NZ796418A - Compounds for treating huntington's disease - Google Patents

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 bicyclic heteroaryl compounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

Description

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

NZ 796418 COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE This application is a divisional of New Zealand patent application 759824, which is the national phase entry of P.C.T. international ation , filed June 5, 2017 and published as WO 26622, the contents of each of which are incorporated by reference herein in their ties.

An aspect of the present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof useful for treating or rating gton’s e. In particular, another aspect of the present description relates to substituted bicyclic heteroaryl compounds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or itions thereof for treating or ameliorating Huntington’s disease.

BACKGROUND Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of ms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western 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 t” huntingtin (Htt) gene, leading to tion of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies ing the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or rating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.

All other documents ed to herein are incorporated by reference into the present application as though fully set forth herein.

SUMMARY An aspect of the t description includes compounds comprising, a compound of Formula (I): or a form thereof, wherein R1, R2, W1, W2, W3, W4, W5 and W6 are as defined herein.

An aspect of the present description includes a method 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 f.

An aspect of the present description includes a method for use of a compound of Formula (I) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an ive amount of the nd of a (I) or a form or composition thereof.

An aspect of the present ption includes a use for a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, stering to the subject an ive amount of the compound of Formula (I) or a form thereof.

An aspect of the present description includes a use for a nd 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 to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in a combination t with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

DETAILED DESCRIPTION An aspect of the present description s to compounds comprising, a compound of Formula (I): or a form f, wherein: W1, W2, W3, W4, W5 and W6 are independently C-Ra, C-Rb or N, wherein, when one, two or three of W1, W5 and W6 are N, then W2, W3 and W4 are C-Ra or C-Rb, wherein, when one, two or three of W2, W3 and W4 are N, then W1, W5 and W6 are C-Ra or C-Rb; R1 is aryl, heterocyclyl, heterocyclyl-amino, (heterocyclyl)(C1-8alkyl)amino or heteroaryl, wherein, each instance of heterocyclyl is optionally substituted with one, two or three R3 tuents and optionally, with one additional R4 tuent, or, n, alternatively, each instance of heterocyclyl is optionally substituted with one, two, three or four R3 substituents; R2 is aryl, heteroaryl, heteroaryl-amino or oaryl)(C1-8alkyl)amino, wherein, each instance of aryl and heteroaryl is optionally substituted with one, two or three R6 substituents and optionally, with one additional R7 substituent; Ra is, in each instance, independently selected from hydrogen, halogen or C1-8alkyl; Rb is, in each instance, independently selected from hydrogen, halogen or kyl; R3 is, in each instance, ndently selected from cyano, halogen, hydroxy, C1-8alkyl, halo-C1-8alkyl, C1-8alkyl-carbonyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl]2-amino, (C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, [(C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-carbonyl-amino, C1-8alkoxy-carbonyl-amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino; R4 is C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, C3-14cycloalkyl-amino, aryl-C1-8alkyl, aryl-C1-8alkoxy-carbonyl, aryl-sulfonyloxy-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heteroaryl or heteroaryl-C1-8alkyl; wherein, each instance of ycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R5 tuents; R5 is, in each instance, ndently ed from halogen, hydroxy, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino or C1-8alkyl-thio; R6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C1-8alkyl, C2-8alkenyl, cyano-C1-8alkyl, halo-C1-8alkyl, y-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl, C1-8alkyl)amino or C1-8alkyl-thio; and, R7 is C3-14cycloalkyl, C3-14cycloalkyl-oxy, aryl, heterocyclyl, heteroaryl or heteroaryl-C1-8alkoxy; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, te, omer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

