NZ743147B2 - Methods for treating huntington's disease - Google Patents

Methods for treating huntington's disease Download PDF

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Publication number
NZ743147B2
NZ743147B2 NZ743147A NZ74314716A NZ743147B2 NZ 743147 B2 NZ743147 B2 NZ 743147B2 NZ 743147 A NZ743147 A NZ 743147A NZ 74314716 A NZ74314716 A NZ 74314716A NZ 743147 B2 NZ743147 B2 NZ 743147B2
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NZ
New Zealand
Prior art keywords
methyl
amino
tetramethylpiperidinyl
pyridazinyl
phenol
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NZ743147A
Other versions
NZ743147A (en
Inventor
Suresh Babu
Anuradha Bhattacharyya
Seongwoo Hwang
Minakshi Jani
Young Choon Moon
Nadiya Sydorenko
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Ptc Therapeutics Inc
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Application filed by Ptc Therapeutics Inc filed Critical Ptc Therapeutics Inc
Priority claimed from PCT/US2016/066042 external-priority patent/WO2017100726A1/en
Publication of NZ743147A publication Critical patent/NZ743147A/en
Publication of NZ743147B2 publication Critical patent/NZ743147B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted monocyclic heteroaryl compounds of Formula (Ia), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. ounds of Formula (Ia), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

Description

METHODS FOR TREATING HUNTINGTON’S DISEASE The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such nds, forms, or compositions thereof for treating or ameliorating Huntington’s e. In particular, the t description relates to substituted monocyclic heteroaryl nds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington’s disease.
BACKGROUND gton’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary nts, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in tions of n European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the "mutant" huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly—glutamine (polyQ) stretch, also known as a "CAG repeat" sequence. There are no current small molecule ies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.
All other documents referred to herein are incorporated by nce into the present application as though fully set forth herein.
SUMMARY The present description relates to methods for ng or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I): n W, X, A and B are as defined herein, or forms and compositions thereof.
In particular, the present description relates to a use of a compound of Formula (I) or a form or composition thereof in a method for treating or ameliorating HD in a subject in need thereof comprising, administering an effective amount of the compound or a form or composition thereof, to the t.
The present description r relates to the use of a compound of Formula (I) or a form thereof in combination with agents having additive or synergistic activity, thus providing a ation product for the treatment of HD.
DETAILED DESCRIPTION The present description relates to a method or use of a compound 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, wherein W is CH=CH or S; X is CH2, CH(C1-4alkyl), C(C1-4alkyl)2, CH=CH, O, NR5, or a bond; A is aryl, heteroaryl, heterocyclyl, or C9-10cycloalkyl, wherein aryl is selected from phenyl and naphthyl, each optionally substituted with 1, 2, 3, or 4 tuents each selected from R1, wherein heteroaryl is a monocyclic, bicyclic or polycyclic ic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural ity, with one or more heteroatoms, such as O, S, or N atom, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R1, wherein heterocyclyl is a saturated or partially unsaturated clic, bicyclic or tricyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 tuents each selected from R2, and wherein C9-10cycloalkyl is a saturated or partially unsaturated ic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; B is heterocyclyl, wherein heterocyclyl is a saturated or partially rated monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3 atom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R4; R1 is halogen, hydroxyl, cyano, C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, C1-4alkyl-amino-carbonyl, (C1-4alkyl)2-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, (C1-4alkyl)2-aminocarbonyl-C1-4alkyl , C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, hydroxyl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, yl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, C1-4alkoxy- C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, koxy-carbonylamino-C1-4alkoxy , C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, aryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, heterocyclyl-C1-4alkoxy, , or -C1-4alkoxy, wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms such as an O, S, or N atom, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring s selected from N, O, and S, and n each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R3; R2 is halogen, hydroxyl, cyano, oxo, hydroxyl—imino, kyl, halo—C1_4alkyl, amino, C1_4alkyl—amino, (C1_4alkyl)2—amino, amino—C1_4alkyl, C1_4alkyl-amino—C14alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, hydroxyl-C1_4alkyl, Claalkoxy, C1_4all An embodiment of the present ption further relates to a method or use of a nd 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) selected from a compound of Formula (Ia) and Formula (Ib): (Ia) (Ib) or a form thereof, wherein X is CH2, CH(C1-4alkyl), C(C1-4alkyl)2, CH=CH, O, NR5, or a bond; A is aryl, heteroaryl, heterocyclyl, or C9-10cycloalkyl, wherein aryl is selected from phenyl and yl, each optionally substituted with 1, 2, 3, or 4 substituents each selected from R1, wherein heteroaryl is a clic, bicyclic or polycyclic aromatic carbon atom ring ure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S, or N atom, each ally substituted with 1, 2, 3, 4, or 5 substituents each selected from R1, wherein cyclyl is a saturated or partially unsaturated monocyclic, bicyclic or lic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2, and wherein C9-10cycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; B is heterocyclyl, wherein heterocyclyl is a saturated or partially rated monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3 heteroatom ring s independently ed from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R4; R1 is halogen, hydroxyl, cyano, C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, C1-4alkyl-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, hydroxyl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo- C1-4alkoxy, amino-C1-4alkoxy, hydroxyl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino- C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, C1-4alkoxy- C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, C1-4alkoxy-carbonyl-amino- C1-4alkoxy, C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, aryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, heterocyclyl-C1-4alkoxy, phenyl, or -C1-4alkoxy, wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure l in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms such as an O, S, or N atom, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R3; R2 is halogen, hydroxyl, cyano, oxo, yl-imino, kyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, amino-carbonyl, hydroxyl-C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, kenyl, C3-7cycloalkyl, or heterocyclyl-C1-4alkyl; R3 is halogen, hydroxyl, nitro, oxo, yl-imino, C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, kyl-amino-carbonyl, kyl-amino-carbonyl-C1-4alkyl, C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, hydroxyl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, hydroxyl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkylcarbonyl-amino-C1-4alkoxy , C1-4alkoxy-C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonylamino , koxy-carbonyl-amino-C1-4alkoxy, C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, heteroaryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, phenyl, or phenyl-C1-4alkoxy; R4 is independently selected from halogen, C1_4alkyl, hydroxyl—C1_4alkyl, amino, Claalkyl— amino, (Claalkylh—amino or hydroxyl—C1_4alkyl—amino; and R5 is hydrogen, CMalkyl, or hydroxyl-C1_4alkyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and er form thereof. r embodiment of the present description further relates to methods 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) selected from a nd of Formula (Ia) and Formula (lb): N=N B (Ia) (Ib) or a form thereof, n X is O, NH, N(CH3) or a bond; A is aryl, heteroaryl or heterocyclyl, wherein aryl is ed from the group consisting of z 2; R1a// ,R1a/R/1b// R////1a ’and R1b a1 a2 a3 wherein heteroaryl is selected from the group consisting of a4 a5 a6 a7 R1a/ Another aspect of the present description relates to a compound of Formula (I) selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or a (Ib1): (Ia11), (Ia15), (Ia18), (Ib1) or a form thereof, wherein (when present), X is selected from O, NR5, or a bond; A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy, wherein phenyl and phenoxy are each optionally tuted with 1, 2 or 3 substituents each selected from R1a, wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from R1a, B is selected from 1H-pyrazolyl, piperidinyl, 6-tetrahydropyridinyl, (1R,5S) azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octenyl, 2,6-diazaspiro[3.4]octyl or 2,7- diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2 substituents each selected from R4a; R1a is ed from halogen, hydroxyl, C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkoxy, or aryl, wherein heteroaryl is a monocyclic, bicyclic or clic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been ed, where allowed by structural stability, with one or more heteroatoms such as an O, S, or N atom, optionally substituted with 1 or 2 substituents each selected from R3a; R3a is selected from nitro or C1-4alkyl; and, R4a is C1-4alkyl; R5a is en, C1-4alkyl, or hydroxyl-C1-4alkyl; wherein a form of the compound is ed from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, reomer, stereoisomer, polymorph and tautomer form thereof.
Another aspect of the present description relates to a compound of Formula (I) selected from a nd of Formula (Ial 1), Formula (IalS), a (Ial8) or Formula (Ibl): or a form thereof, wherein (when present), Rla is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy or 1H— pyrazolyl or lH—imidazol—l—yl, n lH—pyrazolyl is optionally substituted with l or 2 substituents each selected from Rga; Rga is selected from nitro or methyl or amino; and, R421 is methyl or ethyl; R521 is hydrogen or ; wherein a form of the compound is selected from the group consisting of a prodrug, salt, e, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the method of the present description includes the use of a nd of Formula (Ia) or a form thereof selected from a compound of Formula (Ial) or a form thereof, wherein substituents Rla, Rlb, and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, "—— H indicates that one or more R13, Rlb, and X substituents are not present: l—CHZCHzCHz, 2—OH N(CH3) Another embodiment of the method of the t description includes the use of a compound of a (Ia) or a form thereof selected from a compound of Formula (Ia2) or a form thereof, wherein substituents Rla, Rlb, and R431, when present, are indicated in the table below with multiple substituents separated by a comma; an H H —— indicates that one or more Rla,' Rlb, and R421 substituents are not present: N,_.O 2"5" \] O: NNu—c ca 225 3—(l-CH3-1H-imidazoly—l) 7—OH 3—(1H—imidazol— l—y—l) 7—OH N \l 3—OH 7—OH N GO 3 CH2CH3 7OH NN 3 CH(CH3)2 7OH 2 CH3, 4—OCH3, 2—CH3, 4—(pyrrolidin— 1——yl) 0ua. R1a Rlb 2—CH3, No.)A 4-(m0rpholiny1) 7-OH 2—CH3, Nmon 2—CH3, Nuex 2—CH3, 237 4—(1—CH3—1H—pyrazol—4—y1) 7—OH 240 3—(tetrahydr0 2H pyran 4 yl) 7—OH N4;\9 4—OCH3 7 OH 2—CH3, N01e 4—(azetidin— 1—y1) 7—OH 2—CH3, 251 4-CN 7-OH 2—CH3, 4—Cyclopr0pyl 7—OH 2—CH3, 4—(3,6—dihydr0—2H—pyran—4—yl) 7—OH 2—CH3, 4—(tetrahydr0—2H—pyran—4—yl) 7—OH 2—CH3, N55 tan—3—yl) 7—OH NNN09%5030! 2—CH3, 296 4—C1 7—OH Another embodiment of the method of the present description includes the use of a compound of a (Ia) or a form thereof ed from a compound of Formula (Ia3) or a form thereof, wherein substituents Rla, Rlb and X, when present, are indicated in the table below with multiple substituents ted by a comma; an —— indicates that one or more R1 2,, R113 and X substituents are not present: N(CH3) 7-OH N(CH3) l—CN 7-OH N(CH3) l-CH3 7-OH N(CH3) l—CN, 3—CH3 7—OH N(CH3) 3—(OCH2—phenyl) —— N(CH3) Another ment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia4) or a form thereof, wherein substituents X, Rla, Rlb and R421, when present, are indicated in the table below; and, "——" indicates that one or more X, Rla, R113 and R4,, substituents are not present: R13 2"5" X E" 14—||I I N(CH3 - m» 211— C."OI N(CH3) CH3 212— 6—OH N(CH3) 215 6—OH N(CH3) 216 6—OH N(CH3) 217 6—OH N(CH3) 264 6—OH N(CH3) 273 6—OH N(CH3) 274 6—OH N(CH3) 276 6—OH N(CH3 283 6-OH N(CH3 285 6—OH N(CH3) 286 N(CH3 287 6—OH N(CH3 288 6—OH N(CH3) 289 6—OH N(CH3) Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a nd of a (IaS) or a form thereof, wherein substituents Rla and Rlb, when present, are indicated in the table below with multiple substituents separated by a comma; and, "—— H indicates that one or more R1 a and Rlb substituents are not present: r embodiment of the method of the present description includes the use of a compound of a (Ia) or a form thereof selected from a nd of Formula (Ia6) or a form thereof, wherein substituents Rla, when present, are indicated in the table below; and, "--" indicates that one or more R1a substituents are not present: Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia7) or a form thereof, wherein substituents Rla, when present, are indicated in the table below; and, "——" indicates that one or more Rla substituents are not present: Another embodiment of the method of the present ption includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia8) or a form thereof, wherein substituents Rla and B, when present, are indicated in the table below; and, H__H tes that one or more Rla and B substituents are not present: -_6—((3aR,6aS)5CH3—hexahydropyrrolo[3,4-c]pyrrol--2(1H)yl) Another ment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia9) or a form thereof, wherein substituents Rla and B, when present, are indicated in the table below; and, "——" indicates that one or more Rla and B substituents are not present: Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (IalO) or a form thereof, wherein tuents Rla and B, when present, are indicated in the table below; and, H H —— indicates that one or more Rla and B substituents are not present: -——- piperazin—l—yl 271 1,2,3,6-tetrahydropyridinyl r embodiment of the method of the t description includes the use of a compound of Formula (Ia) or a form thereof selected from a nd of Formula (Ial l) or a form thereof, wherein substituents A, X and R431, when present, are indicated in the table below; and, "——" indicates that one or more A, X and R421 substituents are not present: \ /N N A N \R4a (Ial 1) de A X R43 2 benzo[b]thiophen—2—yl N(CH3) —- 4 5—CN—benzo[b]thiophen—2—yl N(CH3) —- quinolin—3—yl NH —— 6 benzo[b]thiophen—2—yl O —— 9 benzo[b]thiophen—2—yl NH —— 16 o[ l ,2—a]pyridin—6—yl N(CH3) -— 17 6—phenyl—pyridin—3—yl N(CH3) —— 18 6—(lH—pyrrol—l—yl)—pyridin—3—yl N(CH3) —— 19 6—(lH—pyrazol—1—yl)—pyridin—3—yl N(CH3) —— de A quinoxalin—Z—yl N(CH3) 21 quinolinyl N(CH3) 22 phthalazin—6—y1 N(CH3) 23 c] [1,2,5]0xadiazol—5—y1 NH 24 benzo[d]thiazol—5—y1 NH 2—CH3—benzo[d]oxazol—6—y1 NH 2—(4—CN—phen01) N(CH3) 32 2—(4—CF3—phen01) N(CH3) 33 6—(2—F—phen01) N(CH3) 34 2— [3 ,5-(OCH3)2—phenol] N(CH3) 2— [4,5—(OCH3)2—phenol] N(CH3) 37 2—(4,5—F2—phen01) N(CH3) 41 benzo[b]thiopheny1 NH 53 2—[4-(1H—pyrazol—1—y1)—phenol] N(CH3) 115 H—5—( 1 H—pyrazol—4—y1)—phenol] N(CH3) 116 2—[3—OCH3—5—( 1H—pyrazol—4—y1)—phenol] N(CH3) 117 2—[5—(1H—pyrazol—4—y1)—3 —OCF3—phen01] NH 118 2—[5—(1—CH3—1H—pyrazol—4—y1)—3—OCF3—phen01] N(CH3) 119 2—[5—(1H—pyrazol—4—y1)—3 —OCF3—phen01] N(CH3) 120 2—[5-(1—CH3—pyridin—2(1H)—0ne)—3—OCF3—phenol] N(CH3) 121 2—[3—OCH3—5—(1—CH3—1H—pyrazol—4—y1)—phenol] N(CH3) 2—[3—OCH3—5—(5,6,7,8—tetrahydroimidazo—[1,2— 122 a]pyridin—3—y1)—phenol] N(CH3) 123 CH3(pyridiny1)-phenol] N(CH3) 2—[3—OCH3(1-cyclopenty1—1H—pyrazol—4—y1)— 124 phenol] N(CH3) 125 2—[5-(3—OCH3—pheny1)—3—OCH3—phenol] N(CH3) 126 2—[3—benzyloxy—5—(5—CH3—0xazol—Z—y1)—phen01] N(CH3) 127 CH2CH3—5—(5—CH3—0xazol—Z—y1)—phen01] N(CH3) 2—[3—(OCHz—cyclopropyl)—5—(5—CH3—0xazol—2—y1)— 128 phenol] N(CH3) 129 5—(2—CH3—1H—benzo[d]imidazol—6—ol) N(CH3) 134 2—[4—(1H—pyrazol—4—y1)—phenol] N(CH3) 2—[4—(4,5,6,7—tetrahydr0pyrazolo[1,5—a]pyridin—3— 135 y1)—phenol] N(CH3) de A 2—[4—(4,5,6,7—tetrahydr0pyrazolo[1,5—a]pyrazin—3— 136 y1)-phenol] N(CH3) 137 2-[4-(1H-indolyl)-phenol] N(CH3) 138 2—[4—(cyclopent— 1—en—1—y1)—phenol] N(CH3) 139 1H—pyrazol—3—y1)—phenol] N(CH3) 140 2— [4—(2—OH—pyridin—4—yl)—phenol] N(CH3) 141 2[4—(1—CH3—pyridin—2(1H)—0ne)—phenol] 142 2— [4—(2—OH—pyridin—4—yl)—phenol] 144 2— [4—C1—5—(1H—pyrazol—4—yl)—phenol] N(CH3) 145 2—[4—F—5—( 1H—pyrazol—4—y1)—phenol] N(CH3) 146 2— [5—F—4—( 1 H—imidazol—4—y1)—phenol] N(CH3) 147 2—[5—F—4—(1H—pyraz01—4—y1)—phenol] N(CH3) 148 2-[5-F-( 1 H-pyrazol-S-y1)-phenol] N(CH3) 149 -oxo-2,3-dihydro-1H—indeny1 N(CH3) 150 6—(1,4—dihydroindeno[1,2—C]—1H—pyrazol—7—ol) N(CH3) 151 6—OH— 1—OH—imino—2,3—dihydr0— 1H—inden—5 —y1 N(CH3) 152 6—OH—1—OH—2,3—dihydro— 1H—inden—5—y1 N(CH3) 153 H2—8H—inden0[1,2—d]thiazol—5—01) N(CH3) 154 9—(5,6—dihydr0imidazo[5,1—a]is0quin01in—8—01) N(CH3) 2—{4—[C(O)NHCH2—(1—CH3—1H—pyrazol—4—yl)]— 155 phenol} N(CH3) 156 2—[4—(4—CH20H— 1H—pyrazol— 1 —y1)—phen01] N(CH3) 158 3—(OCHz—phenyl)—isoquinolin—6—y1 N(CH3) 160 2-[3-F(2-OCHg-pyridiny1)-phenol] N(CH3) 161 4-[ 1-(4-pyridin-2(1H)-one)FOH-pheny1] N(CH3) 4—{ 1-CH3—pyridin-2(1H)-one)]—3-F-5—OH— 162 phenyl} N(CH3) 4—{ 1—[5—(1—CH3—pyridin—2(1H)—0ne)]—3—F—5—OH— 163 phenyl} N(CH3) 164 2—[3—F—5—( 1H—pyrazol—4—y1)—phenol] 165 2-(5—C1—3—F—phen01) N(CH3) 166 2—[3—F—5—( 1H—pyrazol—4—y1)—phenol] N(CH3) 167 2—[3—F—5—(1—CH3—1H—pyrazol—4—y1)—phenol] N(CH3) 219 8—(quin01in—7—01) N(CH3) 230 6—(7—OH—quinolin—2( 1H)—one) N(CH3) de A X R43 231 6—(7—OH— 1 uinolin—2( 1H)—one) N(CH3) —— 245 7-(6-OHCH3-quinolin-4(1H)-one) N(CH3) -- 257 6-(7-OH-quinazolin—4(1H)—one) N(CH3) —— 259 6—(7—OH— l—CH3—3,4—dihydroquinolin—2(lH)—one) N(CH3) —— 7—OH— l ,3-(CH3)2-quinazolinyl-2,4(1H,3H)- 277 dione N(CH3) —— 278 6-OH—benzo[d]oxazol—5—yl—2(3H)—one N(CH3) —— 279 2—CH3OH-2H-indazolyl N(CH3) -- 280 l-CH3OH- lH-indazol-S-yl N(CH3) -- 281 7-(6—OH—2—CH3—isoquinolin— l(2H)—one) N(CH3) —— 282 7—(6—OH—2—CH2CH3—isoquinolin— l(2H)—one) O —— Another ment of the present description includes a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ial 1) or a form thereof, wherein substituents A, X and R431, when present, are indicated in the table below; and, "—— indicates that one or more A, X and R4a tuents are not present: \ .N NH II'5a.420 2—OCH3—4—(4—N02—1H—pyrazol—1—yl)phenyl N(CH3) 428 2,5-F2( 1H—pyrazolyl)phenyl N(CH3) 430 —4—( lH—pyrazol—4—yl)phenyl N(CH3) 431 2,5—F2—4—( lH—pyrazol—4—yl)phenyl 434 —4—( lH—pyrazol—4—yl)phenyl 435 4—( lH—pyrazol—4—yl)phenyl 437 2—F—4—( lH—pyrazol—4—yl)phenyl 438 4—( 1 —CH3— lH—pyrazol—4—yl)thiophen—2—yl 2—F—4—OH—phenyl N(CH3) -[3 5-(CH3)2-1H-pyrazoly1]phenyl 454 2—OCH3—4—(4—N02— 1H—pyrazol— 1—y1)pheny1 2,4—(OH)2—pheny1 456 2—C1—4—(1H—pyrazol—4—yl)pheny1 N(CH3) 457 5—amin0—2—(1H—pyrazol—4—y1)pyrimidin—4—y1 458 2,6—F2—4—( 1H—pyrazol—4—y1)pheny1 464 2-(CHF2)(1H-pyraz01—4-yl)phenyl 2-(CHF2)—4—(1H—pyrazol—4—y1)phenyl Another ment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof ed from a nd of Formula (Ial 1) or a form f, wherein substituents A, X and R421, when present, are indicated in the table below; and, "——" indicates that one or more A, X and R421 substituents are not present: \ .N NH A N II'5a.420 2—OCH3—4—(4—N02— lH—pyrazol— l—yl)phenyl N(CH3) 428 2,5—F2—4—( 1H—pyrazol—4—yl)phenyl N(CH3) 430 2,3-F2(1H—pyrazolyl)phenyl N(CH3) 431 2,5—F2—4—( lH—pyrazol—4—yl)phenyl 434 2—OCH3—4—( lH—pyrazol—4—yl)phenyl 435 4—( lH—pyrazol—4—yl)phenyl 437 2—F—4—( lH—pyrazol—4—yl)phenyl 438 4—( 1 —CH3— lH—pyrazol—4—yl)thiophen—2—yl 2—F—4—OH—phenyl 2-CH3-2H-indazolyl 2-CH3—2H-indazol—5—yl 4—Cl—2—OCH3—phenyl 2—CH3—pyrazolo[ l ,5—a]pyridin—3—yl imidazo[ l ,2—a]pyridin—6—yl 2—OCH3—4—( lH—pyrazol— l —yl)phenyl —( lH—pyrazol—4—yl)thiophen—2—yl —( 1 —CH3— lH—pyrazol—4—yl)thiophen—2—yl 450 4—( lH—pyrazol—4—yl)thiophen—2—yl 451 2—OH—4— [3 ,5—(CH3)2— 1H—pyrazol—4—yl]phenyl Cd A 452 2—F—4—(1H—pyrazol 4 yl)phenyl 453 2-OCH3-4 OH phenyl 454 2-OCH3—4—(4—N02— lH—pyrazol— l—yl)phenyl 455 2,4—(OH)2—phenyl 456 2—Cl—4—(lH—pyrazol—4—yl)phenyl 457 5—amino—2—( lH—pyrazol—4—yl)pyrimidin—4—yl 458 —4—( lH—pyrazol—4—yl)phenyl 2—(CHF2)—4—(lH—pyrazol—4—yl)phenyl 465 2—(CHF2)—4—(1H—pyrazol—4—yl)phenyl Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof ed from a compound of Formula (Ial2) or a form thereof, wherein substituents X, Rla and B, when present, are ted in the table below; H H an —— indicates that one or more X, Rla and B substituents are not present: 9a. m" >4 U! NH azetidin—3—yl as OE piperazin— l—yl %m —— 1,2,3 ,6—tetrahydropyridin—4—yl 1,2,3 ,6—tetrahydropyridin—4—yl 6—tetramethyl—( 1 ,2,3,6— as 000III tetrahydropyridin—4—yl) l—CHg—(l,2,3,6—tetrahydropyridin—4—yl) piperidin—4—yl m CH2 piperidin—4—yl Another embodiment of the method of the t description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia13) or a form thereof, wherein substituents X, Rla and R421, when present, are indicated in the table below; and, "—— indicates that one or more X, Rla and R421 substituents are not t: X R13 --—_ "II—— -_—H_— m m77:77(CH3) 103 7 m227 -Z«:H» r embodiment of the method of the present description includes the use of a compound of a (Ia) or a form thereof selected from a compound of Formula (Ia14) or a form thereof, wherein substituents X and B, when present, are indicated in the table below; and, H H —— indicates that one or more X and B substituents are not present: OM U! piperidin—4—yl -U]OK (ZS ,4R,6R)-2,6-(CH3)2-Piperidinyl 2,6—(CH3)2—piperidin—4—yl pyrrolidin—3—yl 2—CH3—piperidin—4—yl m8m.oEoooo lH—pyrrolidin—3—yl 3—F—piperidin—4—yl z. piperazin— l—yl azetidin—3—yl m 3 ,5—(CH3)2—piperazin— l—yl u 7—CH3—2,7—diazaspiro[4.4]non-2—yl [1,4]diazepanyl 4-CH2CHzOH-piperazinyl 2,7—diazaspiro[3 .5]non—7—yl 2,7—diazaspiro[3 .5]non—7—yl 3—CHZOH—piperazin— l—yl azaspiro[4.4]non—7—yl 4—CH3—piperidin— l—yl 3—N(CH3)2—piperidin— l —yl 3 ,3—(CH3)2—piperazin— l—yl m 7—CH2CHZOH—2,7—diazaspiro[4.4] —nonan—2—yl 1,2,3 ,6—tetrahydropyridin—4-yl m piperidin—4-yl -n (6S)[(S)-CH(OH)CH3]—2,2—(CH3)2-piperidin—4—yl -n 2,2-(CH3)2-piperidinyl Another embodiment of the method of the present description includes the use of a compound of a (Ia) or a form thereof selected from a nd of Formula (Ia15) or a form thereof, wherein substituents X, Rla and R421, when t, are indicated in the table below; H H an —— indicates that one or more X, Rla and R4a substituents are not present: N\R4a X RIa R4a NH H __ N(CH3) H __ N(CH3) C1 CH3 NH Cl CH3 N 0cm -- N(CH3) F -— N(CH3) CN —— N(CH3) C(O)NHCH2CH=CH2 —— N(CH3) lH—pyrazol—l-yl —— u N(CH3) 5-CH3-oxazolyl —— N(CH3) 4—CH20H—1H—pyrazole—1—yl —— m N(CH3) lH—imidazole—l—yl __ N(CH3) 4—NH2-lH—pyrazol—l—yl —— m N(CH3) lH—pyrazol—4—yl -— u N(CH3) 3—NH2—lH—pyrazol—l—yl —— - l—(CH2CH2—morpholin—4—yl)—1H— 50 N(CH3) pyrazol—4—yl -- N(CH3) l—CHg—lH—pyrazol—4—yl —— N(CH3) 5—NH2—lH—pyrazol—l—yl —— N(CH2CH20H) lH-pyrazol-l-yl —— 0 Rla GK 1H—pyraz01—1—y1 OK 00094 1H-pyrazoly1 1H—pyrazol—4—y1 -~l NH 1H—pyrazol— 1 —y1 u—tu—t 03¢©© CH2 1H—pyrazol— 1 —y1 N(CH3) C1 u—tu—tr—t humMNi—i NH 1H—pyrazol— 1 —y1 NH CN N(CH3) 1H—indazol—7—y1 t—tu—t GNU]005.] CH2 1H—pyrazol—4—y1 N(CH3) 5—OCH3—pyridin—3—y1 E!I—Kl—t NON N(CH3) 5—pyridin—2—01 N(CH3) 4-pyridin-2—ol HN] H N(CH3) 6—OCH3—pyridin—3—y1 172 N(CH3) 5—(3—CF3-Pyridin—2—ol) 173 N(CH3) 5—( 1 —CH3—pyridin—2(1H)—one) 174 N(CH3) 4—( 1 —CH3—pyridin—2(1H)—one) 175 N(CH3) —pyridin—4—y1 176 din—2—01 t—tu—tu—t NIH" @0054 N(CH3) 6—N(CH3)2—pyridin—3—y1 4—( 1 —CH3—pyridin—2(1H)—0ne) N(CH3) din—S—yl H00¢ N(CH3) 5—pyridin—3—01 I 4-(1-cyclopropy1-pyridin-2(1H)- H H N(CH3) one) HHHH common Ul-BOJN N(CH3) 1,2,3 ,6—tetrahydropyridin—4—y1 N(CH3) cyclopent— 1—en— 1 —y1 N(CH3) 3,6—dihydr0—2H—pyran—4—y1 N(CH3) imidazo[1,5—a]pyridin—7—y1 Hon3‘ N(CH3) imidazo[1,2—a]pyridin—7—y1 187 N(CH3) 2-CH3-pyridiny1 188 N(CH3) 1H—imidazol—2—y1 189 N(CH3) 1H—imidazol—4—y1 190 N(CH3) imidaz0[1,2—a]pyraziny1 X R12 R42. - 5,6,7,8—tetrahydroimidazo[1,2- 191 N(CH3) a]pyrazinyl -- N(CH3) 4-CH3-1H—imidazolyl —— 193 N(CH3) l—CHg—lH—imidazol-4—yl __ N(CH3) l—CHg—lH—imidazol—S—yl —— N(CH3) lH-imidazolyl —— N(CH3) 2—CH3—lH—imidazol—4—yl -— 197 N(CH3) l,2—(CH3)2—lH—imidazol—4—yl -— N(CH3) 4-C(O)NH2—lH—pyrazol-l—yl —_ 206 N(CH3) H -— Another embodiment of the present description includes a compound of Formula (Ia) or a form thereof selected from a nd of a (IalS) or a form thereof, wherein substituents X, Rla and R4a, when present, are indicated in the table below; and, "--" indicates that one or more X, Rla and R4a substituents are not present: \N , N N H R1a OH (IalS) NH lH—pyrazol—4—yl —— 414 O 1—CH3— lH—pyrazolyl —— la|—l6 ZOE 5—CH3— 1H—pyrazolyl -- A1-.1 O lH—imidazol— l —yl —— his-BANNHH oar-teen 5-CH3— azol—4—yl —— ZO0090 4—NOZ— lH—pyrazol— l —yl —— 4—NH2— lH—pyrazol— l —yl —— 4—N02— lH—pyrazol— l —yl —- Z0E lH—pyrazol—4—yl -- .5ONH O lH—pyrazol—4—yl —— Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia15) or a form thereof, n substituents X, Rla and R421, when present, are indicated in the table below; and, "—— indicates that one or more X, Rla and R4a substituents are not present: azol—4—yl 1—CH3—1H—pyrazolyl Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of a (Ia16) or a form thereof, wherein substituents Rla and R421, when present, are indicated in the table below; H H an —— indicates that one or more Rla and R4a substituents are not present: lH—pyrazolyl lH—pyrazol—4—yl (CH2)20H lH—pyrazol—4—yl —— lH—pyrazol—4—yl CH3 4—( l —CH3—pyridin—2(lH)—one) CH3 4—( l —CH3—pyridin—2(lH)—one) CH3 Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a nd of Formula (Ial7) or a form thereof, n substituent R13, when present, is indicated in the table below; and, "——" indicates that one or more R1 a substituents are not present: lH—pyrazol—4—yl 4—(1—CH3—pyridin—2(1H)—one) Another embodiment of the present description includes a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia18) or a form thereof, wherein tuents X and B, when present, are indicated in the table below; and, "-- tes that one or more X and B substituents are not present: (1R,SS)azabicyclo[3.2. 1]octyl (1R,SS)azabicyclo[3.2.1]octyl 1,2,3 ,6—tetrahydropyridin—4—yl l—CHgCHz—(l,2,3,6—tetrahydropyridin—4—yl) piperidin—4—yl (lR,SS)—8—azabicyclo[3.2. l]oct—3-yl 2,6—(CH3)2—piperidinyl 2,7-diazaspiro[3 .5]non-2—yl 2,6—(CH3)2—piperidin—4—yl 2,6—diazaspiro[3 .4]oct—2—yl Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof ed from a compound of Formula (Ia18) or a form thereof, wherein substituents X, Rla and B, when present, are indicated in the table below; and, "—— 1ndicates that one or more X, Rla and B substituents are not present: (1R,53)azabicyclo[3.2.1]octyl (1R,SS)azabicyclo[3.2.1]octyl 1,2,3 rahydropyridin—4—yl Hz—(l,2,3,6—tetrahydropyridin—4—yl) piperidin—4—yl (1R,SS)—8—azabicyclo[3.2. l]oct—3-yl 2,6—(CH3)2—piperidinyl 2,7-diazaspiro[3 .5]non-2—yl 2,6—(CH3)2—piperidin—4—yl 2,6—diazaspiro[3 .4]oct—2—yl Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, n substituent A is indicated in the table below: 6—(naphthalen—2—ol) 6—(naphthalen—2,7—diol) 7-OCH3-quinolinyl 7-OH-quinolinyl 2-CN—7—OCHg—quinolin—6—yl 3—F—5 —( lH—pyrazol—4—yl)—pyridin—2—yl 2—(6—OCH3—3,4—dihydroisoquinolin— l ne) 6—OH— l —oxo—2,3—dihydro— lH—inden—S —yl 3—(4—OCH3— l —CH3—quinolin—2(1H)—one) 3—(4—OH— l—CH3—quinolin—2(lH)—one) 3—(quinolin—2( lH)—one) 3—( l —OCH3—quinolin—2( lH)—one) —CN—benzo[b]thiophen—2—yl 3-Cl-benzo[b]thiophen-2—yl Another embodiment of the present ption includes a nd of Formula (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, n substituent A is indicated in the table belowzc 3—( lH—pyrazol—4—yl)phenoxy 4—( lH—pyrazol—4—yl)phenoxy Another embodiment of the method of the present description includes the use of a compound of a (lb) or a form thereof selected from a compound of Formula (Ibl) or a form thereof, wherein substituent A is ted in the table below: 3—( lH—pyrazol—4—yl)phenoxy 4—( lH—pyrazol—4—yl)phenoxy Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form f selected from a compound of Formula (Ib2) or a form thereof, wherein tuent A is indicated in the table below: A\<_7/" 1"" (Ib2) 6——naphthal:n—2,7—diol Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib3) or a form f, wherein substituents Rla, Rlb and B, when present, are indicated in the table below; and, "——" indicates that one or more Rla, Rlb and B substituents are not present: \ 87/ B/ R1b de R13 Rlb B 329 lH—pyrazol— 1 —yl OCH3 1,2,3 ,6—tetrahydropyridin—4—yl 330 lH-pyrazoly1 OH piperazin- 1-yl —((3aR,6aR)—1—CH3—hexahydropy1rolo[3,4- 381 lH—pyrazol—l—yl Cl b]pyrrol—5(lH)—yl) 382 lH—pyrazol— 1 —yl Cl (CH3)2—morpholin—4—yl 383 lH—pyrazol— 1 —yl Cl 2—OCH3—2,7—diazaspiro[4.5]decan—7—yl R,6aS)—5—CH3—hexahydropyrrolo[3 ,4— 385 1—CH3—1H—pyrazol—4—yl OCH3 c]pyrrol—2(1H)—yl) -((3aR,6aS)—5—CH3—hexahydropyrrolo[3 ,4— 394 1—CH3—1H-pyrazol—4—yl OH c]pyrrol—2(lH)—yl) 406 lH—pyrazol— l —yl Cl 2,7—diazaspiro[4.5]decan—2—yl 407 lH—pyrazol— l —yl Cl (3R)—(3—(R)—CH20H)—piperazin— l —yl Another embodiment of the ent description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib4) or a form thereof, wherein substituents Rla, Rlb, Rlc, Rld (each representative of the scope of R1) and X, when present, are indicated in the table below; and, "—— 1"indicates that one or more Rla, Rlb, Rlc, Rld and X substituents are not present: (H34) -———m--———-- _-—-- -—-—-- — -—-—--—EEEEE _---— _—--—m: -——I -312 4(1CH3pyr1d1n——2(1H)one) -—--— --—— ---—--- -—~— - 1H——pyra:zol— 1——y1 - n - - O - — - — —o ZnE - - Z00FE -33 — 2A V -333 inE -- 8E --—’— -——-E I inE 4,5,6,7— tetrahydropyrazolo[1,5—a] pyridin———3—y1 --—n _——-- --—III —1Hp—y—razol5—yl _-—- _-—-- _-—- -—-—- _-—- -—-—--iijiiEmu-1mm: 2-NH2-pyrimidin- 357 H C1 4-yl H N(CH3 —--—mam) ———-New) ———-mm —-—-m» ———-New ———-m» ———-m» —-—-w» ———-mmEEEEEEEWEE :EIIEEETJ m: I: (CH3) E I ———-New)E I New) C1 m» Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a nd of Formula (IbS) or a form thereof, wherein tuents Rla, Rlb, Rlc, Rld (each representative of the scope of R1) and R4a, when present, are indicated in the table below; and, "—— H indicates that one or more Rla, Rlb, Rlc, Rld and R421 substituents are not present: R1d c ,— N/R4a N .
