Compounds for treating Huntington's disease

Abstract

This specification relates to compounds of formula (I), forms thereof, and pharmaceutical compositions, and methods of using such compounds, forms thereof, or compositions for treating or ameliorating Huntington's disease. [Formula 1] TIFF2023522177000220.tif48164

Description

[Technical Field]

[0001] Aspects of the present specification relate to compounds, forms thereof, and pharmaceutical compositions useful for treating or ameliorating Huntington's disease, as well as methods of using such compounds, forms thereof, or compositions. In particular, another aspect of the present specification relates to substituted monocyclic and bicyclic heteroaryl compounds, forms thereof, and pharmaceutical compositions, as well as methods of using such compounds, forms thereof, or compositions, for treating or ameliorating Huntington's disease. [Background technology]

[0002] Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain with symptoms characterized by involuntary movements, cognitive impairment, and mental decline. Death is typically caused by pneumonia or coronary artery disease and usually occurs 13–15 years after the onset of symptoms. The prevalence of HD is 3–7 per 100,000 people in populations of Western European descent. In North America, an estimated 30,000 people have HD, with an additional 200,000 at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of consecutive trinucleotide CAG repeats in the "mutant" huntingtin (Htt) gene, which produces HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as the "CAG repeat" sequence. Current small molecule therapies do not target the underlying cause of the disease, and there remains a significant unmet need for drugs that can be used to treat or ameliorate HD. As a result, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD. International Application Publication No. WO / 2019 / 191229A1 describes triazine compounds that may be suitable for treating or ameliorating Huntington's disease.

[0003] However, IC 50 It is more potent as measured by efflux transport, tissue exposure, absorption, distribution, metabolism, excretion, and time to maximum plasma concentration (T max ), maximum concentration (Cmax ), concentration at 24 hours (C 24 ), area under the concentration-time curve (AUC), and terminal elimination half-life (t 1 / 2 There remains a need to develop new compounds with improved pharmacokinetic properties (PK), as measured by parameters such as pharmacokinetics (PK). All other documents referred to herein are incorporated by reference into this application as if fully set forth herein. Summary of the Invention

[0004] Another aspect of the present specification is a compound of formula (I): [ka] or the form thereof, wherein A, B, X, R W and n is as defined herein. B can be a monocyclic and / or bicyclic ring structure. Embodiments herein include a method of treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Embodiments herein include methods of using a compound of formula (I), or a form or composition thereof, for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form or composition thereof.

[0005] Embodiments herein include the use of a compound of formula (I), or a form thereof, for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof. Embodiments herein include the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject. Embodiments herein include the use of a compound of formula (I), or a form thereof, in a combination product with one or more therapeutic agents for the treatment or amelioration of HD in a subject in need thereof, comprising administering to a subject an effective amount of a compound of formula (I), or a form thereof, in combination with an effective amount of the one or more agents. DETAILED DESCRIPTION OF THE INVENTION

[0006] A compound of formula (I), [ka] or a salt, solvate, hydrate, ester, prodrug, enantiomer, stereoisomer, rotamer, tautomer, positional isomer, or racemate thereof, wherein: A, [ka] and any stereoisomer thereof; R1 is hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R2 is independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; and C 1-4 Alkyl, C 3-6 each instance of cycloalkyl, phenyl, pyridonyl, and heterocyclyl is optionally substituted with one or two R3 substituents; R3 is independently a halogen, a hydroxyl, or a C1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, phenyl optionally substituted with one or two independently selected R4 substituents; Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with one R4 substituent, or heteroaryl is a 9- or 10-membered bicyclic aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, optionally substituted with one or two independently selected R4 substituents); and heterocyclyl (heterocyclyl is an 8-10 membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and optionally substituted with one or two independently selected R4 substituents); R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C1-4 Alkyl)2-amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1.

[0007] One embodiment includes compounds of formula (I), wherein A is [ka] and any stereoisomers thereof. A is, [ka] [ka] may be selected from the group consisting of:

[0008] A is, [ka] may be selected from the group consisting of:

[0009] A is, [ka] may be selected from the group consisting of:

[0010] A is, [ka] or any stereoisomer thereof. A is, [ka] or any stereoisomer thereof. A is selected from the group consisting of: [ka] May be: [ka]

[0011] A is, [ka] It may be. A is, [ka] It may be.

[0012] A is, [ka] or any stereoisomer thereof. A is selected from the group consisting of: [ka] May be: [ka]

[0013] A is, [ka] It may be. A is, [ka] It may be.

[0014] A is, [ka] or any stereoisomer thereof. A is, [ka] or any stereoisomer thereof. A is, [ka] or any stereoisomer thereof.

[0015] A is, [ka] or any stereoisomer thereof. A is, [ka] or any stereoisomer thereof. A is, [ka] or any stereoisomer thereof.

[0016] A is, [ka] or any stereoisomer thereof. A is selected from the group consisting of: [ka] May be: [ka] A is, [ka] It may be.

[0017] A is, [ka] It may be. A is, [ka] or any stereoisomer thereof.

[0018] A is, [ka] or stereoisomers thereof, such as, but not limited to: [ka] It may be.

[0019] A is, [ka] It may be. A is, [ka] or any stereoisomer thereof. A is selected from the group consisting of: [ka] May be: [ka]

[0020] A is, [ka] It may be. A is, [ka] It may be.

[0021] A is, [ka] It may be. A is, [ka] It may be. A is, [ka] or any stereoisomer thereof.

[0022] One embodiment includes compounds of formula (I), wherein R is hydrogen or C 1-4 R1 is alkyl. R1 may be hydrogen. R1 is a C1 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1-4 R1 may be alkyl. R1 may be methyl or ethyl. R1 may be methyl. R1 may be ethyl. One embodiment includes compounds of formula (I), wherein R is a C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 R1 is cycloalkyl. R1 may be cyclopropyl. One embodiment includes compounds of formula (I), wherein R2 is independently C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S, and C 1-4 Alkyl, C 3-6 Each example of cycloalkyl, phenyl, pyridonyl, and heterocyclyl is optionally substituted with one or two R3 substituents.

[0023] Another embodiment includes compounds of formula (I) wherein R2 is independently C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 3-6 It is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3-4 membered carbon atom ring structure radical containing one heteroatom ring member selected from N and O, and each R2 is optionally substituted with one R3 substituent. Another embodiment includes compounds of formula (I) wherein R2 is independently C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, and C 3-6 cycloalkyl, and each R2 is optionally substituted with one R3 substituent.

[0024] R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1-4 R2 may be alkyl. R2 may be methyl. R2 may be ethyl. R2 may be propyl. R2 may be isopropyl. R2 may be butyl. R2 may be tert-butyl. R2 is hydroxyl-C 1-4 alkyl, C 1-4 Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and butyl, partially or fully substituted with one or more hydroxyl groups, where available valences allow. R2 is a hydroxyl-C 1-4 alkyl, C 1-4 The alkyl is selected from methyl and isopropyl substituted with one hydroxyl group. R2 may be hydroxymethyl. R2 may be isopropyl substituted with one hydroxyl group. R2 may be 2-hydroxypropan-2-yl.

[0025] R2 is Halo-C 1-4 alkyl, C 1-4Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, partially or fully substituted with one or more halogen atoms, where permitted by available valences. R2 can be difluoroethyl. R2 is C 1-4 Alkoxy-C 1-4 alkyl, C 1-4 Alkyl may be one or more C alkoxy groups selected from methoxy, ethoxy, propoxy, and butoxy, where available valences permit. 1-4 R2 may be methoxymethyl, selected from the group consisting of methyl, ethyl, propyl, and butyl, partially or fully substituted with alkoxy groups.

[0026] R2 is a C selected from ethenyl, propenyl, and butenyl 2-4 R2 may be alkenyl. R2 may be ethenyl. R2 is a C selected from cyclopropyl, cyclobutyl, cyclopenyl, and cyclohexyl optionally substituted with one or two R3 substituents. 3-6 R2 may be a C cycloalkyl selected from cyclopropyl and cyclobutyl, optionally substituted with one or two R3 substituents. 3-6 It may be cycloalkyl.

[0027] R2 may be cyclopropyl substituted with 0 to 2 R3 substituents. R2 may be unsubstituted cyclopropyl. R2 may be cyclopropyl unsubstituted or substituted with one R3 substituent, where R3 is selected from halogen, hydroxyl, C 1-4 Alkyl, or C 1-4 R2 can be cyclopropyl unsubstituted or substituted with one R3 substituent, where R3 is halogen, hydroxyl, methyl, ethyl, methoxy, or ethoxy. R2 may be cyclobutyl optionally substituted with one or two R3 substituents. R2 may be unsubstituted cyclobutyl. R2 may be phenyl optionally substituted with one or two R3 substituents. R2 may be unsubstituted phenyl.

[0028] R2 may be pyridinyl optionally substituted with one or two R3 substituents. R2 may be unsubstituted pyridinyl. R2 may be unsubstituted pyridin-4-yl. R2 is C optionally substituted with one or two R3 substituents; 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 It may be alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl. R2 can be a heterocyclyl selected from the group consisting of aziridinyl, odilanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolinyl, tetrahydrofuranyl, tilolanyl, piperidinyl, piperazinyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, and thianyl, each instance of heterocyclyl optionally substituted with one or two R3 substituents.

[0029] R2 may be oxetanyl optionally substituted with one or two R3 substituents. R2 is C optionally substituted with one or two R3 substituents; 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 R2 may be an unsubstituted C 1-4 Alkyl, unsubstituted halo-C 1-4 Alkyl, unsubstituted hydroxyl-C 1-4 It may be alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted phenyl, or unsubstituted oxetanyl.

[0030] One embodiment includes compounds of formula (I), wherein R3 is independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6R3 is independently selected from the group consisting of halogen, hydroxyl, C 1-4 Alkyl and C 1-4 It may be selected from the group consisting of alkoxy. R3 may be a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. R3 may be fluoro. R3 can be hydroxyl.

[0031] R3 is a C selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1-4 R3 may be alkyl. R3 may be methyl or ethyl. R3 may be methyl. R3 is a C selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 R3 may be alkoxy. R3 may be methoxy. R3 may be halogen, hydroxyl, C 1-4 It may be alkyl, or methoxy. R3 is a C selected from the group consisting of cyclopropyl, cyclobutyl, cyclopenyl, and cyclohexyl. 3-6 R3 may be cycloalkyl. R3 may be cyclopropyl.

[0032] One embodiment includes compounds of formula (I), wherein B is phenyl optionally substituted with one or two independently selected R4 substituents; Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with one R4 substituent, or heteroaryl is a 9- or 10-membered aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, optionally substituted with one or two independently selected R4 substituents); and heterocyclyl (heterocyclyl is an 8-10 membered bicyclic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R4 substituents).

[0033] B can be phenyl optionally substituted with one or two independently selected R4 substituents. B can be unsubstituted phenyl or phenyl substituted with one R4 substituent. One embodiment includes compounds of formula (I), wherein B is heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent. B can be heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and optionally a second heteroatom selected from O and S, and is optionally substituted with one R4 substituent. B can be heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 2 or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent. B may be heteroaryl, which is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing two or three N atoms and optionally a second heteroatom selected from O and S, and is optionally substituted with one R4 substituent.

[0034] B can be a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 1,3-oxazolyl, tetrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, optionally substituted with one R4 substituent. B can be a heteroaryl selected from the group consisting of 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,3-oxazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, optionally substituted with one R4 substituent.

[0035] B can be a heteroaryl selected from the group consisting of 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,3-oxazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, substituted with one R4 substituent. B is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, yl, 1,3-thiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, tetrazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazo 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1, and may be a heteroaryl selected from the group consisting of 2,4-triazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, optionally substituted with one R4 substituent.

[0036] B is 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2 ... and optionally substituted with one R4 substituent. B is 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3 ... and may be heteroaryl selected from the group consisting of 1,2,4-thiadiazol-3-yl, 1H-1,2,4-triazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, and substituted with one R4 substituent.

[0037] One embodiment includes compounds of formula (I), wherein B is heteroaryl, wherein heteroaryl is a 9- or 10-membered aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R substituents. B can be heteroaryl, wherein heteroaryl is a 9- or 10-membered bicyclic carbon atom ring structure radical containing at least one N atom ring member and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R substituents. B can be heteroaryl, wherein heteroaryl is a 9- or 10-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R substituents. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and is optionally substituted with one or two independently selected R4 substituents. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents. B may be heteroaryl, wherein the heteroaryl is an unsubstituted 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is unsubstituted or substituted with one R4 substituent.

[0038] B is 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothiophenyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyrazinyl, pyrrolo[1,2-c ... 1H-pyrazolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidin-2-yl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl nyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, thiazolo[4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, quinolinyl, isoquinolinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl and heteroaryl selected from the group consisting of pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, optionally substituted with one or two independently selected R4 substituents.

[0039] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a]pyridinyl nyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo[4,5-b ]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b] and may be heteroaryl selected from the group consisting of pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, optionally substituted with one or two independently selected R4 substituents.

[0040] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a ]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thia 1H-pyrazolo[4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl ]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, and may be heteroaryl selected from the group consisting of triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, substituted with one R4 substituent.

[0041] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a] Pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl and may be heteroaryl selected from azolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, and is substituted with two independently selected R4 substituents.

[0042] B is 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3 -benzothiazol-6-yl, 1,3-benzodioxol-5-yl, 1,2,3-benzotriazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, 1,3-oxazolo[5,4-b]pyridin-5-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazine- 2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 5H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyrazin-5-yl, 1H-pyrazolo[3,4-c]pyridin Lysin-1-yl, 1H-pyrazolo[3,4-c]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 2H-pyrazolo[4,3-b]pyridin-5-yl, 2H-pyrazolo[4,3-c]pyridin-5-yl, 1H-pyrazolo[4,3-d]pyrimidin-5-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-5-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazole- 6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1 ,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl , quinolin-6-yl, isoquinolin-6-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,and thiazolo[5,4-b]pyridin-2-yl, optionally substituted with one or two independently selected R substituents.