ASPECTS OF THE DESCRIPTION Another aspect of the present description includes a compound of Formula (I) comprising, a nd of Formula (I.1): (I.1) or a form thereof, wherein: W1, W2, W3, W4, W5 and W6 are independently C-Ra, C-Rb or N, wherein, when one, two or three of W1, W5 and W6 are N, then W2, W3 and W4 are C-Ra or C-Rb, wherein, when one, two or three of W2, W3 and W4 are N, then W1, W5 and W6 are C-Ra or C-Rb; R1 is C1-8alkyl, amino, C1-8alkyl-amino, lkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, koxy-C1-8alkyl-amino-C1-8alkyl, (C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, amino-C1-8alkyl-amino, (amino-C1-8alkyl)2-amino, (amino-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl)2-amino, (C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, C1-8alkoxy, C1-8alkyl-amino-C1-8alkoxy, lkyl)2-amino-C1-8alkoxy, C1-8alkoxy-C1-8alkyl-amino-C1-8alkoxy, koxy-C1-8alkyl-amino-C1-8alkoxy, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy, amino-C2-8alkenyl, C1-8alkyl-amino-C2-8alkenyl, (C1-8alkyl)2-amino-C2-8alkenyl, amino-C2-8alkynyl, C1-8alkyl-amino-C2-8alkynyl, (C1-8alkyl)2-amino-C2-8alkynyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, (halo-C1-8alkyl)(C1-8alkyl)amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino, (hydroxy-C1-8alkyl)(C1-8alkyl)amino, hydroxy-C1-8alkyl-amino-C1-8alkyl, (hydroxy-C1-8alkyl)2-amino-C1-8alkyl, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, hydroxy-C1-8alkyl-amino-C1-8alkoxy, (hydroxy-C1-8alkyl)2-amino-C1-8alkoxy, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy, hydroxy-C1-8alkyl-amino-C1-8alkyl-amino, (hydroxy-C1-8alkyl-amino-C1-8alkyl)2-amino, (hydroxy-C1-8alkyl)2-amino-C1-8alkyl-amino, (hydroxy-C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl-amino, [(hydroxy-C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, [(hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl](C1-8alkyl)amino, ycloalkyl, aryl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl)2-amino, (aryl-C1-8alkyl)(C1-8alkyl)amino, aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, (aryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C1-8alkyl)amino, heterocyclyl-amino-C1-8alkyl, heterocyclyl-C1-8alkyl-amino, (heterocyclyl-C1-8alkyl)2-amino, (heterocyclyl-C1-8alkyl)(C1-8alkyl)amino, heterocyclyl-C1-8alkyl-amino-C1-8alkyl, (heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, (heterocyclyl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-C1-8alkoxy, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl)2-amino, (heteroaryl-C1-8alkyl)(C1-8alkyl)amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl, (heteroaryl-C1-8alkyl)2-amino-C1-8alkyl or (heteroaryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, wherein, each instance of C3-14cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R3 substituents and optionally, with one additional R4 substituent, or, n, atively, each instance of C3-14cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R3 substituents; R2 is aryl, heteroaryl, heteroaryl-amino or (heterocyclyl)(C1-8alkyl)amino, wherein, each instance of aryl and heteroaryl is ally substituted with one, two or three R6 substituents and optionally, with one additional R7 substituent; Ra is, in each instance, independently selected from en, or C1-8alkyl; Rb is, in each instance, independently selected from en, or halogen; R3 is, in each instance, independently selected from cyano, n, y, C1-8alkyl, halo-C1-8alkyl, C1-8alkyl-carbonyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, kyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl]2-amino, (C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, [(C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-carbonyl-amino, C1-8alkoxy-carbonyl-amino, y-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino; R4 is C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, C3-14cycloalkyl-amino, aryl-C1-8alkyl, aryl-C1-8alkoxy-carbonyl, aryl-sulfonyloxy-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heteroaryl or heteroaryl-C1-8alkyl; wherein, each instance of C3-14cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R5 substituents; R5 is, in each instance, independently selected from n, hydroxy, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxy-C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-thio or heteroaryl-C1-8alkyl; R6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C1-8alkyl, C2-8alkenyl, cyano-C1-8alkyl, halo-C1-8alkyl, hydroxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, (C1-8alkyl)2-amino-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, koxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl, C1-8alkyl)amino or C1-8alkyl-thio; and, R7 is ycloalkyl, C3-14cycloalkyl-oxy, aryl, cyclyl, heteroaryl or heteroaryl-C1-8alkoxy.

One aspect includes a compound of Formula (I), wherein W1 is N.

Another aspect includes a compound of Formula (I), wherein W1 is N, W4 is C-Rb and W2, W3, W5 and W6 are C-Ra.

One aspect includes a compound of Formula (I), wherein W2 is N.

Another aspect includes a compound of Formula (I), wherein W2 is N, W4 is C-Rb and W1, W3, W5 and W6 are C-Ra.

One aspect includes a compound of Formula (I), wherein W3 is N.

Another aspect includes a nd of Formula (I), wherein W3 is N, W4 is C-Rb and W1, W2, W5 and W6 are C-Ra.

One aspect es a nd of Formula (I), wherein W4 is N.

Another aspect includes a compound of Formula (I), wherein W4 is N and W1, W2, W3, W5 and W6 are independently C-Ra.

One aspect includes a compound of Formula (I), wherein W5 is N. r aspect includes a compound of Formula (I), wherein W5 is N, W4 is C-Rb and W1, W2, W3 and W6 are C-Ra.

One aspect includes a nd of a (I), wherein W6 is N.

Another aspect includes a compound of Formula (I), wherein W6 is N, W4 is C-Rb and W1, W2, W3 and W5 are C-Ra.

Another aspect includes a nd of Formula (I), wherein R1 is aryl, heterocyclyl, heterocyclyl-amino, (heterocyclyl)(C1-8alkyl)amino, or heteroaryl.

Another aspect includes a nd of a (I), wherein R1 is aryl or heteroaryl.

Another aspect includes a nd of Formula (I), wherein R1 is aryl.

Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl.

Another aspect es a compound of Formula (I), wherein R1 is cyclyl, cyclyl-amino or ocyclyl)(C1-8alkyl)amino.

Another aspect includes a compound of Formula (I), wherein R1 is heterocyclyl.

Another aspect includes a compound of Formula (I), wherein R1 is heterocyclyl-amino.

Another aspect includes a compound of Formula (I), n R1 is (heterocyclyl)(C1-8alkyl)amino.

