etc., to make them more suitable for delivery (e.g., to increase solubility, biological activity, palatability, reduce adverse reactions, etc.).

[0349] In certain aspects, the compounds described herein are formulated for oral administration in lipid-based compositions suitable for low solubility compounds. Lipid-based formulations can generally improve the oral bioavailability of such compounds. Thus, the pharmaceutical compositions described herein may include an effective amount of a compound of formula (I) or a form thereof, and at least one pharmaceutically acceptable excipient selected from medium-chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids (e.g., caprylic and capric fatty acids)), and a pharmaceutically acceptable surfactant (e.g., polysorbate 20 or 80 (also known as 20 or 80) or polyoxyethylene 40 hydrogenated castor oil).

[0350] In other aspects, the bioavailability of low solubility compounds can be improved using particle size optimization techniques, including the preparation of nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such formulations include amorphous, partially amorphous, partially crystalline or crystalline forms.

[0351] In alternative aspects, the pharmaceutical composition may further include one or more water-soluble enhancers, such as cyclodextrins. Non-limiting examples of cyclodextrins include derivatives of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In certain aspects, the pharmaceutical composition further includes HPBC in the range of about 0.1% to about 20%, about 1% to about 15%, or about 2.5% to about 10%. The amount of the solubility enhancer used depends on the amount of the compound in the composition.

[0352] Preparation of compounds

[0353] Specific Synthesis Example

[0354] In order to describe in more detail and help understand, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein, and should not be interpreted as specifically limiting the scope thereof. Such variants of the compounds described herein, now known or developed later, are considered to belong to the scope of the compounds described herein and the claims below, as long as they can be determined by those skilled in the art. These examples illustrate the preparation of certain compounds. It will be understood by those skilled in the art that the techniques described in these examples represent techniques that work well in synthetic practice as described by those of ordinary skill in the art, and therefore constitute a preferred mode of their practice. However, it should be understood that, according to the disclosure of the present invention, those skilled in the art should recognize that many changes can be made to the disclosed specific methods, and the same or similar results are still obtained without departing from the subject matter and scope of this specification.

[0355] In the case where the preparation method thereof is not described in the examples, the compound of formula (I) and all intermediates can be prepared according to similar methods or according to the methods described herein. The starting material is commercially available, known in the art, or can be prepared by methods known in the art, including the methods provided by International Application No. PCT / US2019 / 038889 filed on June 25, 2019, and International Publication No. WO 2020 / 005873 published on January 2, 2020, the entire contents of which are hereby incorporated by reference, or disclosed or disclosed by analogy therein.

[0356] Except for the examples of compounds embodied below, unless otherwise stated, all the numbers used in the specification and claims indicating the quantity of ingredients, reaction conditions, experimental data, etc. should be understood to be modified by the term "about". Therefore, all these numbers represent approximate values ​​and may vary depending on the expected characteristics to be obtained by the reaction or as a result of varying experimental conditions. Therefore, within the expected range of experimental reproducibility, the term "about" in the context of the result data refers to the range of the data provided, which may vary according to the standard deviation of the mean value. Similarly, for the experimental results provided, the result data can be rounded to present the data consistently without losing significant figures. At least, it is not intended to limit the application of the doctrine of equivalents to the scope of the claims, and each numerical parameter should be interpreted according to the number of significant figures and rounding techniques used by those skilled in the art.

[0357] Although the numerical ranges and parameters of the broad range specified in this specification are approximate, the numerical values ​​specified in the examples listed below are reported as accurately as possible. However, any numerical value itself contains certain errors, which are inevitably caused by the standard deviation found in its respective test measurements.

[0358] Compound Examples

[0359] As used above, and throughout this specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0360]

[0361]

[0362]

[0363]

[0364] Example 1 Preparation of Compound 3

[0365]

[0366] Step 1: To a dry screw cap vial was added: 3-chloro-7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethyl-4-piperidinyl]pyrrolo[2,3-c]pyridazine (0.040 g, 0.13 mmol), 5-methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (0.041 g, 0.085 mmol) and Pd(dppf)Cl2 (0.009 g, 0.0013 mmol). The mixture was degassed with argon for 10 min, then dioxane (0.6 mL) and K2CO3 (2.0 M, 0.19 mL, 0.38 mmol) in water were added and the mixture was sparged with argon for 5 min. The reaction was heated at 90 °C for 5 h. The reaction was cooled to room temperature, partitioned between EtOAc and water, and the organic portion was dried over Na2SO4, concentrated, and purified by silica gel column chromatography using a gradient of CH2Cl2 / MeOH (0-10% MeOH) to afford 6-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-methoxy-2-methylbenzo[d]oxazole (63 mg, 64% yield). MS m / z 438.5 [M+H]] + .