[0043] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo [4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl , thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H-[1,2, and thiazolo[5,4-b]pyridin-2-yl, optionally substituted with one or two independently selected R substituents.

[0044] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, 1H-[1,2,3]triazolo[1,5-a]pyrid ... Triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin Lysin-6-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6 -yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-7-yl, pyrazolo[1,5-a]pyrimidin-3-yl, thiazolo[5,4-b]pyridin-2-yl, and substituted with one R4 substituent.

[0045] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H- ...3-yl, 2H-[1,2,3]triazolo[1,5-a]pyridin-3-yl, 2H-[1,2,3]triazolo[1,5-a]pyridin-5-yl, 1H-[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin- 6-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H and may be a heteroaryl selected from the group consisting of -[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-7-yl, pyrazolo[1,5-a]pyrimidin-3-yl, and thiazolo[5,4-b]pyridin-2-yl, substituted with two independently selected R4 substituents.

[0046] One embodiment includes compounds of formula (I), wherein B is heterocyclyl, where heterocyclyl is an 8- to 10-membered bicyclic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, where heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, where heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, optionally substituted with one or two independently selected R4 substituents, or heterocyclyl, which is an 8-membered bicyclic carbon atom ring structure radical containing 2 or 3 N, substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is an unsubstituted 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S.B may be heterocyclyl, which is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is unsubstituted or substituted with one R4 substituent.

[0047] B can be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, optionally substituted with one or two independently selected R4 substituents.

[0048] B may be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, substituted with two independently selected R4 substituents. B may be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, substituted with one R4 substituent.

[0049] B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3 ...4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, optionally substituted by one or two independently selected R4 substituents. B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 5,6-dihydro-4H-pyrrolo and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and ... may be a heterocyclyl selected from the group consisting of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, substituted by one R4 substituent.

[0050] B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2 and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and is substituted with two independently selected R4 substituents. B is phenyl optionally substituted with one or two independently selected R4 substituents; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing at least one N atom (or at least two N atoms) and optionally containing a second heteroatom selected from O and S, optionally substituted with one R4 substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing at least two N atoms and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; and Heterocyclyl (Heteroaryl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N atom (or at least two N atoms) and optionally containing a second heteroatom ring member selected from O or S, and optionally substituted with one or two independently selected R4 substituents).

[0051] B is phenyl unsubstituted or substituted with one R4 substituent; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and substituted with one or two independently selected R4 substituents. B can be heteroaryl or heterocyclyl; Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally containing a second heteroatom ring member selected from O or S when the ring structure contains 2 or 3 N, and is optionally substituted with one or two independently selected R4 substituents.

[0052] B can be heteroaryl; Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents. One embodiment includes compounds of formula (I), wherein R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4Alkyl)2-amino, C 3-6 It is selected from the group consisting of cycloalkyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S.

[0053] R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 It may be selected from the group consisting of cycloalkyl, and heterosilyl. R4 may be a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. R4 may be a halogen selected from the group consisting of chloro and fluoro. R4 may be chloro. R4 may be fluoro. R4 can be cyano.

[0054] R4 is a C selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 1-4 R4 may be alkyl. R4 may be methyl or ethyl. R4 may be methyl. R4 may be ethyl. R4 is Halo-C 1-4 alkyl, C 1-4 Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, partially or fully substituted with one or more deuterium atoms, where possible depending on available valences. R4 is ( 2 H3) may be methyl.

[0055] R4 is Halo-C 1-4 alkyl, C 1-4Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, partially or fully substituted with one or more halogen atoms, where permitted by available valences. R4 is halo-C selected from the group consisting of difluoromethyl and trifluoromethyl. 1-4 R4 may be alkyl. R4 may be difluoromethyl. R4 may be trifluoromethyl. R4 is a C selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 R4 may be alkoxy. R4 may be methoxy.

[0056] R4 is deuterium C 1-4 Alkoxy, C 1-4 Alkoxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy, partially or fully substituted with one or more deuterium atoms, where possible depending on available valences. R4 is ( 2 H3) may be methoxy. R4 is a C selected from the group consisting of cyclopropyl, cyclobutyl, cyclopenyl, and cyclohexyl. 3-6 R4 may be cycloalkyl. R4 may be cyclopropyl.

[0057] R4 is C 1-4 alkyl-amino, C 1-4 The alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. R4 can be methylamino. R4 can be heterocyclyl, which is a 3-6 membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S. R4 can be a heterocyclyl selected from the group consisting of aziridinyl, odilanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolinyl, tetrahydrofuranyl, tilolanyl, piperidinyl, piperazinyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, and thianyl. R4 is azetidinyl.

[0058] R4 is halogen, cyano, methyl, ethyl, ( 2 H3) methyl, ( 2 H3) Ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H3) may be selected from the group consisting of methoxy, methylamino, ethylamino, cyclopropyl, and azetidinyl. Some embodiments include compounds of formula (I) where X is CH. In other embodiments, X is CF. In other embodiments, X is N.

[0059] One embodiment includes compounds of formula (I), wherein R w is halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy and halo-C 1-4 R is selected from the group consisting of alkoxy. w is hydrogen and C 1-4 R may be selected from the group consisting of alkyl. w R may be a halogen selected from the group consisting of bromo, chloro, fluoro, and iodo. w R may be fluoro. w is selected from methyl, ethyl, propyl, isopropyl, and tert-butyl 1-4R may be alkyl. w R may be methyl. w may be fluoro, chloro, bromo, methyl, or ethyl. Certain embodiments include compounds of formula (I) wherein n is 0. In other embodiments, n is 1.

[0060] One embodiment includes compounds of formula (I), wherein n is 0 and R is hydrogen or C 1-4 In one embodiment, n is 0 and X is C. One embodiment includes compounds of formula (I) wherein n is 0 and R2 is C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, and R1 is hydrogen or C 1-4 alkyl, optionally substituted with one or two R3 substituents. One embodiment includes compounds of formula (I), wherein A is A1, A2, A3, A4, A5, or A6, n is 0, and R1 is hydrogen or C 1-4 In another embodiment, A is A1, A2, A3, A4, A5, or A6, n is 0, X is C, and R1 is hydrogen or C 1-4 It is alkyl.

[0061] One embodiment includes compounds of formula (I), wherein: n is 0, X is C, R2 is C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, optionally substituted with one or two R3 substituents; R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterosilyl; R1 is hydrogen or C 1-4 is alkyl, B is phenyl unsubstituted or substituted with one R4 substituent; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally, if the ring structure contains 2 or 3 N, containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents).

[0062] One embodiment includes compounds of formula (I), wherein: n is 0, X is C, R2 is C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, optionally substituted with one or two R3 substituents; R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterosilyl; R1 is hydrogen or C 1-4 is alkyl, A is A1 to A24, B is phenyl unsubstituted or substituted with one R4 substituent; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally, if the ring structure contains 2 or 3 N, containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents).

[0063] One embodiment includes compounds of formula (I), wherein: n is 0, X is C, R2 is C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, optionally substituted with one or two R3 substituents; R4 is halogen, cyano, methyl, ethyl, ( 2 H3) methyl, ( 2 H3) Ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H3) selected from the group consisting of methoxy, methylamino, ethylamino, cyclopropyl, and azetidinyl; R1 is hydrogen or C 1-4 is alkyl, A is A1 to A6, B is selected from the group consisting of heteroaryl and heterocyclyl; Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, optionally substituted with one R4 substituent; or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and optionally, if the ring structure contains 2 or 3 N, a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents; Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally containing a second heteroatom ring member selected from O or S when the ring structure contains 2 or 3 N, and is optionally substituted with one or two independently selected R4 substituents.

[0064] In one embodiment, B is unsubstituted. In another embodiment, B is heteroaryl, unsubstituted, or substituted with one R4 substituent. In another embodiment, B is a 9-membered bicyclic carbon atom ring structure radical. In another embodiment, B is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical. In one embodiment, B is heterocyclyl, unsubstituted, or substituted with one R4 substituent.

[0065] Another embodiment includes a compound of formula (I), or a form thereof: [ka] During the ceremony, A, [ka] and any stereoisomer thereof; R1 is hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R2 is independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; and C 1-4 Alkyl, C 3-6 each instance of cycloalkyl, phenyl, pyridonyl, and heterocyclyl is optionally substituted with one or two R3 substituents; R3 is independently a halogen, a hydroxyl, or a C 1-4 Alkyl, C 1-4 Alkoxy, and C3-6 cycloalkyl; B, phenyl optionally substituted with one or two independently selected R4 substituents; and heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent); R4 is halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1; The form of the compound is selected from the group consisting of its salts, hydrates, solvates, and tautomeric forms.

[0066] Except where provided, each of the terms and definitions in this aspect are the same as those defined above. In this embodiment, B can be a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing one, two, or three heteroatoms selected from N, O, and S. B can be selected from the group consisting of phenyl and heteroaryl, optionally substituted with one or two independently selected R4 substituents, where heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing at least one N atom. B can be selected from the group consisting of phenyl and heteroaryl, optionally substituted with one R4 substituent, where heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing one, two, or three N atoms and, optionally, if the ring structure contains one or two N atoms, a second heteroatom selected from O and S, optionally substituted with one R4 substituent. B can be heteroaryl, where heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing one, two, or three N atoms and optionally substituted with one R4 substituent.

[0067] One embodiment includes compounds of formula (I), wherein B is phenyl optionally substituted with one or two independently selected R4 substituents; Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent). B can be phenyl optionally substituted with one or two independently selected R4 substituents. B can be unsubstituted phenyl or phenyl substituted with one R4 substituent.

[0068] One embodiment includes compounds of formula (I), wherein B is heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent. B can be heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and optionally a second heteroatom selected from O and S, and is optionally substituted with one R4 substituent. B can be heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 2 or 3 heteroatoms selected from N, O, and S, and is optionally substituted with one R4 substituent. B may be heteroaryl, which is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing two or three N atoms and optionally a second heteroatom selected from O and S, and is optionally substituted with one R4 substituent.

[0069] B can be a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 1,3-oxazolyl, tetrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, optionally substituted with one R4 substituent. B can be a heteroaryl selected from the group consisting of 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,3-oxazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, optionally substituted with one R4 substituent.

[0070] B can be a heteroaryl selected from the group consisting of 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,3-oxazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, substituted with one R4 substituent. B is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, yl, 1,3-thiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, tetrazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazo 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1, and may be a heteroaryl selected from the group consisting of 2,4-triazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, optionally substituted with one R4 substituent.

[0071] B is 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-2 ... and optionally substituted with one R4 substituent. B is 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-4-yl, pyrazol-2-yl, pyrazol-3 ... and may be heteroaryl selected from the group consisting of 1,2,4-thiadiazol-3-yl, 1H-1,2,4-triazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, and substituted with one R4 substituent.

[0072] Compounds of formula (I), or embodiments of the form thereof, are [ka] wherein: A, [ka] and any stereoisomer thereof; R1 is hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R2 is independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; and C 1-4 Alkyl, C 3-6 each instance of cycloalkyl, phenyl, pyridonyl, and heterocyclyl is optionally substituted with one or two R3 substituents; R3 is independently a halogen, a hydroxyl, or a C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, Heteroaryl (heteroaryl is a 9- or 10-membered bicyclic aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R4 substituents); and heterocyclyl (heterocyclyl is an 8-10 membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and optionally substituted with one or two independently selected R4 substituents); R4 is halogen, cyano, C1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1; The form of the compound is selected from the group consisting of its salts, hydrates, solvates, and tautomeric forms.

[0073] Except where provided, each of the terms and definitions in this aspect are the same as those defined above. B can be heteroaryl, which is a 9- or 10-membered bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S. B can be heteroaryl, which is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and is optionally substituted with one or two independently selected R4 substituents.

[0074] B can be heterocyclyl, which is an 8-10 membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S. B is Heteroaryl (heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing at least two N atoms), and It may be selected from the group consisting of heterocyclyl (heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N atom).

[0075] B is Heteroaryl (heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, optionally substituted with one or two independently selected R4 substituents); and Heterocyclyl (heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and optionally substituted with one or two independently selected R4 substituents).

[0076] One embodiment includes compounds of formula (I), wherein B is heteroaryl, wherein heteroaryl is a 9- or 10-membered aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R substituents. B can be heteroaryl, wherein heteroaryl is a 9- or 10-membered bicyclic carbon atom ring structure radical containing at least one N atom ring member and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R substituents. B can be heteroaryl, wherein heteroaryl is a 9- or 10-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R substituents. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and is optionally substituted with one or two independently selected R4 substituents. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents. B may be heteroaryl, wherein the heteroaryl is an unsubstituted 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S. B may be heteroaryl, wherein the heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is unsubstituted or substituted with one R4 substituent.

[0077] B is 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothiophenyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyrazinyl, pyrrolo[1,2-c ... 1H-pyrazolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidin-2-yl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl nyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, thiazolo[4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, quinolinyl, isoquinolinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl and heteroaryl selected from the group consisting of pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, optionally substituted with one or two independently selected R4 substituents.

[0078] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a]pyridinyl nyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo[4,5-b ]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b] and may be heteroaryl selected from the group consisting of pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, optionally substituted with one or two independently selected R4 substituents.

[0079] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a ]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thia 1H-pyrazolo[4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl ]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, and may be heteroaryl selected from the group consisting of triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, substituted with one R4 substituent.

[0080] B is 2H-indazolyl, 7H-purinyl, furo[3,2-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, [1,2,3]triazolo[1,5-a] Pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [4,5-b]pyrazinyl, thiazolo[5,4-c]pyridinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 2H-[1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl and may be heteroaryl selected from azolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridinyl, benzo[c][1,2,5]thiadiazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and thiazolo[5,4-b]pyridinyl, and is substituted with two independently selected R4 substituents.