EEEEE 0E lH—pyrazol—4—yl E ('3 s lH—pyrazol—4—yl o3: - lH—pyrazol—4—yl a: Another embodiment of the method of the present description es the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib6) or a form thereof, wherein substituents Rla, Rlb, Rlc and Rld (each representative of the scope of R1), when present, are indicated in the table below; an —— tes that one or more Rla, Rlb, Rlc and Rld substituents are not present: \ 87’"/ -—-i——— -—--- _——— Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib7) or a form thereof, wherein substituent Rlb, when t, is indicated in the table below: Another embodiment of the method of the present description includes the use of a compound of Formula (lb) or a form thereof selected from a compound of Formula (Ib8) or a form thereof, wherein substituent Rlb, when present, is indicated in the table below: s N’ An embodiment of the use of a compound of a (I) or a form thereof includes a method of use of a compound of Formula (I) or a form f for treating or ameliorating HD in a subject in need f, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject, selected from the group consisting of: \,N NH NH CO N x ,N NH NH N N‘ / 21 22 H H N N / / I I N x ,N NH N \ ,N NH I \ N N 0‘ , <’ N S 23 24 H I N N / / I I \N'N NH \N'N NH N OH 26 l H N N / / I l \N’N N\ \ CO N’N NH Cl OH OH 27 28 H | N N /| /| \N.N N\ NC \N,N NH Cl OH OH 29 30 / N l /I so NH 31 32 \ ,N NH N NH 33 34 \ .N NH 0 OH \0 OH 36 | l N N ,/ l/ I I F \N,N NH \N.N NH F OH F OH 37 38 | N ,/ I I \N,N NH \N,N NH i] ll Nc OH 39 40 H N N x’ // I I \N,N NH \\ \N,N N\ s OH 41 42 | | N N ,/ // I I \N,N NH \N,N NH C" OH OH ’N ‘6'\ N 43 44 | l N N ,/ // I I \N,N NH \N,N NH L—<€:N OH H / \ ,N N CC HO OH 81 82 NH NH x ,N H /| ,H \ ,N \ ,N N N \ OH \ OH \N’ /N / 201 202 239 240 z’\/o NH N OH \N,N NH 0 N OH / \N,N NH NC N \ .N NH / N / \N,N NH H2N \N OH \ \ / N'N N ’ N'N NC \N \ OH OH 269 270 \ OH 289 290 \ NH \ NH N N s s’\( 305 306 307 308 309 310 OCF3 311 312 NH NH 313 314 315 316 319 320 325 326 327 328 NC NC 335 336 337 338 339 340 341 342 343 344 345 346 353 354 355 356 359 360 \ . N H N H Imv\ N \N N. F \N N.
N/.NH m x O \N NI 363 364 NH NH NH NH 367 368 369 370 373 374 NH NH 381 382 383 384 385 386 389 390 395 396 399 400 401 402 405 406 (N’)"I \ NH N \EN Nf | NC 407 408 \ NH \N NH N s/\< S \ ‘..N Cl N N \ ,N N \N,N NH 415 416 x ,N NH ‘ —N NH 449 450 NH NH 461 462 \ NH ‘N‘ N \N,N HN / S’\( F ,N , \ N. I o HN F 463 464 \N,N NH N_/[ HN F n a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, reomer, stereoisomer, polymorph and tautomer form thereof.
In another aspect, the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of: 415 416 449 450 461 462 \,N NH wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another ment of the use of a compound of Formula (I) or a form thereof includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof (wherein compound number (#1) indicates that the salt form was ed) to the subject, selected from the group consisting of: de Name 1 6-(naphthalen—2—yl)—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3—amine 6-(benzo[b]thiophen—2—y1)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3— (AN amine 2,2,6,6-tetramethylpiperidinyl-amino)-pyridazinyl)phenol 2—(6—(methyl—(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)benzo[b] - \OOOQONUl-B thiophene—S—carbonitrile 6—(quinolin—3—yl)—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3—amine 3—(benzo[b]—thiophen—2—yl)—6—(2,2,6,6—tetramethylpiperidin—4—yl—oxy)pyridazine 2—(6—(methyl—(2,2,6,6—tetramethylpiperidin—4—yl)amino)—pyridazin—3—yl)phenol 6—(6—(methyl—(2,2,6,6—tetramethylpiperidin—4—yl)amino)—pyridazin—3—yl)naphthalen—2—ol zo[b]-thiophen—2—yl)—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin-3—amine 7—(6—((2,2,6,6—tetramethylpiperidin—4—yl)oxy)pyridazin—3—yl)isoquinoline 11 6-(6—((2,2,6,6—tetramethylpiperidin—4—yl)oxy)pyridazin—3—yl)isoquinoline 12 N-methyl—6—(quinolin—7—y1)—N—(2,2,6,6—tetramethylpiperidinyl)pyridazin—3—amine Cpd Name 13 N-methyl(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 14 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(imidazo[1,2-a]pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 16 yl)pyridazinamine yl(6-phenylpyridinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin 17 amme 6-(6-(IH-pyrrol-l-yl)pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 18 yl)pyridazinamine 6-(6-(IH-pyrazol-l-yl)pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 19 yl)pyridazinamine methyl-(6-quinoxalinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine 21 methyl-(6-quinolinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine 22 N-methyl(phthalazinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[c] [ l ,2,5]oxa-diazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin 23 amme 24 6-(benzo[d]thiazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(2-methylbenzo-[d]oxazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amme 26 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalenol 27 5-chloro(6-(methyl(l,2,2,6,6-pentamethylpiperidinyl)amino)pyridazinyl)phenol 28 2,2,6,6-tetramethylpiperidinyl-amino)pyridazinyl)naphthalenol 29 5-chloro(6-( 1,2,2,6, 6-pentamethylpiperidinylamina)pyridazinyI)phenol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzonitrile 31 3-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)naphthalenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) 321 (trifluoromethyl)phenol 33 2-fluoro(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl)phenol 3,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 34 yl)phenol 4,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 36 5-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 37 yl)phenol 38 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol Cpd Name 3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 39 yl)benzonitrile l(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 40 yl)naphthalenol 41 zo[b]thiophenyl)-N-(1,2,2,6,6-pentamethylpiperidinyl)pyridazinamine N-allylhydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 42 yl)benzamide methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)( IH-pyrazol 43 yl)phenol -(5-methyl-oxazolyl)(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)- 44 pyridazinyl)phenol -(4-(hydroxymethyl)-1H-pyrazole- l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidin 45 yl)amino)pyridazinyl)phenol -(1H-imidazol-l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 46 3-yl)phenol -(4-amino-1H-pyrazole-l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidin 47 yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol 48 yl)phenol -(3-amino-1H-pyrazol-l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidin 49 yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)( 1-(2- 50 morpholino-ethyl)-IH-pyrazolyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)( l -methyl- IH- 51 pyrazolyl)phenol -(5-amino-IH-pyrazol-l-yl)(6-(methyl-(2,2,6,6-tetramethylpiperidin 52 yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)( IH-pyrazol 531 yl)phenol 2-( (6-((2-hydroxy-ethyl)-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl) 54 pyrazolyl)phenol 55 2-(6-(piperidinyloxy)pyridazinyl)( IH-pyrazolyl)phenol 2-(6-(((2S,4R,6R)-2,6-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazol-l- 56 yl)phenol 57 2-(6-((-2,6-dimethylpiperidinyl)oxy)pyridazinyl)( IH-pyrazolyl)phenol 58 5-( IH-pyrazol- l-yl)(6-(pyrrolidinyl-oxy)pyridazinyl)phenol 59 2-(6-( ((2S ,4S )methylpiperidinyl)oxy)pyridazinyl)( IH-pyrazolyl)phenol 60 (5-(IH-pyrazol-l-yl)(6-(pyrrolidinylmethoxy)pyridazinyl)phenol de Name 61 2-(6—((3—flu0r0piperidin—4—y1)0xy)pyridazin—3—y1)—5—(1H—pyrazol- 1—yl)phen01 2-(6-(1,2,2,6,6-pentamethy1-piperidiny1-oxy)-pyridaziny1)(1H-pyrazol 62 y1)phenol 63 5—1H—pyrazol—1-y1—2-(6—(2,2,6,6—tetramethy1piperidin—4—yl—oxy)—pyridazin—3—yl)phen01 64 5—(1H—pyrazol—4—y1)—2—(6—((2,2,6,6—tetramethy1piperidin—4—y1)oxy)pyridazin—3—y1)phen01 2—(6—piperazin—1—y1—pyridazin—3—y1)—5—(1H—pyrazol— hen01 66 3—(6—(azetidin—3—ylamin0)—pyridazin—3—y1)naphthalen—2—01 67 2—(6—(azetidin—3—ylamin0)pyridazin—3—y1)—5—(1H—pyrazol— henol 68 2—(6—(3,5—dimethy1piperazin—1—y1)pyridazin—3—y1)—5—(1H—pyraz01—1—y1)phen01 2—(6—(7—methy1—2,7—diazaspir0[4.4]nonan—Z—y1)pyridazin—3—y1)—5—(1H—pyrazol— 1 — 69 y1)phen01 70 2-(6—( 1 ,4—diazepan— 1—y1)pyridazin—3—y1)—5—(1H—pyraz01— 1—y1)phen01 71 2-(6—(4—(2—hydr0xyethy1)piperazin—1—y1)pyridazin—3—y1)(lH-pyrazol— 1—y1)phen01 72 2-(6-(3,6-diazabicyclo[3.2.1]octany1)pyridazin-3 -y1)(1H-pyrazoly1)phen01 73 2—(6—(2,7—diazaspiro[3.5]nonan—7—y1)pyridazin—3—y1)—5—(1H—pyrazol—1—yl)phenol 74 2—(6—(3—(hydroxymethy1)piperazin—1—y1)pyridazin—3—y1)—5—(1H—pyrazol— 1—y1)phen01 75 1,7—diazaspiro[4.4]nonan—7—y1)pyridazin—3—y1)—5—(1H—pyrazol—1—y1)phen01 76 2—(6—(4—amino—4—methy1piperidin—1—y1)pyridazin—3—y1)—5—(1H—pyrazol— 1—y1)phen01 77 2—(6—(3—(dimethylamino)piperidin—1—y1)pyridazin—3—y1)—5—(1H—pyrazol—1—yl)phen01 2—(6—(12,2,6,6—pentamethy1piperidin—4—ylamin0)—pyridazin—3—y1)—5—lH—pyrazol—l—yl— 78 phenol 79 2—(6—(3,3—dimethy1piperazin— 1—y1)pyridazin—3—y1)—5—(1H—pyraz01— 1—y1)phen01 2-(6—(7—(2—hydr0xyethy1)—2,7—diazaspir0[4.4] —n0nan—2—y1)pyridazin—3—yl)—5—(1H—pyrazol— 80 1-y1)phen01 2-(6—((3aR,6aS)—hexahydropyrrolo[3 yrr01—2( 1H)-y1)pyridazin—3—yl)—5—( 1 H— 81 pyrazol- 1-yl)phen01 821 piperazin—1—y1)pyridazin—3—y1)naphthalene—2,7—diol 83 5—(1H—pyrazol—1—y1)—2—(6—(1,2,3 ,6—tetrahydropyridin—4—y1)pyridazin—3—y1)phen01 84 2—(6—piperidin—4—y1—pyridazin—3—y1)—5— 1H—pyrazol— 1—y1—phen01 85 3—(6—(1,2,3,6—tetrahydr0pyridin—4—y1)pyridazin—3—y1)naphthalen—2—ol 861 3—(6—(1,2,3,6—tetrahydropyridin—4—y1)pyridazin—3—y1)naphthalene—2,7—di01 3 —(6—(2,2,6,6—tetramethy1— 1,2,3 ,6—tetrahydropyridin—4—y1)pyridazin—3—y1)naphthalene—2,7— diol 3—(6—(1—methy1—1,2,3 ,6—tetrahydr0pyridin—4—y1)pyridazin—3—y1)naphthalene—2,7—di01 3-(6—(piperidin—4—y1)pyridazin—3—y1)naphthalene—2,7 —di01 3-(6—((2,2,6,6—tetramethylpiperidin—4—y1)0xy)pyridazin—3-yl)naphthalene—2,7—diol de Name 3-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—yl)naphthalene—2,7— 91 diol 92 3-(6-((2,2,6,6-tetramethylpiperidiny1)amino)pyridaziny1)naphthalene-2,7-diol tefi—butyl —hydr0xy—6—(6—(methy1(2,2,6,6—tetramethy1piperidin—4— 93 y1)amin0)pyridazin—3—y1)naphthalen—2—y1)0xy)propy1)carbamate 7—(3—amin0—pr0poxy)—3—(6—(methy1—(2,2,6,6—tetramethylpiperidin—4—yl)—amino)— 94 pyridazin—3—y1)naphthalen—2—01 N—(3—((7—hydroxy—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 95 yl)naphthalen—2—y1)0xy)pr0py1)acetamide 7—(3 —hydr0xypr0p0xy)—3—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin— 96 3—y1)naphthalen—2—01 7—(3—meth0xyprop0xy)—3 —(6—(methy1(2,2,6,6—tetramethy1piperidin—4—yl)amino)pyridazin— 97 3-y1)naphthalen—2—01 7-(2—m0rpholinoethoxy)—3—(6—((2,2,6,6—tetramethylpiperidinyl)0xy)pyridazin—3— 98 y1)naphthalen01 99 3—(6—(piperidin—4-ylmethy1)pyridazin—3—y1)naphthalen—2—ol —( 1 H—pyrazol— 1 —y1)—2—(6—((2,2,6,6—tetramethy1piperidin—4—y1)methyl)pyridazin—3— 100 y1)phen01 3—meth0xy—2—(6—(methy1(2,2,6—trimethy1piperidin—4—y1)amino)pyridazin—3—y1)—5—(5— 101 methyloxazol—Z—y1)phen01 2—(6—((6S )—6—((S)— 1—hydr0xyethy1)—2,2—dimethylpiperidin—4—y10xy)pyridazin—3—y1)—5 — 102 (1H—pyrazol—1—y1)phen01 7—hydr0xy—6-(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)—2— 103 naphthonitrile 3-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amin0)pyridazin-3—yl)—7— 104 (piperidinylmethyl)naphthalen—2—01 methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl) 105 (pyrrolidinylmethyl)naphthalen01 1—bromo—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 106 hthalene—2,7—diol 1—ch10r0—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 107 y1)naphthalene—2,7—di01 7—meth0xy—3—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)pyridazin—3— 108 y1)naphthalene—2—01 0xy-3—(6—(methy1(1,2,2,6,6—pentamethylpiperidin—4—y1)amin0)pyridazin—3 — 109 y1)naphthalen—2—01 7—(3,6—dihydr0—2H—pyran—4—y1)—3—(6—(methy1(2,2,6,6—tetramethy1piperidin—4— 110 yl)amin0)pyridazin—3—y1)naphthalen—2—01 de Name 3-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—yl)—7—(tetrahydr0—2H— 111 pyranyl)naphthaleneol 7-(difluoromethyl)(6-(methy1(2,2,6,6-tetramethy1piperidiny1)amin0)pyridazin 112 yl)naphthalen—2-ol 7—((4—hydroxy—2—methy1butan—2—y1)oxy)—3—(6—(methy1(2,2,6,6—tetramethylpiperidin—4— 113 y1)amin0)pyridazin—3—y1)naphthalen—2—01 7—(3—hydr0xy—3—methy1butoxy)—3 —(6—(methy1(2,2,6,6—tetramethylpiperidin—4— 114 y1)amin0)pyridazin—3—y1)naphthalen—2—01 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)—5—(1H—pyrazol—4— 115 y1)benzene-1,3—di01 3—meth0xy—2—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)pyridazin—3—y1)—5— 116 (1H—pyrazol—4—y1)phen01 -(1H—pyrazol—4—y1)—2—(6—((2,2,6,6—tetramethy1piperidin—4—y1)amin0)pyridazin—3—y1)—3— 117 (trifluoromethoxy)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl)( 1 l- 1H- 118 pyrazolyl)(trifluoromethoxy)phenol 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5—( 1H—pyrazol—4— 119 y1)—3—(triflu0r0methoxy)phen01 4—(3—hydr0xy—4—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)—5 — 120 (trifluoromethoxy)pheny1)— 1—methy1pyridin—2(1H)—0ne 3—meth0xy—2—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)pyridazin—3—y1)—5—( 1 — 121 methyl—1H-pyrazol—4—y1)phen01 3—meth0xy-2—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)pyridazin—3—y1)—5— 122 (5,6,7,8—tetrahydr0imidazo[1,2—a]pyridin—3—y1)phen01 3—meth0xy—2—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)pyridazin—3—y1)—5— 123 (pyridine—3—y1)phen01 -(1-cyclopenty1-1H-pyraz01y1)meth0xy(6-(methy1(2,2,6,6- 124 tetramethylpiperidiny1)amino)pyridaziny1)phenol 3 ’ ,5—dimethoxy—4—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—yl)amino)pyridazin—3—yl)— 125 (1, 1'—bipheny1)-3 —01 3—(benzy10xy)—2—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)—5 — 126 (5—methyloxazol—Z—y1)phen01 3—ethoxy—2—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—5—(5 — 127 oxazol—Z—y1)phen01 3—(cyclopr0py1meth0xy)—2—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)— 128 zin—3-y1)—5—(5—methyloxazol—Z—y1)phenol 2—methyl—5—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3 —y1)— 1H— 129 benzo[d]imidazol—6—01 130 5-ch10r0—2—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)phen01 Cpd Name -( lH-pyrazol- l -(6-( (2,2,6,6-tetramethylpiperidinyl)amino )pyridazin 131 yl)phenol 132 3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)benzonitrile 133 2-( 6-( (2,2-dimethylpiperidinyl)oxy )pyridazinyl)( 1H-pyrazolyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol 134 yl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4,5,6,7- 135 tetrahydropyrazolo[l,5-a]pyridinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4,5,6,7- 136 tetrahydropyrazolo[l,5-a]pyrazinyl)phenol 4-(1H-indolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 137 yl)phenol 4-( cyclopent-l-enyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 138 yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol 139 yl)phenol 4-(4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 140 nyl)pyridinol 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy )pyridazinyl)phenyl) 141 methylpyridin-2(1H)-one 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin 142 yl)phenyl)pyridinol -(1H-indazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 143 yl)phenol 4-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- 144 pyrazolyl)phenol 4-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- 145 pyrazolyl)phenol -fluoro(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 146 yl)amino)pyridazinyl)phenol -fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- 147 pyrazolyl)phenol -fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- 148 pyrazolyl)phenol 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- 149 dihydro-lH-indenone 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-l,4- 150 dihydroindeno[l,2-c]-lH-pyrazolol Cpd Name 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- 1511 dihydro-lH-indenone oxime -( 6-(methy1(2,2,6, 6-tetramethylpiperidiny1)amino)pyridaziny1)-2,3-dihydro-1 H- 152 indene-1,6-diol 2-amino(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-8H- 1531 indeno[l,2-d]thiazolol 9-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-5,6- 1541 dihydroimidazo[5, l-a]isoquinolinol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-N-((1- 155 methyl-lH-pyrazolyl)methyl)benzamide 4-(4-(hydroxymethyl)-1H-pyrazol-l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidin 156 yl)amino)pyridazinyl)phenol -(lH-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)methyl)pyridazin 157 yl)phenol benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 158 idazinamine 6-( 1-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 159 yl)pyridazinamine 3-fluoro(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 1601 yl)amino)pyridazinyl)phenol 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 1611 3-yl)phenyl)pyridin-2(1H)-one 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 1621 3-yl)phenyl)-l-methylpyridin-2(1H)-one luorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 1631 3-yl)phenyl)-l-methylpyridin-2(1H)-one 3-fluoro(lH-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin 1641 yl)phenol -chlorofluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 1651 yl)phenol 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- 1661 pyrazolyl)phenol 3-fluoro(6-(methy1(2,2,6, amethylpiperidinyl)amino)pyridaziny1)( 1- 1671 methyl-lH-pyrazolyl)phenol -(5-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 168 yl)amino)pyridazinyl)phenol -(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 169 yl)phenyl)pyridinol Cpd Name 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 170 yl)phenyl)pyridinol -(6-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 171 yl)amino )pyridazinyl)phenol -(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 172 yl)phenyl)(trifluoromethyl)pyridinol -(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 173 nyl)methylpyridin-2( IH)-one 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 174 yl)phenyl)-l-methylpyridin-2(1H)-one -(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 175 yl)amino )pyridazinyl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin 176 nyl)pyridinol -(6-(dimethylamino)pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 177 yl)amino )pyridazinyl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl)-l- 178 methylpyridin-2(1H)-one 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(pyrimidin 179 yl)phenol -(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 180 yl)phenyl)pyridinol l-cyclopropyl(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidin 181 yl)amino)pyridazinyl)phenyl)pyridin-2(1H)-one methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(l,2,3,6- 182 tetrahydropyridinyl)phenol -( cyclopent-l-en-l-yl)(6-(methyl(2,2,6,6-tetramethylpiperidin 183 yl)amino)pyridazinyl)phenol -(3,6-dihydro-2H-pyranyl)(6-(methyl(2,2,6,6-tetramethylpiperidin 184 yl)amino)pyridazinyl)phenol -(imidazo[ 1,5-a]pyridinyl)( 6-(methyl(2,2,6,6-tetramethylpiperidin 185 yl)amino)pyridazinyl)phenol -(imidazo[ 1,2-a]pyridinyl)( 6-(methyl(2,2,6,6-tetramethylpiperidin 186 no)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(2- 187 methylpyridinyl)phenol -(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 188 3-yl)phenol de Name -(1H—imidazol—4—y1)—2—(6—(methy1(2,2,6,6—tetramethy1piperidin-4—yl)amin0)pyridazin— 189 3-y1)phenol -(imidazo[1,2-a]pyraziny1)(6-(methy1(2,2,6,6-tetramethylpiperidin 190 yl)amino)pyridazin-3—y1)phenol 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—5—(5,6,7,8— 191 tetrahydroimidazo[ 1 ,2—a]pyrazin—3 —y1)phen01 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—5—(4—methy1— 1H— 192 imidazol—Z—y1)phenol 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—5—(l—methyl— 1H— 193 ol—4-y1)phen01 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—5—(l-methyl— 1H— 194 imidazol—S—y1)phen01 2-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—yl)—5—(4—nitr0— 1H— 195 imidazol—Z—yl)phen01 2-(6-(methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl)(2-methy1-1H- 196 imidazoly1)phenol —(1,2—dimethy1—1H—imidazol—4—y1)—2—(6—(methy1(2,2,6,6—tetramethylpiperidin—4- 197 yl)amin0)pyridazin—3—y1)phen01 1—(3—hydr0xy—4—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 198 y1)pheny1)— 1H—pyrazole—4—carboxamide 2—(6—((3aR,6aS)—5—(2—hydr0xyethy1)hexahydropyrrolo[3 ,4—C]pyrrol—2(1H)—y1)pyridazin— 199 3—y1)—5—( 1 H—pyrazol—4—y1)phen01 2—(6—((3aR,6aS)—hexahydr0pyrrolo[3 ,4—c]pyrr01—2(1H)—y1)pyridazin—3—y1)-5—(1H— 200 pyrazol—4—y1)phen01 2—(6—((3aR,6aS)—5—methy1hexahydr0pyrrolo[3 ,4—c]pyrr01—2(1H)-yl)pyridazin—3—y1)—5— 201 (1H—pyrazol—4—yl)phen01 ydroxy—4—(6—(5—methy1hexahydropyrr010[3 ,4—c]pyrr01-2( 1 H)—yl)pyridazin—3— 202 y1)phenyl)methy1pyridin-2(1H)-one 4—(3—hydroxy—4—(6—((3aR,6aR)—1—methy1hexahydropyrrolo[3 ,4—b]pyrrol—5( 1 H)— 203 y1)pyridazin—3—y1)pheny1)—1—methy1pyridin—2(1H)—one 204 2,7—diazaspiro[4.5]decan—Z—y1)pyridazin—3—y1)—5—(1H—pyrazol—4—y1)phen01 4—(4—(6—(2,7—diazaspiro[4.5]decan—Z—y1)pyridazin—3—y1)—3—hydroxyphenyl)— 1— 205 methylpyridin—2(1H)—0ne 206 2—(6—(methyl—(2,2,6,6—tetramethy1piperidin—4—y1)—amino)—pyridazin—3—y1)phen01 207 6—(6—(methyl(2,2,6,6—tetramethy1piperidin—4—y1)amin0)pyridazin—3—y1)quin01in—7—01 208 methyl(1,2,2,6,6—pentamethy1piperidin—4—y1)amino)pyridazin—3—y1)quin01in—7—01 6—(6—((3aR,6aS)—5—methy1hexahydr0pyrrolo[3 ,4—C]pyrr01—2(1H)—y1)pyridazin—3— 209 yl)quin01in—7—01 de Name yl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)quinolin— 210 7-01 211 7-(6-(methyl(1,2,2,6,6-pentamethy1piperidiny1)amino)pyridazinyl)isoquinolinol 212 7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)isoquinolin—6—01 213 7—(6—((2,2,6,6—tetramethy1piperidin—4—y1)0xy)pyridazin—3—y1)isoquin01ine—6—01 7—(6—((3aR,6aS)—5—methy1hexahydr0pyrrolo[3 ,4—c]pyrr01—2(1H)—y1)pyridazin—3— 214 y1)isoquin01in—6—01 1—cyclopr0py1—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 215 y1)isoquinolin—6—01 7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3 —y1)isoquin01ine— 1 ,6— 216 diol 6—hydr0xy—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 217 y1)isoquin01ine—1—carb0nitrile 218 methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl)isoquinolinol 219 8-(6-(methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl)quinolinol 220 6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—yl)quinolin—6—ol 2—methyl—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)quinolin 221 6—01 3—ch10r0—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)quinolin— 222 7—01 3 —br0mo—6-(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)quinolin— 223 7—01 7—hydr0xy—6-(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3— 224 y1)quinoline—3—Carb0nitrile 6-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—yl)—3—( 1 —methyl— 1H— 225 imidazol—4—yl)quinolin—7—ol 3-(1H-imidazoly1)(6-(methy1(2,2,6,6-tetramethylpiperidinyl)amin0)pyridazin- 2261 uinolin—7-ol 227 6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—yl)quin01ine—3 ,7—diol 3—ethyl—6—(6—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)pyridazin—3—y1)quinolin— 228 7—01 3—isopr0pyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 229 y1)quinolin—7—01 7—hydr0xy-6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 230 y1)quinolin-2(1H)—0ne 7—hydr0xy—1—methy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—yl)amin0)pyridazin—3— 2311 yl)quin01in—2( 1H)—0ne de Name 0xy—2—methyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin-4—yl)amin0)pyridazin—3— 232 yl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridaziny1) 233 (pyrrolidin—1—y1)quinolin—7—ol 