[0367] Step 2: A solution of 6-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-methoxy-2-methylbenzo[d]oxazole (60 mg, 0.014 mmol) in CHCl (0.9 mL) was cooled to -50 °C and BBr (1.0 M in CHCl, 1.40 mL, 1.40 mmol) was added. The reaction was warmed to room temperature and stirred for 2 h until UPLC showed complete consumption of the starting material. After completion of the reaction, the reaction was quenched with MeOH (0.5 mL) and stirred for 10 min. The reaction was diluted with CHCl (20 mL) and washed with saturated NaHCO. The organic phase was separated, dried over Na2SO4, concentrated, and purified by silica gel column chromatography using a gradient (0-10%) CH2Cl2 / MeOH to give 6-(7-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (27 mg, 46% yield). MS m / z 424.1 [M+H] + ; 1H NMR (400 MHz, methanol-d4) δ: 8.61 (s, 1H), 8.18 (s, 1H), 8.05-8.02 (m, 1H), 7.16 (s, 1H), 6.75 (d, J=3.50 Hz, 1H), 5.86-5.73 (m, 1H), 4.60 (d, J=51.04 Hz, 1H), 2.64 (s, 3H), 2.39-2.30 (m, 1H), 1.89-1.86 (m, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.33 (s, 3H), 1.26 (s, 3H); 2H (NH and OH) were not observed.

[0368] Using the steps described in Example 1 above, by replacing appropriate starting materials, suitable reagents and reaction conditions, other compounds described herein can be prepared to obtain, for example, a compound selected from the following:

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382] Example 2 Preparation of Compound 19

[0383]

[0384] Step 1: To a dry screw cap vial was added: (3R,4R)-4-(3-chloro-4a,5,6,7a-tetrahydropyrrolo[2,3-c]pyridazin-7-yl)-3-fluoro-2,2-dimethyl-piperidine-1-carboxylic acid benzyl ester (0.230 g, 0.546 mmol), 5-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (0.230 g, 0.683 mmol) and Pd(dppf)Cl2 (0.032 g, 0.044 mmol). The mixture was degassed with argon for 10 min, then dioxane (2.75 mL) and K2CO3 (2M, 0.82 mL, 1.64 mmol) in water were added and the mixture was sparged with argon for 5 min. The reaction was heated at 90°C for 3.5h, then cooled to room temperature, partitioned between EtOAc and water, and the organic portion was dried over Na2SO4, concentrated, and purified by silica gel column chromatography using a gradient of CH2Cl2 / MeOH (0-5% MeOH) to give (3R,4R)-3-fluoro-4-(3-(6-(methoxymethoxy)-2-methylbenzo[d]thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-2,2-dimethylpiperidine-1-carboxylic acid benzyl ester (320 mg, 99% yield). MS m / z 592.2 [M+H] + .

[0385] Step 2: To a solution of (3R,4R)-3-fluoro-4-[3-[5-(methoxymethoxy)-2-methyl-1,3-benzothiazol-6-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]-2,2-dimethyl-piperidine-1-carboxylic acid benzyl ester (0.170 g, 0.287 mmol) in toluene (1.9 mL) was added MnO2 (0.375 g, 4.31 mmol) and the reaction was heated to 95°C for 16 hours. The crude material was passed through a shot pad and rinsed with MeOH and ACN. The solvent was evaporated and the crude (3R,4R)-3-fluoro-4-[3-[5-(methoxymethoxy)-2-methyl-1,3-benzothiazol-6-yl]pyrrolo[2,3-c]pyridazin-7-yl]-2,,2-dimethyl-piperidine-1-carboxylic acid benzyl ester was used in the next step without purification.