[0081] B is 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3 -benzothiazol-6-yl, 1,3-benzodioxol-5-yl, 1,2,3-benzotriazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, 1,3-oxazolo[5,4-b]pyridin-5-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazine- 2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 5H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyrazin-5-yl, 1H-pyrazolo[3,4-c]pyridin Lysin-1-yl, 1H-pyrazolo[3,4-c]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 2H-pyrazolo[4,3-b]pyridin-5-yl, 2H-pyrazolo[4,3-c]pyridin-5-yl, 1H-pyrazolo[4,3-d]pyrimidin-5-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-5-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazole- 6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1 ,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl , quinolin-6-yl, isoquinolin-6-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,and thiazolo[5,4-b]pyridin-2-yl, optionally substituted with one or two independently selected R substituents.

[0082] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo [4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl , thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H-[1,2, and thiazolo[5,4-b]pyridin-2-yl, optionally substituted with one or two independently selected R substituents.

[0083] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, 1H-[1,2,3]triazolo[1,5-a]pyrid ... Triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin Lysin-6-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6 -yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-7-yl, pyrazolo[1,5-a]pyrimidin-3-yl, thiazolo[5,4-b]pyridin-2-yl, and substituted with one R4 substituent.

[0084] B is 1H-indazol-5-yl, 7H-purin-2-yl, furo[3,2-b]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-1-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H- ...3-yl, 2H-[1,2,3]triazolo[1,5-a]pyridin-3-yl, 2H-[1,2,3]triazolo[1,5-a]pyridin-5-yl, 1H-[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl, [1,2,4]triazolo[1,5-a]pyrimidin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-a]pyridin- 6-yl, thiazolo[4,5-b]pyrazin-2-yl, thiazolo[5,4-c]pyridin-2-yl, [1,2,5]thiadiazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, 2H and may be a heteroaryl selected from the group consisting of -[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl, benzo[c][1,2,5]thiadiazol-5-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-7-yl, pyrazolo[1,5-a]pyrimidin-3-yl, and thiazolo[5,4-b]pyridin-2-yl, substituted with two independently selected R4 substituents.

[0085] One embodiment includes compounds of formula (I), wherein B is heterocyclyl, where heterocyclyl is an 8- to 10-membered bicyclic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, where heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, where heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, optionally substituted with one or two independently selected R4 substituents, or heterocyclyl, which is an 8-membered bicyclic carbon atom ring structure radical containing 2 or 3 N, substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is optionally substituted with one or two independently selected R4 substituents. B can be heterocyclyl, which is an unsubstituted 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S.B may be heterocyclyl, which is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and optionally containing a second heteroatom ring member selected from O or S, and is unsubstituted or substituted with one R4 substituent.

[0086] B can be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, optionally substituted with one or two independently selected R4 substituents. B may be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, substituted with two independently selected R4 substituents.

[0087] B may be a heterocyclyl selected from the group consisting of 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, substituted with one R4 substituent. B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3 ...4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, optionally substituted by one or two independently selected R4 substituents.

[0088] B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 5,6-dihydro-4H-pyrrolo and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and ... may be a heterocyclyl selected from the group consisting of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, substituted by one R4 substituent. B is 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl, 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2 and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, and is substituted with two independently selected R4 substituents.

[0089] Embodiments of the compounds of formula (I) or forms thereof include compounds selected from the group consisting of: 「#」 indicates that the compound is a racemic mixture of enantiomers, 「&」 indicates that the compound can exist as the opposite enantiomer, [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0090] Compounds of formula (I) or embodiments thereof (compound no. 1 ) indicates that the salt form is isolated; and ) comprises a compound selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] The form of the compound is selected from the group consisting of its salts, hydrates, solvates, and tautomeric forms.

[0091] Another embodiment of the compound of formula (I) or a form thereof is a salt of a compound selected from the group consisting of: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] The form of the compound is selected from the group consisting of its hydrates, solvates, and tautomeric forms.

[0092] chemical definition The chemical terms used above and throughout the description herein shall be understood by those skilled in the art to have the meanings indicated below, unless otherwise defined. As used herein, "C 1-44 The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 4 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl (also called butyl or butanyl), isobutyl, sec-butyl, tert-butyl, and the like. 1-44Alkyl radicals are optionally substituted, where available valences allow, with substituent types described herein.

[0093] As used herein, "C 2-4 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon radical having 2 to 4 carbon atoms in a straight or branched arrangement and one or more carbon-carbon double bonds therein, and includes, but is not limited to, ethenyl (also called vinyl), allyl, propenyl, and the like. 2-4 Alkenyl radicals are optionally substituted, where available valences allow, with the types of substituents described herein. As used herein, "C 2-8 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 8 carbon atoms in a linear or branched arrangement and one or more carbon-carbon triple bonds therein, and includes, but is not limited to, ethynyl, propynyl, butynyl, and the like. In some embodiments, C 2-8 Alkynyl is C 2-6 Alkynyl, C 2-4 Alkynyl and the like are included, but are not limited to. 2-8 Alkynyl radicals are optionally substituted, where available valences allow, with substituent types described herein.

[0094] As used herein, "C 1-4 The term "alkoxy" generally refers to a group of the formula: -OC 1-4 Alkyl refers to a saturated hydrocarbon radical having 1 to 4 carbon atoms in a straight or branched chain configuration, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. 1-44 Alkoxy radicals are optionally substituted, where available valences allow, with substituent types described herein. As used herein, "C 3-6The term "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Cycloalkyl radicals are optionally substituted, where available valences allow, with substituent types described herein.

[0095] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl radicals are optionally substituted, where available valences allow, with substituent types described herein. As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members are replaced, where structural stability permits, by one or more heteroatoms, e.g., O, S, or N atoms, and includes furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl. , tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b] Pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]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 [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, etc. Heteroaryl radicals are optionally substituted on carbon or nitrogen ring members, where available valences allow, with substituent types described herein.

[0096] In some embodiments, the nomenclature of heteroaryl radicals may vary, such as, by way of non-limiting example, furanyl may also be called furyl, thiophenyl may also be called thienyl, pyridinyl may also be called pyridyl, benzothiophenyl may also be called benzothienyl, and 1,3-benzoxazolyl may also be called 1,3-benzooxazolyl. In certain other aspects, the terms relating to heteroaryl radicals include, for example, the term pyrrolyl can include 2H-pyrrolyl, 3H-pyrrolyl, etc., the term pyrazolyl can include 1H-pyrazolyl, etc., the term imidazolyl can include 1H-imidazolyl, etc., the term triazolyl can include 1H-1,2,3-triazolyl, etc., the term oxadiazolyl can include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc. In non-limiting examples, the term may also include other positional isomers such as azolyl, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl, the term indolyl may also include 1H-indolyl, the term indazolyl may also include 1H-indazolyl, 2H-indazolyl, the term benzimidazolyl may also include 1H-benzimidazolyl, the term purinyl may also include 9H-purinyl, etc.

[0097] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members are replaced, where structural stability permits, by a heteroatom, such as an O, S, or N atom, and includes oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolinyl, isothiazolyl, and isothiazolyl. lysinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4 -benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)- yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin- (1H)-yl, 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]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[2.2.2]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, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, 7-azadispiro[5.1.5, 8 .3 6 Heterocyclyl radicals include, but are not limited to, hexadecanyl, etc. Heterocyclyl radicals are optionally substituted on carbon or nitrogen ring atoms, where available valences allow, with substituent types described herein.

[0098] In certain embodiments, the nomenclature of heterocyclyl radicals may differ, for example, in non-limiting example, 1,3-benzodioxolyl may also be called benzo[d][1,3]dioxolyl, and 2,3-dihydro-1,4-benzodioxinyl may also be called 2,3-dihydrobenzo[b][1,4]dioxinyl. As used herein, "C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-OC 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to an alkyl radical.

[0099] As used herein, "(C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 It refers to the radical (alkyl)2. As used herein, "C 1-4 The term "alkyl-carbonyl" refers to a group of the formula: -C(O)-C 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-carbonyl-amino" refers to a group of the formula: -NH-C(O)-C 1-4 Refers to an alkyl radical.

[0100] As used herein, "C 1-4 The term "alkyl-thio" refers to a group of the formula: -SC 1-4 Refers to an alkyl radical. As used herein, "amino-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to the alkyl-NH2 radical. As used herein, "deuterium-C" refers to 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-deuterated radical, C 1-4Alkyl is partially or fully substituted with one or more deuterium atoms, where available valences permit.

[0101] As used herein, the term "halo" or "halogen" generally refers to halogen atom radicals, including fluoro, chloro, bromo, and iodo. As used herein, "halo-C" refers to 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Refers to alkyl-halo radicals, C 1-4 The alkyl is partially or fully substituted with one or more halogen atoms, where available valences allow.

[0102] As used herein, "halo-C" refers to 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to alkyl-halo radicals, C 1-4 The alkyl is partially or fully substituted with one or more halogen atoms, where available valences allow. As used herein, "halo-C" refers to 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to alkyl-halo radicals. As used herein, the term "hydroxy" refers to a radical of the formula: --OH.

[0103] As used herein, "hydroxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to the alkyl-OH radical, C 1-4 The alkyl is partially or fully substituted, where available valences allow, with one or more hydroxy radicals. As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that replaces one or more hydrogens on the designated atom and is substituted at the designated atomic position, provided that the normal valence of the designated atom is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that any carbon and heteroatom that appears to have unsatisfied valences, as described or shown herein, is presumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valences. In certain instances, one or more substituents having a double bond as a point of attachment (e.g., "oxo" or "=O") may be described, shown, or listed within a substituent herein, and a structure may show only a single bond as the point of attachment to the core structure of Formula (I). Those of skill in the art will understand that a double bond is intended for such substituents, even if only a single bond is shown.

[0104] As used herein, with respect to the definitions of chemical terms provided herein, the term "such as" means that variations in chemical structure that one of ordinary skill in the art would expect include, but are not limited to, isomers (including chain, branched, or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring structures), and all other variations that result in stable compounds, where available valences allow. For purposes of this description, when a compound of formula (I) or one or more substitute variables of a form thereof includes a functional group incorporated into a compound of formula (I), each functional group appearing anywhere within the disclosed compound can be independently selected and, where appropriate, independently and / or optionally substituted.

[0105] As used herein, the terms "independently selected" or "each selected" refer to a functional variable in a list of substituents that may occur more than once on the structure of Formula (I), and the substitution pattern at each occurrence is independent of the pattern at any other occurrence. Furthermore, the use of a generic substituent variable in any formula or structure for the compounds described herein includes replacement of the generic substituent with a species of substituent included within the particular genus; for example, aryl can be replaced with phenyl or naphthalenyl, etc., and it is understood that the resulting compound would be within the scope of the compounds described herein. As used herein, the terms "in each instance" or "in each instance, if present" are used interchangeably with "...C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 When used preceding the term "alkyl," each, when present alone or as a substituent, is C 3-14 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. As used herein, the term "optionally substituted" means optional substitution with the specified substituted variable, group, radical or moiety.

[0106] compound form As used herein, the term "form" means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, hydrate, solvate, ester, stereoisomer, and tautomeric form. In certain embodiments described herein, the compound of formula (I) is in the form of a free acid, a free base, or a salt thereof. In certain embodiments described herein, the compound of formula (I) is in the form of a salt thereof.

[0107] In certain embodiments described herein, the form of the compound of formula (I) is its tautomer. In certain embodiments described herein, the compound of formula (I) is in a pharmaceutically acceptable form. In certain embodiments described herein, the compound of formula (I) or a form thereof is isolated for use.

[0108] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof after it has been isolated and / or purified from a synthetic process (e.g., from a reaction mixture), or from a natural source, or a combination thereof, in sufficient purity to be characterized by an isolation or purification process or processes described herein or known to those of skill in the art (e.g., chromatography, recrystallization, etc.), or by standard analytical techniques described herein or known to those of skill in the art. As used herein, the term "protected" means that a functional group in a compound of formula (I) or in its form is in a modified form so as to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art and by reference to standard textbooks, such as T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino, and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. In some instances, the protecting group may be a polymer resin, such as a Wang resin or a 2-chlorotrityl chloride resin. Protecting groups may be added and removed according to standard techniques well known to those skilled in the art and described herein.

[0109] 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 the solvated and unsolvated forms. 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 certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. As used herein, the term "hydrate" refers to a solvate where the solvent molecule is water.

[0110] The compound of formula (I) can form salts, which are intended to be included within the scope of this specification. Reference herein to a compound of formula (I) or a form thereof is understood to include a reference to its salt forms, unless otherwise indicated. As used herein, the term "salt(s)" refers to acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Furthermore, when a compound of formula (I) or a form thereof contains both a basic moiety, such as, but not limited to, an amine moiety, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and may be included within the term "salt(s)" as used herein. As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of formula (I) can be formed, for example, by reacting the compound of formula (I) or a form thereof with an amount, e.g., an equivalent amount, of an acid or base in a medium, e.g., in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0111] Pharmaceutically acceptable salts include salts of one or more acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain detailed embodiments of acid addition salts include chlorides or dichlorides. Additionally, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York, and in The Orange Book (on the Food & Drug Administration, Washington, DC website), the disclosures of which are incorporated herein by reference.

[0112] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts. All such acid and base salts are intended to be included within the scope of pharmaceutically acceptable salts described herein, and furthermore, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes herein.

[0113] Compounds of formula (I) and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are assumed and intended to be included within the scope of the compounds of formula (I) and forms thereof described herein. The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. This specification is intended to include all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures.

[0114] The compounds described herein may contain one or more chiral centers and, as such, may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereoisomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one detailed aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions comprising substantially only the (S) isomer. In another detailed aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions comprising substantially only the (R) isomer. As one of ordinary skill in the art will recognize, 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. As used herein, the term "chiral" refers to a carbon atom bonded to four nonidentical substituents. Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. When describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). Substituents attached to a given chiral center are ranked according to the Cahn-Ingold-Prelog ranking rules (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0115] As used herein, the term "substantially pure" refers to a compound that consists essentially of a single isomer in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100% of a single isomer. In one aspect herein, the compound of formula (I)) or a form thereof is a substantially pure (S) enantiomeric form present in an amount of 90% or greater, in an amount of 92% or greater, in an amount of 95% or greater, in an amount of 98% or greater, in an amount of 99% or greater, or in an amount equal to 100%.