2—methyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—4— 234 morpholinoquinolin—7—01 4—(dimethylamino)—2—methy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4— 235 yl)amin0)pyridazin—3—y1)quin01in—7—01 4—ethoxy—2-methyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 236 y1)quinolin-7—01 2—methyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—y1)—4—( 1 — 237 methyl— 1H—pyrazol—4—y1)quin01in—7—01 4-meth0xy—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 2381 yl)quinolin—6—01 2391 7-(6-(methyl(2,2,6,6-tetramethylpiperidiny1)amino)pyridazinyl)quin0xalinol 6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—yl)—3—(tetrahydro-2H— 240 pyran—4—yl)quinolin—7—01 3 —ch10r0—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)quinolin— 241 6—01 3 —brom0—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)quin01in— 242 6—01 3—methy1—7-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)quin01in— 243 6—01 —br0m0—3—methy1—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 244 y1)quin01in—6—01 6-hydr0xy—1—methy1—7—(6—(methyl(2,2,6,6—tetramethylpiperidin-4—yl)amin0)pyridazin—3— 245 yl)quinolin-4(1H)-one 2,3-dimethyl(6-(methy1(2,2,6,6-tetramethy1piperidinyl)amino)pyridazin 246 yl)quinolin—6—ol 2—methyl—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 247 n0xalin—6—ol 3—methy1—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 248 yl)quin0xalin—6—01 4—m6thoxy—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 249 nolin-7—01 4—(azetidin—1-y1)—2—methy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4— 250 y1)amin0)pyridazin—3—y1)quin01in—7—01 7-hydr0xy—2—methy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidinyl)amin0)pyridazin—3— 251 yl)quinolone—4—carb0nitrile de Name 4-cyclopropyl—2—methyl—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4— 252 n0)pyridaziny1)-quinolinol 4-(3,6-dihydr0—2H-pyranyl)methy1(6-(methy1(2,2,6,6-tetramethylpiperidin 253 yl)amino)pyridazin—3-y1)quinolin—7—ol yl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—4— 2541 (tetrahydro—2H—pyran—4—y1)quinolin—7—01 2—methyl—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3—y1)—4— 255 n—3—yl)quinolin—7—01 4—(dimethylamino)—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3— 2561 y1)—quinolin-7—01 7—hydr0xy—6-(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3— 257 y1)quinazolin—4(1H)—0ne 258 6-(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—yl)quinazolin—7—01 7-hydr0xy— 1 —methy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidin-4—yl)amin0)pyridazin—3— 259 yl)-3,4-dihydr0quinolin-2(1H)-one 2—methyl—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 260 yl)quinazolin—7—01 7—hydr0xy—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 261 yl)isoquinoline— onitrile 7—hydr0xy—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 262 yl)quinoline—Z—carbonitrile 6—hydroxy-7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 263 y1)quin01in-2—carb0nitrile 6—hydr0xy—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3— 264 y1)isoquinoline—1—Carb0xamide 7-hydroxy—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amin0)pyridazin—3— 265 yl)quinolincarboxamide 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 266 yl)quinoline—Z—carboxamide methyl 6—hydr0xy—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 267 yl)quinoline—Z—carboxylate 268 6—hydr0xy—7—(6—(piperazin—1—y1)pyridazin—3—yl)quinoline—2—carbonitrile 269 7—hydr0xy—6—(6—(piperazin—1—y1)pyridazin—3—yl)quinoline—2—carbonitrile 270 7—(6—(piperazin— 1—y1)pyridazin—3—y1)isoquin01in—6—01 271 7—(6—(1,2,3 ,6—tetrahydr0pyridin—4—yl)pyridazin—3 —y1)quinolin—6—01 1—methyl—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 272 y1)isoquinolin—7—01 1-methyl—7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amin0)pyridazin—3— 273 yl)isoquinolin—6—ol de Name 1,3—dimethyl—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—yl)amin0)pyridazin—3— 274 yl)isoquinolinol 7-hydroxymethy1(6-(methy1(2,2,6,6-tetramethylpiperidinyl)amin0)pyridazin 275 yl)isoquinoline-1—carbonitrile 1—amin0—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 276 yl)isoquinolin—6—ol 7—hydr0xy—1,3—dimethy1—6—(6—(methy1(2,2,6,6—tetramethylpiperidin—4— 277 n0)pyridazin—3—y1)quinazoline—2,4(1H,3H)—di0ne 6—hydroxy—5—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 278 y1)benzo[d]0xazol—2(3H)—0ne 2—methyl—5—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin-3—y1)—2H— 279 indaz01—6—01 y1—5—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3 —y1)— 1H— 280 indazol—6—01 6-hydroxymethyl(6-(methy1(2,2,6,6-tetramethylpiperidinyl)amin0)pyridazin 2811 yl)isoquinolin-1(2H)-one 2—ethyl—6—hydr0xy-7—(6—((2,2,6,6—tetramethylpiperidin—4—y1)0xy)pyridazin—3— 282 yl)isoquinolin—1(2H)—one 1—eth0xy—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)pyridazin—3— 283 yl)isoquin01in—6—01 284 7—(6—((2,2,6,6—tetramethylpiperidin—4—y1)0xy)pyridazin—3—y1)isoquinoline— 1,6—di01 7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)—pyridazin—3—yl)—3- 285 phenylisoquinolin—6—01 y1—7—(6—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 286 y1)isoquinolin—6—01 3-cyclopropyl—7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4-yl)amin0)pyridazin—3— 287 yl)isoquinolinol 3-isopropyl(6-(methy1(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 288 yl)isoquinolin—6—ol 289 3—pr0pyl—7—(6—((2,2,6,6—tetramethylpiperidin—4—y1)oxy)—pyridazin—3—yl)isoquinolin—6—ol 3—isopr0pyl—7—(6—((2,2,6,6—tetramethylpiperidin—4—y1)0xy)—pyridazin—3—yl)isoquinolin—6— 290 01 291 3 —methy1—7—(6—(piperazin— 1—y1)pyridazin—3 —y1)isoquin01in—6—01 6—(3 —(benzyloxy)isoquinolin—6—y1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 292 y1)pyridazin-3—amine r0—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3—y1)quin01in— 293 7—01 3-isopr0pyl—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)pyridazin—3— 294 yl)quinolin—7—01 Cpd Name 3-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 295 yl)quinoxalinol 4-chloromethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 296 yl)quinolinol 4-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 297 6-ol 300 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol ethoxy( lH-pyrazol- l -yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 301 yl)-1,3,4-thiadiazolamine 6-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-l,3,4-thiadiazolyl)naphthalen- 302 2-ol -(2-methoxyquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- l ,3 ,4- 303 thiadiazolamine -(3-methoxy-naphthalenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)-1,3,4- 304 thiadiazolamine -(2-methoxy( lH-pyrazol-1 yl)phenyl)-N-( 1,2,2,6,6-pentamethylpiperidinyl)- 305 1,3,4-thiadiazolamine -(2-methoxy(l-methyl- lH-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- 306 tetramethylpiperidinyl)-1,3,4-thiadiazolamine -(2-methoxy(lH-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 307 3,4-thiadiazolamine 4-(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-l,3,4-thiadiazol 308 yl)phenyl)-l-methylpyridin-2(1H)-one -(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-l,3,4-thiadiazol 309 yl)phenyl)pyridinol -(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-l,3,4-thiadiazol 310 yl)phenyl)-l-methylpyridin-2(1H)-one N-methyl(2-methyl( l-methyl- lH-pyrazolyl)phenyl)-N-(2,2,6,6- 311 tetramethylpiperidinyl)-1,3,4-thiadiazolamine l -methyl(4-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3 ,4-thiadiazol 312 yl)(trifluoromethoxy)phenyl)pyridin-2(1H)-one -(4-(3,5-dimethyl-lH-pyrazolyl)methoxyphenyl)-N-methyl-N-(2,2,6,6- 313 tetramethylpiperidinyl)-1,3,4-thiadiazolamine N-methyl(4-(1-methyl-1H-pyrazolyl)(trifluoromethyl)phenyl)-N(2,2,6,6-tetramethylpiperidinyl)-1,3,4-thiadiazolamine 2-( 5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3 ,4,-thiadiozolyl( 1lH-pyrazolyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3 ,4,-thiadiozolyl( lH- 316 pyrazolyl)phenol de Name -(3—hydr0xy—4—(5—(methy1(2,2,6,6—tetramethylpiperidin—4-yl)amin0)— 1,3 ,4—thiadiaz01—2— 317 y1)phenyl)methy1pyridin-2(1H)-one 4-(3-hydroxy(5-(methy1(2,2,6,6-tetramethylpiperidiny1)amino)-1,3 ,4-thiadiazol 318 y1)phenyl)—1—methy1pyridin—2(1H)—one —(3—hydr0xy—4—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)— 1 ,3,4—thiadiaz01—2— 319 y1)phenyl)pyridin—2—ol 3—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)— 1 ,3 ,4—thiadiazol—2— 320 hthalene—2,7—di01 3—(5—((3aR,6aS)—hexahydropyrrolo[3 ,4—c]pyrr01—2(1H)—y1)— 1,3 ,4—thiadiazol—2— 321 hthalene—2,7—di01 3—(5—(methyl(2,2,6,6—tetramethy1piperidin—4—y1)amino)— 1 ,3 ,4—thiadiazol—2—y1)naphthalen— 3221 2—01 3 -(5—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amin0)—1,3 ,4—thiadiazol—2—y1)quinolin—Z— 323 01 2-(5-(methyl(2,2,6,6-tetramethylpiperidiny1)amino)- 1 ,3,4-thiadiazoly1)(1H- 324 pyrazol- 1-yl)phenol —(2—Ch10r0—4—( 1 -methyl— 1H—pyraz01—4—y1)pheny1)—N—methy1—N—(2,2,6,6— 325 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 3 —ch10r0—2—(5—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)— 1 ,3 ,4—thiadiaz01—2—y1)— 326 5—( 1 —methyl— 1H—pyrazol—4—y1)phen01 —(2—ch10r0—4—(1—methy1—1H—pyrazol—4—y1)pheny1)—N—(2,2,6,6—tetramethylpiperidin—4—y1)— 327 1,3 ,4—thiadiazol—2—amine 0xy-2—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)—1,3,4-thiadiazol—2— 328 y1)—5—methy10xazol—2—y1)phen01 2—(2—meth0xy—4—(1H—pyrazol— 1 —y1)pheny1)—5—( 1 ,2,3 rahydr0pyridin—4—y1)— 1 ,3 ,4— 329 thiadiazole 330 2-(5-(piperaziny1)-1,3,4-thiadiazoly1)(1H-pyrazoly1)phen01 -(7-methoxyquinoliny1)-N-methy1-N-(2,2,6,6-tetramethylpiperidiny1)-1 ,3,4- 331 thiadiazole—Z—amine 6—(5—(methyl(2,2,6,6—tetramethy1piperidin—4—y1)amino)— 1 ,3 ,4—thiadiazol—2—y1)quinolin—7— 332 01 3—meth0xy—4—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)—1,3,4—thiadiazol—2— 333 zonitrile 3 —fluoro—4—(5—(rnethy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)— 1 ,3 ,4—thiadiazol—2— 334 y1)b6nzonitrile methyl—3—flu0r0—4—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)—1,3 ,4—thiadiazol— 335 2—y1)benzoate -(2—meth0xy—4—(3—(methy1amin0)—1H—pyrazol—1—y1)pheny1)—N-methyl—N—(2,2,6,6— 336 tetramethylpiperidin—4—y1)—1,3,4—thiadiaz01—2—amine de Name 7-meth0xy—6—(5—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)—1,3,4—thiadiazol—2— 337 yl)quinoline-Z-carbonitrile 4-(3-methoxy(5-((2,2,6,6-tetramethylpiperidiny1)oxy)- 1,3 adiazol 338 y1)phenyl)— 1 lpyridin—2( 1H)—one 4—(3—ch10r0—4—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)— 1 ,3 ,4—thiadiazol—2— 339 y1)pheny1)—1—methy1pyridin—2(1H)—one —(2—ch10r0—4—(1H—pyrazol—4—yl)pheny1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 340 y1)—1,3 ,4—thiadiazol—2—amine —(2—ch10r0—4—(4,5 ,6,7 —tetrahydr0pyrazolo[ 1 ,5—a]pyridin—3—y1)phenyl)—N—methy1—N— 341 (2,2,6,6—tetramethylpiperidin—4—y1)— 1 ,3 ,4—thiadiazol—2—amine N—methyl—S-(5—( 1 —methyl— azol—4—y1)pyridin—2—y1)—N—(2,2,6,6— 3421 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 2-(2—ch10r0—4—(1—methy1—1H—pyrazol—4—yl)phenyl)—5—((2,2,6,6-tetramethylpiperidin—4— 343 y1)0xy— 1 hiadiazole -(2-chlor0(6-methoxypyridiny1)pheny1)-N-methy1-N-(2,2,6,6- 344 tetramethylpiperidiny1)-1,3,4-thiadiazolamine —(4—(6—amin0pyridin—3—yl)—2—flu0r0pheny1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin— 345 4—y1)—1,3 ,4—thiadiazol—2—amine —(2—flu0r0—4—(3 —methy1—1H—pyrazol—S—yl)pheny1)—N—methy1—N—(2,2,6,6— 346 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine —(2—flu0r0—4—(1H—pyrazol—S—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 347 y1)—1,3 ,4—thiadiazol—2—amine —(2,3—diflu0r0—4—(1H—pyrazol—4—y1)pheny1)—N—methyl—N—(2,2,6,6—tetramethylpiperidin— 348 4—y1)—1 ,3 ,4—thiadiazol—2—amine —(2,3—diflu0ro—4—(1H—pyrazol—5—y1)pheny1)—N—methy1—N—(2,2,6,6-tetramethylpiperidin— 349 4-y1)—1,3,4—thiadiazol—2—amine -(2,5—diflu0r0—4—( 1 H—pyraz01—4—y1)pheny1)—N—methyl-N-(2,2,6,6—tetramethylpiperidin— 350 4-y1)-1,3,4-thiadiazol-2—amine —(2,5—difluoro—4-(1H-pyrazol—5—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin— 351 4—y1)—1,3,4—thiadiaz01—2—amine —(2,6—diflu0r0—4—(1H—pyrazol—4—y1)pheny1)—N—methyl—N—(2,2,6,6—tetramethylpiperidin— 352 4—y1)—1 ,3 ,4—thiadiazol—2—amine 2—(2,5—diflu0ro—4—( 1H—pyrazol—4—y1)phenyl)—5—((3aR,6aS)—hexahydropyrrolo[3 ,4— 353 c]pyrrol—2(1H)—y1)—1,3 ,4—thiadiazole —(2—ch10r0-5—flu0r0—4—( 1 H—pyrazol—4—yl)pheny1)—N—methy1—N—(2,2,6,6— 354 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine —(3 —flu0r0—5—(1H—pyrazol—4—y1)pyridin—2—yl)—N—methy1—N—(2,2,6,6—tetramethylpiperidin— 355 4-y1)—1,3,4—thiadiazol—2—amine de Name -(4—(2—amin0pyrimidin—4—y1)—2—ch10r0phenyl)—N—methyl—N-(2,2,6,6— 356 tetramethylpiperidiny1)-1,3,4-thiadiaz01-2—amine -(5-(2-aminopyrimidinyl)chloropheny1)-N-methyl-N-(2,2,6,6- 357 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 2,4—dimethy1thiazol—5—y1)—2,5—diflu0ropheny1)—N—methy1—N—(2,2,6,6— 358 tetramethylpiperidin—4—y1)—1,3 adiazol—2—amine —(4—(2,4—dimethy1thiazol—5—y1)—2,3—diflu0r0pheny1)—N—methy1—N—(2,2,6,6— 359 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 4—(3—hydr0xy—4—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amino)—1,3,4—thiadiazol—2— 360 y1)—5—(triflu0r0meth0xy)pheny1)—1—methy1pyridin—2(1H)—one —(2—flu0r0—6—methoxy—4—( 1H—pyrazol—4—y1)pheny1)—N—methy1—N—(2,2,6,6— 361 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 2-(2—flu0r0—6—methoxy—4—(1H—pyrazol—4—y1)pheny1)—5—((3aR,6aS)—5— 362 methylhexahydropyrr010[3,4—c]pyrr01—2(1H)—y1)— 1 hiadiazole -(2,3-diflu0r0—6-methoxy(1H-pyrazoly1)pheny1)-N-methy1-N-(2,2,6,6- 363 tetramethylpiperidiny1)-1,3,4-thiadiazolamine 6—meth0xy—2—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)— 1 ,3 ,4—thiadiazol—2— 364 y1)—3 ,4—dihydr0isoquinolin—1—(2H)—0ne —(2—ch10r0—4—(1H—pyrazol—1—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 365 y1)—1,3 adiazol—2—amine —(2—ch10r0—4—(1H—1,2,3—triazol—1—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin— 366 4—y1)—1 ,3 ,4-thiadiazol—2—amine —(2—Ch10r0-4—(2H—1,2,3—triazol—2—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin— 367 4—y1)—1 ,3 ,4—thiadiazol—2—amine —(2—ch10r0—4—(1H—1,2,4—triazol—1—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin— 368 4-y1)—1,3,4—thiadiazol—2—amine 3—amin0—1H—pyrazol—1—y1)—2—ch10r0pheny1)—N—methy1-N-(2,2,6,6— 369 tetramethylpiperidiny1)-1,3,4-thiadiazolamine 2—(2—chlor0—4—(1H-imidazol—1—y1)pheny1)—5—((3aR,6aS)—5— 370 methylhexahydropyrrolo [3 ,4c]pyrr01—2(1H)—y1)—1,3 ,4—thiadiazole —(2—ch10r0—4—(1H—imidaz01—1—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin—4— 371 y1)—1,3 ,4—thiadiazol—2—amine —(2—flu0r0—4—(1H—imidazol—1—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 372 y1)—1,3 ,4—thiadiazol—2—amine —(2—meth0xy—4—(1H—pyrazol—5—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin—4— 373 y1)—1,3 ,4—thiadiazol—2—amine —(4—(2,4—dimethy1thiazol—5—y1)—2—meth0xypheny1)—N—methy1—N—(2,2,6,6— 374 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine de Name -(2—meth0xy—4—(pyridin—3—y1)pheny1)—N—methyl—N—(2,2,6,6-tetramethylpiperidin—4—y1)— 375 1,3 ,4-thiadiazolamine -(2-fluoro(1H-pyrazoly1)pheny1)-N-methy1-N-(2,2,6,6-tetramethylpiperidin 376 y1)—1,3,4—thiadiazol—2-amine —(2—meth0xy—4—(2—methoxypyridin—4—y1)pheny1)—N—methy1—N—(2,2,6,6— 377 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine —(2—meth0xy—4—(6—meth0xypyridin—3—y1)pheny1)—N—methy1—N—(2,2,6,6— 378 tetramethylpiperidin—4—y1)—1,3 ,4—thiadiazol—2—amine 2—(2—ch10r0—4—(1—methy1—1H—pyrazol—4—y1)pheny1)—5—((3aR,6aS)—5— 379 methylhexahydropyrrolo [3 ,4—c]pyrr01—2( 1 — 1 ,3 ,4—thiadiazole 2—(2—ch10r0—4—( 1H—pyrazol—4—y1)pheny1)—5—((3aR,6aS)—5—methy1hexahydr0pyrrolo[3 ,4— 380 c]pyrr01—2(1H)—y1)—1,3 ,4—thiadiazole 2-(2—ch10r0—4—(1H—pyrazol—4—y1)pheny1)—5—((3aR,6aR)— 1—methy1hexahydr0pyrr010[3 ,4— 381 b]pyrr01—5(1H)—y1)—1,3,4—thiadiazole 1-(4-(5-(2-ch10r0(1H-pyrazoly1)pheny1)-1,3,4-thiadiazol-Z-y1)morph01iny1)- 382 N,N-dimethy1methanamine 2—(2—ch10r0—4—(1H-pyraz01—4—y1)pheny1)—5—(2—methy1—2,7—diazaspir0[4.5]decan-7—yl)— 383 1,3 ,4—thiadiazole 2—(2—flu0r0—4—(1H—pyrazol—4—y1)pheny1)—5 —((3 aR,6aS)—5—methy1hexahydr0pyrrolo[3 ,4— 384 c]pyrrol—2(1H)—y1)—1,3 ,4—thiadiazole 2—(2—meth0xy—4—(1—methy1—1H—pyrazol—4—y1)pheny1)—5—(2,6—diazaspir0[3.5]nonan—2—y1)— 385 1,3 ,4—thiadiazole 2—(2—meth0xy—4—( 1 —methyl— 1H—pyrazol—4—y1)pheny1)—5—(2,7—diazaspir0[3 .5]n0nan—2—y1)— 386 1,3 ,4—thiadiazole 2—(5—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3 ,4—thiadiazol—2—y1)—5—(1H— 387 pyrazol— 1 —y1)phen01 -(3—chlor0—4—(5—(methy1(2,2,6,6—tetramethy1piperidiny1)amino)—1,3 ,4—thiadiazol—2— 388 y1)phenyl)pyridin-2(1H)-one methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3 ,4—thiadiazol—2—y1)—5—(3— 389 (methylamin0)—1H-pyraz01—1—y1)phen01 3—flu0r0—2—(5—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3,4—thiadiazol—2—y1)—5— 390 (1H—pyrazol—4—y1)phen01 3 ,4—diflu0ro—2—(5 —(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3 adiazol—2— 391 y1)—5 —(1H—pyrazol—4—y1)phen01 0xy-5—(5—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amin0)— 1 ,3 ,4-thiadiazol—2— 392 3—dihydr0— 1H—inden— 1—0ne 2—(5—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3 ,4—thiadiazol—2—y1)—5—(1H— 393 pyrazol—4—yl)phen01 de Name 2-(5—(2,6—diazaspir0[3.5]n0nan—2—y1)—1,3,4—thiadiaz01—2—y1)(1-methyl—1H—pyrazol—4— 394 y1)phen01 2-(5-(2,7-diazaspiro[3.5]n0nan-2—y1)-1,3,4-thiadiazolyl)(1-methyl-1H-pyrazol 395 y1)phenol 3—flu0r0—2—(5—((3aR,6aS)—hexahydropyrr010[3 ,4—C]pyrr01—2(1H)—y1)—1,3,4—thiadiazol—2— 3961 y1)—5—( 1H—pyrazol—4—y1)phen01 3 —ch10r0—2—(5—(methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino)— 1 ,3 ,4—thiadiaz01—2—y1)— 397 5—( azol—4—y1)phen01 2—(2—methoxy—4—(1H—pyrazol— 1 —y1)pheny1)—5—((2,2,6,6—tetramethy1piperidin—4— 398 y1)methyl)— 1,3 ,4—thiadiazole 2—(2,3—diflu0r0—4—(1H—pyrazol—4—y1)pheny1)—5—(2,7—diazaspir0[3.5]n0nan—2—y1)—1,3 ,4— 399 thiadiazole 2-(5—(2,7—diazaspir0[3.5]n0nan—2—y1)— 1,3 ,4—thiadiazol—2—y1)—3—f1u0r0—5—(1H—pyrazol—4— 400 y1)phenol 4-methoxymethy1(5-(methy1(2,2,6,6-tetramethy1piperidinyl)amin0)-1,3,4- 401 thiadiazoly1)quinolin-2(1H)-one 4—hydr0xy— y1—3 —(5—(methy1(2,2,6,6—tetramethy1piperidin—4—yl)amin0)— 1 ,3 ,4— 402 azol—2—y1)quinolin—2( 1H)—0ne 3 —(5—(methyl(2,2,6,6—tetrarnethy1piperidin—4—y1)amin0)—1,3 ,4—thiadiazol—2—y1)quinolin— 403 2(1H)—0ne 1—methy1—3—(5—(methy1(2,2,6,6—tetramethy1piperidin—4—y1)amin0)—1,3,4—thiadiazol—2— 404 y1)quinolin-2(1H)—0ne 2—(2—Ch10r0-4—( 1H—pyrazol—4—y1)pheny1)—5—((3aR,6aS)—hexahydr0pyrr010[3,4—c]pyrr01— 4051 2(1H)—y1)—1,3,4—thiadiazole 2—(2—ch10r0—4—(1H—pyrazol—4—y1)pheny1)—5—(2,7—diazaspir0[4.5]decan—2—y1)—1,3 ,4— 4061 thiadiazole (R)-(4-(5-(2-ch10r0(1H-pyrazoly1)pheny1)-1,3,4-thiadiazolyl)piperazin 4071 y1)methanol 2—(5—(methyl(2,2,6,6—tetramethylpiperidin—4—y1)amino)—1,3 ,4—thiadiazol—2— 408 y1)benzo[b]thiophene—S—Carbonitrile —(3—ch10r0benzo[b]thiophen—Z—y1)—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4—y1)— 409 1,3 ,4—thiadiazol—2—amine eth0xy—4—(1H—pyrazol—4—y1)pheny1)—N—methy1—N—(2,2,6,6—tetramethy1piperidin—4— 410 y1)—1,3 ,4—thiadiazol—2—amine 2—{ 6—[(1R,SS)—8—azabicyclo[3 .2. 3—y1(methy1)amin0]pyridazin—3—yl }-5—(1H— 4111 pyrazol—4—y1)phen01 2—[6—((1R,SS)—8—azabicyclo[3.2. 1]oct—3—y1amin0)pyridazin—3—y1]—5—(1H—pyrazol—4— 4121 y1)phen01 de Name -(1H—pyrazol—4—y1)—2—{6—[(2,2,6,6—tetramethylpiperidin—4-yl)amino]pyridazin—3— 413]l yl } phenol ethyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin 414 yl } phenol 2—[6—((1R,SS)—8—azabicyclo[3.2. l]oct—3—yloxy)pyridazin—3—yl]—5—(lH—pyrazol—4- 4151 yl)phenol —(5—methyl— lH—pyrazol—4—yl)—2— { 6—[methyl(2,2,6,6—tetramethylpiperidin—4— 416 yl)amino]pyridazin—3 —yl l —(lH—imidazol— l —yl)—2—{ 6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 417 yl }phenol —(5—methyl- lH—pyrazol—4—yl)—2— { 6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 418 yl }phenol 2-{ 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin-3—yl } —5—(4—nitro— lH— 4191 pyrazol— 1—yl)phenol 6-[2-methoxy(4-nitro- azolyl)phenyl]-N-methyl-N-(2,2,6,6- 420 tetramethylpiperidinyl)pyridazinamine —(4—amino— lH-pyrazol— l —yl)—2— { 6— [(2,2,6,6—tetran1ethylpiperidin—4—yl)oxy]pyridazin—3 — 421 yl }phenol 2—[6—(1—methyl— l ,2,3,6—tetrahydropyridin—4—yl)pyridazin—3—yl]—5—(1H—pyrazol—4— 4221 yl)phenol —(4—nitro— lH—pyrazol— l—yl)—2—{ 6— [(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 423 yl }phenol 4241 5—(lH—pyrazol—4—yl)—2—[6—( l ,2,3 ,6—tetrahydropyridin—4—yl)pyridazin—3—yl]phenol 4251 2—[6—(l—ethyl- l ,2,3 ,6—tetrahydropyridin—4—yl)pyridazin—3—yl] —5—(lH—pyrazol-4—yl)phenol 4261 2-{ 6—[methyl(piperidin—4—yl)amino]pyridazin—3—yl } —5—( lH—pyrazol—4—yl)phenol 4271 2-[6—(piperidin—4—ylamino)pyridazin—3—yl] —5—(1H—pyrazolyl)phenol 6-[2,5-difluoro(1H-pyrazolyl)phenyl]-N—methyl-N-(2,2,6,6-tetramethylpiperidin- 4281 4-yl)pyridazinamine 4291 2—[6—(8—azabicyclo[3 .2. l]oct—2—en—3—yl)pyridazin—3—yl] —5—( 1H—pyrazol—4—yl)phenol 6— [2,3—difluoro—4—( lH—pyrazol—4—yl)phenyl] —N—methyl—N—(2,2,6,6—tetramethylpiperidin— 4301 4—yl)pyridazin—3—amine —difluoro—4—( lH—pyrazol—4—yl)phenyl] —6— [(2,2,6,6—tetramethylpiperidin—4— 4311 ]pyridazine 432 2—[6—(piperidin—4—yloxy)pyridazin—3—yl] —5—( lH—pyrazol—4—yl)phenol 2—{ 6—[(1R,SS)—8—azabicyclo[3 .2. l]oct—3—ylamino]pyridazin—3—yl } —5—( l H—pyrazol—4— 4331 nol 6-[2—methoxy—6—(lH—pyrazol—4—yl)pyridin—3—yl] —N—methyl—N—(2,2,6,6— 4341 tetramethylpiperidin—4—yl)pyridazin—3—amine de Name 435 3-[4—(1H—pyrazol—4—yl)pheny1]—6—[(2,2,6,6—tetramethylpiperidin-4—yl)0xy]pyridazine 4361 2- { 6-[(2,6-dimethylpiperidiny1)oxy]pyridaziny1}(1H-pyrazolyl)phenol 3—[2—flu0r0—4—( 1 zol—4—y1)phenyl] —6—[(2,2,6,6—tetramethylpiperidin—4— 4371 y1)0xy]pyridazine 3—[4—(1—methy1—1H—pyraz01—4—y1)thi0phen—2—yl]—6—[(2,2,6,6—tetramethylpiperidin—4— 438 y1)0xy]pyridazine 4391 2—[6—(2,7—diazaspiro[3.5]non—2—y1)pyridazin—3—y1]—5—(1H—pyrazol—4—yl)phen01 440 3—fluor0—4— { 6—[methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino]pyridazin—3—yl }phenol 441 2—{6—[(2,6-dimethy1piperidin—4—y1)0xy]pyridazin—3—y1}—5—(1H—pyrazol—1-y1)phen01 N—methyl—6-(2—methy1—2H—indazol—5—y1)—N—(2,2,6,6—tetramethy1piperidin—4-y1)pyridazin— 442 3—amine 443 2-methyl—5—{ 6— [(2,2,6,6—tetramethy1piperidin—4—y1)0xy]pyridazin-3—yl } dazole 444 3-(4—chloro—2—methoxyphenyl)—6—[(2,2,6,6—tetramethylpiperidin-4—yl)oxy]pyridazine N-methyl(2-methy1pyrazolo[1,5-a]pyridiny1)-N-(2,2,6,6-tetramethylpiperidin 445 y1)pyridazin—3—amine 446 6—{ 6—[(2,2,6,6—tetramethy1piperidin—4—y1)oxy]pyridazin—3—y1}imidazo[ 1 ,2—a]pyridine 3—[2—meth0xy—4—(1H—pyraz01—1—y1)pheny1]—6—[(2,2,6,6—tetramethy1piperidin—4— 447 y1)oxy]pyridazine 3—[5—(1H—pyraz01—4—y1)thi0phen—2—y1] —6— 6,6—tetramethy1piperidin—4— 4481 y1)0xy]pyridazine 3—[5—(1—methy1—1H—pyrazol—4—y1)thi0phen—2—yl]—6—[(22,6,6—tetramethylpiperidin—4— 449 y1)0xy]pyridazine 3—[4—(1H—pyrazol—4—y1)thi0phen—2—y1] —6— [(2,2,6,6—tetramethy1piperidin—4— 4501 y1)0xy]pyridazine -(3,5—dimethy1—1H—pyraz01—4—y1)—2—{6—[(2,2,6,6—tetramethylpiperidin—4— 451 ]pyridaziny1 }phenol 6-[2-fluoro(1H-pyrazoly1)pheny1]-N-methy1-N-(2,2,6,6-tetramethylpiperidin 452 yl)pyridazin—3—amine 453 3—meth0xy—4—{ 6— [(2,2,6,6—tetramethy1piperidin—4—y1)oxy]pyridazin—3—y1 }phenol 3—[2—meth0xy—4—(4—nitro—1H—pyrazol—1—y1)pheny1]—6—[(2,2,6,6—tetramethylpiperidin—4— 454 y1)oxy]pyridazine 455 4—{6—[(2,2,6,6—tetramethy1piperidin—4—y1)oxy]pyridazin—3—y1}benzene—1,3—diol hloro-4—(1H—pyrazol—4—y1)pheny1]—N—methy1—N—(2,2,6,6—tetramethylpiperidin—4— 4561 y1)pyridazin-3—amine 2—(1H—pyrazol—4—y1)—4—{6—[(2,2,6,6—tetramethy1piperidin—4—y1)0xy]pyridazin—3— 457 y1}pyrimidin—5—amine 3-[2,6—diflu0r0—4—(1H—pyraz01—4—y1)pheny1]—6—[(2,2,6,6—tetramethylpiperidin—4— 4581 y1)oxy]pyridazine de Name 459 2-[6—(2,6—diazaspiro[3 .4]oct—2—yl)pyridazin—3—yl] —5 —( lH—pyrazol-4—yl)phenol 3- { 6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl } ( l H-pyrazol 4601 yl)pyridinol 6—( 1 H—pyrazol—4—yl)—3—{ 6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 461 yl in—2—ol N,2,2,6,6—pentamethyl—N— { lH—pyrazol—4—yl)phenoxy] — l ,3 ,4—thiadiazol—2— 4621 yl }piperidin—4—amine N,2,2,6,6—pentamethyl—N— { 5—[4—(lH—pyrazol—4—yl)phenoxy] — l ,3 ,4—thiadiazol—2— 4631 yl }piperidin—4—amine 3—[2—(difluoromethyl)—4—( lH—pyrazol—4—yl)phenyl] —6— [(2,2,6,6—tetramethylpiperidin—4— 4641 yl)oxy]pyridazine and 6—[2—(difluoromethyl)—4—( lH—pyrazol—4—yl)phenyl] —N—methyl—N—(2,2,6,6— 4651 tetramethylpiperidin—4—yl)pyridazin—3—amine wherein a form of the compound is ed from the group consisting of a prodrug, salt, e, solvate, ate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one aspect, the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of: 2—{ 6—[(1R,SS)—8—azabicyclo[3 .2. l]oct—3—yl(methyl)amino]pyridazin—3—yl }—5—(lH— 4111 pyrazol—4—yl)phenol 2—[6—((1R,SS)-8—azabicyclo[3 .2. l]oct—3—ylamino)pyridazin—3—yl]—5—(lH—pyrazol—4— 4121 yl)phenol -(lH—pyrazol—4—yl)—2—{ 6—[(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3— 4131 yl } phenol -( 1 -methyl- lH-pyrazolyl) { 6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin 414 yl } phenol 2—[6—((1R,SS)—8—azabicyclo[3.2. 