[0386] Step 3: (3R,4R)-3-fluoro-4-[3-[5-(methoxymethoxy)-2-methyl-1,3-benzothiazol-6-yl]pyrrolo[2,3-c]pyridazin-7-yl]-2,2-dimethyl-piperidine-1-carboxylic acid benzyl ester (crude, from Step 2) was dissolved in TFA (2 mL) and heated to 70 °C for 2 h. The mixture was concentrated, diluted with CH2Cl2, washed with saturated NaHCO3 and brine, and concentrated. The residue was purified by reverse phase chromatography eluting with a gradient of ACN / H2O / formic acid (0-100% ACN) to give 5-(7-((3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2-methylbenzo[d]thiazol-6-ol (48 mg, 37% yield over two steps) as a tan solid. MS m / z 412.1 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ: 8.61 (s, 1H), 8.47 (s, 1H), 8.34 (s, 1H, formic acid), 8.03-7.97 (m, 1H), 7.43 (s, 1H), 6.77 (d, J=3.63 Hz, 1H), 5.88-5.72 (m, 1H), 4.96 (d, J=48.40 Hz, 1H), 3.66-3.43 (m, 2H), 2.82 (s, 3H), 2.77-2.62 (m, 1H), 2.32-2.23 (m, 1H), 1.68 (s, 3H), 1.52 (s, 3H); 2H (NH and OH) were not observed.

[0387] Using the steps described in Example 2 above, by replacing appropriate starting materials, suitable reagents and reaction conditions, other compounds described herein can be prepared to obtain, for example, a compound selected from the following:

[0388]

[0389]

[0390] Biological Examples

[0391] The following in vitro biological examples illustrate the usefulness of the compounds of the present description for treating Huntington's disease.

[0392] In order to describe and help understand this specification in more detail, the following non-limiting biological examples are provided to more fully illustrate the scope of this specification and should not be interpreted as specifically limiting its scope. Variants of this specification that are now known or later developed and that can be determined by a person skilled in the art within their authority are all considered to belong to the scope of this specification and the following claims.

[0393] The compound of formula (I) was tested using the Meso Scale Discovery (MSD) assay provided in International Application No. PCT / US2016 / 066042, filed on December 11, 2016, and claiming priority to U.S. Provisional Application No. US62 / 265,652, filed on December 10, 2015, the entire contents of which are incorporated herein by reference.

[0394] The endogenous huntingtin protein detection method used in Example 1 was developed using the MSD electrochemiluminescence detection platform based on ELISA.

[0395] Example 1

[0396] Endogenous Huntington protein detection

[0397] Meso Scale Discovery (MSD) used MW1 (amplified polyglutamine) or MAB2166 monoclonal antibodies (for capture) to coat 96-well or 384-well plates overnight (30 μL per well) in PBS at a concentration of 1 μg / mL at 4° C. The plates were then washed three times with 300 μL of wash buffer (0.05% Tween-20 in PBS) and blocked (100 μL of blocking buffer; 5% BSA in PBS) at room temperature with rotation and shaking for 4-5 hours, and then washed three times with wash buffer.

[0398] The samples (25 μL) were transferred to the antibody-coated MSD plate and incubated overnight at 4°C. After removing the lysate, the plate was washed three times with wash buffer, and then 25 μL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 μg / mL in 0.05% Tween-20 blocking buffer) was added to each well and incubated with shaking at room temperature for 1 hour. After the secondary antibody incubation, the wells were rinsed with wash buffer, and then 25 μL of goat anti-rabbit SULFO TAG secondary antibody detection antibody (MSD system required aspect) (diluted to 0.25 μg / mL in 0.05% Tween-20 blocking buffer) was added to each well and incubated with shaking at room temperature for 1 hour. After rinsing three times with wash buffer, 150 μL of read buffer T (MSD) containing surfactant was added to each empty well, and then the plate was imaged on the SI 6000 imager (MSD) according to the manufacturer's instructions for 96-well or 384-well plates. Table 1 shows the IC values ​​obtained for the tested compounds. 50 Value (μM).

[0399] As shown in Table 1, the test compounds described herein have the following IC 50 Value: IC 50Values ​​between >3 μM and ≤9 μM are indicated by a star (*), IC 50 Values ​​between >1 μM and ≤3 μM are indicated by two stars (**), IC 50 Values ​​between >0.5 μM and ≤1 μM are indicated by three stars (***), IC 50 Values ​​between >0.1 μM and ≤0.5 μM are indicated by four stars (****), IC 50 Values ​​≤ 0.1 μM are indicated by five stars (*****).

[0400] Table 1

[0401]

[0402]

[0403] All documents mentioned herein are incorporated by reference into this application for any and all purposes to the same extent as if each individual reference was fully set forth herein, regardless of whether or not a document cited herein is specifically and individually indicated as incorporated by reference.