[0116] In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount of 90% or greater, in an amount of 92% or greater, in an amount of 95% or greater, in an amount of 98% or greater, in an amount of 99% or greater, or in an amount equal to 100%. As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure," including, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20. Furthermore, all geometric and positional isomers are encompassed herein. For example, if a compound of Formula (I) or a form thereof incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are encompassed within the scope of this specification. Diastereoisomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated using chiral HPLC columns or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting an enantiomeric mixture into a diastereoisomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral alcohol or a chiral auxiliary such as Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this specification.

[0117] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including enantiomeric forms (which may exist even without asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms, including those that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of this specification, as are positional isomers (e.g., 4-pyridyl, 3-pyridyl, etc.). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers or may exist as racemic mixtures, as described above. Use of the terms "salts," "solvates," and the like is intended to apply equally to salts and solvates of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates of the present compounds.

[0118] Use of the compound In accordance with the intended scope of the present specification, embodiments of the present specification include compounds that have been identified and demonstrated to be useful in selectively preventing, treating, or ameliorating HD, and are indicated for use in preventing, treating, or ameliorating HD. Embodiments herein include a method of preventing, treating, or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Embodiments herein include a method of treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0119] Embodiments herein include a method of preventing HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Embodiments herein include a method of treating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Embodiments herein include a method of ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Another aspect herein includes a method of treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0120] Another aspect herein includes a method of treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a compound salt, or a form thereof, together with one or more therapeutic agents in a combination product or as a combination therapy. Embodiments herein include methods of using a compound of formula (I), or a form or composition thereof, for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form or composition thereof.

[0121] Another aspect herein includes a method of using a salt of a compound of formula (I), or a form or composition thereof, for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I), or a form thereof. Embodiments herein include the use of a compound of formula (I), or a form thereof, for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof.

[0122] Another aspect herein includes the use of a salt of the compound of formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of the compound of formula (I) or a form thereof. Embodiments herein include the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[0123] Another aspect herein includes the use of a salt of a compound of formula (I)) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject. Aspects herein include the in vitro or in vivo use of compounds of formula (I) or forms thereof that have activity against HD.

[0124] Embodiments herein include the use of compounds of formula (I) or forms thereof in combination therapy to provide additive or synergistic activity, thereby enabling the development of combination products for treating or ameliorating HD. Another aspect of the present specification includes combination therapies that include a compound described herein in combination with one or more known drugs or one or more known therapies that can be used to treat HD, regardless of whether the HD responds to the known drugs.

[0125] Embodiments herein include the use of a compound of formula (I), or a form thereof, in a combination product with one or more therapeutic agents for the treatment or amelioration of HD in a subject in need thereof, comprising administering to a subject an effective amount of a compound of formula (I), or a form thereof, in combination with an effective amount of the one or more agents. Another aspect herein includes the use of a salt of the compound of formula (I) or a form thereof in a combination product with one or more therapeutic agents for the treatment or amelioration of HD in a subject in need thereof, comprising administering to a subject an effective amount of a salt of the compound of formula (I) or a form thereof in combination with an effective amount of the one or more agents.

[0126] In certain embodiments of the uses or methods provided herein, the compound of Formula (I) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a cell(s) of a subject or patient before, simultaneously with, or after administration to the subject or patient or contacting the cells with the additional agent(s). The compound(s) of Formula (I) or a form thereof and the additional agent(s) can be administered to a subject or contacted with cells in a single composition or in different compositions. In certain embodiments, the compound(s) of Formula (I) or a form thereof is used in combination with gene therapy to inhibit HTT expression (e.g., using a viral delivery vector) or administration of another small molecule HTT inhibitor. In another specific embodiment, the compound(s) of Formula (I) or a form thereof is used in combination with cell replacement using differentiated, non-mutant HTT stem cells. In another specific embodiment, the compound(s) of Formula (I) or a form thereof is used in combination with cell replacement using differentiated HTT stem cells. In one aspect, provided herein is the use of a compound of formula (I) or a form thereof in combination with supportive standard of care therapy, including palliative care.

[0127] In one aspect, in each such embodiment, the subject is treatment naive. In another aspect, in each such embodiment, the subject is not treatment naive. As used herein, the term "preventing" refers to keeping a disease, disorder, or condition from occurring in a subject who may be predisposed to the disease, disorder, and / or condition, but who has not yet been diagnosed with the disease, disorder, and / or condition. As used herein, the term "treating" refers to inhibiting the progression of a disease, disorder, or condition in a subject already exhibiting symptoms of the disease, disorder, and / or condition, i.e., halting the manifestation of a disease, disorder, and / or condition that has already affected the subject.

[0128] As used herein, the term "ameliorating" refers to reducing the symptoms of a disease, disorder, or condition in a subject already experiencing symptoms of the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition already affecting the subject. As used herein, the term "subject" refers to an animal or any living organism that has sensation and the power of voluntary movement and requires oxygen and organic sustenance. Non-limiting examples include humans, primates, members of the Equine, Porcine, Bovidae, Mus, Rattus, Canidae, and Felidae species. In certain aspects, the subject is a mammal or warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human." As used herein, the term "effective amount" or "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 the treatment or amelioration of HD as described herein, thereby producing the desired therapeutic, ameliorative, inhibitory, or preventative effect in a subject in need thereof. In one embodiment, an effective amount can be the amount required for the treatment of HD in a subject or patient, more particularly a human.

[0129] In another embodiment, the concentration-biological effect relationships observed for the compound of Formula (I) or a form thereof indicate target plasma concentrations ranging from about 0.001 μg / mL to about 50 μg / mL, from about 0.01 μg / mL to about 20 μg / mL, from about 0.05 μg / mL to about 10 μg / mL, or from about 0.1 μg / mL to about 5 μg / mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses ranging, for example, but not limited to, from 1.0 ng to 10,000 mg. In one embodiment, the dose administered to achieve an effective target plasma concentration may be administered based on subject or patient-specific factors, and may be administered on a weight basis from about 0.001 mg / kg / day to about 3500 mg / kg / day, or from about 0.001 mg / kg / day to about 3000 mg / kg / day, or from about 0.001 mg / kg / day to about 2500 mg / kg / day, or from about 0.001 mg / kg / day to about 2000 mg / kg / day, or from about 0.001 mg / kg / day to about 1500 mg / kg / day, or from about 0.001 mg / kg / day to about 1000 mg / kg / day. or about 0.001 mg / kg / day to about 500 mg / kg / day, or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or about 0.001 mg / kg / day to about 5 mg / kg / day, or about 0.001 mg / kg / day to about 1 mg / kg / day, or about 0.001 mg / kg / day to about 0.5 mg / kg / day, or about 0.001 mg / kg / day to about 0.1 mg / kg / day, or 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 1500mg / kg / day, or about 0.01mg / kg / day to about 1000mg / kg / day, or about 0.01mg / kg / day to about 500mg / kg / day, or about 0.01mg / kg / day to about 250mg / kg / day, or about 0.01mg / kg / day to about 200mg / kg / day, or about 0.01mg / kg / day to about 150mg / kg / day, or about 0.01mg / kg / day to about 100mg / kg / day, or about 0.01mg / kg / day to about 75mg / kg / day, or about 0.01mg / kg / day to about 50mg / kg / day, or about 0.0.01 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 1 mg / kg / day, or about 0.01 mg / kg / day to about 0.5 mg / kg / day, or about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0. 1 mg / kg / day to about 3500 mg / kg / day, or about 0.1 mg / kg / day to about 3000 mg / kg / day, or about 0.1 mg / kg / day to about 2500 mg / kg / day, or about 0.1 mg / kg / day to about 2000 mg / kg / day, or about 0.1 mg / kg / day to about 1500 mg / kg / day, or about 0.1 mg / kg / day to about 1000 mg / kg / day, or about 0.1 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg / kg / day to about 250 mg / kg / day, or about 0.1 mg / kg / day to about 200 mg / kg / day, or about 0.1 mg / kg / day to about 150 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day, or about 0.1 mg / kg / day to about 75 mg / kg / day, or or from about 0.1 mg / kg / day to about 50 mg / kg / day, or from about 0.1 mg / kg / day to about 25 mg / kg / day, or from about 0.1 mg / kg / day to about 10 mg / kg / day, or from about 0.1 mg / kg / day to about 5 mg / kg / day, or from about 0.1 mg / kg / day to about 1 mg / kg / day, or from about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0130] The effective amount for a given subject can be determined by routine experimentation within the skill and judgment of a clinician or person skilled in the art, taking into account subject-related factors. Dosage regimens can be adjusted to provide sufficient levels of active agent(s) or to maintain the desired effect. Factors that can be considered include genetic screening, severity of the disease state, disease progression status, the subject's overall health, ethnicity, age, weight, sex, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerance / response to treatment. The dose administered to achieve an effective target plasma concentration may be administered orally once (approximately every 24 hours, i.e., "qd"), twice (approximately every 12 hours, i.e., "bid" or "q.12h"), three times (approximately every 8 hours, i.e., "tid" or "q.8h"), or four times (approximately every 6 hours, i.e., "qds", "qid" or "q.6h") daily.

[0131] In certain embodiments, the dose administered to achieve an effective target plasma concentration may be administered as a single, divided, or continuous dose to patients or subjects having a body weight in the range of about 40 to about 200 kg (doses may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). A typical adult subject is expected to have a median body weight in the range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3, or 4 days, once every other week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions described herein can be administered to a subject via any drug delivery route known in the art, including, but not limited to, oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and pulmonary routes of administration.

[0132] In another aspect, the administered dose may be adjusted based on the dosage forms described herein and formulated to deliver about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg / day. For certain compounds, the effective amount can be initially evaluated in cell culture assays or relevant animal models, such as mice, guinea pigs, chimpanzees, marmosets, or tamarins. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic efficacy and toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and the LD 50 / ED 50 In certain embodiments, the effective amount is such that a high therapeutic index is achieved. In further detailed embodiments, the dosage is such that the ED 50 The dosage may vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0133] In one aspect, provided herein is a method for modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of Formula (I), or a form thereof. In particular aspects, provided herein is a method for modulating the amount of HTT, comprising contacting a human cell with a compound of Formula (I)), or a form thereof, that modulates expression of HTT. The human cell can be contacted with a compound of Formula (I)), or a form thereof, in vitro or in vivo, e.g., in a non-human animal or a human. In particular aspects, the human cell is derived from or is within a human. In another particular aspect, the human cell is derived from or is within a human with HD. In another particular aspect, the human cell is derived from or is within a human with HD, where the HD is caused by a CAG repeat in the Htt gene, resulting in loss of HTT expression and / or function. In another aspect, the human cell is derived from a human with HD. In another aspect, the human cell is within a human with HD. In one aspect, the compound is in the form of a compound of Formula (I). In certain embodiments, provided herein are methods for improving inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of Formula (I) or a form thereof. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro or in vivo, e.g., in a non-human animal or a human. In certain embodiments, the human cell is derived from or within a human. In another particular embodiment, the human cell is derived from or within a human with HD. In another particular embodiment, the human cell is derived from or within a human with HD caused by a CAG repeat in the Htt gene, resulting in loss of wild-type, "normal" HTT expression and / or function. In another embodiment, the human cell is derived from or within a human with HD. In another embodiment, the human cell is within a human with HD. In one embodiment, the compound is in the form of a compound of Formula (I).

[0134] In another aspect, provided herein is a method for modulating 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 animal model for HD. In certain aspects, provided herein is a method for modulating 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 animal model for HD. In certain aspects, the compound is in the form of a compound of Formula (I). In another aspect, provided herein are methods for reducing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a particular aspect, provided herein are methods for reducing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I), which inhibits transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another particular aspect, provided herein are methods for reducing the amount of HTT, comprising contacting a human cell with a compound of Formula (I), which inhibits expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of Formula (I), or a form thereof, in vitro or in vivo, e.g., in a non-human animal or a human. In a particular aspect, the human cell is derived from or present in a human. In another particular aspect, the human cell is derived from or present in a human with HD. In another particular aspect, the human cell is derived from or present in a human with HD, which is caused by a CAG repeat in the Htt gene, resulting in loss of HTT expression and / or function. In another embodiment, the human cells are derived from a human with HD. In another embodiment, the human cells are within a human with HD. In one embodiment, the compound is in the form of a compound of formula (I).

[0135] In certain embodiments, treating or ameliorating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic and / or beneficial effect. In particular embodiments, treating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) results in one, two, or more of the following effects: (i) reducing or ameliorating the severity of HD, (ii) delaying the onset of HD, (iii) inhibiting the progression of HD, (iv) reducing the subject's length of hospitalization, (v) reducing the subject's length of hospitalization, (vi) increasing the subject's survival, (vii) improving the subject's quality of life, (viii) reducing the number of symptoms associated with HD, (ix) reducing or ameliorating the severity of symptom(s) associated with HD, (x) reducing the duration of symptoms associated with HD, (xi) preventing the recurrence of symptoms associated with HD, (xii) inhibiting the onset or development of symptoms of HD, and / or (xiii) inhibiting the progression of symptoms associated with HD.

[0136] Metabolites Another aspect included within the scope of this specification is the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, this description includes the use of compounds produced by a process comprising contacting a compound described herein with mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically include radiolabeled isotopologues of the compounds described herein (e.g., 14 C or 3Identification is accomplished by preparing a radiolabeled compound (H), administering a detectable dose (e.g., greater than about 0.5 mg / kg) of the radiolabeled compound to a mammal, such as a rat, mouse, guinea pig, dog, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying metabolic conversion products in urine, bile, blood, or other biological samples. Because the conversion products are "radiolabeled" by being isotopically enriched, they are readily isolated (some are isolated using antibodies capable of binding to antigenic determinants remaining in the metabolite). Metabolite structures are determined by conventional techniques, such as MS or NMR analysis. Metabolite analysis can generally be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Conversion products, even if they themselves possess no biological activity, are useful in diagnostic assays for therapeutic dosing of the compounds described herein, unless otherwise found in vivo.