3—yloxy)pyridazin—3—yl]—5—(lH—pyrazol—4- 4151 yl)phenol —(5—methyl— lH—pyrazol—4—yl)—2— { 6— [methyl(2,2,6,6—tetramethylpiperidin—4— 416 yl)amino]pyridazin—3 —yl }phenol —( lH—imidazol— l —yl)—2—{ 6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 417 yl }phenol —(5—methyl- lH—pyrazol—4—yl)—2— { 6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 418 yl }phenol 2—{ 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin-3—yl } nitro— lH— 4191 pyrazol— l —yl)phenol 6-[2—meth0xy—4—(4—nitr0— 1H—pyrazol—1—y1)pheny1]—N—methy1—N-(2,2,6,6— 420 tetramethylpiperidin—4—y1)pyridazin—3—amine -(4—amin0—1H—pyraz01—1—y1)—2—{6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 421 yl } phenol 2—[6—(1—methy1— 1 ,2,3 ,6—tetrahydropyridin—4—y1)py1°idazin—3—yl] —5—( 1 H—pyrazol—4— 4221 y1)phen01 —(4—nitr0—1H—pyraz01—1—y1)—2—{6—[(2,2,6,6—tetramethy1piperidin—4—yl)0xy]pyridazin—3— 423 yl }phenol 4241 5—( 1H—pyrazol—4—y1)—2—[6—( 1 ,2,3 ,6—tetrahydr0pyridin—4—y1)pyridazin—3—y1]phenol 4251 2—[6—(1—ethy1— 1 ,2,3 ,6—tetrahydr0pyridin—4—y1)pyridazin—3—y1]—5—(1H—pyrazol—4—y1)phen01 4261 2—{ 6—[methyl(piperidin—4—y1)amino]pyridazin—3—y1}—5—(1H—pyrazol—4—yl)phen01 4271 2—[6—(piperidin—4—ylamin0)pyridazin—3—y1]—5—(1H—pyrazol—4—y1)phen01 6—[2,5—diflu0r0—4—(1H—pyrazol—4—y1)pheny1]—N—methy1—N—(2,2,6,6-tetramethylpiperidin— 4281 4-y1)pyridazin—3—amine 4291 2-[6—(8—azabicyclo[3.2.1]oct—2—en—3—y1)pyridazin—3—yl](1H-pyrazol—4—yl)phenol 6-[2,3-diflu0r0—4-( 1 H-pyrazoly1)phenyl] -N-methy1-N-(2,2,6,6-tetramethy1piperidin- 4301 4—y1)pyridazin—3—amine 3—[2,5—diflu0r0—4—( az01—4—y1)pheny1]—6—[(2,2,6,6—tetramethy1piperidin—4— 4311 ]pyridazine 432 2— [6—(piperidin—4—y10xy)pyridazin—3 —y1]—5—( 1H—pyrazol—4—y1)phenol 2—{ ,SS)—8—azabicyclo[3 .2. 1]oct—3—y1amin0]pyridazin—3—y1}—5—(1H—pyraz01—4— 4331 y1)phen01 eth0xy—6—(1H—pyrazol—4—y1)pyridin—3—y1]—N—methy1—N—(2,2,6,6— 4341 tetramethylpiperidin—4—y1)pyridazin—3—amine 435 1H—pyrazol—4—y1)pheny1]—6—[(22,6,6—tetramethylpiperidin—4-yl)oxy]pyridazine 4361 2- { 6—[(2,6—dimethy1piperidin—4—y1)oxy]pyridazin—3—y1}—5—(1H-pyrazol—4—yl)phen01 3-[2-flu0r0(1H-pyrazoly1)phenyl][(2,2,6,6-tetramethy1piperidin 4371 y1)oxy]pyridazine 3—[4—(1—methy1— 1H-pyrazol—4—y1)thiophen—2—yl]—6—[(2,2,6,6—tetramethylpiperidin—4— 438 y1)0xy]pyridazine 4391 2—[6—(2,7—diazaspiro[3.5]non—2—y1)pyridazin—3—y1]—5—(1H—pyrazol—4—yl)phen01 440 3—flu0r0—4— { 6—[methy1(2,2,6,6—tetramethylpiperidin—4—y1)amino]pyridazin—3—y1 }phenol 441 2—{6—[(2,6—dimethy1piperidin—4—y1)0xy]pyridazin—3—y1}—5—(1H—pyrazol—1—yl)phen01 N—methyl—6—(2—methy1—2H—indazol—5—y1)—N—(2,2,6,6—tetramethy1piperidin-4—y1)pyridazin— 442 3—amine 443 2—methyl—5— { 6— [(2,2,6,6—tetramethy1piperidin—4—y1)0xy]pyridazin—3—yl } —2H-indazole 444 3-(4—chlor0—2—methoxyphenyl)—6—[(22,6,6—tetramethylpiperidin-4—yl)0xy]pyridazine N-methyl—6—(2—methy1pyrazolo[1,5—a]pyridin—3—y1)—N—(2,2,6,6-tetramethylpiperidin—4— 445 y1)pyridazinamine 446 6—{ 2,6,6—tetran1ethylpiperidin—4—yl)oxy]pyridazin—3—yl}imidazo[ l ,2—a]pyridine 3-[2—methoxy—4—(1H—pyrazol—1—y1)pheny1]—6—[(2,2,6,6—tetramethylpiperidin—4— 447 ]pyridazine 3-[5-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidin 4481 yl)oxy]pyridazine 3—[5—(1—methyl— 1H—pyrazol—4—yl)thiophen—2—yl]—6—[(2,2,6,6—tetran1ethylpiperidin—4— 449 yl)oxy]pyridazine 3—[4—(1H—pyrazol—4—yl)thiophen—2—yl] —6— [(2,2,6,6—tetramethylpiperidin—4— 4501 yl)oxy]pyridazine —(3 ,5—dimethyl— 1H—pyrazol—4—yl)—2— { 6— [(2,2,6,6—tetramethylpiperidin—4— 451 yl)oxy]pyridazin—3—yl l 6—[2—fluoro—4-(lH—pyrazol—4—yl)pheny1]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— 452 yl)pyridazin—3—an1ine 453 3-methoxy—4—{ 6— [(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3—yl l 3-[2—methoxy—4—(4—nitro— lH—pyrazol—1—y1)phenyl]—6—[(2,2,6,6-tetramethylpiperidin—4— 454 yl)oxy]pyridazine 455 4— { 6—[(2,2,6,6—tetramethylpiperidin—4—y1)oxy]pyridazin—3—yl}benzene— 1 ,3—diol 6—[2—chloro—4—(1H—pyrazol—4—yl)phenyl]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— 4561 yl)pyridazin—3—an1ine 2—(1H—pyrazol—4—yl)—4—{6—[(2,2,6,6—tetramethylpiperidin—4—yl)oxy]pyridazin—3— 457 yl }pyrimidin—S—amine 3—[2,6—difluoro—4—(1H—pyrazol—4—yl)phenyl]—6—[(2,2,6,6—tetramethylpiperidin—4— 4581 yl)oxy]pyridazine 459 2—[6—(2,6—diazaspiro[3.4]oct—2—yl)pyridazin—3—yl]—5—(1H—pyrazol—4—yl)phenol 3—{ 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl } —6—( lH—pyrazol—4— 4601 yl)pyridin—2—ol 6-(1H—pyrazol—4—y1)—3—{6—[(2,2,6,6—tetramethylpiperidin—4-yl)oxy]pyridazin—3— 461 yl } pyridinol N,2,2,6,6-pentamethyl-N—{5-[3-(1H-pyrazoly1)phenoxy]-1,3,4-thiadiazol 4621 yl } piperidin—4—amine N,2,2,6,6—pentamethyl—N— { 5—[4—(1H—pyrazol—4—yl)phenoxy] — 1 ,3 ,4—thiadiazol—2— 4631 yl }piperidin—4—amine 3—[2—(difluoromethyl)—4—(1H—pyrazol—4—yl)pheny1]—6—[(2,2,6,6—tetramethylpiperidin—4— 4641 ]pyridazine and 6—[2—(difluoromethyl)—4—(1H—pyrazol—4—yl)pheny1]—N—n1ethyl—N—(2,2,6,6— 4651 tetramethylpiperidin—4—yl)pyridazin—3—amine wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereorner, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the use of a compound salt of Formula (I) or a form thereof includes a method of use of a compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an ive amount of the nd salt of Formula (I) or a form f to the t, selected from the group consisting of: de Name 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—4— 32 (trifluoromethyl)phenol hydrochloride 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3 —yl)—4—( l H—pyrazol— l— 53 yl)phenol hydrochloride 65 2—(6—piperazin— l—yl—pyridazin—3—yl)—5— lH—pyrazol— l—yl—phenol hloride 82 3—(6-(piperazin— l ridazin—3 —yl)naphthalene—2,7 —diol trifluoroacetate 86 3-(6-(1,2,3,6—tetrahydropyridin—4—yl)pyridazin—3—yl)naphthalene-2,7—diol trifluoroacetate 3-(6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazin-3 -yl)naphthalene-2,7-diol 88 trifluoroacetate 89 3—(6—(piperidin—4—yl)pyridazin—3—yl)naphthalene—2,7—diol trifluoroacetate 6—hydroxy—5—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—2,3— 151 dihydro— 1 H—inden— 1 —one oxime hydrochloride 2—amino—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—8H— 153 indeno[ l ,2—d] thiazol—S—ol hydrochloride 9—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5,6— 154 dihydroimidazo[5 , l —a] isoquinolin—8—ol hydrochloride 3—fluoro—S—(2—methoxypyridin—4—yl)—2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4— 160 yl)amino)pyridazin—3—yl)phenol hydrochloride 4-(3-fluoro—S—hydroxy—4—(6—(methyl(2,2,6,6—tetramethylpiperidinyl)amino)pyridazin—3— 161 yl)phenyl)pyridin—2(1H)—one hydrochloride 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 162 yl)phenyl)— 1—methylpyridin—2(1H)—one hloride —(3—fluoro—5—hydroxy—4—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3— 163 yl)phenyl)— ylpyridin—2(1H)—one hydrochloride 3—fluoro—5—( l H—pyrazol—4—yl)—2—(6—((22,6,6—tetramethylpiperidin—4—yl)oxy)pyridazin—3— 164 yl)phenol hydrochloride —chloro—3—fluoro—2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3— 165 yl)phenol hydrochloride 3—fluoro—2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5—( 1H— 166 pyrazol—4—yl)phenol hydrochloride 3—fluoro—2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5—( l — 167 methyl—1H—pyrazol—4—yl)phenol hydrochloride de Name 3-(1H—imidazol—1—yl)—6—(6—(methyl(2,2,6,6—tetramethylpiperidinyl)amino)pyridazin—3— 226 nolinol hydrochloride 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline-3 ,7-diol 227 formate 7—hydroxy—1—methyl-6—(6—(rnethyl(2,2,6,6—tetrarnethylpiperidin—4—yl)amino)pyridazin—3— 231 yl)quinolin—2( l H)—one hydrochloride 4—rnethoxy—7—(6—(rnethyl(2,2,6,6—tetrarnethylpiperidin—4—yl)amino)pyridazin—3—yl)quinolin— 238 6—ol formate 7—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)quinoxalin—6—ol 239 hydrochloride 2—rnethyl—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—4— 254 (tetrahydro—2H—pyran—4—yl)quinolin—7—ol formate 4—(dimethylamino)—6—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)— 256 quinolin—7—ol formate oxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin 281 yl)isoquinolin-1(2H)-one hydrochloride 3—(5—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)arnino)— 1,3 adiazol—2—yl)naphthalen— 322 2—ol hydrobromide N—methyl—S—(5—( 1 —methyl— lH—pyrazol—4—yl)pyridin—2—yl)—N—(2,2,6,6—tetramethylpiperidin— 342 4—yl)— 1,3,4—thiadiazol—2—amine hydrochloride 3—fluoro—2—(5—((3aR,6aS)—hexahydropyrrolo[3 ,4—c]pyrrol—2(lH)—yl)— l ,3,4—thiadiazol—2—yl)— 396 5—( l H—pyrazol—4—yl)phenol ochloride 2—(2—chloro—4-( l H—pyrazol—4—yl)phenyl)—5 —((3 aR,6aS)—hexahydropyrrolo[3,4-c]pyrrol— 405 2( lH)—yl)— l ,3 ,4-thiadiazole hydrochloride 2—(2—chloro—4—(lH—pyrazol—4—yl)phenyl)—5—(2,7—diazaspiro[4.5]decan—2—yl)— 1,3,4— 406 thiadiazole hydrochloride —(5—(2—chloro—4—(1H—pyrazol—4—yl)phenyl)— l,3,4—thiadiazolyl)piperazin—2— 407 yl)methanol hydrochloride 2— { 6—[8—azabicyclo[3 .2. l]oct—3—yl(methyl)amino]pyridazin—3—yl } —5 —( 1 H—pyrazol—4- 411 nol hydrochloride 2— [6—(8—azabicyclo[3 .2. l]oct—3—ylamino)pyridazin—3—yl] —5—( lH—pyrazol—4—yl)phenol 412 hydrochloride —(lH—pyrazol—4—yl)—2— { 6— [(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3— 413 yl }phenol hydrochloride 2— azabicyclo[3 .2. l]oct—3—yloxy)pyridazin—3—yl] —5 —( lH—pyrazol—4—yl)phenol 415 hydrochloride 2— { 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl } —5—(4—nitro— lH— 419 pyrazol— l—yl)phenol dihydrochloride de Name 2-[6-(1—methyl—1,2,3,6—tetrahydropyridin—4—yl)pyridazin—3—yl](1H—pyrazol—4—y1)phenol 422 trihydrochloride -( 1 H-pyrazolyl) [6-( 1 ,2,3 ,6-tetrahydropyridiny1)pyridazinyl]phenol 424 trihydrochloride 2—[6—(1—ethyl— 1,2,3 rahydropyridin—4—yl)pyridazin—3—yl]—5—(1H—pyrazol—4—yl)phenol 425 trihydrochloride 2— { 6—[methyl(piperidin—4—yl)amino]pyridazin—3—yl } —5 —(lH—pyrazol—4—yl)phenol 426 tetrahydrochloride 427 2— [6—(piperidin—4—ylamino)pyridazin—3 —yl] —5—( lH—pyrazol—4—yl)phenol tetrahydrochloride 6— [2,5—difluoro-4—(lH—pyrazol—4—yl)phenyl] —N—rnethyl—N—(2,2,6,6—tetramethylpiperidin—4— 428 yl)pyridazin—3-arnine tetrahydrochloride 2— [6—(8—azabicyclo[3 .2. 2—en—3 —yl)pyridazin—3 —yl] —5—( l H—pyrazol—4—yl)phenol 429 hydrochloride 6-[2,3—difluoro—4—(1H—pyrazol—4—y1)phenyl]—N—methyl—N—(2,2,6,6-tetramethylpiperidin—4— 430 yl)pyridazinamine hloride 3— [2,5—difluoro—4—( 1 H—pyrazol—4—yl)pheny1] —6—[(2,2,6,6—tetramethylpiperidin—4— 431 yl)oxy]pyridazine trihydrochloride 2— { 6—[(1R,SS)—8—azabicyclo[3 .2. l]oct—3—ylamino]pyridazin—3—yl}—5—(lH—pyrazol—4— 433 yl)phenol hydrochloride nethoxy—6—(1H—pyrazol—4—yl)pyridin—3 —yl] —N—rnethyl—N—(2,2,6,6— 434 tetramethylpiperidin—4—yl)pyridazin—3—amine hydrochloride 2— { 6—[(2,6—dimethylpiperidin—4—yl)oxy]pyridazin—3—yl } —5 —( lH—pyrazol—4—yl)phenol 436 trihydrochloride uoro—4—(1H—pyrazol—4—yl)phenyl]—6—[(2,2,6,6—tetramethylpiperidin—4— 437 yl)oxy]pyridazine hydrochloride 2- [6-(2,7—diazaspiro[3 .5]non—2—yl)pyridazin—3—yl] —5 —(1H—pyrazolyl)phenol 439 tetrahydrochloride 3- [5 -( 1 H-pyrazolyl)thiopheny1] [(2,2,6,6-tetramethylpiperidin 448 yl)oxy]pyridazine hloride 3— [4—( l H—pyrazol—4—yl)thiophen—2—yl] —6—[(22,6,6—tetrarnethylpiperidin—4— 450 yl)oxy]pyridazine hydrochloride 6— [2—chloro—4—( 1 H—pyrazol—4—yl)phenyl] —N—rnethyl—N—(2,2,6,6—tetrarnethylpiperidin—4— 456 yl)pyridazin—3—arnine trihydrochloride 3— ifluoro—4—(lH—pyrazol—4—yl)phenyl] —6—[(22,6,6—tetramethylpiperidin—4— 458 yl)oxy]pyridazine trihydrochloride 3— { 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl}—6—( 1H-pyrazol—4— 460 yl)pyridin—2—ol hydrochloride N,2,2,6,6—pentamethyl—N—{ 5—[3—(lH—pyrazol—4—yl)phenoxy]— 1,3 ,4-thiadiazol—2— 462 yl }piperidin—4—amine hydrochloride de Name N,2,2,6,6—pentamethyl—N—{ 5—[4—(lH—pyrazol—4—yl)phenoxy]— 1,3,4-thiadiazol—2— 463 yl } piperidinamine hydrochloride 3-[2-(difluoromethyl)(lH-pyrazolyl)pheny1][(2,2,6,6-tetramethylpiperidin 464 y1)oxy]pyridazine hydrochloride and 6—[2—(difluoromethyl)—4—(lH—pyrazol—4—yl)phenyl]—N—methyl—N—(2,2,6,6— 465 tetramethylpiperidin—4—yl)pyridazin—3—amine hloride wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one aspect, the compound salt of a (I) or a form thereof includes a compound salt selected from the group consisting of: 2- { 6-[8—azabicyclo[3 .2. 1]oct—3—yl(methy1)amino]pyridazinyl } -5 -( l H—pyrazol—4— 411 yl)phenol hydrochloride 2—[6—(8—azabicyclo[3.2. l]oct—3—ylamino)pyridazin—3—y1]—5—(1H—pyrazol—4—yl)phenol 412 hydrochloride —(1H—pyrazol—4—yl)—2— { 6—[(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3 — 413 nol hydrochloride 2— [6—(8—azabicyclo[3 .2. l]oct—3—yloxy)pyridazin—3—yl] —5 —( lH—pyrazol—4—yl)phenol 415 hloride 2— { 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl } —5—(4-nitro— lH— 419 pyrazol— l —yl)phenol dihydrochloride 2— [6—( 1 —methyl— 1,2,3 ,6—tetrahydropyridin—4—yl)pyridazin—3—yl] —5—(lH—pyrazol—4—yl)phenol 422 trihydrochloride -(1H—pyrazol—4—y1)—2— [6—( l ,2,3 ,6—tetrahydropyridin—4—yl)pyridazin-3—yl]phenol 424 rochloride 2-[6-(l-ethyl-1,2,3,6-tetrahydropyridinyl)pyridaziny1](lH-pyrazolyl)phenol 425 trihydrochloride 2— { 6— [methyl(piperidin—4—yl)amino]pyridazin—3 —yl } —5 —( l H—pyrazol—4—yl)phenol 426 tetrahydrochloride 427 2—[6—(piperidin—4—ylamino)pyridazin—3—yl]—5—(lH—pyrazol—4—yl)phenol tetrahydrochloride 6—[2,5—difluoro—4—(lH—pyrazol—4—yl)phenyl]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— 428 yl)pyridazin—3—amine tetrahydrochloride 2— [6—(8—azabicyclo[3 .2. 2—en—3 ridazin—3 —yl] —5—( l H—pyrazol—4—yl)phenol 429 hydrochloride 6—[2,3—difluoro—4—(lH—pyrazol—4—yl)phenyl]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— 430 yl)pyridazin—3—amine hydrochloride 3— [2,5-difluoro—4—(lH—pyrazol—4—yl)phenyl] —6—[(2,2,6,6—tetramethylpiperidin—4— 431 yl)oxy]pyridazine trihydrochloride 2-{6-[(1R,SS)—8—azabicyclo[3.2.1]oct—3—ylamino]pyridazinyl}(1H—pyrazol—4— 433 yl)phenol hydrochloride ethoxy—6—(1H—pyrazol—4—yl)pyridin—3 —yl] —N—methyl—N—(2,2,6,6— 434 tetramethylpiperidin-4—yl)pyridazin—3—amine hydrochloride 2— { 6—dimethylpiperidin—4—yl)oxy]pyridazin—3—yl } —5 —( lH—pyrazol—4—yl)phenol 436 trihydrochloride 3—[2—fluoro—4—(1H—pyrazol—4—yl)phenyl]—6—[(2,2,6,6—tetramethylpiperidin—4— 437 yl)oxy]pyridazine hydrochloride 2— [6—(2,7—diazaspiro[3 .5]non—2—yl)pyridazin—3—yl] —5 —(lH—pyrazol—4—yl)phenol 439 tetrahydrochloride 3— [5—(lH—pyrazol—4—yl)thiophen—2—yl] —6—[(22,6,6—tetramethylpiperidin—4— 448 yl)oxy]pyridazine hydrochloride 3-[4-(1H—pyrazol—4—yl)thiophen—Z—yl]—6—[(2,2,6,6—tetramethylpiperidin—4— 450 yl)oxy]pyridazine hydrochloride 6-[2-chloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin 456 yl)pyridazin—3—amine trihydrochloride 3— [2,6—difluoro—4-(lH—pyrazol—4—yl)phenyl] 2,6,6—tetramethylpiperidin—4— 458 yl)oxy]pyridazine trihydrochloride 3— { 6—[methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl}—6—( 1H—pyrazol—4— 460 yl)pyridin—2—ol hydrochloride 6,6—pentamethyl—N—{ 5—[3—(lH—pyrazol—4—yl)phenoxy]— 1,3 ,4—thiadiazol—2— 462 yl idin—4-amine hydrochloride N,2,2,6,6—pentamethyl—N—{ 5—[4—(lH—pyrazol—4—yl)phenoxy]— 1,3 ,4—thiadiazol—2— 463 yl }piperidin—4—amine hydrochloride 3- [2-(difluoromethyl)—4—( lH—pyrazol—4—yl)phenyl] —6— [(2,2,6,6—tetramethylpiperidin—4— 464 ]pyridazine hydrochloride and 6-[2—(difluoromethyl)(1H-pyrazolyl)pheny1]-N-methyl-N-(2,2,6,6- 465 ethylpiperidin-4—yl)pyridazin—3—amine hydrochloride wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, ologue, racemate, omer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.
Another embodiment of the present description includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (I) or a form thereof to the subject.
Another embodiment of the present description includes a use of the compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need f, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.
Another embodiment of the present description includes a use of the compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (I) or a form thereof to the subject. al tions As used herein, the term "C1_4alkyl" generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n—propyl, isopropyl, n—butyl, isobutyl, tyl, tert—butyl, and the like. In some embodiments, C1_4alkyl includes C1_3alkyl, C1_zalkyl, and the like. A C1_4alkyl radical may be ally substituted where allowed by available valences.
As used herein, the term "C2_6alkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to five carbon atoms in a straight or branched chain configuration and one or more —carbon double bonds therein, including, without limitation, l, allyl, propenyl and the like. In some embodiments, C2-6alkenyl includes C2_4alkenyl, C2_3alkenyl, and the like. A C2_6alkenyl radical may be optionally tuted where allowed by available valences.
As used , the term "C1_4alkoxy" generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a ht or branched chain configuration of the formula: —O—C1_4alkyl, including, without limitation, methoxy, ethoxy, n—propoxy, isopropoxy, n—butoxy, oxy, sec—butoxy, tert—butoxy, and the like. In some embodiments, C1_4alkoxy includes C1_3a]koxy, C1_2alkoxy and the like. A koxy radical may be ally substituted where allowed by available valences.
As used herein, the term "C3_14cycloalkyl" generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without tion, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro—naphthalenyl and the like. In some embodiments, C3_14cycloalkyl includes ycloalkyl, C3_gcycloalkyl, C3_7cycloalkyl, C5_gcycloalkyl, C9_10cycloalkyl and the like. A C3_14cycloalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "C3_14cycloalkenyl" generally refers to a partially unsaturated monocyclic, ic or polycyclic arbon radical having one or more chemically stable carbon—carbon double bonds therein, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. In some embodiments, C3_14cycloalkenyl includes C3_7cycloalkenyl, C3_gcycloalkenyl, C5_gcycloalkenyl, C3_locycloalkenyl and the like. A C3_l4cycloalkenyl radical may be optionally substituted where allowed by ble valences.
As used herein, the term "aryl" generally refers to a monocyclic, ic or polycyclic aromatic carbon atom ring structure radical, including, without tion, phenyl, yl, anthracenyl, yl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.
As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring ure l in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, l, indazolyl, indolizinyl, benzofuranyl, hienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H—purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, olinyl, acridinyl, phthalazinyl, imidazo[l,2— a]pyridinyl, imidazo[ l ,5—a]pyridinyl, imidazo[5 , l —a]isoquinolinyl, l,4—dihydroindeno[ l ,2—c] — lH— pyrazolyl, 2,3—dihydro—lH—inden—l—one, 2,3—dihydro—lH—indenyl, 3,4—dihydroquinolin—2(1H)— one, 5,6—dihydroimidazo[5 , l—a]isoquinolinyl, 8H—indeno[ l ,2—d]thiazolyl, c][1,2,5]oxadiazolyl, benzo[d]oxazol—2(3H)—one, in—2(lH)-one, quinazolin—4(lH)— one, quinazoline—2,4(1H,3H)—dione, [d]oxazolyl, pyrazolo[1,5-a]pyridinyl, and the like.
A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term "heterocyclyl" generally refers to a saturated or lly unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without tion, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, ydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, lidinyl, oimidazolyl, imidazolinyl, olidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, lidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, olinyl, tetrazolidinyl, dihydro—2H-pyranyl, dihydro-pyridinyl, tetrahydro—pyridinyl, 1,2,3,6—tetrahydropyridiny1, hexahydro—pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5 ,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro—pyrazinyl, dihydro—pyridazinyl, tetrahydro—pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro—triazinyl, tetrahydro—triazinyl, hexahydro—triazinyl, 1,4—diazepanyl, dihydro—indolyl, indolinyl, tetrahydro—indolyl, dihydro—indazolyl, tetrahydro—indazolyl, dihydro—isoindolyl, dihydro—benzofuranyl, tetrahydro—benzofuranyl, dihydro—benzothienyl, tetrahydro—benzothienyl, dihydro—benzimidazolyl, ydro—benzimidazolyl, o—benzooxazolyl, 2,3—dihydrobenzo[d]oxazolyl, tetrahydro—benzooxazolyl, dihydro—benzooxazinyl, 3 ,4—dihydro—2H—benzo [b] [ 1,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxoly1, benzo[ 1 ,4]dioxany1, dihydro—purinyl, tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydro—isoquinolinyl, 3,4-dihydroisoquinolin—(1H)—yl, tetrahydro—isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, dihydro—quinazolinyl, tetrahydro—quinazolinyl, dihydro—quinoxalinyl, ydro—quinoxalinyl, 1,2,3,4—tetrahydroquinoxalinyl, oxolanyl, 2,5—dihydro—1H— pyrrolyl, 4,5—dihydro—lH—imidazolyl, tetrahydro—ZH—pyranyl, hexahydropyrrolo[3,4— b] [1,4]oxazin—(2H)—yl, (4aR,7aS)—hexahydropyrrolo[3 ,4—b] [1,4]oxazin—(4aH)—yl, 3,4—dihydro—2H— pyrido[3 ,2—b] [1,4]oxazinyl, (cis)—octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3 ,4— b]pyrrol—(1H)—yl, (3aR,6aR)—hexahydropyrrolo[3,4—b]pyrrol—(1H)—yl, (3aR,6aS)— hexahydropyrrolo[3,4—c]pyrrol—(1H)—yl, 5H—pyrrolo[3,4—b]pyridin—(7H)-yl, 5,7—dihydro—6H— pyrrolo[3,4-b]pyridinyl, ydro—1H—pyrrolo[3,4—b]pyridin—(ZH,7H,7aH)—yl, hexahydro— 1H— o[3,4-b]pyridin—(2H)—yl, (4aR,7aR)—hexahydro— lH—pyrrolo[3,4—b]pyridin—(2H)—yl, dro-6H—pyrrolo[3,4—b]pyridinyl, 2,3,4,9—tetrahydro—lH—carbazolyl, 1,2,3,4— tetrahydropyrazino[1,2-a]indolyl, hydro-1H-pyrrolo[1,2—a]indolyl, aR)- hexahydrocyclopenta[c]pyrrol—( lH)—yl, (3aR,4R,6aS)—hexahydrocyclopenta[c]pyrrol—( 1 H)—yl, (3aR,4S,6aS)—hexahydrocyclopenta[c]pyrrol—(lH)—yl, (3aR,5r,6aS)— hexahydrocyclopenta[c]pyrrol—(lH)—yl, l,3—dihydro—2H—isoindolyl, octahydro—2H—isoindolyl, (3aS)—l,3,3a,4,5,6—hexahydro—2H—isoindolyl, (3aR,4R,7aS)—lH—isoindol— (3H,3aH,4H,5H,6H,7H,7aH)—yl, (3aR,7aS)—octahydro—2H—isoindolyl, (3aR,4R,7aS)—octahydro— 2H—isoindolyl, (3aR,4S,7aS)—octahydro—2H—isoindolyl, 2,5—diazabicyclo[2.2.l]heptanyl, 2— azabicyclo[2.2.l]heptenyl, 3—azabicyclo[3.l.0]hexanyl, 3,6—diazabicyclo[3.l.0]hexanyl, (lR,SS)— 3—azabicyclo[3.1.0]hexanyl, (lS,5R)—3—azabicyclo[3.2.0]heptanyl, 5—azaspiro[2.4]heptanyl, 2,6— diazaspiro[3.3]heptanyl, 2,5—diazaspiro[3.4]octanyl, 2,6—diazaspiro[3.4]octanyl, 2,7— piro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decanyl, 3 ,6-diazabicyclo[3 .2. l]octyl, hydroindeno[ l ,2—c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H—indeno[l,2—d]thiazolyl, tetrahydroimidazo[1,2—a]pyridinyl, n—2(lH)—one, (lR,SS)—8—azabicyclo[3.2.l]octyl, 8—azabicyclo[3.2. 2—enyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term "C2_4alkenyl—amino—carbonyl" refers to a radical of the formula: —C(=O)—NH—C2_4alkenyl.