[0404] After fully describing the subject matter of the claims, those skilled in the art will appreciate that the same operations can be performed within a broad range of equivalents without affecting the scope of the subject matter or specific aspects described herein. The appended claims are intended to be interpreted as including all such equivalents.

Claims

1. A compound of formula (I): or a form thereof in which: R A Represented by the following structure: R B is represented by a structure selected from the group consisting of: Where available valences permit, W 1 Selected by CR W1 , C-(R W1 )2 and N; Where available valences permit, W 2 Selected by CR W2 , C-(R W2 )2 and N; Each R W1 and R W2 independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-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 Alkylamino, (C 1-4 alkyl)2-amino, amino-C 1-4 Alkyl and hydroxyl C 1-4 A group consisting of alkyl groups; R 1 Selected from hydrogen and C 1-4 A 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 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and hydroxy-C 1-4 alkyl; or R 2 and R 3 Together with the atoms to which it is attached, it forms a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S; or R 2 and R 4 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or R 2 and R 7 Together with the atoms to which they are attached, they form a saturated 5-10 membered ring system; or R 4 and R 5 Together with the atoms to which they are attached, they form a saturated 3-6 membered ring containing 0 or 1 heteroatom ring member selected from N, O and S; X 1 , X 2 , X 3 and X 4 Each independently selected from CR X , C-(R X )2. C=O, C=NR X’ , N, NR X’ , O and S; Each R X are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deuterated-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkylamino, (C 1-4 Alkyl) 2-amino, C 1-4 Alkoxy, halo-C 1-4 Alkoxy and C 1-4 A group consisting of alkylthio groups; Each R X’ independently selected from hydrogen, hydroxyl, C 1-4 Alkyl and C 1-4 A group consisting of alkoxy groups; R B1 For halogen, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy and halo-C 1-4 Alkoxy; n is 0 or 1; p is 0 or 1; q is 0 or 1; and If valence permits, independently represents a single bond or a double bond; Provided that the compound of formula (I) is not 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol, (3E)-3-(hydroxyimino)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-2,3-dihydro-1H-indene-5-ol, l-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol, 2-Methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1H-benzimidazol-6-ol; The compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomers thereof.