[0137] Pharmaceutical Composition In accordance with the intended scope of the present specification, embodiments of the present specification include compounds that have been identified and demonstrated to be useful in selectively preventing, treating, or ameliorating HD and are indicated for use as one or more pharmaceutical compositions for preventing, treating, or ameliorating HD. Aspects herein include the use of a compound of formula (I), or a form thereof, in the preparation of a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof, in admixture with one or more pharmaceutically acceptable excipients. An embodiment herein includes the use of a compound of formula (I) or a pharmaceutical composition thereof in the preparation of a kit for the treatment or amelioration of HD in a subject in need thereof, the kit comprising the compound of formula (I) or a pharmaceutical composition thereof and instructions for administering the pharmaceutical composition.

[0138] As used herein, the term "composition" means a product containing specified ingredients in specified amounts, as well as any product resulting, directly or indirectly, from the combination of specified ingredients in specified amounts. The pharmaceutical composition may be formulated to achieve a physiologically compatible pH ranging from about pH 3 to about pH 11. In one embodiment, the pharmaceutical composition is formulated to achieve a pH of about pH 3 to about pH 7. In another embodiment, the pharmaceutical composition is formulated to achieve a pH of about pH 5 to about pH 8.

[0139] The term "pharmaceutically acceptable excipient" refers to an excipient for administering a pharmaceutical agent, such as a compound described herein. This term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients can be determined in part by the particular composition being administered, as well as by the particular mode of administration and / or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, and the like. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions for the compounds of the invention described herein (see, e.g., Remington's Pharmaceutical Sciences). Suitable excipients may be carrier molecules, including large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inert antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting or emulsifying agents; pH buffering substances, etc. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

[0140] The pharmaceutical compositions described herein may be formulated in any form suitable for the intended uses described herein. Formulations suitable for oral administration include solids, liquid solutions, emulsions, and suspensions, while inhalable formulations suitable for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids that can be reconstituted with a physiologically compatible solvent before administration. If intended for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, non-aqueous liquids, dispersible powders or granules (including micronized or nanoparticles), emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for producing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to obtain a palatable preparation.

[0141] Pharmaceutically acceptable excipients suitable for use with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate, disintegrants such as croscarmellose sodium, cross-linked povidone, corn starch, or alginic acid, binders such as povidone, starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as cellulose, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a non-aqueous or oily medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

[0142] In other aspects, the pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients suitable for the preparation of a suspension. In yet other aspects, the pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for the preparation of a suspension by the addition of one or more excipients. Excipients suitable for use in connection with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate), and thickening agents such as carbomer, beeswax, hard paraffin, or cetyl alcohol. Suspensions may also contain one or more preservatives, such as acetate, methyl and / or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweeteners, such as sucrose or saccharin.

[0143] The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum; naturally occurring phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain analgesics, preservatives, flavorings, or coloring agents. Furthermore, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsions or suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile fixed oils may be used as a solvent or suspending medium. For this purpose, any sterile fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0144] The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but are generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides, and in propylene glycol esters of medium-chain fatty acids. Thus, compounds that have been modified by substitution or addition of chemical or biochemical moieties, such as by esterification, glycosylation, PEGylation, etc., that make the compounds more suitable for delivery (e.g., improved solubility, biological activity, palatability, reduced side effects, etc.), are contemplated herein. In some embodiments, the compounds described herein are formulated for oral administration as lipid-based compositions suitable for low-solubility compounds. Lipid-based formulations can generally improve the oral bioavailability of such compounds. Thus, the pharmaceutical compositions described herein may contain an effective amount of a compound of Formula (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from a medium-chain fatty acid or its propylene glycol ester (e.g., a propylene glycol ester of an edible fatty acid such as caprylic or capric fatty acid), and a pharmaceutically acceptable surfactant such as polysorbate 20 or 80 (also known as Tween® 20 or Tween® 80, respectively), or polyoxyl 40 hydrogenated castor oil.

[0145] In other aspects, the bioavailability of poorly soluble compounds can be enhanced using particle size optimization techniques, including preparing nanoparticles or nanosuspensions using techniques known to those skilled in the art. The form of the compound present in such preparations can include amorphous, partially amorphous, partially crystalline, or crystalline forms. In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancers, such as cyclodextrins. Non-limiting examples of cyclodextrins include hydroxypropyl, hydroxyethyl, glycosyl, maltosyl, and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, as well as hydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in the range of about 0.1% to about 20%, about 1% to about 15%, or about 2.5% to about 10%. The amount of solubility enhancer used may depend on the amount of compound in the composition.

[0146] Preparation of compounds General synthesis method As disclosed herein, general methods for preparing the compounds of formula (I) described herein or forms thereof can be utilized by well-known standard synthetic methodologies. Many of the starting materials are commercially available, or if unavailable, can be prepared using the routes described below using techniques known to those skilled in the art. The synthetic schemes provided herein include multiple reaction steps, each of which is intended to stand alone and can be carried out with or without any preceding or subsequent step(s). In other words, isolation is contemplated for each of the individual reaction steps of the synthetic schemes shown herein. A, B, X, R W Compounds of formula GS1-8, where n is as defined for formula (I), may be prepared as described in general Scheme 1 below.

[0147] [ka] Compound GS1-1 (W1 is bromine, chlorine, etc.) can be converted to compound GS1-4 by Suzuki coupling with aryl-boronic acid (or pinacol boronate ester) GS1-2 (W2 is bromine, chlorine, etc.; R1 is hydrogen, fluorine, chlorine, hydroxy, methoxy, aryl, or heteroaryl; and P is a protecting group such as MOM) in the presence of a catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., aqueous KCO3) in a suitable solvent (e.g., 1,4-dioxane). Alternatively, compound GS1-1 can be converted to compound GS1-4 by Stille coupling with aryl-stannane GS1-3 (W2 is bromine, chlorine, etc.; P is a protecting group such as MOM) in the presence of a catalyst (e.g., Pd(PPh3)2Cl2) and an additive (e.g., CuI) in a suitable solvent (e.g., 1,4-dioxane). Compound GS1-4 is converted to compound GS1-5 by treatment with an oxidizing agent (e.g., mCPBA or oxone) in a suitable solvent (e.g., dichloromethane). Compound GS1-5 is converted to compound GS1-6 by nucleophilic substitution with piperazine ring A in the presence of a suitable base (e.g., EtN) in a suitable solvent (e.g., DMF). Compound GS1-6 is converted to compound GS1-7 by Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) in a suitable solvent (e.g., 1,4-dioxane). Alternatively, compound A7 can be converted to compound GS1-7 by Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (e.g., Pd2(dba)3), a ligand (e.g., X-Phos), and a base (e.g., CsF) in a suitable solvent (e.g., 1,4-dioxane).Alternatively, compound GS1-6 can be converted to compound GS1-7 by treatment with pinacolatodiboron and a base (e.g., KOAc) in the presence of a catalyst (e.g., Pd(dppf)Cl) in a suitable solvent (e.g., 1,4-dioxane), followed by the addition of an aryl or heteroaryl halide. Alternatively, compound GS1-6 can be converted to compound GS1-7 by Buchwald-Hartwig coupling with a heteroaryl or amine in the presence of a catalyst (e.g., Pd(dba)), a ligand (e.g., tBuX-Phos), and a base (e.g., KPO) in a suitable solvent (e.g., 1,4-dioxane). Compound GS1-7 can be converted to compound GS1-8 upon treatment with conditions suitable for removing the protecting group (e.g., HCl in dioxane for the MOM protecting group) in a suitable solvent (e.g., dioxane).

[0148] Specific Synthesis Examples To further illustrate and aid in understanding, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein, but are not intended to specifically limit that scope. Such variations of the compounds described herein that may be currently known or later developed within the knowledge of one of ordinary skill in the art are considered to be within the scope of the compounds described herein and are claimed below. These examples illustrate the preparation of certain compounds. Those skilled in the art will understand that the techniques described in these examples, as explained by those skilled in the art, represent techniques that function well in synthetic practice and thus constitute preferred modes for that practice. However, it should be appreciated that those skilled in the art, in light of the present disclosure, will recognize that many variations can be made in the specific methods disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure. Except for the following examples of embodied compounds, unless otherwise indicated, all numbers expressing amounts of raw materials, reaction conditions, experimental data, and the like used in the specification and claims are understood to be modified by the term "about." Accordingly, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained from the reactions or as a result of varying experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in reference to resulting data refers to the range of the data, provided that it may vary according to the standard deviation from the mean. Similarly, for experimental results obtained, the resulting data may be consistently rounded up or down without loss of significant digits. At the very least, without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding techniques employed by those of ordinary skill in the art.

[0149] Notwithstanding that the numerical ranges and parameters setting forth the broad scope herein are approximations, the numerical values ​​set forth in the examples set forth below are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Starting materials used in the examples shown are commercially available, can be prepared according to methods known to those skilled in the art, or can be prepared by procedures disclosed herein. 1 H or 13 Structural confirmation was previously established using analytical techniques known to those skilled in the art, such as C nuclear magnetic resonance spectroscopy or mass spectrometry. Compounds of formula (I) were synthesized using procedures similar to those described in International Publication No. WO / 2019 / 191229A1, filed March 27, 2019, which claims priority to U.S. Provisional Application No. US 62 / 648,699, filed March 27, 2018, by substituting the appropriate starting materials, reagents, and reaction conditions.

[0150] Compound example As used above, and throughout the specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: [Table 3-1] [Table 3-2] [Table 3-3]

[0151] Example 1 Preparation of Compound 213 [ka] Step 1: To a dry round-bottom flask was added 6-bromo-3-methylsulfanyl-1,2,4-triazine (7.0 g, 34.0 mmol), 2-[4-chloro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 33.5 mmol), K2CO3 (9.5 g, 68 mmol), and PddppfCl2 (3.8 g, 5.1 mmol). The mixture was degassed with argon for 10 minutes, then dioxane (100 mL) and water (20 mL) were added, and the reaction was heated at 90 °C for 16 hours (overnight). The reaction was cooled to room temperature and partitioned between EtOAc and water. The organic portion was dried over Na2SO4, concentrated, and purified by silica gel column chromatography eluting with a gradient of 0–20% EtOAc in pentane. 6-[4-chloro-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (4.5 g, 44% yield) was obtained as a yellow solid. MS m / z 298.1, 300.1 [M+H] + . Step 2: 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (750 mg, 2.9 mmol), KOAc (575 mg, 5.86 mmol), X Phos Pd in ​​dry dioxane (5 mL) A suspension of 6-[4-chloro-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (350 mg, 1.18 mmol) with G4 (175 mg, 0.20 mmol) was sparged with argon for 10 minutes and then heated to 90° C. under an argon atmosphere for 2 hours, after which complete conversion to 6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(methylthio)-1,2,4-triazine was observed. The reaction mixture was then cooled to room temperature and used directly in the next step. MS m / z 390.4 [M+H] +.

[0152] Step 3: To the mixture from Step 2 above was added 3-bromo-1,2,4-thiadiazole (0.15 g, 0.91 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.16 g, 0.181 mmol), and potassium carbonate (0.38 g, 2.72 mmol). The reaction was degassed by bubbling nitrogen through for 5 minutes and continued under nitrogen. 1,4-Dioxane (3 mL) and water (3 mL) were added to the mixture, and the reaction was stirred at 90 °C for 2 hours. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phase was dried over MgSO and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient (0-100%) of EtOAc / hexane to give 3-[3-(methoxymethoxy)-4-(3-methylsulfanyl-1,2,4-triazin-6-yl)phenyl]-1,2,4-thiadiazole (0.2 g, 60% yield). MS m / z 348.2 [M+H] + . Step 4: To a solution of 3-[3-(methoxymethoxy)-4-(3-methylsulfanyl-1,2,4-triazin-6-yl)phenyl]-1,2,4-thiadiazole (0.2 g, 0.6 mmol) in CHCl (5 mL) was added 3-chloroperbenzoic acid (0.2 g, 1.0 mmol) in small portions. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with a gradient (0-10%) of CHCl / MeOH to give 3-[3-(methoxymethoxy)-4-(3-methylsulfonyl-1,2,4-triazin-6-yl)phenyl]-1,2,4-thiadiazole (0.1 g, 50% yield). MS m / z 380.3 [M+H] + .

[0153] Step 5: To a solution of 3-[3-(methoxymethoxy)-4-(3-methylsulfonyl-1,2,4-triazin-6-yl)phenyl]-1,2,4-thiadiazole (0.1 g, 0.3 mmol) in ACN (3 mL) was added (2S)-2-cyclopropylpiperazine (0.07 g, 0.6 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol). The reaction mixture was stirred at 80 °C for 30 min. The solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with a gradient (0 to 20%) of CHCl / MeOH to give 3-[4-[3-[(3S)-3-cyclopropylpiperazin-1-yl]-1,2,4-triazin-6-yl]-3-(methoxymethoxy)phenyl]-1,2,4-thiadiazole (0.07 g, 60% yield). MS m / z 426.5 [M+H] + . Step 6: To a solution of 3-[4-[3-[(3S)-3-cyclopropylpiperazin-1-yl]-1,2,4-triazin-6-yl]-3-(methoxymethoxy)phenyl]-1,2,4-thiadiazole (0.07 g, 0.2 mmol) and 2 drops of MeOH in CHCl (1 mL) was added HCl (4 mol / L) in 1,4-dioxane (0.1 mL, 0.4 mmol). The reaction was stirred for 1 h until UPLC showed complete consumption of the starting material. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC eluting with a gradient of 5-40% ACN in water (containing 0.1% formic acid) to give 2-[3-[(3S)-3-cyclopropylpiperazin-1-yl]-1,2,4-triazin-6-yl]-5-(1,2,4-thiadiazol-3-yl)phenol (55 mg, 90% yield). MS m / z 382.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 10.99 (s, 1H), 10.39 (s, 1H), 9.16 (s, 1H), 9.10 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 4.83 - 4.67 (m, 2H), 3.59 - 3.35 (m, 3H), 3.18 - 3.07 (m, 1H), 2.77 - 2.63 (m, 1H), 1.04 (tt, J = 8.4, 3.9 Hz, 1H), 0.67 (ddp, J = 17.3, 8.5, 4.2 Hz, 2H), 0.56 (dq, J = 9.9, 4.7 Hz, 1H), 0.45 (dq, J = 8.8, 4.5 Hz, 1H).