As used herein, the term "C1_4a1koxy—C1_4alkoxy" refers to a radical of the formula: -O-C14alkyl-O-C1.4alkyl.
As used herein, the term "C1_4alkoxy—carbonyl" refers to a radical of the formula: —C(=O)—O—C1_4alkyl.
As used herein, the term "C1-4alkoxy—carbonyl—amino" refers to a radical of the a: —NH—C(=O)—O—C1_4alkyl.
As used herein, the term "C1-4alkoxy—carbonyl—amino—C1-4alkoxy" refers to a radical of the formula: —O—C14all As used herein, the term "C1_4alkyl—C1_4alkoxy" refers to a radical of the formula: —O-C14alkyl—C1_4all As used , the term "C1_4alkyl—amino" refers to a radical of the formula: -NH—C14alkyl.
As used herein, the term "(C1_4alkyl)2-amino" refers to a radical of the formula: —N(C14alkyl)2.
As used herein, the term "C1-4alkyl—amino—C1-4alkoxy" refers to a radical of the formula: —O—C14alkyl—NH—C1_4alkyl.
As used herein, the term "(C1-4alkyl)2—amino—C1-4alkoxy" refers to a radical of the formula: —O—C1_4alkyl—N(C1-4alkyl)2.
As used herein, the term "C1-4alkyl—amino—C1_4alkyl" refers to a radical of the formula: —C1_4alkyl—NH—C1_4alkyl.
As used , the term "(C1-4alkyl)2—amino—C1-4alkyl" refers to a radical of the formula: -C14alkyl—N(C1_4alkyl)2.
As used herein, the term "C1.4alkyl-amino-carbonyl" refers to a radical of the formula: —C(=O)—NH—C1_4alkyl.
As used herein, the term "(C1-4alkyl)2—amino—carbonyl" refers to a radical of the formula: —C(=O)-N(C14alkyl)2.
As used herein, the term "C1-4alkyl—amino—carbonyl—C1-4alkyl" refers to a radical of the formula: —C1_4a]kyl-C(=O)—NH—C1-4alkyl.
As used herein, the term "(C1-4alkyl)2—amino—carbonyl—C1-4alkyl" refers to a radical of the formula: —C1_4alkyl—C(=O)—N(C1-4alkyl)2.
As used herein, the term lkyl—carbonyl" refers to a radical of the a: -C(=O)-C14alkyl.
As used herein, the term "C1_4a]l As used herein, the term "C1-4alkyl—carbonyl—amino—C1-4alkoxy" refers to a radical of the formula: —O—C14alkyl—NH—C(=O)—C1-4alkyl.
As used herein, the term "C1-4alkyl—carbonyl—amino—C1-4alkyl" refers to a l of the formula: —C1_4a]kyl-NH—C(=O)—C1-4alkyl.
As used herein, the term "amino" refers to a radical of the formula: —NH2.
As used herein, the term —C1_4alkoxy" refers to a l of the formula: -O—C14alkyl—NH2.
As used herein, the term "amino—C1_4alkyl" refers to a l of the formula: -C1_4alkyl—NH2.
As used herein, the term "amino-carbonyl" refers to a radical of the formula: —C(=O)—NH2.
As used herein, the term "cyano" refers to a radical of the formula: —CN.
As used herein, the term "C3_7cycloalkyl—C1-4alkoxy" refers to a radical of the formula: —O—CMalkyl—ngcycloalkyl.
As used , the term C1_4alkoxy" refers to a radical of the formula: —O—C1_4alkyl—halo, wherein C1_4alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo—C1_4alkoxy es 1_6alkoxy, halo—C1_4alkoxy and the like.
As used herein, the term "halo—C1_4alkyl" refers to a radical of the formula: kyl-halo, wherein C1-4alkyl may be partially or tely substituted where allowed by ble valences with one or more halogen atoms. In some embodiments, halo—C1_4alkyl includes halo—C1_6alkyl, halo—C1_4alkyl and the like.
As used herein, the term "heteroaryl—C1_4alkyl" refers to a radical of the formula: —C1_4alkyl—heteroaryl.
As used herein, the term "heteroaryl—C1-4alkyl—amino" refers to a radical of the formula: —NH—C14alkyl—heteroaryl.
As used herein, the term "heteroaryl—C1-4alkyl—amino—carbonyl" refers to a radical of the formula: -C(=O)—NH—C1-4alky1—heteroaryl.
As used herein, the term "heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl" refers to a radical of the formula: -C1_4alkyl-C(=O)-NH-C1-4alkyl-heteroaryl.
As used herein, the term "heteroaryl—C1-4alkyl—carbonyl—amino" refers to a radical of the formula: —NH—C(=O)—C1-4alkyl—heteroaryl.
As used , the term "heteroaryl—C1-4alkyl—carbonyl—amino—C1-4alkyl" refers to a radical of the formula: —C1-4alkyl—NH—C(=O)—C1-4alkyl—heteroaryl.
As used herein, the term "heterocyclyl—C1-4alkoxy" refers to a radical of the formula: —C1_4a]koxy-heterocyclyl.
As used herein, the term "heterocyclyl—C1-4alkyl" refers to a radical of the formula: -C1_4alkyl—heterocyclyl.
As used herein, the term xyl" refers to a radical of the formula: —OH.
As used herein, the term "hydroxyl—C1_4a1koxy" refers to a l of the formula: -O-C14alkyl-OH, wherein kyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.
As used herein, the term "hydroxyl—C1_4alkyl" refers to a radical of the formula: —C1_4alkyl—OH, wherein C1_4alkyl may be partially or tely substituted where allowed by available valences with one or more hydroxy ls.
As used herein, the term "hydroxyl—C1-4alkyl—amino" refers to a radical of the formula: —NH—C14alkyl—OH, wherein C1_4alkyl may be partially or completely substituted where allowed by available es with one or more hydroxyl radicals.
As used herein, the term "hydroxyl—imino" refers to the =NOH radical of the formula: C(=NOH).
As used herein, the term "oxo" refers to the radical of the formula: C=O.
As used herein, the term "phenyl—C1_4alkoxy" refers to a radical of the formula: koxy—phenyl.
As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a ated atom on, replacing one or more hydrogens on the ated atom, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such ations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "20") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (I). A person of ry skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
As used herein, the term "and the like," with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, s (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or clic ring structures) and all other variations where allowed by available valences which result in a stable compound.
For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as riate, independently and/or optionally substituted.
As used herein, the terms "independently selected," or "each selected" refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence.
Further, the use of a generic tuent le on any formula or structure for a compound described herein is understood to e the replacement of the generic substituent with species substituents that are included within the particular genus, e. g., aryl may be replaced with phenyl or alenyl and the like, and that the resulting compound is to be included within the scope of the nds described .
As used herein, the terms "each instance of" or "in each instance, when present," when used preceding a phrase such as . .C3_14cycloalkyl, C3_14cycloalkyl—C1-4alkyl, aryl, aryl—C1_4alkyl, heteroaryl, heteroaryl—C1_4alkyl, heterocyclyl and heterocyclyl—C14alkyl," are intended to refer to the ycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.
As used herein, the term "optionally substituted" means optional substitution with the specified substituent variables, groups, ls or moieties.
Compound Forms As used herein, the term "form" means a compound of Formula (I) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, te, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In certain embodiments described herein, the form of the compound of a (I) is a free acid, free base or salt thereof.
In certain embodiments bed herein, the form of the compound of a (I) is a salt thereof.
In certain ments described herein, the form of the compound of Formula (I) is an isotopologue thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
In certain ments described herein, the form of the compound of Formula (I) is a tautomer thereof.
In certain embodiments described herein, the form of the nd of Formula (I) is a pharmaceutically acceptable form.
In certain embodiments described herein, the nd of Formula (I) or a form thereof is isolated for use.
As used herein, the term ted" means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or ed from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the d artisan (e. g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard ical ques described herein or well known to the skilled artisan.
As used herein, the term "protected" means that a functional group in a compound of Formula (I) or a form f is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and ylic 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 ylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a polymer resin, such as a Wang resin or a 2—chlorotrityl— chloride resin. ting groups may be added or removed in accordance with standard techniques, which are nown to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected derivatives of nds bed herein may not possess pharmacological activity as such, they may be administered to a t and thereafter metabolized in the body to form compounds described herein which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds described herein are included within the scope of the use described herein.
As used herein, the term "prodrug" means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (2.g. lic and/or , by non—metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A sion of the use of prodrugs is ed by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical ation and Pergamon Press, 1987.
In one e, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a onate ester and the like. In r example, when a compound of Formula (I) or a form thereof contains an amine onal group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono—, di— or triphosphate esters or alkyl substituents, where riate. As described herein, it is tood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof as a prodrug.
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 embrace both solvated and unsolvated forms.
As used herein, the term "solvate" means 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 the solvate will be capable of isolation, for example when one or more solvent molecules are orated in the crystal lattice of the crystalline solid. As used herein, "solvate" encompasses both on— phase and isolatable solvates. Non—limiting examples of le solvates include ethanolates, methanolates, and the like.
As used herein, the term "hydrate" means a solvate wherein the solvent molecule is water.
The nds of Formula (I) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I) or a form thereof herein is understood to include reference to salt forms thereof, unless ise indicated. The term s)", as employed herein, s acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) or a form thereof contains both a basic , such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a ylic acid, rions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective (i.€., non-toxic, physiologically able) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of Formula (I) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. ceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. ments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, ate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, ate, iodide, isonicotinate, lactate, e, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain embodiments of acid addition salts include de, dichloride, trichloride, bromide, acetate, formate or trifluoroacetate salts.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley—VCH; S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1) 1—19; P. Gould, International J. maceutics (1986) 33, 201—217; Anderson et al, The Practice ofMedicinal Chemistry , ic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, DC. on their e). These disclosures are incorporated herein by reference thereto.
Suitable basic salts include, but are not limited to, aluminum, um, calcium, m, magnesium, potassium, sodium and zinc salts.
All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.
Compounds of Formula (I) and forms thereof, may r exist in a tautomeric form. All such tautomeric forms are plated and intended to be included within the scope of the compounds of a (I) or a form thereof as described herein.
The compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) as well as es thereof, including racemic mixtures.
The compounds described herein may include one or more chiral centers, and as such may exist as c mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions ntially comprising only the (S) isomer. In another embodiment, the nds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as 21 (RR), (RS), (SR) or (S, S) isomer, as defined by IUPAC Nomenclature Recommendations.
As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount r than or equal to 95%, in an amount r than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
As used herein, a ate" is any mixture of ric forms that are not "enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.
In addition, the present description embraces all geometric and positional isomers. For example, if a compound of a (I) or a form thereof incorporates a double bond or a fused ring, both the cis— and trans—forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be ted into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional llization. Enantiomers can be ted by use of chiral HPLC column or other chromatographic methods known to those d in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., yzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), ric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional s (such as, for example, 4—pyridyl and 3—pyridyl). Individual stereoisomers of the compounds described herein may, for e, be substantially free of other isomers, or may be t in a racemic e, as described supra.
The use of the terms "saltH H solvate H ‘Eester97 H , , , g" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of omers, stereoisomers, rotamers, ers, positional isomers, racemates or isotopologues of the instant compounds.
The term "isotopologue" refers to isotopically—enriched nds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine 13 35 and chlorine, such as 2H, 3H, C, 14C, 15N, 18O, 17O, 31F, 32F, S, 18F, 35Cl and 36Cl, respectively, each of which are also within the scope of this description.
Certain isotopically-enriched compounds described herein (e. g., those d with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. ted (i.e., H) and carbon—l4 (i.e., 14C) es are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half—life or reduced dosage requirements) and hence may be preferred in some circumstances.
Polymorphic crystalline and ous forms of the compounds of Formula (I) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of a (I) are further intended to be included in the present ption. nd Uses The present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an ive amount of the compound or a form thereof to the subject.
The present description further relates to use of the compound of Formula (I)or a form thereof for ng or ameliorating HD in a subject in need thereof.
The present ption further relates to use of the nd of Formula (I) or a form thereof having activity toward HD.
The present description further relates to use of the compound of Formula (I) or a form thereof in a combination therapy to e additive or istic activity, thus enabling the development of a combination product for treating or ameliorating HD.
In addition to monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of agents, having additive or synergistic activity with one or more known agents.
A combination therapy comprising compounds described herein in combination with one or more known drugs may be used to treat HD regardless of whether HD is sive to the known drug.
Embodiments of the present description include the use of a compound of Formula (I)or a form thereof in a combination therapy for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more agent(s).
Embodiments of the present description include the use of a compound of Formula (I) or a form thereof in a combination therapy for treating or ameliorating HD in a t in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more s).
In an embodiment of a use or method provided herein, compounds of a (I) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a subject or patient cell(s) prior to, concurrently with, or subsequent to administering to the subject or patient or ting the cell with an additional agent(s). A compound(s) of Formula (I) or a form thereof and an additional agent(s) can be administered to a subject or contacted with a cell in single composition or different compositions. In a specific embodiments, a compound(s) of Formula (I) or a form f is used in combination with gene therapy to inhibit HTT expression (using, e.g., viral delivery vectors) or the administration of another small le HTT tor. In another specific embodiment, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated non—mutant HTT stem cells. In another specific embodiment, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated HTT stem cells.
In one embodiment, provided herein is the use of nds of Formula (I) or a form thereof in combination with supportive rd of care therapies, including tive care.
An embodiment of the t description es the use of a compound of Formula (I) or a form thereof in the preparation of a kit comprising the compound of a (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more s) in a combination therapy for treating or ameliorating HD in a subject in need thereof.
Accordingly, the present description relates to use of a compound of Formula (I) or a form thereof for treating or ameliorating HD. In accordance with the use of the present description, compounds that are useful in ively treating or ameliorating HD, have been identified and use of these compounds for treating or ameliorating HD has been provided.
One embodiment of the use of the present description relates to use of a nd of a (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.
One embodiment of the use of the present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a t in need thereof, comprising stering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present ption relates to 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.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or a form thereof in the preparation of a kit comprising the compound of a (I) or a form thereof and instructions for administering the compound for treating or ameliorating HD in a subject in need thereof.
In one respect, for each of such embodiments, the t is treatment naive. In r respect, for each of such embodiments, the subject is not ent naive.
As used herein, the term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or ion, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or ion, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food.
Nonlimiting examples include members of the human, primate, , porcine, bovine, murine, rattus, canine and feline specie. In some embodiments, the subject is a mammal or a warm— blooded vertebrate animal. In other embodiments, the t is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human".
As used herein, the terms "effective amount" or "therapeutically effective amount" mean an amount of compound of Formula (I) or a form, composition or medicament thereof effective in inhibiting the above—noted diseases and thus producing the d therapeutic, rative, inhibitory or preventative effect in a subject in need thereof.
The dose administered to achieve an ive target plasma concentration may also be administered based upon the weight of the subject or patient. Doses administered on a weight basis may be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 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 40 mg/kg/day, or about 0.001 mg/kg/day to about 30 mg/kg/day, or about 0.001 mg/kg/day to about 20 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount is orally administered once (once in approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.
In certain embodiments, the ive amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in , divided, or a uous dose for a patient or t having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, ularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.
In another embodiment, where daily doses are adjusted based upon the weight of the subject or t, compounds described herein may be formulated for delivery at 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 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a , divided, or continuous dose. In embodiments where a dose of nd is given more than once per day, the dose may be administered twice, thrice, or more times per day.
Within the scope of the present description, the "effective amount" of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, for use in the preparation of a pharmaceutical kit or in a method of use for ng or ameliorating HD in a subject in need f is intended to include an amount in a range of from about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 100 day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 day to about 50 day, or about 0.001 mg/kg/day to about 40 mg/kg/day, or about 0.001 mg/kg/day to about 30 mg/kg/day, or about 0.001 mg/kg/day to about 20 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.01 day to about 2000 day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount is administered once (once in imately a 24 hour period; i.e., "q.d."), twice (once in approximately a 12 hour period; i.e., "b.i.d." or "q.l2h"), thrice (once in approximately an 8 hour period; i.e., "t.i.d." or "q.8h"), or four times (once in approximately a 6 hour period; i.e., "q.d.s.", "q.i.d." or "q.6h") daily according to subject weight.
Such amounts may further include an amount in a range of from about 0.001 mg to about 3500 mg stered daily; 0.001 mg to about 3000 mg administered daily; 0.001 mg to about 2500 mg administered daily; 0.001 mg to about 2000 mg administered daily; 0.001 mg to about 1500 mg administered daily; 0.001 mg to about 1000 mg administered daily; 0.001 mg to about 500 mg administered daily; 0.001 mg to about 250 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily.
For example, the effective amount may be the amount ed to treat HD in a subject or, more specifically, in a human. The effective amount for a subject will depend upon various s, including the subject’s body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and nt of the clinician.
For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard ceutical ures in cell es or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the tion) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In r embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More ically, the concentration—biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 ug/mL to approximately 50 ug/mL, from approximately 0.01 ug/mL to approximately 20 ug/mL, from approximately 0.05 ug/mL to approximately 10 ug/mL, or from approximately 0.1 ug/mL to approximately 5 ug/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient ng between about 10 to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the ty of the disease state, general health of the t, ethnicity, age, , gender, diet, time of day and frequency of administration, drug combination(s), on sensitivities, ence with other ies, and tolerance/response to therapy. cting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
The compounds and compositions described herein may be administered to the t via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, and ary routes of administration.
In one aspect, ed herein are methods for modulating the amount of HTT ngtin protein), comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein are methods for modulating the amount of HTT, sing contacting a human cell with a compound of Formula (I) or a form thereof that modulates the expression of HTT. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in viva, e. g., in a non-human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another embodiment, the human cell is from a human with HD.
In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is a form of the compound of Formula (I).
In a specific embodiment, provided herein is a method for enhancing the inhibition of mutant HTT transcribed from the Htt gene, sing contacting a human cell with a compound of Formula (I) or a form f. The human cell can be contacted with a nd of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non—human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of wild—type "normal" HTT expression and/or function. In another embodiment, the human cell is from a human with HD. In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is a form of the compound of Formula (I).
In another aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form thereof. In a specific embodiment, the compound is a form of the compound of Formula (I).
In another , provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific embodiment, provided herein is a method for decreasing the amount of HTT, comprising contacting a human cell with a nd of a (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a nd of Formula (I) or a form thereof in vitro, or in viva, e. g., in a non-human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In r embodiment, the human cell is from a human with HD.
In another embodiment, the human cell is in a human with HD. In one ment, the compound is a form of the compound of Formula (I).
In certain ments, treating or ameliorating HD with a nd of Formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or beneficial effect. In a specific embodiment, 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) reduces or ameliorates the ty of HD; (ii) delays onset of HD; (iii) inhibits the progression of HD; (iv) reduces alization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a t; (Vii) improves the y of life for a subject; (viii) reduces the number of symptoms associated with HD; (ix) reduces or ameliorates the severity of a symptom(s) associated with HD; (x) reduces the duration of a symptom associated with HD; (xi) prevents the recurrence of a symptom associated with HD; (xii) inhibits the development or onset of a symptom of HD; and/or (xiii) inhibits of the progression of a symptom associated with HD.
Metabolites of the Compounds Also included within the scope of the present description are 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 and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the ption includes the use of compounds produced by a process comprising contacting a compound bed herein with a mammalian tissue or a mammal for a period of time sufficient to yield a lic product thereof.
Such products typically are identified by preparing a radio—labeled isotopologue (e.g., 14C or H) of a compound described herein, administering the labeled compound in a detectable dose (6.3., greater than about 0.5 mg/kg) 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 , and fying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are "radiolabeled" by virtue of being isotopically—enriched (others are ed by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well—known to those skilled in the art. The sion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds bed herein even if they possess no ical activity of their own.
Pharmaceutical Compositions Embodiments of the present description e the use of a compound of Formula (I) or a form thereof in a ceutical composition for treating or ameliorating HD in a t in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).
An embodiment of the present description includes the use of a pharmaceutical ition of the compound of Formula (I) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating HD in a subject in need thereof.
As used herein, the term "composition" means a t comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the ied ingredients in the specified amounts.
The ceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH ll. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8.
The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds bed herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity.
Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. iting examples of pharmaceutically able excipients include carriers, solvents, izers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compounds described herein (see, e.g., Remington’s Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., ypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, ol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also ed within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions bed herein may be ated in any form suitable for the intended use described herein. le formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration e liquids and powders. Alternative formulations e syrups, , ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
When ed for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non—aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may n one or more agents including ning agents, flavoring agents, coloring agents, and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets e, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, , gelatin or acacia; and lubricating agents, 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 and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or yl distearate alone or with a wax may be ed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium ate, or kaolin, or as soft gelatin es wherein the active ingredient is mixed with non- aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.
In other ments, pharmaceutical compositions described herein may be formulated as sions comprising a compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s) suitable for the manufacture of a sion. In yet other embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules le for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum , dispersing or g agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a sation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin, or cetyl l. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n—propyl p—hydroxy—benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
The pharmaceutical compositions described herein may also be in the form of oil—in— water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally—occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, 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. The emulsion may also n sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
Additionally, the pharmaceutical compositions described herein may be in the form of a e able ation, such as a sterile injectable s emulsion or oleaginous suspension. Such emulsion or sion may be formulated according to the known art using those suitable dispersing or wetting agents and ding agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable on or suspension in a non—toxic parenterally acceptable diluent or solvent, such as a solution in 1,2—propanediol.
The sterile able preparation may also be prepared as a lyophilized powder. Among the acceptable es and ts that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, e fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono— or di—glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The nds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically able protic solvents and vegetable oils, but 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, contemplated in the description are nds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc), for example by esterification, glycosylation, PEGylation, etc.
In some embodiments, the compound bed herein is formulated for oral administration in a lipid—based composition suitable for low solubility compounds. Lipid—based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a nd of Formula (I) or a form thereof, together with at least one ceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, tively) or polyoxyl 40 hydrogenated castor oil.
In other embodiments, the bioavailability of low solubility compounds may be enhanced using le size optimization techniques including the preparation of nanoparticles or nanosuspensions using ques known to those skilled in the art. The compound forms present in such preparations include amorphous, lly amorphous, partially lline or crystalline forms.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of a—, [3-, and y—cyclodextrin, and hydroxypropyl—B—cyclodextrin (HPBC). In some ments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.
Preparation of Compounds Compounds provided herein can be prepared by those skilled in the art, such as, by the synthetic methods set forth in International ation Publication Number WO2014/028459 A1, published February 20, 2014, International Application Publication Number WO2014/116845 A1, published July 31, 2014, and International Application Publication Number WO2015/017589 A1, published February 5, 2015, each of which are herein incorporated by nce.
General s The following reaction schemes illustrate methods to make compounds described herein.
It is understood that one skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art.
In general, starting components and reagents may be commercially obtained from various sources such as commercial vendors, sized according to methodology known to those skilled in the art, or prepared as described herein. It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
In general, compounds of a (I) described herein can be synthesized following the general procedure for Scheme 1.
Schemel H.a ?R X’s H B W w ‘x’ A/ ‘OR w H..A~\ 1b A \ \N 1d \ _. NI _. AN»: 1a 1c (I) General Procedure for Scheme 1 The ng materials for the above reaction scheme are commercially available or can be prepared ing to methods known to one skilled in the art or by methods disclosed herein.
In general, the compounds described herein are prepared in the above reaction Scheme 1 as follows: a halogenated nd 1a in Hal is a n selected from bromine or chlorine) is reacted with a Compound lb (wherein H is a reactive hydrogen atom in an amine or alcohol X functional group, wherein X and B for a compound of Formula (I) are as described herein) using a displacement or a metal-mediated cross coupling reaction, such as a Buchwald reaction, to provide an intermediate nd 1c. Compound 1c is carried forward and reacted with a boronate acid or boronate ester Compound ld (where B represents a boron atom, R represents a an acid or ester functional group or, when taken together with boron, form a ring system and A for a compound of Formula (I) is as described herein) using a transition metal— mediated cross coupling reaction, such as a Suzuki reaction, to provide a Compound of a (I).
In a complementary , compounds of Formula (I) may also be synthesized in reverse order n the te Compound 1d is reacted first with Compound 1a followed by reaction of the intermediate with amine Compound 1b. Other variations representing different combinations for substituting either or both boronate Compound 1d and amine Compound 1b on nd la are ed to be included within the scope of the tic methodologies described herein.
Specific Examples To assist in understanding the present description, the following specific examples are included. The experiments relating to this description should not, of course, be construed as ically limiting the description and such variations of the description, now known or later developed, which would be within the purview of one d in the art are considered to fall within the scope of the description as bed herein and hereinafter claimed.
Other than in the working examples, unless indicated to the contrary, all numbers expressing quantities of materials, reagents, reaction conditions, experimental data, and so forth used in the ication and claims are to be understood as being modified by the term "about".
Accordingly, all such numbers represent approximations that may vary depending upon the desired properties sought to be obtained by a reaction or as a result of variable experimental conditions. Therefore, within an expected range of experimental reproducibility, the term " in the t of the resulting data, refers to a range for data provided that may vary ing to a standard deviation from the mean. As well, for experimental results provided, the resulting data may be rounded up or down to present data consistently, without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.
While the numerical ranges and parameters setting forth the broad scope of the description are approximations, the numerical values set forth in the working examples are reported as precisely as le. Any numerical value, r, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
The column chromatography system used for product purification was an ISCO CombiFlashTM brand chromatography system actured by Teledyne Isco).
Synthetic Examples Greater details of the present description are provided with reference to the following non-limiting es, which are offered to more fully illustrate the description, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds described herein, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these es represent techniques described by the inventors to function well in the practice of the ption, and as such constitute preferred modes for the practice thereof. r, those of skill in the art should appreciate in light of the present disclosure that many changes can be made to the ic methods that are disclosed and still obtain a like or r result without departing from the spirit and scope of the description.
As used above, and throughout this description, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: Abbreviation Meaning AcOH or HOAc acetic acid ACN or MeCN acetonitrile Bn benzyl BnBr benzyl bromide BnO or OBn benzyloxy Boc tert—butoxycarbonyl BoczO or (Boc)20 di—tert—butyl dicarbonate [(2—di—tert—butylphosphino—Z',4 ',6 '—triisopropyl— l , l ’-biphenyl)— IBUXPhOSPd—G?) 2—(2'—amino—l,l'—biphenyl)] palladium(II) esulfonate Cbz benzyloxycarbonyl DCE dichloroethane DCM romethane (CHzClz) H diisobutylaluminium hydride Abbreviation Meaning DIPEA N,N—diisopropylethylamine DMF yl formamide DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMB 2,4—dimethoxybenzyl DMS0 dimethylsulfoxide EA or EtOAc ethyl acetate EtOH ethanol EtzO diethyl ether HCl hydrochloric acid HPLC high performance liquid chromatography rs/min/s hour(s)(h, hr or hrs)/minute(s)(min/mins)/second(s) K2C03 potassium carbonate KOAc potassium e K3PO4 potassium phosphate LAH lithium ium hydride LC/MS, LCMS or LC-MS liquid chromatographic mass spectroscopy LDA lithium diisopropylamide LiHMDS m bis(trimethylsilyl)amide di—tert—butyl(2',4',6'—triisopropyl—3 ,4,5 ,6—tetramethyl—[ l , l '— Me4tBu—XPhos biphenyl]—2—yl)phosphine Mel methyl iodide MeOH methanol MezNH or NHMez dimethyl amine MS mass spectroscopy N2 nitrogen NagsO4 sodium sulfate NaBH(OAc)3 sodium triacetoxyborohydride NaHMDS sodium bis(trimethylsilyl)amide NBS N—bromosuccinimide NH4OH ammonium hydroxide NMO N-methylmorpholine-N-oxide NMP N-methyl—2—pyrrolidone n—BuLi n—butyl lithium NMR nuclear magnetic resonance Pd/C palladium on carbon Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pdc12 [l, l '—bis(diphenylphosphino)ferrocene] dichloropalladium(ll) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium Pin pinacol psi pounds per square inch pressure S—Phos 2—dicyclohexylphosphino—2',6'—dimethoxybiphenyl TBDPSCl utyldiphenylchlorosilane TBS tert—butyldimethylsilyl TBSCl tert—butyldimethylsilyl chloride Abbreviation g t—BuOK potassium tert—butoxide TEA or NEt3 triethylamine TFA trifluoroacetic acid THF tetrahydrofuran THF tetrahydro—2H—pyranyl THPO or OTHP tetrahydro—2H—pyran—2—yl—oxy TIPS—H or TIPSH triisopropyl silane TLC thin layer chromatography TMP 2,2,6,6—tetramethylpiperidinyl TMPMgCl—LiCl 2,2,6,6—tetramethylpiperidinylmagnesium de lithium chloride TMSI trimethylsilyl iodide TMSOK potassium hylsilanolate e 1 (Compound 411) 2—{6-[8-Azabicyclo[3.2.1]oct—3—y1(methyl)amino]pyridazin—3—yl}(1H—pyrazol—4—y1)phenol hydrochloride m3,6-Dibromopyridazine (133.7 mg, 0.56 mmol), tert-butyl (1R,SS)(methylamino) azabicyclo[3.2.l]octane-8—carboxylate (85 mg, 0.28 mmol) and DIPEA (0.15 mL, 0.84 mmol) were mixed in 1 mL of ACN and heated to 100 °C for l h until LC—MS showed complete consumption of the starting material. The reaction mixture was concentrated and purified Via column chromatography: eluting with gradient CHzClz/MeOH (0% to 30% MeOH), column: silica 4g to afford tert—butyl (lS,5R)—3—[(6—bromopyridazin—3—yl)—methyl—amino]-8— azabicyclo[3.2.l]octane—8—carboxylate (55 mg, 49.25% yield).
Sip—2: tert-Butyl 3—[(6—bromopyridazin—3—yl)—methyl—amino]—8—azabicyclo[3.2. l]octane—8— carboxylate (55 mg, 0.14 mmol), 4—[3—(methoxymethoxy)—4—(4,4,5 ,5 -tetramethyl—1,3,2— dioxaborolanyl)phenyl]tetrahydropyranyl-pyrazole (68.82 mg, 0.17 mmol), Pd(dppf)C12 (10.34 mg, 0.01 mmol), K2CO3 (57.98 mg, 0.42 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The organic layers were dried over NaZSO4, trated under , purified Via column chromatography: eluting with gradient CH2C12/EtOAc (0% to 80%), column: silica 4g, to providetert—butyl (lS,5R)—3—[[6—[2—(methoxymethoxy)-4—(l— tetrahydropyran—2—ylpyrazol—4—yl)phenyl]pyridazin—3—yl]—methyl—amino]—8— azabicyclo[3.2.l]octane—8—carboxylate (52 mg, 62%) as a tan solid. mTo a solution of utyl (15,5R)—3—[[6—[2—(methoxymethoxy)—4-(1—tetrahydropyran—2— ylpyrazol—4-yl)pheny1]pyridazin—3—y1]—methyl—amino]—8—azabicyclo[3.2.1]octane—8—carboxy1ate (52 mg, 0.086 mmol) in a 1 mL mixture of CHzClz and 0.5 mL of MeOH was added HCl (4 mol/L) in 1,4-dioxane (0.06 mL). The reaction was stirred overnight. The precipitate was filtered, then dried under vacuum to provide 2—[6—[8—azabicyclo[3.2.1]octan—3— yl(methyl)amino]pyridazin—3—yl]—5—(1H—pyrazol—4—yl)phenol; hydrochloride (15 mg, 42.25% yield) as a yellow solid.