2. The compound according to claim 1, wherein the compound of formula (I) is: or its form.

3. The compound according to claim 1, wherein the compound of formula (I) is: or its form.

4. The compound according to claim 1, wherein R A Selected from the group consisting of: and any stereoisomers thereof.

5. A compound or a form thereof selected from the group consisting of: 6-Hydroxy-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-2,3-dihydro-1H-inden-1-one; 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinoxalin-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-6-ol; 5-[3-(5,5-dimethyl-4-azaspiro[2.5]octan-7-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1-methyl-1H-benzotriazol-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-6-ol; 6-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(7S)-5,5-dimethyl-4-azaspiro[2.5]octan-7-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-[3-(5,5-dimethyl-4-azaspiro[2.5]octan-7-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-2-methyl-1,3-benzothiazol-5-ol; 2-ethyl-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-1,3-benzoxazol-6-ol; 2-ethyl-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-1,3-benzothiazol-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinazolin-7-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-1-methylquinolin-4(1H)-one; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 4-Chloro-6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-7-ol; 6-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 5-{7-[(7S)-5,5-dimethyl-4-azaspiro[2.5]octan-7-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-(trifluoromethyl)-1,3-benzoxazol-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methoxy-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-1-methylquinoxalin-2(1H)-one; 2-methyl-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1,3-benzothiazol-5-ol; 3-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}naphthalen-2-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}isoquinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinolin-6-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methoxyquinoxalin-6-ol; 5-{7-[(8R,9R)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-6-ol; 5-{7-[(8S,9S)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinolin-7-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-hydroxy-1,3-benzoxazol-2(3H)-one; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-benzotriazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-indazol-5-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinazolin-6-ol; 3-Fluoro-7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-benzotriazol-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-benzotriazol-5-ol; 6-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinoxalin-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1H-benzimidazol-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1H-benzotriazol-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1,2-dimethyl-1H-benzimidazol-6-ol; 7-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinoxalin-6-ol; 5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-benzotriazol-6-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dimethylquinoxalin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}isoquinolin-6-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinoxalin-6-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinoxalin-6-ol; 5-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-6-hydroxy-2,3-dihydro-1H-inden-1-one; 6-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-2H-1-benzopyran-2-one; (3Z)-6-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-(methoxyimino)-2,3-dihydro-1H-inden-5-ol; 6-{7-[(7S,8R)-7-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(7R,8S)-7-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-indazol-5-ol; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4-methyl-2H-1-benzopyran-2-one; 6-{7-[(7S)-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4-methyl-2H-1-benzopyran-2-one; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-2H-1-benzopyran-2-one; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-2-methyl-4H-1-benzopyran-4-one; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4H-1-benzopyran-4-one; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}isoquinolin-7-ol; 6-[7-(4-azabispiro[2.1.2 5 .3 3 ]decane-9-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl]-2-methyl-1,3-benzothiazol-5-ol; 6-[7-(4-azabispiro[2.1.2 5 .3 3 ]decane-9-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl]-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-3-methyl-2H-1-benzopyran-2-one; 5-{7-[(8R,9R)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-6-ol; 5-{7-[(8S,9S)-9-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-6-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4-methoxy-2H-1-benzopyran-2-one; 6-{7-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4-methyl-2H-1-benzopyran-2-one; 6-{7-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-4-methyl-2H-1-benzopyran-2-one; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinolin-7-ol; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-6-hydroxy-4H-1-benzopyran-4-one; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-6-hydroxy-2-methyl-4H-1-benzopyran-4-one; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methoxyquinoxalin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2,1,3-benzothiadiazole-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-hydroxy-1,3-benzoxazol-2(3H)-one; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinazolin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-benzotriazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-indazol-5-ol; 3-Fluoro-7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol; 7-{7-[(2R,3S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinoxalin-6-ol; 7-{7-[(2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylquinoxalin-6-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-benzotriazol-5-ol; 3-Fluoro-6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-7-ol; 3-Fluoro-6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-7-ol; 6-{7-[(7R)-5,5-dimethyl-4-azaspiro[2.5]octan-7-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methoxy-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methoxy-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-(methylthio)-1,3-benzothiazol-5-ol; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-(methylthio)-1,3-benzothiazol-5-ol; 7-Fluoro-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-indazol-6-ol; 7-Fluoro-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-2H-indazol-6-ol; 7-Fluoro-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-6-ol; and 7-Fluoro-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-6-ol; The compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomers thereof.

6. A compound salt or a form thereof, wherein the compound salt or a form thereof is selected from the group consisting of: 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol hydrobromide; 6-[3-(5,5-dimethyl-4-azaspiro[2.5]octan-7-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-2-methyl-1,3-benzothiazol-5-ol hydrochloride; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methylquinazolin-7-ol formate; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol hydrochloride; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol formate; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methoxy-1,3-benzoxazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-7-hydroxy-1-methylquinoxalin-2(1H)-one formate; 2-Methyl-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1,3-benzothiazol-5-ol hydrochloride; 3-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}naphthalen-2-ol hydrochloride; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methoxyquinoxalin-6-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-hydroxy-1,3-benzoxazol-2(3H)-one formate; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dimethylquinoxalin-6-ol dicarboxylate; 6-{7-[(7S,8R)-7-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol formate; 6-{7-[(7R,8S)-7-fluoro-5-azaspiro[3.5]nonan-8-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-1-methyl-1H-indazol-5-ol carboxylate; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzothiazol-5-ol formate; 6-{7-[(3R,4R)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2-dimethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-5-ol formate; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}quinolin-6-ol formate; 7-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methoxyquinoxalin-6-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-hydroxy-1,3-benzoxazol-2(3H)-one formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-2-(methylthio)-1,3-benzothiazol-5-ol formate; 6-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-(methylthio)-1,3-benzothiazol-5-ol formate, and 7-Fluoro-5-{7-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2-methyl-1,3-benzoxazol-6-ol and formate; The salt form of the compound is selected from the group consisting of pharmaceutically acceptable hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers and tautomers thereof.

7. A method for treating or ameliorating Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 6.

8. The method of claim 7, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

9. Use of the compound according to any one of claims 1 to 6 for treating or improving Huntington's disease in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

10. The use according to claim 9, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

11. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for treating or ameliorating Huntington's disease in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

12. The use according to claim 11, wherein the effective amount of the compound in the medicament ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

13. Use of a pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6 and one or more pharmaceutically acceptable excipients for treating or ameliorating Huntington's disease in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition to the subject.

14. The use according to claim 13, wherein the effective amount of the compound in the pharmaceutical composition ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

15. A pharmaceutical composition for treating or improving Huntington's disease, comprising an effective amount of the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

Images