[0154] Additional compounds described herein can be prepared using the procedures described in Example 1 above, by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as selected from the following: [Table 4-1] Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 [Table 4-19] [Table 4-20] [Table 4-21] [Table 4-22]

[0155] Example 2 Preparation of Compound 100 [ka] Step 1: To a stirred solution of 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(methylthio)-1,2,4-triazine (2.0 g, 6.7 mmol) in CHCl (35 mL), mCPBA (4.6 g, 20 mmol) was added in small portions, and the reaction was stirred at room temperature for 5 h. It was then quenched with saturated aqueous NaHCO. The organic layer was dried over MgSO and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of EtOAc / hexane (0 to 100% EtOAc) to afford 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(methylsulfonyl)-1,2,4-triazine (1.75 g, 79% yield) as a tan solid. 1 H NMR (500 MHz, CDCl3) δ: 9.40 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.27 (dd, J=8.5, 1.2 Hz, 1H), 5.32 (s, 2H), 3.56 (s, 3H), 3.52 (s, 3H). Step 2: To a stirred solution of 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(methylsulfonyl)-1,2,4-triazine (900 mg, 2.73 mmol) in ACN (10 mL) was added cis-2,6-dimethylpiperazine (400 mg, 3.5 mmol) and DIPEA (1.0 mL, 5.73 mmol). The reaction mixture was heated at 50 °C for 1 h until UPLC showed complete conversion to the desired product. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0 to 20% MeOH) to give 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(cis-3,5-dimethylpiperazin-1-yl)-1,2,4-triazine (993 mg, 70.5% yield) as a yellowish solid. MS m / z 364.2, 366.2 [M+H] + .

[0156] Step 3: 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(cis-3,5-dimethylpiperazin-1-yl)-1,2,4-triazine (650 mg, 1.79 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (780 mg, 2.68 mmol), KOAc (525 mg, 5.35 mmol), X Phos Pd in ​​dry dioxane (12 mL) A suspension of G4 (80 mg, 0.09 mmol) was sparged with argon for 10 min and then heated to 90 °C under an argon atmosphere for 2 h. After this, complete conversion to 3-(cis-3,5-dimethylpiperazin-1-yl)-6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-triazine was observed. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0–15% MeOH) to afford 3-(cis-3,5-dimethylpiperazin-1-yl)-6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-triazine (800 mg, 98% yield) as a brown crystalline solid. MS m / z 456.5 [M+H] + . Step 4: 3-(cis-3,5-dimethylpiperazin-1-yl)-6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-triazine (60 mg, 0.13 mmol), 6-bromo-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine (42.0 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.5 mg, 0.013 mmol) in dioxane (1 mL) A mixture of 1H HCl (1H, 2H, 3H) and aqueous potassium carbonate (0.2 mL, 2 M) was degassed with argon for 10 minutes and then heated to 90 °C for 1 hour. The mixture was cooled to room temperature and directly purified by silica gel column chromatography eluting with a gradient of 0 to 20% methanol in dichloromethane to give 6-[4-[3-[cis-3,5-dimethylpiperazin-1-yl]-1,2,4-triazin-6-yl]-3-(methoxymethoxy)phenyl]-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine (50 mg, 83% yield). MS m / z 462.4 [M+H] + .

[0157] Step 5: 6-[4-[3-[cis-3,5-dimethylpiperazin-1-yl]-1,2,4-triazin-6-yl]-3-(methoxymethoxy)phenyl]-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine (50 mg, 0.11 mmol) was dissolved in methanol (2 mL) and HCl (4 mol / L) in 1,4-dioxane (0.2 mL, 0.8 mmol) was added. The reaction was stirred at room temperature for 2 hours, concentrated, and purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (10-30% MeOH) to give 2-[3-[cis-3,5-dimethylpiperazin-1-yl]-1,2,4-triazin-6-yl]-5-(2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)phenol; dihydrochloride salt (30 mg, 47% yield) as a yellow solid. MS m / z 418.4 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 9.90 (s, 1H), 9.57 (s, 1H), 9.11 (s, 1H), 8.41 (d, J = 9.5 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 4.85 (d, J = 14.0 Hz, 2H), 3.35-3.38 (m, 2H), 3.19-3.23 (m, 2H), 3.17 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H).

[0158] Additional compounds described herein can be prepared using the procedure described in Example 2 above, by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12]

[0159] Example 3 Preparation of Compound 142 [ka] Step 1: To a solution of 6-(4-chloro-2-(methoxymethoxy)phenyl)-3-(methylsulfonyl)-1,2,4-triazine (1.0 g, 3.2 mmol) and (S)-1-Boc-2-isopropylpiperazine (873 mg, 3.81 mmol) in ACN (6 mL) was added DIPEA (1.1 mL, 6.4 mmol). The mixture was heated at 70 °C for 3 h until UPLC indicated complete consumption of the starting material. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0 to 15% MeOH) to afford tert-butyl (S)-4-(6-(4-chloro-2-(methoxymethoxy)phenyl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (1.02 g, 67% yield) as an off-white foam. MS m / z 478.4 [M+H] + . Step 2: A mixture of Pd2(dba)3 (10.0 mg, 0.01 mmol), Me4tButylXphos (10 mg, 0.01 mmol), 1,4-dioxane (0.2 mL), and toluene (0.8 mL) was purged with Ar and then heated at 120 °C for 10 min. The reaction was cooled to room temperature and then transferred to a vial containing tert-butyl (S)-4-(6-(4-chloro-2-(methoxymethoxy)phenyl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (100 mg, 0.21 mmol), K3PO4 (90 mg, 0.42 mmol), and imidazole (28 mg, 0.42 mmol). The combined mixture was then purged with Ar and then heated at 120 °C for 4 h. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0-10% MeOH) to give tert-butyl (S)-4-(6-(4-(1H-imidazol-1-yl)-2-(methoxymethoxy)phenyl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (76 mg, 71% yield) as a yellow solid. MS m / z 510.4 [M+H] + .

[0160] Step 3: To a solution of tert-butyl (S)-4-(6-(4-(1H-imidazol-1-yl)-2-(methoxymethoxy)phenyl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (76 mg, 0.15 mmol) in methanol (2 mL) was added HCl (4 mol / L) in 1,4-dioxane (0.2 mL, 0.8 mmol). The reaction was stirred at room temperature for 2 h, concentrated, and purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH / NHOH (10-30% MeOH / NHOH) to give (S)-5-(1H-imidazol-1-yl)-2-(3-(3-isopropylpiperazin-1-yl)-1,2,4-triazin-6-yl)phenol (30 mg, 47% yield). MS m / z 366.3 [M+H] + ;1 H NMR (500 MHz, methanol-d₄) δ: 9.14 (s, 1H), 8.22 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.22–7.17 (m, 3H), 5.08 (br d, J = 13.6 Hz, 1H), 5.02–4.93 (m, 1H), 3.59–3.45 (m, 2H), 3.31–3.23 (m, 2H), 3.18–3.11 (m, 1H), 2.11–2.02 (m, 1H), 1.19 (d, J = 6.9 Hz, 6H); 2H was not observed (NH and OH).

[0161] Additional compounds described herein can be prepared using the procedures described in Example 3 above, by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 6-1] [Table 6-2]

[0162] Example 4 Preparation of Compound 180 [ka] Step 1: To a flask containing the HCl salts of 3-(methylsulfonyl)-1,2,4-triazine (3.3 g, 21.0 mmol, 1.0 equiv.) and (S)-2-cyclopropylpiperazine (5.0 g, 25.1 mmol, 1.2 equiv.), DMF (100 mL) was added, followed by DIPEA (11 mL, 63.0 mmol, 3.0 equiv.), and stirred at 22 °C for 12 h. The solvent was then removed, and the crude oil was purified by silica gel chromatography using a gradient of 100% CHCl to 20% MeOH / CHCl to afford (S)-3-(3-cyclopropylpiperazin-1-yl)-1,2,4-triazine (4.1 g, 20.1 mmol, 96% yield) as a brown solid. MS m / z 206.3 [M+H] + . Step 2: To a flask containing (S)-3-(3-cyclopropylpiperazin-1-yl)-1,2,4-triazine (4.1 g, 20.1 mmol, 1.0 equiv.), BocO (6.0 g, 27.0 mmol, 1.3 equiv.), NEt (8.6 mL, 68.0 mmol, 3.0 equiv.), and CHCl (100 mL) were added. DMAP (0.5 g, 4.0 mmol, 0.2 equiv.) was then added, and the mixture was stirred at 22 °C for 12 h. The solvent was removed, and the crude oil was purified by silica gel chromatography using a gradient of 100% hexanes up to 50% EtOAc / hexanes to afford tert-butyl (S)-2-cyclopropyl-4-(1,2,4-triazin-3-yl)piperazine-1-carboxylate (3.4 g, 11.3 mmol, 55% yield) as an oil. MS m / z 306.3 [M+H] + .

[0163] Step 3: To a flask containing tert-butyl (S)-2-cyclopropyl-4-(1,2,4-triazin-3-yl)piperazine-1-carboxylate (3.4 g, 11.3 mmol, 1.0 equiv.), acetonitrile (90 mL) and water (30 mL) were added, and NBS (2.4 g, 13.0 mmol, 1.2 equiv.) was added, and the mixture was stirred at 22 °C for 12 h. The mixture was then diluted with EtOAc and water. The organic layer was separated, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography using a gradient of 100% hexanes up to 50% EtOAc / hexanes afforded tert-butyl (S)-4-(6-bromo-1,2,4-triazin-3-yl)-2-cyclopropylpiperazine-1-carboxylate (2.9 g, 7.5 mmol, 67% yield) as an orange oil. MS m / z 384.1, 386.1 [M+H] + . Step 4: To a flask containing tert-butyl (S)-4-(6-bromo-1,2,4-triazin-3-yl)-2-cyclopropylpiperazine-1-carboxylate (1.0 g, 2.6 mmol, 1.0 equiv.), tributyl(4-chloro-2-(methoxymethoxy)phenyl)stannane (1.4 g, 3.0 mmol, 1.2 equiv.), PdCl(PPh) (0.2 g, 0.3 mmol, 0.1 equiv.), and CuI (0.1 g, 0.5 mmol, 0.2 equiv.), dioxane (20 mL) was added and purged with Ar. The flask was stirred under Ar at 100 °C for 2 h. After cooling, the crude mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a gradient of 100% hexanes up to 50% EtOAc / hexanes to give tert-butyl (S)-4-(6-(5-chloro-3-(methoxymethoxy)pyridin-2-yl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (0.4 g, 0.9 mmol, 34% yield) as a yellow oil. MS m / z 477.1, 479.1 [M+H] + .

[0164] Step 5: To a vial containing tert-butyl (S)-4-(6-(5-chloro-3-(methoxymethoxy)pyridin-2-yl)-1,2,4-triazin-3-yl)-2-cyclopropylpiperazine-1-carboxylate (0.05 g, 0.1 mmol, 1.0 equiv.), (2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)boronic acid (0.04 g, 0.2 mmol, 1.5 equiv.), KCO (0.05 g, 0.4 mmol, 3.0 equiv.), XPhos Pd G (0.01 g, 0.01 mmol, 0.1 equiv.), dioxane (1 mL), and water (1 mL) were added. The mixture was stirred at 100 °C for 1 h. After cooling, the mixture was purified by silica gel chromatography using a gradient of 100% hexanes to 50% EtOAc / hexanes to give tert-butyl (S)-2-cyclopropyl-4-(6-(3-(methoxymethoxy)-5-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)pyridin-2-yl)-1,2,4-triazin-3-yl)piperazine-1-carboxylate (0.02 g, 0.03 mmol, 28% yield) as a yellow solid. MS m / z 475.4 [M+H] + . Step 6: To a vial containing tert-butyl (S)-2-cyclopropyl-4-(6-(3-(methoxymethoxy)-5-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)pyridin-2-yl)-1,2,4-triazin-3-yl)piperazine-1-carboxylate (0.02 g, 0.03 mmol, 1.0 equiv.) dissolved in MeOH (1 mL) was added 4.0 M HCl / dioxane. The mixture was stirred at 22 °C for 1 h. The mixture was then concentrated and purified by silica gel chromatography using a gradient of 100% CHCl up to 15% MeOH / CHCl to give the HCl salt of (S)-2-(3-(3-cyclopropylpiperazin-1-yl)-1,2,4-triazin-6-yl)-5-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)pyridin-3-ol (0.01 g, 0.02 mmol, 58% yield) as a white solid upon drying. MS m / z 431.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 12.02 (s, 1H), 9.45 (s, 1H), 9.25 (s, 1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.78 (s, 1H), 7.99 (s, 1H), 4.77 (d, J = 14.0 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 4.60 (s, 3H), 3.54-3.46 (m, 3H), 3.11 (t, J = 11.5 Hz, 1H), 2.70 (t, J = 9.0 Hz, 1H), 1.09-1.02 (m, 1H), 0.72-0.64 (m, 2H), 0.57-0.54 (m, 1H), 0.46-0.43 (m, 1H).