LC-MS: 377 [M+H]+. 1H NMR (500 MHz, 6) 6: 9.37-9.51 (m, 1H), 8.87—8.96 (m, 1H), 8.31 (d, J=9.8 Hz, 1H), 8.12 (s, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.19-7.27 (m, 2H), .92 (m, 1H), 4.08-4.14 (m, 3H), 3.07 (s, 3H), 2.30 (td, , 2.8 Hz, 2H), 1.99-2.15 (m, 4H), 1.74-1.87 (m, 2H) Using the procedure described for e 1 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining nds such as those selected from: de Data LC—MS: 363 [M+H]+. 1H NMR (500 MHZ, DMSO—dé) 6: 9.24—9.34 (m, 1H), 9.09— 9.21 (m, 1H), 8.30 (d, J=9.8 HZ, 1H), 8.09 (s, 2H), 7.64—7.67 (m, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.25—7.27 (m, 1H), 7.24 (s, 1H), 5.42 (br s, 2H), 4.23—4.31 (m, 1H), 4.00— 4.13 (m, 2H), 2.17 (s, 4H), 1.97—2.02 (m, 2H), 1.94 (td, J=12.6, 2.5 Hz, 2H) LC—MS: 393 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 8: 9.34—9.49 (m, 1H), 8.43— 8.56 (m, 1H), 8.30 (d, J=9.8 Hz, 1H), 8.10 (s, 2H), 7.63 (s, 2H), 7.19—7.30 (m, 2H), .77 (br s, 2H), .62 (m, 1H), 2.08 (dd, J=11.7, 2.8 Hz, 2H), 1.72 (td, J=12.1, 2.8 Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H) LC—MS: 364 [M+H]+. 1H NMR (500 MHz, methanol-d4) 6: 8.61 (d, J=9.5 Hz, 1H), 8.24 (s, 2H), 7.85 (d, J=8.2 Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.38 (dd, J=8.2, 1.6 Hz, 415 1H), 7.32 (d, J=1.6 Hz, 1H), 5.65 (spt, J=5.7 Hz, 1H), 4.25 (dd, 123.6, 2.8 Hz, 2H), 4.17—4.32 (m, 2H), 2.24 (s, 4H), 2.11 (tt, J=11.2, 2.8 Hz, 2H) (3 hydrogens corresponding to OH and NH unobserved) LC—MS: 363 . 1H NMR (500 MHz, methanol-d4) 6: 8.42 (d, J=9.5 Hz, 1H), 8.34 (s, 2H), 7.80 (d, J=9.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.40 (dd, J=8.2, 2.5 433 HZ, 1H), 7.32 (d, J=1.6 Hz, 1H), 4.18 (td, J=6.9, 0.9 Hz, 1H), 4.11-4.16 (m, 2H), 2.42-2.52 (m, 4H), 2.32-2.35 (m, 1H), 2.28-2.32 (m, 1H), 2.15-2.25 (m, 2H), (4 hydrogens corresponding to OH and NH unobserved) Example 2 (Compound 416) —(5—Methyl— l H—pyrazol—4—yl)—2—{ 6— [methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin— 3—yl}phenol m3-Methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl trifluoromethanesulfonate (80 mg, 0.16 mmol), (tert—butyl 3—methyl—4—(4,4,5,5—tetramethyl—1,3,2— dioxaborolan—2—yl)—lH—pyrazole—l—carboxylate (59 mg, 0.19 mmol), Pd(dppf)C12 (7 mg, 0.01 mmol), K2C03 (66 mg, 0.48 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and e (2 mL) and water (0.5 mL) were added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The c layers were dried over NaZSO4, concentrated under vacuum, then purified via column chromatography: eluting with gradient /MeOH (0% to 30% MeOH), column: silica 4g to provide tert—butyl 4—(3—methoxy—4—(6—(methyl(2,2,6,6—tetramethylpiperidin— 4-yl)amino)pyridazinyl)phenyl)methyl-1H-pyrazolecarboxylate (46 mg, 54%) as light brown solid. mA solution of tert—butyl 4—(3—methoxy—4—(6—(methyl(2,2,6,6—tetramethylpiperidin—4— yl)amino)pyridazin—3—yl)phenyl)—3—methyl—1H—pyrazole—1—carboxylate (46 mg, 0.09mmol) in 2 mL of dry CH2C12 was cooled in ice—water bath. Boron tribromide 1.0 M in CH2C12 (0.45 mL, 0.45 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours.
The reaction was quenched with 2 mL of MeOH, stirred for 30 min, then concentrated and purified via column tography: eluting with gradient CHZCIZ/MeOH (2.5% NH4OH) (0% to 30% MeOH/NH4OH), column: silica 4g, to provide tert—butyl methyl(2,2,6,6— tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5—(3—methyl—1H—pyrazol-4—yl)phenol (20 mg, 55%) as a yellow solid.
LC—MS: 421 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5: 13.74 (s, 1H), 12.71 (m, 1H), 8.20 (d, J=9.5Hz, 1H), 8.03—8.04 (m, 1H), 7.86 (d, J=8.0Hz, 1H), 7.73—7.75 (m, 1H), 7.36 (d, J:9.5Hz, 1H), 7.03—7.06 (m, 2H), 4.90—5.05 (m, 1H), 2.92 (s, 3H), 2.43 (s, 3H), 1.43—1.54 (m, 2H), 1.15—1.43 (m, 2H), 1.14 (s, 6H), 1.09 (s, 6H) Using the procedure bed for Example 2 above, additional compounds described herein may be prepared by substituting the appropriate starting materials ts, and reaction conditions, ing compounds such as those selected from: de Data LC—MS: 408 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5: 13.84 (s, 1H), 8.10—8.29 (m, 2H), 7.92 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.36 (d, J=9.8 Hz, 1H),7.08-7.19 (m, 2H), 4.87—5.03 (m, 1H), 3.87 (s, 3H), 2.96 (s, 3H), 1.48—1.59 (m, 2H), 1.38—1.48 (m, 2H), 1.26 (s, 6H), 1.09 (s, 6H) LC—MS: 422 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 6: 12.89 (s, 1H), 12.29—12.48 (m, 1H), 8.41 (dd, J=8.8, 0.9 Hz, 1H), 7.95 (dd, J=7.9, 0.9 Hz, 1H), 7.37 (dd, J=9.1, 418 1.3 Hz, 1H), 6.85—6.94 (m, 2H), 5.61—5.70 (m, 1H), 2.25 (br s., 6H), 2.09 (dd, J=11.8, 3.9 Hz, 2H), 1.25—1.33 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) LC-MS: 408 [M+H]+. 1H NMR (500 MHz, DMSO'dé) 6: 13.00 (s, 1H), 12.80 (m, 1H), 8.42 (d, J=9.5 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.38 (d, J=9.5 Hz, 1H), 451 7.03—7.18 (m, 2H), 5.55-5.78 (m, 1H), 2.39 (br s., 3H), 2.03-2.13 (m, 2H), 1.26-1.41 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) Example 3 und 419) 2— { hyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3—yl } —5 —(4—nitro— lH—pyrazol— 1 — yl)phenol dihydrochloride m3—Methoxy—4—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)phenyl trifluoromethanesulfonate (335 mg, 0.67 mmol), 4—nitro—1H—pyrazole (340 mg, 4.5 mmol), Pd2(dba)3 (67 mg, 0.07 mmol), Me4tBu-XPhos (35 mg, 0.07 mmol), K3PO4 (368 mg, 1.73 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and dioxane (8 mL) was added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, filtered through celite, concentrated, purified via column chromatography: eluting with nt CHgClz/MeOH (0% to 30% MeOH), column: silica 12g, to provide 6—(2—methoxy— 4—(4—nitro—1H—pyrazol—1—yl)phenyl)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3 — amine (202 mg, 65%).
LC—MS: 466 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 8: 9.81-9.85 (m, 1H), 8.61 (d, J=0.6 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.81 (d, J=9.8 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.68 (dd, J=8.2, 2.2 Hz, 1H), .21 (m, 1H), 5.08-5.26 (m, 1H), 3.96 (s, 3H), 2.95 (s, 3H), 1.59—1.75 (m, 4H), 1.40 (s, 6H), 1.33, (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) Sip—2: 6—(2-Methoxy—4—(4—nitro—1H—pyrazol—1—yl)phenyl)—N—methyl—N—(2,2,6,6— tetramethylpiperidin—4—yl)pyridazin—3—amine (150 mg, 0.32 mmol), benzenethiol (33 uL, 0.32 mmol) and K2CO3 (44 mg, 0.32 mmol) were mixed in a ave tube. The reaction was degassed with N; for 15 min and dry NMP (1.5 mL) was added. The reaction was heated in a Biotage microwave at 190 °C for 20 min, then diluted with 10 mL EtOAc, and washed with water and brine. The t was dried over NaZSO4, concentrated under vacuum, then ed via column chromatography: eluting with gradient CHzClz/MeOH (0% to 30% MeOH), column: silica 4g, to provide 2—(6—(methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino)pyridazin—3—yl)—5—(4— nitro—1H—pyrazol—l-yl)phenol (60 mg, 42%) as a brown solid.
LC—MS: 452 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 8: 9.77 (s, 1H), 8.68 (d, J=9.8 Hz, 1H), 8.62 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.87-7.94 (m, 1H), 7.66 (dd, J=8.5, 2.6 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 5.03—5.22 (m, 1H), 3.01 (s, 3H), 1.84—1.94 (m, 2H), .77 (m, 2H), 1.53 (s, 6H), 1.43 (s, 6H), (2 hydrogens corresponding to OH and NH unobserved) Using the procedure described for Example 3 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from: de Data LC—MS: 394 [M+H]+. 1H NMR (500 MHz, 6) 6: 13.49 (br s, 1H), 8.49 (d, J=9.8 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.79-7.92 (m, 1H), 7.43 (d, 417 J=9.5 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.30 (dd, J=8.5, 2.5 Hz, 1H), 7.12 (s, 1H), .61—5.71 (m, 1H), 2.09 (dd, J=12.0, 3.8 Hz, 2H), 1.25-1.32 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) LC-MS: 409 . 1H NMR (500 MHz, methanol-d4) 6: 8.31 (d, J=9.5 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 7.44 (d, J=0.9 Hz, 1H), 7.24-7.33 421 (m, 3H), 5.77 (tt, J=11.2, 4.1 Hz, 1H), 2.28 (dd, J=12.3, 4.2 Hz, 2H), 1.49 (t, J=12.3 Hz, 2H), 1.42 (s, 6H), 1.30 (s, 6H), (4 hydrogens corresponding to OH and NH unobserved) LC-MS: 439 . 1H NMR (500 MHz, DMSO-d6) 6: 9.71 (d, J=0.6 Hz, 1H), 8.58 (d, J=0.6 Hz, 1H), 8.47 (d, J=9.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.59-7.64 423 (m, 2H), 7.44 (d, J=9.5 Hz, 1H), 5.67-5.73 (m, 1H), 2.18-2.28 (m, 2H), 1.45-1.56 (m, 2H), 1.37 (s, 6H), 1.27 (s, 6H), ), (2 hydrogens corresponding to OH and NH unobserved) Example 4 (Compound 424) —( 1H-Pyrazol—4—yl)—2—[6—( 1 ,2,3 ,6—tetrahydropyridin—4—yl)pyridazin—3-yl]phenol trihydrochloride Sip; 3-Bromo(2-methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazol yl)phenyl)pyridazine (100 mg, 0.24 mmol), (1—(tert—butoxycarbonyl)—1,2,3,6—tetrahydropyridin— 4—yl)boronic acid (66 mg, 0.29 mmol), Pddpprlz (8 mg, 0.012 mmol), K2C03 (99 mg, 0.72 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, and partitioned between EtOAc and water. The organic layers were dried over , then concentrated under vacuum, and purified via column chromatography: eluting with gradient CHZCIZ/MeOH (0% to 20% MeOH), column: silica 4g, to provide 5-(1H—pyrazol—4—yl)—2—(6—(1,2,3,6—tetrahydropyridin—4—yl)pyridazin—3—yl)phenol (102 mg, 82%) as an off—white solid. m A on of 5-(1H-pyrazolyl)(6-(1,2,3,6-tetrahydropyridinyl)pyridazin yl)phenol (102 mg, 0.196 mmol) in 2 mL of dry CHZCIZ was cooled in ice—water bath. Boron tribromide 1.0 M in CHzClz (0.98 mL, 0.98 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, d for 30 min, then concentrated and purified using preparative HPLC to provide 5—(1H— pyrazol—4—yl)—2—(6—(1,2,3,6—tetrahydropyridin—4—yl)pyridazin—3—yl)phenol (41 mg, 66%) as an off— white solid.
LC—MS: 320 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 8: 9.19 (br S, 2H), 8.54 (d, J: 9.6Hz, 1H), 8.22, (d, J:9.6Hz, 1H), 8.18 (s, 1H), 8.05 (d, J=8.8Hz, 1H), 7.25-7.29 (m, 2H), 6.92 (s, 1H), 3.85-3.92 (m, 2H), 3.38—3.41 (m, 2H), 2.88—2.98 (m, 2H), (1 en corresponding to OH or NH unobserved) Using the procedure described for Example 4 above, additional compounds described herein may be prepared by substituting the riate starting materials reagents, and reaction conditions, obtaining nds such as those selected from: LC—MS: 334 [M+H]+. 1H NMR (500 MHZ, DMSO—d6) 5: 11.06 (br s, 1H), 8.56 (d, J=9.2Hz, 1H), 8.25 (d, Z, 1H), 8.20 (s, 2H), 8.05 (d, J=8.8Hz, 1H), 7.22—7.31 (m, 2H), 6.92 (s, 1H),4.06—4.12(m, 1H), .94 (m, 1H), 3.62—3.70 (m, 1H), 3.21—3.30 (m, 1H), .12(m, 2H), 3.03 (s, 3H), (1 hydrogen corresponding to OH or NH unobserved) de Data LC—MS: 348 [M+H]+. 1H NMR (500 MHz, DMSO-dé) 8: 10.94 (br S, 1H), 8.56 (d, J=9.6Hz, 1H), 8.26 (d, J=9.6Hz, 1H), 8.19-8.23 (m, 2H), 8.05 (d, J=8.4Hz, 1H), 425 7.26—7.31 (m, 2H), 6.93 (s, 1H), 4.07-4.13 (m, 1H), 3.85—3.91 (m, 1H), 3.70-3.74 (m, 1H), 3.22-3.30 (m, 3H), .14 (m, 2H), 1.33 (t, J=7.2Hz, 3H), (1 hydrogen corresponding to OH or NH unobserved) LC—MS: 346 . 1H NMR (500 MHz, methanol—d4) 5: 1.79 — 1.89 (m, 1H) 1.98 - 2.11 (m, 1H) 2.11 - 2.33 (m, 2H) 2.65 - 2.80 (m, 1H) 3.09 - 3.21 (m, 1H) 4.02 - 4.16 (m, 2H) 7.02 - 7.14 (m, 1H) 7.24 (s, 2 H) 7.85 - 7.97 (m, 1H) 8.04 (d, J=9.46 HZ, 3H) 8.33 (d, J=9.46 Hz, 1H) Example 5 (Compound 427) 2— [6—(Piperidin—4—ylamino)pyridazin—3 —yl] —5—( lH—pyrazol—4—yl)phenol tetrahydrochloride Sip; 3,6-Dibromopyridazine (500 mg, 2.1 mmol), 4—(3—methoxy(4,4,5,5—tetramethyl—1,3,2— dioxaborolanyl)phenyl)(tetrahydro-2H-pyranyl)-1H-pyrazole (970 mg, 2.52 mmol), f)Clg (77 mg, 0.11 mmol), K2C03 (870 mg, 6.3 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and dioxane (8 mL) and water (1 mL) were added and the reaction was heated to 90 °C for 16 h. The on was cooled to room temperature, partitioned n EtOAc and water. The organic layers were dried over NaZSO4, concentrated under vacuum, purified via column tography: eluting with gradient hexanes/EtOAc (0% to 40% EtOAc), column: silica 4g, to provide 3—bromo—6—(2—methoxy—4—(l—(tetrahydro—2H—pyran— 2—yl)—lH—pyrazol—4—yl)phenyl)pyridazine (690 mg, 79%) as an off—white fluffy solid. m3-Bromo—6—(2—methoxy—4—(1—(tetrahydro—2H—pyran—2—yl)— 1H-pyrazol—4— yl)phenyl)pyridazine (50 mg, 0.12 mmol), tert-butyl 4-aminopiperidine-l-carboxylate (36 mg, 0.18 mmol), potassium t—butoxide (41 mg, 0.36 mmol), tBuXPhos—Pd—G3 (10 mg, 0.012 mmol) were mixed in a Schlenk tube. The reaction was degassed with Ar then dry THF (2 mL) was added and the reaction was heated to 80 °C for 12 h. The reaction was cooled to room temperature, then partitioned n EtOAc and water. The organic layers were dried over NaZSO4, concentrated under vacuum, and purified via column chromatography: eluting with gradient CH2C12/MeOH (0% to 15% MeOH), column: silica 4g, to provide tert—butyl 4—((6—(2— methoxy—4—(l—(tetrahydro—2H—pyran—2—yl)— lH—pyrazol—4—yl)phenyl)pyridazin—3— yl)amino)piperidine—l—carboxylate (45 mg, 70%) as a tan solid.
SEQ A on of 4—((6—(2—methoxy—4—(1—(tetrahydro—2H—pyranyl)- 1H—pyrazol—4— yl)phenyl)pyridazin—3—yl)amino)piperidine—1—carboxylate (45 mg, 0.084 mmol) in 2 mL of dry CHzClz was cooled in an ice—water bath. Boron tribromide 1.0 M in CHgClz (0.42 mL, 0.42 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, d for 30 min, then concentrated and purified using preparative HPLC to provide 2—(6—(piperidin—4—ylamino)pyridazin—3—yl)—5—(1H—pyrazol—4— yl)phenol (21 mg, 73%) as a yellowish solid.
LC-MS: 377 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 6: 8.95 (s, 2H), 8.25 (d, J=9.6 Hz, 1H), 8.09 (s, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.49-7.41 (m, 1H), 7.21-7.24 (m, 2H), 4.11—4.15 (m, 1H), 3.34-3.39 (m, 4H), 3.01-3.08 (m, 2H), 2.11-2.17 (m, 2H), 1.79 (q, J=9.2 Hz, 2H) Using the procedure described for Example 5 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from: de Data LC—MS: 351 [M+H]+. 1H NMR (500 MHZ, DMSO—d6) 6: 9—22—9.28 (m, 2H), 8.34 (d, J=9.6Hz, 1H), 8.06—8.11 (m, 2H), 78.5—7.89 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.20—7.27 (m, 2H), .75 (m, 2H), 3.35—3.39 (m, 2H), 3.07—3.09 (m, 2H), 3.05 (s, 3H), 2.21 (q, J=10.2HZ, 2H), .88 (m, 2H) LC—MS: 338 . 1H NMR (500 MHz, methanol-d4) 6: 8.72 (d, J=9.6Hz, 1H), 8.41-8.54 (m, 2H), .08 (m, 1H), 7.82 (d, J=8.0Hz, 1H), 7.49 (d, J=8.2 Hz, 432 1H), 7.38 (s, 1H), 5.51 (quint, J=2.8Hz, 1H), .46 (m, 2H), 3.28—3.31 (m, 2H), 2.33—2.38 (m, 2H), 2.25—2.32 (m, 2H), (3 hydrogens corresponding to OH and NH unobserved) LC—MS: 366 [M+H]+. 1H NMR (500 MHz, DMSO-dé) 6: 9.17-9.30 (m, 1H), 8.81— 8.95 (m, 1H), 8.49 (d, J=9.8 Hz, 1H), 8.17 (s, 2H), 7.94 (d, J=8.8 Hz, 1H), 7.46 (d, 436 J=9.8 Hz, 1H), 7.18-7.29 (m, 2H), 5.47 (spt, J=5.7 Hz, 1H), 3.31—3.52 (m, 2H), 2.41 (dd, , 5.7 Hz, 2H), 1.68 (q, J=12.0 Hz, 2H), 1.34 (d, J=6.3 Hz, 6H), (1 en corresponding to OH or NH unobserved) LC—MS: 363 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 6: 9.07 (s, 2H), 8.28 (d, J=10Hz, 1H), 1.7 (s, 2H), 7.81 (d, J=8.8Hz, 1H), 7.73 (d, J=9.6Hz, 1H), 7.19-7.22 (m, 2H), 3.75-3.81 (m, 4H), 3.58-3.69 (m, 4H), 1.85-1.89 (m, 4H), (1 hydrogen corresponding to OH or NH unobserved) LC—MS: 349 [M+H]+. 1H NMR (500 MHz, DMSO-dé) 5: 10.53 (s, 1H), 10.40 (s, 1H), 9.79 (br s, 1H), 9.67 (br s, 1H), 8.28 (d, J=9.6Hz, 1H), 8.06 (s, 2H), 7.65 (d, J=9.6Hz, 1H), 7.58 (d, J:8.4Hz, 1H), 7.21—7.25 (m, 1H), 4.53 (q, J=14Hz, 2H), 3.64 (d, Hz, 1H), 3.52 (d, J=12.8Hz, 1H), 3.37—3.40 (m, 2H), 3.15—3.24 (m, 2H), 1.92—2.02 (m, 2H) Example 6 (Compound 430) 6—[2,3—Difluoro—4—(1H—pyrazol—4—yl)phenyl]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— yl)pyridazin—3—amine hloride Sip; To a RBF, equipped with a N2 inlet, were added: o—N—methyl—N—(2,2,6,6— tetramethyl-4—piperidyl)pyridazin—3—amine (90 mg, 0.28 mmol),4—[2,3—difluoro—4—(4,4,5,5— tetramethyl-1,3,2—dioxaborolan—2—y1)pheny1]—1—tetrahydropyran—2—yl-pyrazole (128.8 mg, 0.33 mmol), Pd(PPh3)4 (31.8 mg, 0.03 mmol), Na2C03 (87.43 mg, 0.83 mmol). The reaction was degassed with N; for 15 min then dioxane (8 mL) and water (2 mL) were added. The reaction was heated to 90 °C for 16 h, then cooled to room temperature, and partitioned n EtOAc and water. The organic layers were dried over NaZSO4, concentrated on a rotavap, and purified via column chromatography: eluting with gradient CHzClz/MeOH (0% to 30%), column: silica 4g to provide 6—(2,3—Difluoro—4—(1—(tetrahydro—2H—pyran—2—yl)—1H—pyrazol—4—yl)phenyl)—N— —N—(2,2,6,6-tetramethylpiperidin—4—yl)pyridazin—3—amine (88 mg, 63%) as a grey solid. 3—Difluoro—4—(1—tetrahydropyran—2—ylpyrazol—4—yl)phenyl]—N—methyl—N-(2,2,6,6— tetramethyl-4—piperidyl)pyridazin—3—amine (88 mg, 0.17 mmol) was dissolved in MeOH (2 mL) and 4M HCl in dioxane (90 11L, 0.34 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min until LC-MS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to provide 6—(2,3— difluoro—4—(1H—pyrazol—4—yl)phenyl)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3— amine hydrochloride salt.
LC—MS: 427 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 5: 9.21—9.33 (m, 1H), 8.27—8.43 (m, 1H), 8.20 (s, 2H), 8.01 (d, J=9.8 Hz, 1H), 7.60—7.79 (m, 3H), .14(m, 1H), 3.05 (s, 3H), 2.10 (td, J=13.2, 1.6 Hz, 2H), 1.79 (dd, J=12.9, 4.1 Hz, 2H), 1.55 (s, 6H), 1.50 (s, 6H) Using the procedure described for Example 6 above, additional compounds described herein may be ed by substituting the appropriate starting materials reagents, and reaction conditions, ing compounds such as those selected from: de Data LC—MS: 427 [M+H]+. 1H NMR (500 MHz, DMSO—dé) 8: 9.22-9.38 (m, 1H), 8.33- 8.45 (m, 1H), 8.21 (d, J=1.9 Hz, 2H), 7.97 (dd, J:10.4, 2.8 Hz, 1H), 7.86 (d, 1:5.7 426 Hz, 1H), 7.81 (dd, J=11.7, 6.6 Hz, 1H), 7.54—7.63 (m, 1H), 5.09—5.16(m, 1H), 3.03 (s, 3H), 2.09 (t, J=12.9 Hz, 2H), 1.78 (dd, 1:129, 3.8 Hz, 2H), 1.55 (s, 6H), 1.51 (s, LC—MS: 414 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 8: 9.24—9.35 (m, 1H), 8.43— 8.58 (m, 1H), 8.22 (d, J=1.6 Hz, 2H), 8.06 (dd, J=9.1, 1.9 Hz, 1H), 7.87 (dd, J:12.1, 431 6.5 Hz, 1H), 7.83 (dd, , 6.5 Hz, 1H), 7.37 (d, J=9.5 Hz, 1H), 5.77 (11, J=10.7, 4.1 Hz, 1H), 2.33 (dd, J=13.1, 3.9 Hz, 2H), 1.84 (dd, 1:129, 11.3 Hz, 2H), 1.54 (s, 6H), 1.52 (s, 6H) LC—MS: 378 [M+H]+. 1H NMR (500 MHZ, methanol-d4) 6: 8.57—8.58 (m, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.45 (s, 2H), 8.05-8.10 (m, 1H), 7.95-7.99 (m, 1H), 7.86 (s, 1H), 435 7.82 (d, J=9.5 Hz, 1H), 5.79 (tt, J=lO.4, 4.4 Hz, 1H), 2.53 (dd, J=l4.5, 4.5 Hz, 2H), 1.86—2.01 (m, 2H), 1.66 (s, 6H), 1.60 (s, 6H), (2 ens corresponding to NH unobserved) LC—MS: 396 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 6: 9.28—9.44 (m, 1H), 8.47— 8.61 (m, 1H), 8.25 (s, 2H), 8.01 (dd, 1:9.3, 2.0 Hz, 1H), 7.92 (t, 1:8.2 Hz, 1H), 7.69 437 (dd, 1:128, 1.7 Hz, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.34 (d, 1:9.1 Hz, 1H), 5.76 (a, 1:107, 4.1 Hz, 1H), 2.33 (dd, 1:132, 3.9 Hz, 2H), 1.85 (dd, 1:132, 10.1 Hz, 2H), 1.54 (s, 6H), 1.53 (s, 6H) LC—MS: 359 [M+H]+. 1H NMR (500 MHz, methanol-d4) 6: .06 (d, J=10.1 Hz, 1H), 7.78 (dd, J=9.5, 6.3 Hz, 1H), 7.32 (d, J=9.8 Hz, 1H), .76 (m, 2H), 5.11 (tt, J=12.0, 4.1 Hz, 1H), 3.02 (s, 3H), 1.73 (dd, J=12.9, 3.5 Hz, 2H), 1.63 (t, J=12.5 Hz, 2H), 1.43 (s, 6H), 1.27 (s, 6H), (1 hydrogen corresponding to NH unobserved) LC—MS: 364 [M+H]+. 1H NMR (500 MHZ, DMSO—d6) 6: 1.33 (d, J=6.62 Hz, 6H) 1.65 (q, J=12.40 Hz, 2H) 2.42 (d, J=12.61 Hz, 2H) 3.38 — 3.50 (m, 2H) 5.48 (s, 1H) 441 6.51 — 6.63 (m, 1H) 7.42 — 7.57 (m, 3H) 7.80 (d, J=1.58 Hz, 1H) 8.09 (d, J=8.83 Hz, 1H) 8.50 (d, J=9.46 Hz, 1H) 8.61 (d, J=2.52 Hz, 1H) 8.76 (br s., 1H) 9.12 (br s., 1H) 13.18 (s, 1H) de Data LC—MS: 379 [M+H]+. 1H NMR (500 MHz, DMSO-dé) 6: 8.42 (s, 1H), 8.28 (dd, J=1.6, 0.9 Hz, 1H), 8.03 (dd, J=9.1, 1.6 Hz, 1H), 7.95 (s, 1H), 7.67 (d, J=9.1 Hz, 442 1H), 7.14 (d, J=9.1 Hz, 1H), 5.03-5.17 (m, 1H), 4.19 (s, 3H), 2.94 (s, 3H), .58 (m, 2H), 1.37—1.48 (m, 2H), 1.27 (s, 6H), 1.10 (s, 6H), (1 hydrogen corresponding to NH unobserved) LC—MS: 366 [M+H]+. 1H NMR (500 MHz, methanol—d4) 6: 8.35 (s, 1H), 8.31 (dd, J=1.6, 0.9 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.99 (dd, J=9.1, 1.9 Hz, 1H), 7.75 (dt, 443 J=9.1, 0.9 Hz, 1H), 7.21 (d, J=9.5 Hz, 1H), 5.81 (tt, J=11.2, 4.1 Hz, 1H), 4.27 (s, 3H), 2.28 (dd, , 4.1 Hz, 2H), 1.48 (t, J=12.3 Hz, 2H), 1.41 (s, 6H), 1.30 (s, 6H), (1 hydrogen corresponding to NH unobserved) LC—MS: 379 [M+H]+. 1H NMR (500 MHz, acetone—d6) 6: 8.52 (dt, J=7.0, 1.1 Hz, 1H), 8.13 (dt, J=8.8, 1.3 Hz, 1H), 7.66 (d, J=9.8 Hz, 1H), 7.28 (ddd, J=9.0, 6.8, 1.3 445 Hz, 1H), 7.13 (d, J=9.5 Hz, 1H), 6.89 (td, J=6.9, 1.4 Hz, 1H), 5.22 (tt, J=12.3, 3.5 Hz, 1H), 3.04 (s, 3H), 2.63 (s, 3H), 1.67 (dd, J=12.3, 3.5 Hz, 2H), 1.56 (t, J=12.3 Hz, 2H), 1.36 (s, 6H), 1.18 (s, 6H), (1 hydrogen corresponding to NH unobserved) LC—MS: 352 [M+H]+. 1H NMR (500 MHZ, acetone—d6) 6: 9.14 (dd, J=1.6, 0.9 Hz, 1H), 7.98 (dd, J=9.5, 1.9 Hz, 1H), 7.94 (t, J=0.9 Hz, 1H), 7.89 (d, J=9.5 Hz, 1H), 446 7.63 (dt, J=9.5, 0.8 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.14 (d, J=9.5 Hz, 1H), 5.34 (tt, J=12.6, 3.5 Hz, 1H), 1.67 (dd, J=12.3, 3.8 Hz, 2H), 1.55 (t, J=12.1 Hz, 2H), 1.36 (s, 6H), 1.17 (s, 6H), (1 en corresponding to NH unobserved) LC—MS: 394 . 1H NMR (500 MHz, acetone—d6) 6: 8.47 (d, J=2.5 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.59 (dd, J=8.5, 2.2 Hz, 1H), 7.06 (d, J=9.1 Hz, 1H), 6.57 (dd, J=2.4, 1.7 Hz, 1H), 5.85 (tt, J=11.3, 4.1 Hz, 1H), 2.21 (dd, , 3.9 Hz, 2H), 2.04—2.08 (m, 2H), 1.35 (s, 6H), 1.18 (s, 6H), (2 hydrogens corresponding to OH and NH unobserved) LC-MS: 409 [M+H]+. 1H NMR (500 MHZ, acetone-d6) 6: 7.59 (dd, J=8.5, 6.0 Hz, 1H), 7.46 (s, 2H), 7.31 (dd, J=10.1, 2.5 Hz, 1H), 7.15 (td, J=8.5, 2.5 Hz, 1H), 7.04 452 (d, J=9.5 Hz, 1H), 6.91 (d, J=9.5 Hz, 1H), 5.23 (tt, J=12.3, 2.8 Hz, 1H), 3.00 (s, 3H), 1.65 (dd, J=12.3, 3.5 Hz, 2H), 1.51 (t, J=12.1 Hz, 2H), 1.33 (s, 6H), 1.15 (s, 6H), (2 hydrogens corresponding to NH unobserved) LC—MS: 344 [M+H]+. 1H NMR (500 MHz, methanol-d4) 6: 8.17 (d, J=9.5 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.19 (d, J=9.5 Hz, 1H), 6.44 (dd, J=8.7, 2.4 Hz, 1H), 6.41 455 (d, J=2.5 Hz, 1H), 5.71 (tt, J=11.0, 3.8 Hz, 1H), 2.23 (dd, J=12.6, 4.1 Hz, 2H), 1.40- 1.47 (m, 2H), 1.39 (s, 6H), 1.27 (s, 6H), (3 hydrogens corresponding to OH and NH unobserved) de Data LC—MS: 425 [M+H]+. 1H NMR (500 MHz, DMSO-dé) 5: 9.23-9.39 (m, 1H), 8.39— 8.52 (m, 1H), 8.26 (s, 2H), 8.00-8.08 (m, 1H), 7.93 (s, 1H), 7.81-7.85 (m, 1H), 7.78 (d, 1:7.9 Hz, 1H), 7.63 (d, J:8.2 Hz, 1H), 4.95—5.03 (m, 1H), 3.08 (s, 3H), 2.13 (t, 1:129 Hz, 2H), 1.81 (dd, 1:129, 3.5 Hz, 2H), 1.56 (s, 6H), 1.52 (s, 6H) LC—MS: 414 [M+H]+. 1H NMR (500 MHz, DMSO—dé) 6: .36 (m, 1H), 8.29 (s, 2H), 7.85 (d, J:9.1Hz, 1H), 7.60 (d, J:9.5 Hz, 1H), 7.33—7.39 (m, 1H), 5.59—5.68 (m, 1H), .33 (m, 2H), 1.72—1.82 (m, 2H), 1.50 (s, 6H), 1.48 (s, 6H), (2 hydrogens corresponding to NH unobserved) Example 7 (Compound 434) 6—[2—Methoxy—6—(1H—pyrazol—4—yl)pyridin—3—yl]—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— yl)pyridazin—3—amine hydrochloride 6-(2-Methoxy(1-(tetrahydro-2H-pyranyl)-1H-pyrazolyl)pyridinyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidinyl)pyridazinamine (6 mg) was dissolved in 1 mL of 4N HCl/dioxane and the resulting mixture was d at RT for 20 minutes. The mixture was evaporated and triturated with ether to provide ethoxy—6—(1H—pyrazol—4—yl)pyridin—3—yl)— N—methyl—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3—amine 4 mg, 75%).
LC—MS: 422 [M+H]+. 1H NMR (500 MHz, methanol—d4) 8: 8.42 — 8.47 (m, 1H), 8.33 — 8.42 (m, 2 H), 8.09 - 8.17 (m, 1H), 7.99 - 8.08 (m, 1H), 7.50 - 7.56 (m, 1H), 5.0 (m, 1H), 4.16 (s, 3H), 3.20 (s, 3H), 1.94 — 2.15 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H) Example 8 (Compound 460) 3 —{ 6- [Methyl(2,2,6,6—tetramethylpiperidin—4—yl)amino]pyridazin—3 -yl}—6—(1H—pyrazol—4— y1)pyridin—2—ol hydrochloride Sip; 6-Chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine (280 mg, 1.0 mmol) was ved in 10 mL, a mixture of dioxane and water (4:1). To the solution was added sodium carbonate (190 mg, 3 eq), (6—chloro—2—methoxypyridin—3—yl)boronic acid (190 mg, 1 eq) and Pd(Ph3P)4 (70 mg, 0.1 eq). The reaction mixture was stirred at 90 °C for 16 h, then applied to a column and purified using DCM/MeOH to yield (133 mg, 55%) 6—(6—chloro—2— methoxypyridin—3—yl)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3—amine.
LC—MS: 390 [M+H]+. 1H NMR (500 MHz, DMSO—d6) 5: 8.25 (d, J=7.88 Hz, 1H), 7.83 (d, J:9.77 Hz, 1H), 7.24 (d, J=7.88 Hz, 1H), 7.11 (d, J:9.77 Hz, 1H), 5.00 — 5.24 (m, 1H), 3.93 (s, 3 H), 2.87 — 2.96 (m, 3H), 1.40 — 1.57 (m, 4H), 1.21 — 1.29 (m, 7H), 1.10 (br s, 6H Step 2: 6-(6—Chloro—2—methoxypyridin—3—y1)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— yl)pyridazin—3—amine (90 mg) was dissolved in a mixture of dioxane and water (4:1, 5 mL). To the solution was added sodium carbonate (100 mg, 3 eq), 1—(tetrahydro-2H—pyran—2—yl)—4— (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (70 mg, 1.1 eq) and Pd(Ph3P)4 (27 mg, 0.1 eq). The reaction mixture was stirred at 90 °C for 16 h, then purified by column chromatography using DCM/MeOH to yield 80 mg (68%) of 6—(2—methoxy—6—(1—(tetrahydro—2H— pyran—2—yl)—1H—pyrazol—4—yl)pyridin—3—yl)—N—methyl—N—(2,2,6,6—tetramethylpiperidin—4— yl)pyridazin—3—amine.
M6—(2—Methoxy—6—(1—(tetrahydro—2H—pyran—2—yl)—1H—pyrazol—4—yl)pyridin—3—yl)—N—methyl— N—(2,2,6,6—tetramethylpiperidin—4—yl)pyridazin—3—amine (45 mg) was dissolved in 4 mL of 4N HCl/dioxane and the ing mixture was heated for 2 hours at 60 °CF. The resulting mixture was evaporated and triturated with ether to provide 3—(6—(methyl(2,2,6,6-tetramethylpiperidin—4— yl)amino)pyridazin—3—yl)—6—(1H—pyrazol—4—yl)pyridin—2—ol (24 mg, 61%).
LC-MS: 408 [M+H]+; 1H NMR (500 MHz, ol-d4) 5: 8.62 - 8.69 (m, 1H), 8.55 - 8.61 (m, 1H), 8.39 (s, 2H), 7.95 — 8.06 (m, 1H), 7.04 — 7.14 (m, 1H), 5.02 — 5.24 (m, 1H), 3.18 (s, 3H), 2.03 (s, 4H), 1.67 (s, 6H), 1.57 (s, 6H) Using the procedure described for Example 8 above, an additional compound described herein may be prepared by substituting the riate starting materials reagents, and on conditions, obtaining nds such as those selected from: LC—MS: 395 [M+H]+. 1H NMR (500 MHZ, methanol—d4) 6: 8.46 (d, J=9.5 Hz, 1H), 8.33—8.42 (m, 1H), 8.29 (d, J=7.6 Hz, 1H), 8.10—8.23 (m, 1H), 7.20 (d, J=9.1 HZ, 1H), 6.86 (d, J=7.3 Hz, 1H), 5.84 (tt, J=10.4, 3.8 Hz, 1H), 2.49 (dd, J=13.9, 4.1 Hz, 2H), 1.86 (dd, J=13.9, 10.4 Hz, 2H), 1.65 (s, 6H), 1.56 (s, 6H), (3 hydrogens corresponding to OH and NH unobserved) Biological Examples The following in vitro biological examples demonstrate the usefulness of the compounds of the t description for treating Huntington’s e.
To describe in more detail and assist in understanding the present description, the following non—limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically ng the scope thereof. Such variations of the present ption that may be now known or later developed, which would be within the w of one skilled in the art to ascertain, are considered to fall within the scope of the present ption and as hereinafter d.
Example 1 pment and Validation of Meso Scale Discovery (MSD) Assay to Quantify Mutant and Total Huntingtin Protein (HTT) — Best Pair Analysis for Endogenous HTT Detection To identify orally bioavailable small molecules useful for HTT reduction, high throughput ELISA methods to detect and measure both total HTT (wild—type and mutant)(tHTT) and mutant HTT (mHTT) in cells and tissues from HD patients and animal models are needed.
The method bed herein permits relatively high hput protein measurement of tHTT and mHTT levels in cells and tissues from HD patients and in HD animal models. The ELISA method described herein enables screening of molecules for their ability to decrease the level of HTT and to identify and optimize small molecules for use in treating HD.
To determine the combination of antibodies that detect HTT (wild type and ) in a sensitive, high throughput format, multiple commercially available antibodies (Table 1) were screened in capture/detection combinations.
Protocol for Best Pair Analysis for Antibody Comparison in Detecting Total and Mutant HTT in Cells 1. Cells were cultured in a cell culture—compatible 96—well plate. 2. The medium was removed and 50—100 uL of lysis buffer per well sition described below) was added to cells to provide a "cell lysate". The plate was placed on a shaker at 4° C for 30 minutes, then stored at —20° C. 3. A Capture Antibody Diluent was prepared by ng the capture antibody in PBS for standard plates as described in the plate layout, then 30 uL of the Capture Antibody Diluent was added per well. The plate was sealed and ted at 4° C overnight. 4. The plate was washed 3X with 200 uL of Wash Buffer. Blocking Buffer (150 uL per well) was added, then the plate was sealed and incubated on a plate shaker for 3—4 hours at room temperature (RT).
. The Blocking Buffer was decanted and the plate was washed 3X with 200 ML of Wash Buffer. The cell lysate (25 uL per well) was then added. The plate was sealed and incubated at 4° C overnight. 6. A First Detection Antibody Diluent was prepared by ng a first detection antibody for pairing in an Assay Antibody t. The plate was washed 3X with 200 uL of Wash Buffer, then 25 uL of the First Detection Antibody Diluent was added per well.
The plate was sealed and incubated on a plate shaker for 1 hour at RT. 7. A Second Detection Antibody Diluent was prepared by diluting a second detection antibody for pairing in an Assay Antibody t. The plate was washed 3X with 200 uL of Wash Buffer, then 25 uL of the Second Detection Antibody Diluent was added per well. The plate was sealed and incubated on a plate shaker for 1 hour at RT. 8. The Read Buffer was diluted 4X. The plate was washed 3X with 200 "L of Wash Buffer, then 150 uL of the Read Buffer was added per well. The plate were read immediately following.
The various commercially available antibodies screened in the Best Pair Analysis, providing different capture/detection ations are shown in Table 1. The capture/detection antibody pairs evaluated are shown in Table 2. The two antibody pairs that gave the maximum spread of values (higher signal to noise ratio) were selected for polyglutamine—expanded (mHTT) and total human HTT detection.
Table 1 Species Antibody Epitope monoclonal mouse MAB2166 Huntingtin fragment from aa 181—810 as a fusion protein Huntingtin fusion protein 549—679, fused to Glutathione S— monoclonal rat MAB2174 tranferase onal GST fusion protein from the first 256 amino acids from human mouse MAB5374 huntingtin with the on of the polyglutamine tract Peptide mapping near the N—terminus of Huntingtin of human goat polyclonal sc—8767 origin (N18) onal GST human Huntingtin minal fragment of 171 amino mouse P1874 acids containing 65Q) monoclonal mouse MAB 1574 lymeric glutamine stretch monoclonal Synthetic peptide corresponding to residues surrounding rabbit #5656S Prol220 of human huntingtin protein monoclonal mouse MW1 DRPLA— 19Q Table 2 Pair HTT MSD ID Signal to Noise ratio Capture/Detection Total MAB2166/MAB2174 \0U] Capture/Detection Total MAB2166/sc—8767 e/Detection Total sc-8767/#5656 Capture/Detection Total 6/#5656S Capture/Detection Mutant MAB5374/#5656S Capture/Detection Mutant MAB 1574/#5656S [0U1 Capture/Detection Mutant P l 874/#5656S [\J Capture/Detection Mutant MWl/#5656S 4; (II teristics for Best Pair capture/detection antibody pairs are those combinations that give minimum background and maximum signal. Such highly sensitive ELISA assays would be useful to detect HTT in the context of drug discovery for ing agents (small and large molecules and gene ies) and for use in detecting HTT as a biomarker in clinical studies.
Such capture/detection antibody pairs for quantifying total HTT are selected from MAB2166/MAB2174 and MAB2166/#5656S. Such capture/detection antibody pairs for quantifying mutant HTT are selected from MAB 1574/#5656S, Pl874/#5656S and MWl/#5656S. The antibody pair for mHTT (MW1/#5656S) and the other for total HTT (MAB2166/#5656S) from this analysis were further optimized and ted to provide high— throughput assays that enabled HTT detection in patient fibroblasts and lymphocytes.
The Endogenous Huntingtin n assay used in Example 2 was developed using the Best Pair antibodies identified in Table 2, providing highly sensitive, hroughput detection assays for polyglutamine—expanded (mHTT) and total human HTT in multiple cell systems. The platform used for the assay is the ELISA—based Meso Scale Discovery (MSD) electrochemiluminescence assay platform.
Example 2 Endogenous Huntingtin Protein Assay Meso Scale Discovery (MSD) 96—well or 384—well plates were coated overnight at 4°C with MWl (expanded polyglutamine) or 6 monoclonal antibody (for capture) at a concentration of 1 ug/mL in PBS (30 uL per well). Plates were then washed three times with 300 uL wash buffer (0.05% Tween—20 in PBS) and blocked (100 uL blocking buffer; 5% BSA in PBS) for 4-5 hours at room temperature with rotational shaking and then washed three times with wash buffer.
Samples (25 pL) were transferred to the antibody—coated MSD plate and incubated ght at 4°C. After removal of the lysates, the plate was washed three times with wash , and 25 uL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 ug/mL in 0.05% Tween—20 in blocking buffer) was added to each well and incubated with shaking for lHour at room temperature. Following incubation with the secondary antibody, the wells were rinsed with wash buffer after which 25 uL of goat anti—rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) ed to 0.25 ug/mL in 0.05% Tween— in blocking buffer) was added to each well and incubated with shaking for 1 hour at room temperature. After rinsing three times with wash , 150 uL of read buffer T with surfactant (MSD) were added to each empty well, and the plate was imaged on a SI 6000 imager (MSD) according to manufacturers’ ctions provided for 96— or 384—well plates. The resulting IC50 values (uM) for compounds tested are shown in Table 3.
As shown in Table 3, test compounds described herein had the following IC50 values, an IC50 value between > 3 uM and S 9 uM is indicated by a single star (*), an IC50 value between > 1 uM and S 3 uM is indicated by two stars (**), an IC50 value between > 0.5 uM and S 1 uM is ted by three stars (***), an IC50 value between > 0.1 uM and S 0.5 uM is indicated by four stars (****) and an IC50 value of S 0.1 uM is indicated by five stars (*****).
Table3 de IC50 de IC50 de IC50 460 * 416 ***** 444 * 39 * 417 ***** 445 * de IC50 de IC50 de IC50 207 **** 428 **** 456 * 258 **** 431 **** 457 * 307 **** 432 **** 458 * 318 ***** 434 *** 460 * 348 ***** 435 *** 461 * 350 ***** 436 *** 462 * 352 **** 437 ** 463 * 393 ***** 438 ** 464 * 411 ***** 439 ** 465 * 412 ***** 440 * Without regard to whether a document cited herein was specifically and individually indicated as being orated by reference, all documents referred to herein are orated by reference into the present application for any and all es to the same extent as if each individual reference was fully set forth herein.
Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein.
It is intended that the appended claims be interpreted to include all such equivalents.

Claims (15)

What is claimed is:
1. Use of a compound of Formula (Ia) in the cture of a medicament for treating or ameliorating Huntington’s Disease in a subject in need thereof: A X N N B (Ia) or a form thereof, n X is O, NH, N(CH3) or a bond; A is aryl or heterocyclyl, wherein, aryl is selected from the group consisting of: , and R1b a1 a2 a3 wherein, heterocyclyl is selected from the group consisting of: R2b R2c R2a R2c O R2c N R2c R2a N R2b N O N R2b N R2a , O , R2b , R2a , a37 a38 a39 a40 R2a R2a R2b R2b N N O O N N O , R2b R2a R2a , and R2a , , a41 a42 a43 a44 R2b R2b R2a S R2a N R2c N N R2c R2a , R2a , R2b ; a45 a46, and a47 B is monocyclic heterocyclyl selected from the group consisting of: R4d R4c R4c R4b R4b N N N O N R4a R4g R4a R4e R4d R4c R4a R4f R4e , , , b1 b2 b3 b14 N NH N N , R4a , R4a , b15 b16 b17 b18 N N N R4b NH N R4a R4a OH , R4a R4d , b19 b20 b21, and b23 R1a and R1b are each, where allowed by ble valences, one or more substituents each selected from halogen, hydroxyl, cyano, C1-4alkyl, 1-4alkyl, amino, C1-4alkyl-amino, lkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, C1-4alkyl-amino-carbonyl, (C1-4alkyl)2-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, (C1-4alkyl)2-aminocarbonyl-C1-4alkyl , C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, hydroxyl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, yl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, C1-4alkoxy- C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, C1-4alkoxy-carbonyl- amino-C1-4alkoxy, C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, heteroaryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, cyclyl-C1-4alkyl, heterocyclyl-C1-4alkoxy, phenyl, or phenyl-C1-4alkoxy, n: heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical having one or more heteroatoms independently ed from N, O, and S, heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and each instance of phenyl, heteroaryl or cyclyl is optionally substituted with 1 or 2 substituents each selected from R3; R2a, R2b and R2c are each, where allowed by available valences, one or more substituents each selected from halogen, cyano, oxo, hydroxyl-imino, C1-4alkyl, halo-C1-4alkyl, amino, kyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, kyl-amino-C1-4alkyl, lkyl)2-amino-C1-4alkyl, amino-carbonyl, hydroxyl-C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, C2-4alkenyl, C3-7cycloalkyl, or heterocyclyl-C1-4alkyl, wherein: heterocyclyl is a saturated or lly unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and each instance of heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R3; R3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, C1-4alkyl-amino-carbonyl, (C1-4alkyl)2-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, (C1-4alkyl)2-aminocarbonyl-C1-4alkyl , C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, yl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, hydroxyl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, C1-4alkoxy- koxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, C1-4alkoxy-carbonylamino-C1-4alkoxy , C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, cloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, aryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, heteroaryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, phenyl, or phenyl-C1-4alkoxy; and R4a, R4b, R4c, R4d, R4e, R4f and R4g are independently selected from halogen, kyl, hydroxyl-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino or hydroxyl-C1-4alkyl-amino; wherein a form of the compound is selected from the group consisting of a salt, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
2. Use of a compound of Formula (Ia) in the cture of a medicament for treating or ameliorating Huntington’s Disease in a subject in need thereof: A X N N B (Ia) or a form thereof, wherein X is O, NH, N(CH3) or a bond; A is aryl, heteroaryl or heterocyclyl, n, aryl is selected from the group consisting of: , and R1b a1 a2 a3 wherein, aryl is selected from the group consisting of: N N R1a R1b R1a R1b R1a , R1b R1a , , R1b , a4 a5 a6 a7 N N N R1a R1b R1a , R1b R1a R1a , R1b , R1b , a8 a9 a10 a11 N N N N N N N N R1a R1b R1a , R1b R1a , R1b R1a , R1b , a12 a13 a14 a15 R1b R1c N R1b R1c N N R1a N R1a R1b R1a , R1b , N , R1a , a16 a17 a18 a19 N N R1a R1b R1a , R1b R1a R1a , R1b , R1b , a20 a21 a22 a23 N R1a R1a R1b R1a R1a N , R1b , R1b , N , a24 a25 a26 a27 R1b R1b R1a S N N S R1a R1a R1a R1b , N , , , a28 a29 a30 a31 R1a N O R1a R1a S N N N , R1b , R1b , a32 a34 a35, and R1a ; a36; and wherein, heterocyclyl is ed from the group consisting of: R2c R2a O R2b R2c O R2c N R2c R2a N R2b N O N R2b N R2a , O , R2b , R2a , a37 a38 a39 a40 R2b R2b N R2a R2b O N O O N O N R2a O , R2a R2a , , , a41 a42 a43 a44 R2b R2b R2a S R2a N R2c N N R2c R2a , R2a , R2b ; a45 a46, and a47 B is monocyclic heterocyclyl selected from the group consisting of: R4d R4c R4c R4b R4b N N N O N R4a R4g R4a R4e R4d R4c , , R4a R4f R4e , b1 b2 b3 b14 N NH N N , R4a , R4a , b15 b16 b17 b18 N N N R4b NH N R4a R4a OH R4a R4d , , b19 b20 b21, and b23 R1a, R1b, and R1c are each, where allowed by available valences, one or more substituents each selected from halogen, cyano, C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, C1-4alkyl-amino-carbonyl, (C1-4alkyl)2-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, (C1-4alkyl)2-aminocarbonyl-C1-4alkyl , C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, yl-C1-4alkyl, C1-4alkyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, yl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, (C1-4alkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, koxy- C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, koxy-carbonylamino-C1-4alkoxy , C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, heteroaryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, heterocyclyl-C1-4alkoxy, phenyl, or phenyl-C1-4alkoxy, wherein: heteroaryl is a monocyclic, bicyclic or polycyclic aromatic carbon atom ring ure radical having one or more heteroatoms independently selected from N, O, and S, heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R3; R2a, R2b and R2c are each, where allowed by ble valences, one or more substituents each selected from halogen, cyano, oxo, hydroxyl-imino, C1-4alkyl, halo-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, C1-4alkyl-amino-C1-4alkyl, (C1-4alkyl)2-amino-C1-4alkyl, amino-carbonyl, hydroxyl-C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, C2-4alkenyl, C3-7cycloalkyl, or heterocyclyl-C1-4alkyl, wherein: heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 atom ring s selected from N, O, and S, and each ce of heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R3; R3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino, amino-C1-4alkyl, kyl-amino-C1-4alkyl, lkyl)2-amino-C1-4alkyl, carbonyl, C1-4alkyl-amino-carbonyl, (C1-4alkyl)2-amino-carbonyl, C1-4alkyl-amino-carbonyl-C1-4alkyl, (C1-4alkyl)2-aminocarbonyl-C1-4alkyl , C1-4alkyl-carbonyl-amino, C1-4alkyl-carbonyl-amino-C1-4alkyl, hydroxyl-C1-4alkyl, kyl-carbonyl, C1-4alkoxy, halo-C1-4alkoxy, amino-C1-4alkoxy, hydroxyl-C1-4alkoxy, C1-4alkyl-C1-4alkoxy, C1-4alkyl-amino-C1-4alkoxy, lkyl)2-amino-C1-4alkoxy, C1-4alkyl-carbonyl-amino-C1-4alkoxy, C1-4alkoxy- C1-4alkoxy, C1-4alkoxy-carbonyl, C1-4alkoxy-carbonyl-amino, C1-4alkoxy-carbonylamino-C1-4alkoxy , C2-4alkenyl, C2-4alkenyl-amino-carbonyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkoxy, C3-7cycloalkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroaryl-C1-4alkyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl, heteroaryl-C1-4alkyl-carbonyl-amino, heteroaryl-C1-4alkyl-amino-carbonyl-C1-4alkyl, aryl-C1-4alkyl-carbonyl-amino-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, phenyl, or phenyl-C1-4alkoxy; and R4a, R4b, R4c, R4d, R4e, R4f and R4g are independently selected from halogen, C1-4alkyl, hydroxyl-C1-4alkyl, amino, C1-4alkyl-amino, (C1-4alkyl)2-amino or hydroxyl-C1-4alkyl-amino; wherein a form of the compound is selected from the group ting of a salt, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
3. Use of a compound, or form thereof, in the manufacture of a medicament for treating or ameliorating Huntington’s Disease in a subject in need thereof, wherein the compound is ed from the group ting of: 6-(naphthalenyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[b]thiophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine 2-(6-(2,2,6,6-tetramethylpiperidinyl-amino)-pyridazinyl)phenol 2-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)benzo[b]-thiophene- 5-carbonitrile 6-(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 3-(benzo[b]-thiophenyl)(2,2,6,6-tetramethylpiperidinyl-oxy)pyridazine 2-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazinyl)phenol 6-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazinyl)naphthalenol zo[b]-thiophenyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 7-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinoline 6-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinoline N-methyl(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine N-methyl(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(imidazo[1,2-a]pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine methyl-(6-quinoxalinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine methyl-(6-quinolinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine N-methyl(phthalazinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[c][1,2,5]oxa-diazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[d]thiazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(2-methylbenzo-[d]oxazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalenol 5-chloro(6-(methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazinyl)phenol 3-(6-(2,2,6,6-tetramethylpiperidinyl-amino)pyridazinyl)naphthalenol 5-chloro(6-(1,2,2,6,6-pentamethylpiperidinylamino)pyridazinyl)phenol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzonitrile 3-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)naphthalenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethyl)phenol 2-fluoro(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl)phenol 3,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 4,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 4,5-difluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzonitrile 1-allyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalen 6-(benzo[b]thiophenyl)-N-(1,2,2,6,6-pentamethylpiperidinyl)pyridazinamine N-allylhydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzamide 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol ethyl-oxazolyl)(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)- zinyl)phenol hydroxymethyl)-1H-pyrazoleyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(4-amino-1H-pyrazoleyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 5-(3-amino-1H-pyrazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-(2-morpholinoethyl )-1H-pyrazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- pyrazolyl)phenol 5-(5-amino-1H-pyrazolyl)(6-(methyl-(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 2-((6-((2-hydroxy-ethyl)-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl) pyrazolyl)phenol 2-(6-(piperidinyloxy)pyridazinyl)(1H-pyrazolyl)phenol ((2S,4R,6R)-2,6-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazol yl)phenol 2-(6-((-2,6-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 5-(1H-pyrazolyl)(6-(pyrrolidinyl-oxy)pyridazinyl)phenol 2-(6-(((2S,4S)methylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol (5-(1H-pyrazolyl)(6-(pyrrolidinylmethoxy)pyridazinyl)phenol 2-(6-((3-fluoropiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,2,2,6,6-pentamethyl-piperidinyl-oxy)-pyridazinyl)(1H-pyrazolyl)phenol 5-1H-pyrazolyl(6-(2,2,6,6-tetramethylpiperidinyl-oxy)-pyridazinyl)phenol pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenol 2-(6-piperazinyl-pyridazinyl)(1H-pyrazolyl)phenol 3-(6-(azetidinylamino)-pyridazinyl)naphthalenol 2-(6-(azetidinylamino)pyridazinyl)(1H-pyrazolyl)phenol 3,5-dimethylpiperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,4-diazepanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(4-(2-hydroxyethyl)piperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3-(hydroxymethyl)piperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(4-aminomethylpiperidinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3-(dimethylamino)piperidinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,2,2,6,6-pentamethylpiperidinylamino)-pyridazinyl)1H-pyrazolyl-phenol 2-(6-(3,3-dimethylpiperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 3-(6-(piperazinyl)pyridazinyl)naphthalene-2,7-diol 5-(1H-pyrazolyl)(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)phenol 2-(6-piperidinyl-pyridazinyl)1H-pyrazolyl-phenol 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalenol 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7- diol 1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-(piperidinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)naphthalene-2,7-diol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene-2,7-diol 3-(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene-2,7-diol tert-butyl (3-((7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)naphthalenyl)oxy)propyl)carbamate 7-(3-amino-propoxy)(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazin yl)naphthalenol N-(3-((7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin hthalenyl)oxy)propyl)acetamide 7-(3-hydroxypropoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-(3-methoxypropoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-(2-morpholinoethoxy)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin yl)naphthalenol 3-(6-(piperidinylmethyl)pyridazinyl)naphthalenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)methyl)pyridazinyl)phenol 3-methoxy(6-(methyl(2,2,6-trimethylpiperidinyl)amino)pyridazinyl)(5- methyloxazolyl)phenol 2-(6-((6S)((S)hydroxyethyl)-2,2-dimethylpiperidinyloxy)pyridazinyl)(1H- pyrazolyl)phenol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) naphthonitrile 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (piperidinylmethyl)naphthalenol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (pyrrolidinylmethyl)naphthalenol 1-bromo(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene- 2,7-diol 1-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene- 2,7-diol oxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthaleneol 7-methoxy(6-(methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-(3,6-dihydro-2H-pyranyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(tetrahydro-2H- pyranyl)naphthaleneol 7-(difluoromethyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-((4-hydroxymethylbutanyl)oxy)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 7-(3-hydroxymethylbutoxy)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)benzene-1,3-diol 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethoxy)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- pyrazolyl)(trifluoromethoxy)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazolyl)- 3-(trifluoromethoxy)phenol 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethoxy)phenyl)methylpyridin-2(1H)-one 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1- methyl-1H-pyrazolyl)phenol 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl)phenol 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (pyridineyl)phenol yclopentyl-1H-pyrazolyl)methoxy(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 3’,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-(1,1'- biphenyl)ol 3-(benzyloxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5- methyloxazolyl)phenol 3-ethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5- methyloxazolyl)phenol 3-(cyclopropylmethoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazin- 3-yl)(5-methyloxazolyl)phenol 5-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)benzonitrile 2-(6-((2,2-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino) pyridazinyl)(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazinyl)phenol 4-(1H-indolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 4-(cyclopentenyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 4-(4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl) methylpyridin-2(1H)-one 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl)pyridin 5-(1H-indazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 4-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol ro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 5-fluoro(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol ro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- dihydro-1H-indenone oxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- dihydro-1H-indenone oxime 5-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3-dihydro-1H- indene-1,6-diol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-N-((1- methyl-1H-pyrazolyl)methyl)benzamide 4-(4-(hydroxymethyl)-1H-pyrazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)methyl)pyridazinyl)phenol 6-(3-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-(1-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 3-fluoro(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin nyl)pyridin-2(1H)-one 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one 5-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one 3-fluoro(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin yl)phenol 5-chlorofluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl- 1H-pyrazolyl)phenol 5-(5-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol ydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 5-(6-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- fluoromethyl)pyridinol 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1-methylpyridin-2(1H)-one 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1-methylpyridin-2(1H)-one 5-(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl)pyridin 5-(6-(dimethylamino)pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl) methylpyridin-2(1H)-one 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(pyrimidin yl)phenol ydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 1-cyclopropyl(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenyl)pyridin-2(1H)-one 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1,2,3,6- tetrahydropyridinyl)phenol 5-(cyclopentenyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(3,6-dihydro-2H-pyranyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(imidazo[1,5-a]pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(imidazo[1,2-a]pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(2-methylpyridin- 4-yl)phenol 5-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol dazo[1,2-a]pyrazinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5,6,7,8- tetrahydroimidazo[1,2-a]pyrazinyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4-nitro-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(2-methyl-1H- imidazolyl)phenol 5-(1,2-dimethyl-1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 1-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1H-pyrazolecarboxamide pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol 5-(1-methyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 5-(5-methyl-1H-pyrazolyl){6-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyridazinyl}phenol 5-(1H-imidazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}phenol 5-(5-methyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 2-{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(4-nitro-1H- pyrazolyl)phenol 6-[2-methoxy(4-nitro-1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyridazinamine 5-(4-amino-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 2-[6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol 5-(4-nitro-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol pyrazolyl)[6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl]phenol 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol 2-{6-[methyl(piperidinyl)amino]pyridazinyl}(1H-pyrazolyl)phenol 2-[6-(piperidinylamino)pyridazinyl](1H-pyrazolyl)phenol 6-[2,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 3-[2,5-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 2-[6-(piperidinyloxy)pyridazinyl](1H-pyrazolyl)phenol 6-[2-methoxy(1H-pyrazolyl)pyridinyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazinamine 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol 3-[2-fluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 3-[4-(1-methyl-1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidin ]pyridazine 3-fluoro{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol N-methyl(2-methyl-2H-indazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine 2-methyl{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}-2H-indazole 3-(4-chloromethoxyphenyl)[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine N-methyl(2-methylpyrazolo[1,5-a]pyridinyl)-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}imidazo[1,2-a]pyridine 3-[2-methoxy(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine 3-[5-(1-methyl-1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 3-[4-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine 5-(3,5-dimethyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 6-[2-fluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin idazinamine 3-methoxy{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}phenol 3-[2-methoxy(4-nitro-1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 4-{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}benzene-1,3-diol 6-[2-chloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 2-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}pyrimidinamine -difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 3-[2-(difluoromethyl)(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine and 6-[2-(difluoromethyl)(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyridazinamine; wherein a form of the compound is selected from the group consisting of a salt, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
4. The use of claim 3, wherein the compound is a compound salt selected from the group consisting of: 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethyl)phenol hydrochloride 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol hydrochloride 3-(6-(piperazinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 3-(6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 3-(6-(piperidinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- dihydro-1H-indenone oxime hydrochloride 3-fluoro(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol hydrochloride 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridin-2(1H)-one hydrochloride 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one hloride 5-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin nyl)methylpyridin-2(1H)-one hydrochloride 3-fluoro(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin nol hydrochloride rofluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol hydrochloride 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol hydrochloride ro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl- 1H-pyrazolyl)phenol hydrochloride 5-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol hydrochloride 2-{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(4-nitro-1H- pyrazolyl)phenol dihydrochloride 2-[6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol trihydrochloride 5-(1H-pyrazolyl)[6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl]phenol trihydrochloride 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol trihydrochloride 2-{6-[methyl(piperidinyl)amino]pyridazinyl}(1H-pyrazolyl)phenol tetrahydrochloride 2-[6-(piperidinylamino)pyridazinyl](1H-pyrazolyl)phenol tetrahydrochloride 6-[2-methoxy(1H-pyrazolyl)pyridinyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazinamine hydrochloride 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol trihydrochloride 3-[5-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine hloride and 3-[4-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine hydrochloride wherein a form of the compound salt is selected from the group consisting of a clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form f.