[0165] Additional compounds described herein can be prepared using the procedures described in Example 4 above, by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 7]

[0166] Example 5 Preparation of Compound 175 [ka] Step 1: To a solution of the HCl salts of 3-(methylsulfonyl)-1,2,4-triazine (3.0 g, 18.8 mmol) and (S)-2-isopropylpiperazine (4.5 g, 22.6 mmol) in DMF (100 mL) was added DIPEA (33 mL, 187 mmol). The reaction mixture was stirred at room temperature for 12 h until UPLC showed complete conversion. The solvent was removed, and the crude oil was purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0–20% MeOH) to give (S)-3-(3-isopropylpiperazin-1-yl)-1,2,4-triazine (1.8 g, 46% yield) as a brown solid. MS m / z 208.3 [M+H] + . Step 2: To a solution of (S)-3-(3-isopropylpiperazin-1-yl)-1,2,4-triazine (1.8 g, 8.7 mmol) in water (100 mL) and MeOH (25 mL), bromine (0.7 mL, 13.0 mmol) was added dropwise, and the mixture was stirred for 1 h. Saturated aqueous sodium thiosulfate solution was added, followed by water and EtOAc. The aqueous layer was then extracted three times with EtOAc. The organic layer was washed with water, brine, dried over MgSO, filtered, and concentrated. The crude oil was purified by silica gel column chromatography eluting with a gradient of CHCl / MeOH (0–10% MeOH) to afford (S)-6-bromo-3-(3-isopropylpiperazin-1-yl)-1,2,4-triazine (1.7 g, 69% yield) as a brown solid. MS m / z 286.1, 288.1 [M+H] + .

[0167] Step 3: To a flask containing (S)-6-bromo-3-(3-isopropylpiperazin-1-yl)-1,2,4-triazine (1.7 g, 6.0 mmol), EtN (2.5 mL, 18.0 mmol), and BocO (1.7 g, 7.8 mmol), CHCl (100 mL) was added. DMAP (0.2 g, 1.2 mmol) was added, and the mixture was stirred at room temperature for 12 h. The solvent was removed, and the crude oil was purified by silica gel chromatography eluting with a gradient of hexane / EtOAc (0 to 100% EtOAc) to afford tert-butyl (S)-4-(6-bromo-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (2.1 g, 90% yield) as a white solid. MS m / z 386.1, 388.1 [M+H] + . Step 4: To a vial containing tert-butyl (S)-4-(6-bromo-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (1.3 g, 3.4 mmol), tributyl(4-chloro-2-(methoxymethoxy)phenyl)stannane (1.9 g, 4.1 mmol), CuI (0.1 g, 0.7 mmol), and PdCl(PPh) (0.2 g, 0.3 mmol) were added, followed by dioxane (10 mL). The mixture was purged with Ar and stirred at 100 °C for 2 h. The crude mixture was filtered and concentrated. The residual oil was purified by silica gel column chromatography eluting with gradient hexane / EtOAc (0-100% EtOAc) to give tert-butyl (S)-4-(6-(5-chloro-3-(methoxymethoxy)pyridin-2-yl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (0.8 g, 51% yield) as a colorless oil. MS m / z 479.2, 481.2 [M+H] + .

[0168] Step 5: To a vial containing tBuXPhos (0.01 g, 0.01 mmol) and Pd2(dba)3 (0.01 g, 0.01 mmol), toluene (1 mL) was added, and the mixture was purged with Ar. The reaction was heated to 110 °C for 10 min and then cooled to room temperature. The catalyst solution was added to a vial containing tert-butyl (S)-4-(6-(5-chloro-3-(methoxymethoxy)pyridin-2-yl)-1,2,4-triazin-3-yl)-2-isopropylpiperazine-1-carboxylate (0.06 g, 0.1 mmol), triazole (0.01 g, 0.15 mmol), and K3PO4 (0.05 g, 0.2 mmol) in toluene (5 mL). The reaction mixture was stirred at 110 °C for 4 h. The crude mixture was filtered, concentrated, and purified by eluting with a gradient of hexane / EtOAc (0 to 50% EtOAc) to give tert-butyl (S)-2-isopropyl-4-(6-(3-(methoxymethoxy)-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-1,2,4-triazin-3-yl)piperazine-1-carboxylate (0.04 g, 72% yield) as a colorless oil. MS m / z 512.5 [M+H] + Step 6: To a vial containing tert-butyl (S)-2-isopropyl-4-(6-(3-(methoxymethoxy)-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-1,2,4-triazin-3-yl)piperazine-1-carboxylate (0.04 g, 0.08 mmol) and a stir bar, MeOH (2 mL) was added. 4.0 M HCl / dioxane (2 mL) was added, and the mixture was stirred at room temperature for 1 h. The solvent was removed, and the crude solid was purified by silica gel chromatography using a gradient of CHCl / MeOH (0 to 10% MeOH) to give (S)-2-(3-(3-isopropylpiperazin-1-yl)-1,2,4-triazin-6-yl)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-ol (0.02 g, 73% yield) as a white solid upon drying. MS m / z 368.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 9.26 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.24 (s, 2H), 7.93 (d, J = 2.0 Hz, 1H), 4.65 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 11.0 Hz, 1H), 3.05 (t, J = 11.0 Hz, 2H), 2.82 (t, J = 11.5 Hz, 1H), 2.70 (t, J = 10.5 Hz, 1H), 2.39-2.36 (m, 1H), 1.71-1.60 (m, 1H), 0.97 (d, J = 6.5 Hz, 6H); 2H was not observed (NH and OH).

[0169] Additional compounds described herein can be prepared using the procedure described in Example 5 above, by substituting the appropriate starting materials, suitable reagents, and reaction conditions to give compounds such as: [Table 8]

[0170] Biological Examples The following in vitro biological examples demonstrate the utility of the compounds herein for the treatment of Huntington's disease. To more fully explain and facilitate understanding of the present specification, the following non-limiting biological examples are provided to more fully illustrate the scope of the specification and should not be construed as specifically limiting its scope. Similar variations of the present specification that may be currently known or may be later developed and that would be within the scope of one skilled in the art are considered to be within the scope of the present specification and are claimed below.

[0171] The compound of formula (I) was tested using the Meso Scale Discovery (MSD) assay shown in International Application No. PCT / US2016 / 066042, filed December 11, 2016, which claims priority to U.S. Provisional Application No. US 62 / 265,652, filed December 10, 2015, the entire contents of which are incorporated herein by reference. The endogenous huntingtin protein assay used in Biological Example 1 was developed using the MSD electrochemiluminescence assay platform, which is based on an ELISA.

[0172] Biological Example 1: Endogenous huntingtin protein assay Meso Scale Discovery (MSD) 96- or 384-well plates were coated with MW1 (expanded polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 μg / mL in PBS (30 μL per well) overnight at 4°C. 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) for 4–5 hours at room temperature with end-over-end shaking, followed by three washes with wash buffer. Samples (25 μL) were transferred to antibody-coated MSD plates and incubated overnight at 4°C. After removing the lysate, the plates were washed three times with wash buffer, and 25 μL of #5656S (Cell signaling, rabbit monoclonal) secondary antibody (diluted in blocking buffer to 0.25 μg / mL in 0.05% Tween-20) was added to each well and incubated for 1 hour at room temperature with shaking. Following incubation with the secondary antibody, the wells were rinsed with wash buffer, after which 25 μL of goat anti-rabbit SULFO TAG secondary detection antibody (a required aspect of the MSD system) (diluted in blocking buffer to 0.25 μg / mL in 0.05% Tween-20) was added to each well and incubated for 1 hour at room temperature with shaking. After rinsing three times with wash buffer, 150 μL of Read Buffer T plus surfactant (MSD) was added to each empty well, and the plates were imaged on an SI 6000 Imager (MSD) according to the manufacturer's instructions provided with the 96- or 384-well plates. The IC values ​​obtained for the tested compounds were: 50 Values ​​(nM) are shown in Tables 2 and 3. [Table 9-1] [Table 9-2] [Table 9-3] [Table 10]

[0173] In Table 2, where compounds are reported as "inactive," the results are above the detection limit of the assay and the compound is considered inactive. All documents mentioned in this specification, whether or not the documents cited herein are specifically and individually indicated to be incorporated by reference, are incorporated into this application by reference for any and all purposes to the same extent as if each individual reference were fully set forth herein.

[0174] It will be understood by those skilled in the art that as the claimed subject matter is fully described herein, it may be practiced within a wide range of equivalents without affecting the scope of the subject matter or detailed embodiments described herein, and it is intended that the appended claims be construed to include all such equivalents. Another aspect of the present invention may be as follows. [1] A compound of formula (I) or a form thereof, TIFF0007799618000157.tif48164 During the ceremony, A, TIFF0007799618000158.tif176164 and any stereoisomer thereof; R 1 But hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R 2 are independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; C 1-4 Alkyl, C 3-6 Each example of cycloalkyl, phenyl, pyridonyl, and heterocyclyl may be selected from one or two R 3 may be substituted with a substituent, R 3 are independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, One or two independently selected R 4 optionally substituted phenyl; Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S; one R 4 Heteroaryl is a 9- or 10-membered bicyclic aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with a substituent or one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (heterocyclyl is an 8-10 membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and one or two independently selected R 4 and optionally substituted with a substituent; R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1; The compound of formula (I), or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof. [2] The compound according to [1] above, wherein B is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S. [3] The compound according to [1] above, wherein B is a 9- or 10-membered bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S. [4] The compound according to [1] above, wherein B is heterocyclyl, and the heterocyclyl is an 8- to 10-membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S. [5] B: One or two independently selected R 4 optionally substituted phenyl; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing at least one N atom, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing at least two N atoms); and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N atom). [6] B: One R 4 optionally substituted phenyl; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and if the ring structure contains 1 or 2 N, it may contain a second heteroatom selected from O and S, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and if the ring structure contains 2 or 3 N, it may contain a second heteroatom ring member selected from O or S, and one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and if the ring structure contains 2 or 3 N, optionally containing a second heteroatom ring member selected from O or S, and one or two independently selected R 4 The compound according to [1] above, wherein the compound is selected from the group consisting of: [7] B is heteroaryl or heterocyclyl, Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and one or two independently selected R 4 may be substituted with a substituent, Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and one or two independently selected R 4 The compound according to [1] above, which may be optionally substituted with a substituent. [8] B is heteroaryl, Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and one or two independently selected R 4 The compound according to [1] above, which may be substituted with a substituent. [9] A: TIFF0007799618000159.tif237164 The compound according to any one of [1] to [8] above, which may be selected from the group consisting of:

[10] A, TIFF0007799618000160.tif75164 The compound according to any one of [1] to [9] above, which can be selected from the group consisting of:

[11] A, TIFF0007799618000161.tif32164 The compound according to any one of [1] to

[10] above, which may be or any stereoisomer thereof.

[12] A: TIFF0007799618000162.tif32164 The compound according to any one of [1] to

[11] above, which may be either or any stereoisomer thereof. 〔13〕R 1 is hydrogen or C 1-4 The compound according to any one of the above [1] to

[12] , which is alkyl. 〔14〕R 1 The compound according to any one of the above [1] to

[13] , wherein is hydrogen.

[15] The compound according to any one of the above [1] to

[14] , wherein X is CH.

[16] The compound according to any one of the above [1] to

[14] , wherein X is N.

[17] The compound according to any one of the above [1] to

[14] , wherein X is CF.

[18] The compound according to any one of the above [1] to

[17] , wherein n is 0. 〔19〕R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 The compound according to any one of [1] to

[18] above, which may be substituted with a substituent. 〔20〕R 2 But unsubstituted C 1-4 Alkyl, unsubstituted halo-C 1-4 Alkyl, unsubstituted hydroxyl-C 1-4 The compound according to any one of the above [1] to

[19] , which is alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted phenyl, or unsubstituted oxetanyl.

[21] The compound according to any one of the above [1] to

[20] , wherein B is substituted. 〔22〕R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 The compound according to any one of the above [1] to

[21] , which is cycloalkyl or heterosilyl. 〔23〕R 4 But halogen, cyano, methyl, ethyl, ( 2 H 3 ) methyl, ( 2 H 3 ) ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of the above [1] to

[22] , wherein the aryl group is methoxy, methylamino, ethylamino, cyclopropyl, or azetidinyl. 〔24〕R 4 However, chloro, fluoro, cyano, methyl, ethyl, ( 2 H 3 ) Methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of [1] to

[23] above, wherein R is methoxy, methylamino, or cyclopropyl.

[25] The compound according to any one of the above [1] to

[20] , wherein B is unsubstituted.

[26] n is 0, X is C, R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 may be substituted with a substituent, R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterosilyl; R 1 is hydrogen or C 1-4 is alkyl, A, TIFF0007799618000163.tif206164 TIFF0007799618000164.tif47164 is selected from the group consisting of B, Unsubstituted or one R 4 phenyl substituted with a substituent; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and if the ring structure contains 2 or 3 N, it may contain a second heteroatom ring member selected from O or S, and one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and if the ring structure contains 2 or 3 N, optionally containing a second heteroatom ring member selected from O or S, and one or two independently selected R 4 The compound according to [1] above, wherein the compound is selected from the group consisting of:

[27] A compound comprising: TIFF0007799618000165.tif233164 TIFF0007799618000166.tif233164 TIFF0007799618000167.tif233164 TIFF0007799618000168.tif233164 TIFF0007799618000169.tif233164 TIFF0007799618000170.tif233164 TIFF0007799618000171.tif233164 TIFF0007799618000172.tif220164 TIFF0007799618000173.tif233164 TIFF0007799618000174.tif233164 TIFF0007799618000175.tif233164 TIFF0007799618000176.tif233164 TIFF0007799618000177.tif233164 TIFF0007799618000178.tif233164 TIFF0007799618000179.tif233164 TIFF0007799618000180.tif233164 TIFF0007799618000181.tif233164 TIFF0007799618000182.tif233164 TIFF0007799618000183.tif233164 TIFF0007799618000184.tif233164 and the form of said compound is selected from the group consisting of a salt, hydrate, solvate, and tautomeric form thereof.

[28] The form of the compound is TIFF0007799618000185.tif216168 TIFF0007799618000186.tif238168 TIFF0007799618000187.tif251168 TIFF0007799618000188.tif253168 TIFF0007799618000189.tif245168 TIFF0007799618000190.tif245165 TIFF0007799618000191.tif245166 TIFF0007799618000192.tif245169 TIFF0007799618000193.tif238166 TIFF0007799618000194.tif245167 TIFF0007799618000195.tif245167 TIFF0007799618000196.tif248168 TIFF0007799618000197.tif245165 TIFF0007799618000198.tif244169 TIFF0007799618000199.tif243168 TIFF0007799618000200.tif251168 TIFF0007799618000201.tif102166 The compound according to

[27] above, which is in the form of a salt selected from the group consisting of:

[29] A compound of formula (I) or a form thereof, TIFF0007799618000202.tif48164 During the ceremony, A, TIFF0007799618000203.tif176164 and any stereoisomer thereof; R 1 But hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R 2 are independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; and C 1-4 Alkyl, C 3-6 Each example of cycloalkyl, phenyl, pyridonyl, and heterocyclyl may be selected from one or two R 3 may be substituted with a substituent, R 3 are independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, One or two independently selected R 4 optionally substituted phenyl; and Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S; one R 4 and optionally substituted with a substituent; R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1; The compound of formula (I), or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

[30] The compound according to

[29] above, wherein B is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[31] B, One or two independently selected R 4 optionally substituted phenyl; and The compound according to

[29] , wherein the compound is selected from the group consisting of heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing at least one N atom).

[32] B, One R 4 optionally substituted phenyl; and Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and, if the ring structure contains 1 or 2 N, optionally containing a second heteroatom selected from O and S, and one R 4 The compound according to

[29] above, wherein the compound is selected from the group consisting of:

[33] B is heteroaryl, and heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and one R 4 The compound according to

[29] above, which may be substituted with a substituent.

[34] A, TIFF0007799618000204.tif237164 The compound according to any one of the above

[29] to

[33] , which may be selected from the group consisting of:

[35] A, TIFF0007799618000205.tif75164 The compound according to any one of the above

[29] to

[34] , which may be selected from the group consisting of:

[36] A, TIFF0007799618000206.tif32164 The compound according to any one of

[29] to

[35] above, which may be either or any stereoisomer thereof.

[37] A, TIFF0007799618000207.tif32164 The compound according to any one of

[29] to

[35] above, which may be either or any stereoisomer thereof. 〔38〕R 1 is hydrogen or C 1-4 The compound according to any one of the above

[29] to

[37] , which is alkyl. 〔39〕R 1 The compound according to any one of the above

[29] to

[38] , wherein is hydrogen.

[40] The compound according to any one of the above

[29] to

[39] , wherein X is CH.

[41] The compound according to any one of the above

[29] to

[39] , wherein X is N.

[42] The compound according to any one of the above

[29] to

[39] , wherein X is CF.

[43] The compound according to any one of the above

[29] to

[42] , wherein n is 0. 〔44〕R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 The compound according to any one of the above

[29] to

[43] , which may be substituted with a substituent. 〔45〕R 2 But unsubstituted C 1-4 Alkyl, unsubstituted halo-C 1-4 Alkyl, unsubstituted hydroxyl-C 1-4 The compound according to any one of the above

[29] to

[44] , which is alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted phenyl, or unsubstituted oxetanyl.

[46] The compound according to any one of the above

[29] to

[45] , wherein B is substituted. 〔47〕R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 The compound according to any one of the above

[29] to

[46] , which is cycloalkyl or heterosilyl. 〔48〕R 4 But halogen, cyano, methyl, ethyl, ( 2 H 3 ) methyl, ( 2 H 3 ) ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of the above

[29] to

[47] , wherein the aryl group is methoxy, methylamino, ethylamino, cyclopropyl, or azetidinyl. 〔49〕R 4 However, chloro, fluoro, cyano, methyl, ethyl, ( 2 H 3 ) Methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of the above

[29] to

[48] , wherein R is methoxy, methylamino, or cyclopropyl.

[50] The compound according to any one of the above

[29] to

[45] , wherein B is unsubstituted.

[51] n is 0, X is C, R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 may be substituted with a substituent, R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterosilyl; R 1 is hydrogen or C 1-4 is alkyl, A, TIFF0007799618000208.tif206164 TIFF0007799618000209.tif47164 is selected from the group consisting of B, Unsubstituted or one R 4 phenyl substituted with a substituent; and Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and one R 4 The compound according to

[29] above, wherein the compound is selected from the group consisting of:

[52] A compound of formula (I) or a form thereof, TIFF0007799618000210.tif48164 During the ceremony, A, TIFF0007799618000211.tif176164 and any stereoisomer thereof; R 1 But hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R 2 are independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 is selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, where heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing one or two heteroatom ring members selected from N, O, and S; and C 1-4 Alkyl, C 3-6 Each example of cycloalkyl, phenyl, pyridonyl, and heterocyclyl may be selected from one or two R 3 may be substituted with a substituent, R 3 are independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, Heteroaryl (heteroaryl is a 9- or 10-membered bicyclic aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (heterocyclyl is an 8-10 membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and one or two independently selected R 4 and optionally substituted with a substituent; R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered monocyclic carbon atom ring structure radical containing one or two heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w But halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -Amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; n is selected from the group consisting of 0 or 1; The compound of formula (I), or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

[53] The compound according to

[52] above, wherein B is heteroaryl, and the heteroaryl is a 9- or 10-membered bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S.

[54] The compound according to

[52] above, wherein B is heterocyclyl, and the heterocyclyl is an 8- to 10-membered bicyclic aromatic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S.

[55] B, Heteroaryl (heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing at least two N atoms); and The compound according to

[52] , wherein the heterocyclyl is selected from the group consisting of an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N atom.

[56] B, Heteroaryl (heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and one or two independently selected R 4 The compound according to

[52] above, wherein the compound is selected from the group consisting of:

[57] B is heteroaryl, wherein heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and one or two independently selected R 4 The compound according to

[52] above, which may be substituted with a substituent.

[58] A, TIFF0007799618000212.tif206164 TIFF0007799618000213.tif47164 The compound according to any one of the above

[52] to

[57] , which may be selected from the group consisting of:

[59] A, TIFF0007799618000214.tif75164 The compound according to any one of the above

[52] to

[58] , which may be selected from the group consisting of:

[60] A, TIFF0007799618000215.tif32164 The compound according to any one of

[52] to

[59] above, which may be either or any stereoisomer thereof.

[61] A, TIFF0007799618000216.tif32164 The compound according to any one of

[52] to

[59] above, which may be either or any stereoisomer thereof. 〔62〕R 1 is hydrogen or C 1-4 The compound according to any one of the above

[52] to

[61] , which is alkyl. 〔63〕R 1 The compound according to any one of the above

[52] to

[62] , wherein is hydrogen.

[64] The compound according to any one of the above

[52] to

[63] , wherein X is CH.

[65] The compound according to any one of the above

[52] to

[63] , wherein X is N.

[66] The compound according to any one of the above

[52] to

[63] , wherein X is N.

[67] The compound according to any one of the above

[52] to

[66] , wherein n is 0. 〔68〕R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 The compound according to any one of the above

[52] to

[67] , which may be substituted with a substituent. 〔69〕R 2 But unsubstituted C 1-4 Alkyl, unsubstituted halo-C 1-4 Alkyl, unsubstituted hydroxyl-C 1-4 The compound according to any one of the above

[52] to

[68] , which is alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted phenyl, or unsubstituted oxetanyl.

[70] The compound according to any one of the above

[52] to

[69] , wherein B is substituted. 〔71〕R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 The compound according to any one of the above

[52] to

[70] , which is cycloalkyl or heterosilyl. 〔72〕R 4 But halogen, cyano, methyl, ethyl, ( 2 H 3 ) methyl, ( 2 H 3 ) ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of the above

[52] to

[71] , wherein the aryl group is methoxy, methylamino, ethylamino, cyclopropyl, or azetidinyl. 〔73〕R4 However, chloro, fluoro, cyano, methyl, ethyl, ( 2 H 3 ) Methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, ( 2 H 3 ) The compound according to any one of the above

[52] to

[72] , wherein R is methoxy, methylamino, or cyclopropyl.

[74] The compound according to any one of the above

[52] to

[69] , wherein B is unsubstituted.

[75] n is 0, X is C, R 2 But C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, and one or two R 3 may be substituted with a substituent, R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterosilyl; R 1 is hydrogen or C 1-4 is alkyl, A, TIFF0007799618000217.tif206164 TIFF0007799618000218.tif47164 is selected from the group consisting of B, Heteroaryl (heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and if the ring structure contains 2 or 3 N, it may contain a second heteroatom ring member selected from O or S, and one or two independently selected R 4 optionally substituted with a substituent); and Heterocyclyl (heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and if the ring structure contains 2 or 3 N, optionally containing a second heteroatom ring member selected from O or S, and one or two independently selected R 4 The compound according to

[52] above, wherein the compound is selected from the group consisting of:

[76] A method for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of [1] to

[75] .

[77] Use of a compound according to any one of [1] to

[75] above for the treatment or alleviation of HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

[78] Use of a compound according to any one of [1] to

[75] above in the manufacture of a medicament for treating or alleviating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[79] A pharmaceutical composition comprising the compound according to any one of [1] to

[75] above, mixed with one or more pharmaceutically acceptable excipients.

Claims

1. A compound of formula (I) or a salt, hydrate, or tautomer thereof, 【Chemistry 1】 During the ceremony, A is, 【Chemistry 2】 and any stereoisomer thereof; R 1 But hydrogen, C 1-4 Alkyl, and C 3-6 cycloalkyl; R 2 are independently halogen, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxyl-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 selected from the group consisting of cycloalkyl, phenyl, pyridinyl, and heterocyclyl, wherein heterocyclyl is a 3- to 6-membered carbon atom ring structure radical containing 1 or 2 heteroatom ring members selected from N, O, and S; C 1-4 Alkyl, C 3-6 Each example of cycloalkyl, phenyl, pyridinyl, and heterocyclyl is selected from the group consisting of one or two R 3 may be substituted with a substituent, R 3 are independently selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl; B, one or two independently selected R 4 phenyl which may be substituted; Heteroaryl (heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S; one R 4 Heteroaryl is a 9- or 10-membered bicyclic aromatic carbon atom ring structure radical having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and is optionally substituted with a substituent, or one or two independently selected R 4 optionally substituted with a substituent group; and Heterocyclyl (heterocyclyl is an 8-10 membered bicyclic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and one or two independently selected R 4 and optionally substituted with a substituent; R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 - Amino, C 3-6 is selected from the group consisting of cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3-6 membered monocyclic carbon atom ring structure radical containing 1 or 2 heteroatom ring members independently selected from N, O, or S; X is selected from the group consisting of CH, CF, and N; R w halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 - Amino, C 1-4 Alkoxy and halo-C 1-4 alkoxy; The compound of formula (I) above, or a salt, hydrate, or tautomer thereof, wherein n is selected from the group consisting of 0 or 1.

2. 2. The compound of claim 1, wherein B is heteroaryl, wherein heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 heteroatoms selected from N, O, and S.

3. 2. The compound of claim 1, wherein B is heteroaryl, wherein the heteroaryl is a 9- or 10-membered bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S.

4. 2. The compound of claim 1, wherein B is heterocyclyl, wherein heterocyclyl is an 8-10 membered bicyclic carbon atom ring structure radical containing 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S.

5. B, one or two independently selected R 4 phenyl which may be substituted; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing at least one N atom, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing at least two N atoms; and Heterocyclyl 10. The compound of claim 1, wherein the heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing at least one N atom.

6. B, One R 4 phenyl which may be substituted; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and if the ring structure contains 1 or 2 N, it may contain a second heteroatom selected from O and S, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and if the ring structure contains 2 or 3 N, it may contain a second heteroatom ring member selected from O or S, and one or two independently selected R 4 optionally substituted with a substituent group; and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and if the ring structure contains 2 or 3 N, optionally containing a second heteroatom ring member selected from O or S, and one or two independently selected R 4 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

7. B is heteroaryl or heterocyclyl; Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and one or two independently selected R 4 may be substituted with a substituent, Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N and one or two independently selected R 4 The compound of claim 1, optionally substituted with a substituent.

8. B is heteroaryl; Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms and one or two independently selected R 4 The compound according to claim 1, which may be substituted with a substituent.

9. A is, 【Transformation 3】 The compound according to any one of claims 1 to 8, which may be selected from the group consisting of:

10. The compound of any one of claims 1 to 9, wherein X is CH.

11. The compound according to any one of claims 1 to 9, wherein X is N.

12. R 2 But C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 The compound according to any one of claims 1 to 11, which may be substituted with a substituent.

13. R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 The compound according to any one of claims 1 to 12, which is cycloalkyl and heterocyclyl.

14. n is 0, X is CH; R 2 But C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxyl-C 1-4 alkyl, cyclopropyl, cyclobutyl, phenyl, or oxetanyl, each of which is selected from one or two R 3 may be substituted with a substituent, R 4 But halogen, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deuterium-C 1-4 Alkoxy, C 1-4 Alkyl-amino, C 3-6 selected from the group consisting of cycloalkyl, and heterocyclyl; R 1 is hydrogen or C 1-4 is alkyl, A is, 【Chemistry 7-1】 【Chemistry 7-2】 is selected from the group consisting of B, Unsubstituted or one R 4 phenyl substituted with a substituent; Heteroaryl (Heteroaryl is a 5- or 6-membered monocyclic aromatic carbon atom ring structure radical containing 1, 2, or 3 N atoms and optionally, if the ring structure contains 1 or 2 N, a second heteroatom selected from O and S, and one R 4 may be substituted with a substituent, or Heteroaryl is a 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N atoms, and if the ring structure contains 2 or 3 N, it may contain a second heteroatom ring member selected from O or S, and one or two independently selected R 4 optionally substituted with a substituent group; and Heterocyclyl (Heterocyclyl is an 8- or 9-membered bicyclic carbon atom ring structure radical containing 2, 3, or 4 N, and if the ring structure contains 2 or 3 N, optionally containing a second heteroatom ring member selected from O or S, and one or two independently selected R 4 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

15. 1. A compound, or a salt, hydrate, solvate, or tautomer thereof, comprising: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 or a salt, hydrate, solvate, or tautomer thereof, selected from the group consisting of:

16. The compound is Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 16. The compound of claim 15, or a salt, hydrate, solvate, or tautomer thereof, selected from the group consisting of:

17. A pharmaceutical composition for use in a method for treating or ameliorating Huntington's disease (HD) in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound described in any of claims 1 to 16.

Images