5. The use of any one of claims 1-4, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
6. The use of any one of claims 1-4, wherein the compound is in admixture with one or more pharmaceutically able excipient(s).
7. Use of a compound, or a form thereof, in the manufacture of a medicament for treating or ameliorating Huntington’s Disease in a subject in need thereof, ed from the group consisting of: 6-(naphthalenyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[b]thiophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine 2-(6-(2,2,6,6-tetramethylpiperidinyl-amino)-pyridazinyl)phenol 2-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)benzo[b]-thiophene- 5-carbonitrile 6-(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 3-(benzo[b]-thiophenyl)(2,2,6,6-tetramethylpiperidinyl-oxy)pyridazine 2-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazinyl)phenol 6-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazinyl)naphthalenol 6-(benzo[b]-thiophenyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 7-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinoline 6-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinoline yl(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine N-methyl(quinolinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(imidazo[1,2-a]pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine N-methyl(6-phenylpyridinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(6-(1H-pyrrolyl)pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-(6-(1H-pyrazolyl)pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine methyl-(6-quinoxalinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine methyl-(6-quinolinyl-pyridazinyl)-(2,2,6,6-tetramethylpiperidinyl)-amine N-methyl(phthalazinyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine zo[c][1,2,5]oxa-diazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(benzo[d]thiazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 6-(2-methylbenzo-[d]oxazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazinamine 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalenol 5-chloro(6-(methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazinyl)phenol 3-(6-(2,2,6,6-tetramethylpiperidinyl-amino)pyridazinyl)naphthalenol 5-chloro(6-(1,2,2,6,6-pentamethylpiperidinylamino)pyridazinyl)phenol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzonitrile 3-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)naphthalenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethyl)phenol 2-fluoro(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl)phenol 3,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 4,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 4,5-difluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzonitrile 1-allyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalen 6-(benzo[b]thiophenyl)-N-(1,2,2,6,6-pentamethylpiperidinyl)pyridazinamine N-allylhydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzamide 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 5-(5-methyl-oxazolyl)(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)- pyridazinyl)phenol 5-(4-(hydroxymethyl)-1H-pyrazoleyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(4-amino-1H-pyrazoleyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 5-(3-amino-1H-pyrazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-(2-morpholinoethyl )-1H-pyrazolyl)phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- pyrazolyl)phenol 5-(5-amino-1H-pyrazolyl)(6-(methyl-(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 2-((6-((2-hydroxy-ethyl)-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl) pyrazolyl)phenol 2-(6-(piperidinyloxy)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(((2S,4R,6R)-2,6-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazol yl)phenol 2-(6-((-2,6-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 5-(1H-pyrazolyl)(6-(pyrrolidinyl-oxy)pyridazinyl)phenol ((2S,4S)methylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol (5-(1H-pyrazolyl)(6-(pyrrolidinylmethoxy)pyridazinyl)phenol 2-(6-((3-fluoropiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,2,2,6,6-pentamethyl-piperidinyl-oxy)-pyridazinyl)(1H-pyrazolyl)phenol 5-1H-pyrazolyl(6-(2,2,6,6-tetramethylpiperidinyl-oxy)-pyridazinyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenol iperazinyl-pyridazinyl)(1H-pyrazolyl)phenol 3-(6-(azetidinylamino)-pyridazinyl)naphthalenol azetidinylamino)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3,5-dimethylpiperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(7-methyl-2,7-diazaspiro[4.4]nonanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,4-diazepanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(4-(2-hydroxyethyl)piperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3,6-diazabicyclo[3.2.1]octanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(2,7-diazaspiro[3.5]nonanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3-(hydroxymethyl)piperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,7-diazaspiro[4.4]nonanyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(4-aminomethylpiperidinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(3-(dimethylamino)piperidinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(1,2,2,6,6-pentamethylpiperidinylamino)-pyridazinyl)1H-pyrazolyl-phenol 2-(6-(3,3-dimethylpiperazinyl)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]-nonanyl)pyridazinyl)(1H-pyrazol yl)phenol 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazinyl)(1H-pyrazol yl)phenol 3-(6-(piperazinyl)pyridazinyl)naphthalene-2,7-diol 5-(1H-pyrazolyl)(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)phenol 2-(6-piperidinyl-pyridazinyl)1H-pyrazolyl-phenol 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalenol 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7- diol 1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-(piperidinyl)pyridazinyl)naphthalene-2,7-diol 3-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)naphthalene-2,7-diol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene-2,7-diol 3-(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene-2,7-diol tert-butyl (3-((7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)naphthalenyl)oxy)propyl)carbamate 7-(3-amino-propoxy)(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazin yl)naphthalenol N-(3-((7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenyl)oxy)propyl)acetamide 7-(3-hydroxypropoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-(3-methoxypropoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-(2-morpholinoethoxy)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin yl)naphthalenol 3-(6-(piperidinylmethyl)pyridazinyl)naphthalenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)methyl)pyridazinyl)phenol 3-methoxy(6-(methyl(2,2,6-trimethylpiperidinyl)amino)pyridazinyl)(5- methyloxazolyl)phenol 2-(6-((6S)((S)hydroxyethyl)-2,2-dimethylpiperidinyloxy)pyridazinyl)(1H- pyrazolyl)phenol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) naphthonitrile 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (piperidinylmethyl)naphthalenol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (pyrrolidinylmethyl)naphthalenol o(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene- 1-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)naphthalene- 2,7-diol 7-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthaleneol 7-methoxy(6-(methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazin yl)naphthalenol -dihydro-2H-pyranyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 3-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(tetrahydro-2H- pyranyl)naphthaleneol 7-(difluoromethyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)naphthalenol 7-((4-hydroxymethylbutanyl)oxy)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 7-(3-hydroxymethylbutoxy)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)naphthalenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)benzene-1,3-diol 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) uoromethoxy)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- pyrazolyl)(trifluoromethoxy)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazolyl)- 3-(trifluoromethoxy)phenol 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethoxy)phenyl)methylpyridin-2(1H)-one 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1- methyl-1H-pyrazolyl)phenol 3-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) ,8-tetrahydroimidazo[1,2-a]pyridinyl)phenol oxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (pyridineyl)phenol 5-(1-cyclopentyl-1H-pyrazolyl)methoxy(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 3’,5-dimethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-(1,1'- biphenyl)ol 3-(benzyloxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5- oxazolyl)phenol 3-ethoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5- methyloxazolyl)phenol 3-(cyclopropylmethoxy)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazin- 3-yl)(5-methyloxazolyl)phenol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-1H- benzo[d]imidazolol 5-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenol 3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)benzonitrile 2-(6-((2,2-dimethylpiperidinyl)oxy)pyridazinyl)(1H-pyrazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazinyl)phenol 4-(1H-indolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 4-(cyclopentenyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol 4-(4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl) methylpyridin-2(1H)-one 4-(4-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl)pyridin 5-(1H-indazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 4-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 4-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 5-fluoro(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 5-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- dihydro-1H-indenone 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-1,4- dihydroindeno[1,2-c]-1H-pyrazolol oxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- o-1H-indenone oxime 5-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3-dihydro-1H- indene-1,6-diol 2-amino(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-8H- indeno[1,2-d]thiazolol 9-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-5,6- dihydroimidazo[5,1-a]isoquinolinol 4-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-N-((1- methyl-1H-pyrazolyl)methyl)benzamide 4-(4-(hydroxymethyl)-1H-pyrazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)methyl)pyridazinyl)phenol 6-(3-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-(1-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine ro(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridin-2(1H)-one 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one 5-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin nyl)methylpyridin-2(1H)-one 3-fluoro(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin yl)phenol 5-chlorofluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- pyrazolyl)phenol ro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl- 1H-pyrazolyl)phenol 5-(5-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 5-(6-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 3-(trifluoromethyl)pyridinol 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1-methylpyridin-2(1H)-one 4-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1-methylpyridin-2(1H)-one 5-(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl)pyridin 5-(6-(dimethylamino)pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 4-(3-hydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenyl) methylpyridin-2(1H)-one 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(pyrimidin 5-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridinol 1-cyclopropyl(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenyl)pyridin-2(1H)-one 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1,2,3,6- ydropyridinyl)phenol 5-(cyclopentenyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(3,6-dihydro-2H-pyranyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(imidazo[1,5-a]pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 5-(imidazo[1,2-a]pyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(2-methylpyridin- 4-yl)phenol imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol 5-(imidazo[1,2-a]pyrazinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(5,6,7,8- tetrahydroimidazo[1,2-a]pyrazinyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(4-nitro-1H- imidazolyl)phenol 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(2-methyl-1H- imidazolyl)phenol 5-(1,2-dimethyl-1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol 1-(3-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)phenyl)- 1H-pyrazolecarboxamide (3aR,6aS)(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin yl)(1H-pyrazolyl)phenol 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazinyl)(1H-pyrazol yl)phenol (3aR,6aS)methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazinyl)(1H- pyrazolyl)phenol 4-(3-hydroxy(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin yl)phenyl)methylpyridin-2(1H)-one 4-(3-hydroxy(6-((3aR,6aR)methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)pyridazin- 3-yl)phenyl)methylpyridin-2(1H)-one 2-(6-(2,7-diazaspiro[4.5]decanyl)pyridazinyl)(1H-pyrazolyl)phenol 4-(4-(6-(2,7-diazaspiro[4.5]decanyl)pyridazinyl)hydroxyphenyl)methylpyridin- 2(1H)-one 2-(6-(methyl-(2,2,6,6-tetramethylpiperidinyl)-amino)-pyridazinyl)phenol 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 6-(6-(methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazinyl)quinolinol 6-(6-((3aR,6aS)methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazinyl)quinolin- 7-ol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin methyl(1,2,2,6,6-pentamethylpiperidinyl)amino)pyridazinyl)isoquinolinol 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolinol 7-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinolineol 7-(6-((3aR,6aS)methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin yl)isoquinolinol 1-cyclopropyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinol 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinoline-1,6-diol 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinecarbonitrile 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolinol 8-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin 3-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 3-bromo(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline- 3-carbonitrile 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl-1H- imidazolyl)quinolinol 3-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline-3,7-diol 3-ethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 3-isopropyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 7-ol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 2(1H)-one 7-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolin-2(1H)-one 4-methoxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (pyrrolidinyl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) morpholinoquinolinol 4-(dimethylamino)methyl(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)quinolinol 4-ethoxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol yl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1- methyl-1H-pyrazolyl)quinolinol 4-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 6-ol 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoxalinol 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(tetrahydro-2H- pyranyl)quinolinol 3-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 3-bromo(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 3-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin omethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol 6-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolin-4(1H)-one methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoxalin- 6-ol 3-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoxalin- 6-ol 4-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 7-ol 4-(azetidinyl)methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin- 3-yl)quinolinol 7-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolonecarbonitrile 4-cyclopropylmethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)-quinolinol 4-(3,6-dihydro-2H-pyranyl)methyl(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (tetrahydro-2H-pyranyl)quinolinol 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(oxetan- uinolinol 4-(dimethylamino)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)- quinolinol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinazolin- 4(1H)-one 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinazolinol oxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)- 3,4-dihydroquinolin-2(1H)-one 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinazolin- 7-ol 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinecarbonitrile 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline- 2-carbonitrile 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin carbonitrile 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinecarboxamide 7-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin carboxamide 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline- 2-carboxamide methyl 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinecarboxylate 6-hydroxy(6-(piperazinyl)pyridazinyl)quinolinecarbonitrile 7-hydroxy(6-(piperazinyl)pyridazinyl)quinolinecarbonitrile 7-(6-(piperazinyl)pyridazinyl)isoquinolinol 7-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)quinolinol yl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolin- 7-ol 1-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolin- 6-ol 1,3-dimethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinol 7-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinecarbonitrile 1-amino(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolin- 6-ol 7-hydroxy-1,3-dimethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinazoline-2,4(1H,3H)-dione 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)benzo[d]oxazol-2(3H)-one 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2H-indazol- 6-ol 1-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-1H-indazol- 6-ol 6-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin quinolin-1(2H)-one 2-ethylhydroxy(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinolin- 1(2H)-one xy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolin- 6-ol 7-(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)isoquinoline-1,6-diol 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-pyridazinyl)phenylisoquinolin- 6-ol 3-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)isoquinolin- 6-ol 3-cyclopropyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinol 3-isopropyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolinol 3-propyl(6-((2,2,6,6-tetramethylpiperidinyl)oxy)-pyridazinyl)isoquinolinol 3-isopropyl(6-((2,2,6,6-tetramethylpiperidinyl)oxy)-pyridazinyl)isoquinolinol 3-methyl(6-(piperazinyl)pyridazinyl)isoquinolinol 6-(3-(benzyloxy)isoquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 3-chloro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 3-isopropyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 7-ol 3-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoxalin- 6-ol 4-chloromethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol ro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolinol 5-(2-methoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- thiadiazolamine 6-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)naphthalen 5-(2-methoxyquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)-1,3,4- thiadiazolamine 5-(3-methoxy-naphthalenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)-1,3,4- thiadiazolamine 5-(2-methoxy(1H-pyrazol-1yl)phenyl)-N-(1,2,2,6,6-pentamethylpiperidinyl)-1,3,4- thiadiazolamine 5-(2-methoxy(1-methyl-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(2-methoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 4-(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)methylpyridin-2(1H)-one 5-(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)pyridinol 5-(3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)methylpyridin-2(1H)-one N-methyl(2-methyl(1-methyl-1H-pyrazolyl)phenyl)-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine yl(4-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl) (trifluoromethoxy)phenyl)pyridin-2(1H)-one 5-(4-(3,5-dimethyl-1H-pyrazolyl)methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine N-methyl(4-(1-methyl-1H-pyrazolyl)(trifluoromethyl)phenyl)-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4,-thiadiozolyl(1-methyl- 1H-pyrazolyl)phenol 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4,-thiadiozolyl(1H- pyrazolyl)phenol ydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)methylpyridin-2(1H)-one 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)methylpyridin-2(1H)-one 5-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)pyridinol 3-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)naphthalene- 2,7-diol (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol yl)naphthalene-2,7-diol 3-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)naphthalen 3-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)quinolinol 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)(1H- pyrazolyl)phenol 5-(2-chloro(1-methyl-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 3-chloro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)(1- methyl-1H-pyrazolyl)phenol 5-(2-chloro(1-methyl-1H-pyrazolyl)phenyl)-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine oxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl) methyloxazolyl)phenol 2-(2-methoxy(1H-pyrazolyl)phenyl)(1,2,3,6-tetrahydropyridinyl)-1,3,4- thiadiazole 2-(5-(piperazinyl)-1,3,4-thiadiazolyl)(1H-pyrazolyl)phenol 5-(7-methoxyquinolinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)-1,3,4- thiadiazoleamine 6-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)quinolinol 3-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)benzonitrile 3-fluoro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)benzonitrile methylfluoro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)benzoate 5-(2-methoxy(3-(methylamino)-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 7-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)quinolinecarbonitrile 4-(3-methoxy(5-((2,2,6,6-tetramethylpiperidinyl)oxy)-1,3,4-thiadiazolyl)phenyl) methylpyridin-2(1H)-one hloro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)methylpyridin-2(1H)-one 5-(2-chloro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-chloro(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine N-methyl(5-(1-methyl-1H-pyrazolyl)pyridinyl)-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 2-(2-chloro(1-methyl-1H-pyrazolyl)phenyl)((2,2,6,6-tetramethylpiperidin yl)oxy-1,3,4-thiadiazole hloro(6-methoxypyridinyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 3,4-thiadiazolamine 5-(4-(6-aminopyridinyl)fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(2-fluoro(3-methyl-1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(2-fluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2,3-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 3,4-thiadiazolamine 5-(2,3-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(2,5-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(2,5-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(2,6-difluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 2-(2,5-difluoro(1H-pyrazolyl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole 5-(2-chlorofluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(3-fluoro(1H-pyrazolyl)pyridinyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(4-(2-aminopyrimidinyl)chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 2-aminopyrimidinyl)chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(4-(2,4-dimethylthiazolyl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(4-(2,4-dimethylthiazolyl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 4-(3-hydroxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)- 5-(trifluoromethoxy)phenyl)methylpyridin-2(1H)-one 5-(2-fluoromethoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 2-(2-fluoromethoxy(1H-pyrazolyl)phenyl)((3aR,6aS) methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 5-(2,3-difluoromethoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6- ethylpiperidinyl)-1,3,4-thiadiazolamine 6-methoxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)- 3,4-dihydroisoquinolin(2H)-one 5-(2-chloro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-chloro(1H-1,2,3-triazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine 5-(2-chloro(2H-1,2,3-triazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 3,4-thiadiazolamine 5-(2-chloro(1H-1,2,4-triazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin 3,4-thiadiazolamine 5-(4-(3-amino-1H-pyrazolyl)chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 2-(2-chloro(1H-imidazolyl)phenyl)((3aR,6aS) methylhexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 5-(2-chloro(1H-imidazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-fluoro(1H-imidazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-methoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 2,4-dimethylthiazolyl)methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(2-methoxy(pyridinyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-fluoro(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine 5-(2-methoxy(2-methoxypyridinyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 5-(2-methoxy(6-methoxypyridinyl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)-1,3,4-thiadiazolamine 2-(2-chloro(1-methyl-1H-pyrazolyl)phenyl)((3aR,6aS) methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 2-(2-chloro(1H-pyrazolyl)phenyl)((3aR,6aS)methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 2-(2-chloro(1H-pyrazolyl)phenyl)((3aR,6aR)methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-1,3,4-thiadiazole (R)(4-(5-(2-chloro(1H-pyrazolyl)phenyl)-1,3,4-thiadiazolyl)morpholinyl)- N,N-dimethylmethanamine 2-(2-chloro(1H-pyrazolyl)phenyl)(2-methyl-2,7-diazaspiro[4.5]decanyl)-1,3,4- thiadiazole 2-(2-fluoro(1H-pyrazolyl)phenyl)((3aR,6aS)methylhexahydropyrrolo[3,4- ol-2(1H)-yl)-1,3,4-thiadiazole ethoxy(1-methyl-1H-pyrazolyl)phenyl)(2,6-diazaspiro[3.5]nonanyl)- 1,3,4-thiadiazole 2-(2-methoxy(1-methyl-1H-pyrazolyl)phenyl)(2,7-diazaspiro[3.5]nonanyl)- 1,3,4-thiadiazole 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)(1H- pyrazolyl)phenol 5-(3-chloro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)phenyl)pyridin-2(1H)-one 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)(3- (methylamino)-1H-pyrazolyl)phenol 3-fluoro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl) (1H-pyrazolyl)phenol 3,4-difluoro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)- 5-(1H-pyrazolyl)phenol oxy(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)- 2,3-dihydro-1H-indenone 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)(1H- pyrazolyl)phenol 2-(5-(2,6-diazaspiro[3.5]nonanyl)-1,3,4-thiadiazolyl)(1-methyl-1H-pyrazol yl)phenol 2-(5-(2,7-diazaspiro[3.5]nonanyl)-1,3,4-thiadiazolyl)(1-methyl-1H-pyrazol yl)phenol 3-fluoro(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazolyl) (1H-pyrazolyl)phenol 3-chloro(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl) (1H-pyrazolyl)phenol 2-(2-methoxy(1H-pyrazolyl)phenyl)((2,2,6,6-tetramethylpiperidinyl)methyl)- 1,3,4-thiadiazole 2-(2,3-difluoro(1H-pyrazolyl)phenyl)(2,7-diazaspiro[3.5]nonanyl)-1,3,4- thiadiazole 2-(5-(2,7-diazaspiro[3.5]nonanyl)-1,3,4-thiadiazolyl)fluoro(1H-pyrazol 4-methoxymethyl(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4- thiadiazolyl)quinolin-2(1H)-one 4-hydroxymethyl(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4- thiadiazolyl)quinolin-2(1H)-one 3-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)quinolin- 2(1H)-one 1-methyl(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)quinolin-2(1H)-one 2-(2-chloro(1H-pyrazolyl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- yl)-1,3,4-thiadiazole 2-(2-chloro(1H-pyrazolyl)phenyl)(2,7-diazaspiro[4.5]decanyl)-1,3,4-thiadiazole (R)-(4-(5-(2-chloro(1H-pyrazolyl)phenyl)-1,3,4-thiadiazolyl)piperazin yl)methanol 2-(5-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazol yl)benzo[b]thiophenecarbonitrile 5-(3-chlorobenzo[b]thiophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)-1,3,4- thiadiazolamine 5-(2-methoxy(1H-pyrazolyl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)- 1,3,4-thiadiazolamine (1R,5S)azabicyclo[3.2.1]octyl(methyl)amino]pyridazinyl}(1H-pyrazol yl)phenol 2-[6-((1R,5S)azabicyclo[3.2.1]octylamino)pyridazinyl](1H-pyrazolyl)phenol 5-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol 5-(1-methyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin 2-[6-((1R,5S)azabicyclo[3.2.1]octyloxy)pyridazinyl](1H-pyrazolyl)phenol 5-(5-methyl-1H-pyrazolyl){6-[methyl(2,2,6,6-tetramethylpiperidin yl)amino]pyridazinyl}phenol 5-(1H-imidazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}phenol 5-(5-methyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(4-nitro-1H- pyrazolyl)phenol 6-[2-methoxy(4-nitro-1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyridazinamine 5-(4-amino-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 2-[6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol 5-(4-nitro-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 5-(1H-pyrazolyl)[6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl]phenol 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol 2-{6-[methyl(piperidinyl)amino]pyridazinyl}(1H-pyrazolyl)phenol 2-[6-(piperidinylamino)pyridazinyl](1H-pyrazolyl)phenol 6-[2,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 2-[6-(8-azabicyclo[3.2.1]octenyl)pyridazinyl](1H-pyrazolyl)phenol 6-[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 3-[2,5-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 2-[6-(piperidinyloxy)pyridazinyl](1H-pyrazolyl)phenol 2-{6-[(1R,5S)azabicyclo[3.2.1]octylamino]pyridazinyl}(1H-pyrazolyl)phenol 6-[2-methoxy(1H-pyrazolyl)pyridinyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazinamine 3-[4-(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol 3-[2-fluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 3-[4-(1-methyl-1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 2,7-diazaspiro[3.5]nonyl)pyridazinyl](1H-pyrazolyl)phenol ro{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol N-methyl(2-methyl-2H-indazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)pyridazin amine 2-methyl{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}-2H-indazole 3-(4-chloromethoxyphenyl)[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine N-methyl(2-methylpyrazolo[1,5-a]pyridinyl)-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 6-{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}imidazo[1,2-a]pyridine 3-[2-methoxy(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin ]pyridazine 3-[5-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine 3-[5-(1-methyl-1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 3-[4-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine 5-(3,5-dimethyl-1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}phenol 6-[2-fluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 3-methoxy{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}phenol 3-[2-methoxy(4-nitro-1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 4-{6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}benzene-1,3-diol 6-[2-chloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine 2-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazin yl}pyrimidinamine 3-[2,6-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine 2-[6-(2,6-diazaspiro[3.4]octyl)pyridazinyl](1H-pyrazolyl)phenol 3-{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(1H-pyrazol yl)pyridinol 6-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazinyl}pyridin N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazolyl)phenoxy]-1,3,4-thiadiazolyl}piperidin- 4-amine 6,6-pentamethyl-N-{5-[4-(1H-pyrazolyl)phenoxy]-1,3,4-thiadiazolyl}piperidin- 4-amine difluoromethyl)(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine and 6-[2-(difluoromethyl)(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyridazinamine; wherein a form of the compound is selected from the group consisting of a salt, racemate, enantiomer, reomer, isomer, and tautomer form thereof.
8. The use of claim 7, wherein the compound is a compound salt selected from the group consisting of: 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (trifluoromethyl)phenol hloride 2-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H-pyrazol yl)phenol hydrochloride 2-(6-piperazinyl-pyridazinyl)1H-pyrazolyl-phenol hydrochloride 3-(6-(piperazinyl)pyridazinyl)naphthalene-2,7-diol oroacetate 3-(6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 3-(6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 3-(6-(piperidinyl)pyridazinyl)naphthalene-2,7-diol trifluoroacetate 6-hydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-2,3- dihydro-1H-indenone oxime hydrochloride 2-amino(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-8H- indeno[1,2-d]thiazolol hydrochloride 9-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)-5,6- dihydroimidazo[5,1-a]isoquinolinol hydrochloride 3-fluoro(2-methoxypyridinyl)(6-(methyl(2,2,6,6-tetramethylpiperidin yl)amino)pyridazinyl)phenol hydrochloride 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)pyridin-2(1H)-one hydrochloride 4-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one hydrochloride 5-(3-fluorohydroxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenyl)methylpyridin-2(1H)-one hydrochloride 3-fluoro(1H-pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazin yl)phenol hydrochloride rofluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)phenol hydrochloride 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1H- lyl)phenol hydrochloride 3-fluoro(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)(1-methyl- 1H-pyrazolyl)phenol hydrochloride 3-(1H-imidazolyl)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolinol hydrochloride 6-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoline-3,7-diol 7-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)quinolin-2(1H)-one hydrochloride 4-methoxy(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinolin- 6-ol formate 7-(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)quinoxalinol hydrochloride 2-methyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl) (tetrahydro-2H-pyranyl)quinolinol formate 4-(dimethylamino)(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazinyl)- quinolinol formate 6-hydroxymethyl(6-(methyl(2,2,6,6-tetramethylpiperidinyl)amino)pyridazin yl)isoquinolin-1(2H)-one hydrochloride methyl(2,2,6,6-tetramethylpiperidinyl)amino)-1,3,4-thiadiazolyl)naphthalen ol hydrobromide N-methyl(5-(1-methyl-1H-pyrazolyl)pyridinyl)-N-(2,2,6,6-tetramethylpiperidin yl)-1,3,4-thiadiazolamine hydrochloride 3-fluoro(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazolyl) (1H-pyrazolyl)phenol dihydrochloride 2-(2-chloro(1H-pyrazolyl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole hydrochloride 2-(2-chloro(1H-pyrazolyl)phenyl)(2,7-diazaspiro[4.5]decanyl)-1,3,4-thiadiazole hydrochloride (R)-(4-(5-(2-chloro(1H-pyrazolyl)phenyl)-1,3,4-thiadiazolyl)piperazin yl)methanol hydrochloride 2-{6-[(1R,5S)azabicyclo[3.2.1]octyl(methyl)amino]pyridazinyl}(1H-pyrazol yl)phenol hloride 2-[6-((1R,5S)azabicyclo[3.2.1]octylamino)pyridazinyl](1H-pyrazolyl)phenol hydrochloride 5-(1H-pyrazolyl){6-[(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}phenol hydrochloride 2-[6-((1R,5S)azabicyclo[3.2.1]octyloxy)pyridazinyl](1H-pyrazolyl)phenol hloride 2-{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(4-nitro-1H- pyrazolyl)phenol dihydrochloride 2-[6-(1-methyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol trihydrochloride 5-(1H-pyrazolyl)[6-(1,2,3,6-tetrahydropyridinyl)pyridazinyl]phenol trihydrochloride 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)pyridazinyl](1H-pyrazolyl)phenol rochloride 2-{6-[methyl(piperidinyl)amino]pyridazinyl}(1H-pyrazolyl)phenol tetrahydrochloride piperidinylamino)pyridazinyl](1H-pyrazolyl)phenol tetrahydrochloride 6-[2,5-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine tetrahydrochloride 2-[6-(8-azabicyclo[3.2.1]octenyl)pyridazinyl](1H-pyrazolyl)phenol hydrochloride 6-[2,3-difluoro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine hydrochloride -difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine trihydrochloride 2-{6-[(1R,5S)azabicyclo[3.2.1]octylamino]pyridazinyl}(1H-pyrazolyl)phenol hydrochloride 6-[2-methoxy(1H-pyrazolyl)pyridinyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazinamine hydrochloride 2-{6-[(2,6-dimethylpiperidinyl)oxy]pyridazinyl}(1H-pyrazolyl)phenol trihydrochloride luoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine hydrochloride 2-[6-(2,7-diazaspiro[3.5]nonyl)pyridazinyl](1H-pyrazolyl)phenol tetrahydrochloride 1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine hydrochloride 3-[4-(1H-pyrazolyl)thiophenyl][(2,2,6,6-tetramethylpiperidinyl)oxy]pyridazine hydrochloride 6-[2-chloro(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin yl)pyridazinamine trihydrochloride 3-[2,6-difluoro(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine trihydrochloride 3-{6-[methyl(2,2,6,6-tetramethylpiperidinyl)amino]pyridazinyl}(1H-pyrazol yl)pyridinol hydrochloride N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazolyl)phenoxy]-1,3,4-thiadiazolyl}piperidin- 4-amine hydrochloride N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazolyl)phenoxy]-1,3,4-thiadiazolyl}piperidin- 4-amine hydrochloride 3-[2-(difluoromethyl)(1H-pyrazolyl)phenyl][(2,2,6,6-tetramethylpiperidin yl)oxy]pyridazine hydrochloride and 6-[2-(difluoromethyl)(1H-pyrazolyl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidinyl)pyridazinamine hydrochloride; wherein a form of the compound salt is selected from the group ting of a te, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
9. The use of claim 7 or 8, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
10. The use of claim 7 or 8, wherein the nd is in admixture with one or more pharmaceutically acceptable excipients.
11. The use of any one of claims 1-3 or 7, wherein the form of the compound is selected from the group consisting of a salt, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
12. The use of any one of claims 1-3 or 7, wherein the compound is: pyrazolyl)(6-((2,2,6,6-tetramethylpiperidinyl)oxy)pyridazinyl)phenol, or a form thereof.
13. The use of claim 12, wherein the form of the compound is selected from the group consisting of a salt, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form
14. The use of claim 12, wherein the amount of the compound or form thereof is in a range of from 0.001 mg/kg/day to 500 mg/kg/day.
15. The use of claim 12, wherein the compound or form thereof is in admixture with one or more ceutically acceptable excipients.
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