Another aspect includes a compound of Formula (I), wherein Ra is hydrogen or C1-8alkyl. r aspect includes a compound of Formula (I), wherein Rb is hydrogen or halogen.

Another aspect includes a compound of Formula (I), wherein R4 is heterocyclyl-C1-8alkyl or heteroaryl-C1-8alkyl.

Another aspect includes a compound of Formula (I), wherein R5 is hydroxy-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, or heteroaryl-C1-8alkyl.

Another aspect includes a compound of Formula (I), wherein R6 is halogen, hydroxy, cyano, C1-8alkyl, cyano-C1-8alkyl, halo-C1-8alkyl, y-C1-8alkyl, C1-8alkoxy, (C1-8alkyl)2-amino-C1-8alkoxy-C1-8alkoxy-C1-8alkoxy, or C1-8alkoxy-C1 8alkyl-amino.

Another aspect includes a compound of Formula (I), wherein R7 is ycloalkyl, heterocyclyl, or heteroaryl-C1-8alkoxy.

One aspect includes a compound of Formula (I), wherein W1 and W5 are N.

Another aspect includes a compound of Formula (I), wherein W1 and W5 are N, W4 is C-Rb and W2, W3 and W6 are C-Ra.

One aspect includes a nd of Formula (I), wherein W1 and W6 are N.

Another aspect includes a compound of Formula (I), wherein W1 and W6 are N, W4 is C-Rb and W2, W3 and W5 are C-Ra.

One aspect includes a compound of Formula (I), wherein W2 and W3 are N.

Another aspect includes a compound of Formula (I), wherein W2 and W3 are N, W4 is C-Rb and W1, W5 and W6 are C-Ra.

One aspect includes a compound of a (I), wherein W2 and W4 are N.

Another aspect includes a compound of Formula (I), wherein W2 and W4 are N, and W1, W3, W5 and W6 are independently C-Ra.

One aspect includes a compound of Formula (I), wherein W3 and W4 are N.

Another aspect includes a compound of Formula (I), wherein W3 and W4 are N, and W1, W2, W5 and W6 are independently C-Ra.

One aspect includes a compound of Formula (I), wherein W5 and W6 are N.

Another aspect includes a nd of Formula (I), wherein W5 and W6 are N, W4 is C-Rb and W1, W2 and W3 are C-Ra.

Another aspect includes a compound of Formula (I), wherein W5 and W6 are N, W2 is C-Rb and W1, W3 and W4 are C-Ra.

Another aspect includes a nd of Formula (I), wherein W5 and W6 are N, W3 is C-Rb and W1, W2 and W4 are C-Ra.

One aspect includes a nd of Formula (I), wherein W1, W5 and W6 are N.

Another aspect includes a compound of a (I), wherein W1, W5 and W6 are N, W4 is C-Rb and W2 and W3 are C-Ra.

One aspect includes a compound of Formula (I), wherein W2, W3 and W4 are N.

Another aspect includes a compound of Formula (I), wherein W2, W3 and W4 are N, and W1, W5 and W6 are independently C-Ra.

One aspect includes a compound of Formula (I), wherein R1 is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, dropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, dropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c']dipyrrol-(3H)-yl, octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, icyclo[3.1.0]hexyl, (1R,5S)azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonyl, )azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 1,4-diazabicyclo[3.1.1]heptyl,3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 1,4-diazabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, ,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[4.5]decanyl or 6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 tuents.

Another aspect includes a compound of a (I), wherein R1 is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, dropyrrolo[3,4-c]pyrrol-1(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-5(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-5H- pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c']dipyrrol-2(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]hepantyl, 3,6-diazabicyclo[3.2.0]heptanyl, 3,6-diazabicyclo[3.2.0]hepantyl, 2,5-diazabicyclo[2.2.2]octanyl, azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]ocantyl, 1,4-diazabicyclo[3.2.2]nonanyl, ro[3.3]hepantyl, 4,7-diazaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptananyl, 2,6-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octan- 6-yl, 1,7-diazaspiro[4.4]nonanyl, 1,7,-diazaspiro[4.4]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, ,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, azaspiro[4.5]decanyl or 6,9-diazaspiro[4.5]decanyl; wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

Another aspect includes a compound of Formula (I), wherein R1 is heterocyclyl selected from pyrrolidinyl, piperidinyl, zinyl, azepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3-azabicyclo[3.1.0]hexyl, icyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.5]nonyl, 2,7- diazaspiro[3.5]nonyl.

Another aspect es a compound of a (I), wherein R1 is heterocyclyl selected from idinyl, piperidinyl, piperazinyl, azepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.4]octanyl, azaspiro[3.4]octanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, and 2,7-diazaspiro[3.5]nonanyl.

Another aspect es a compound of Formula (I), n R1 is substituted heterocyclyl selected from N,N-dimethylpyrrolidinamine, N,N-dimethylpiperidinamine, N,Ntrimethylpiperidinamine, 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-(propanyl)piperidinyl, 2-hydroxyethylpiperidinyl, 2-fluoroethylpiperidinyl, 2,2-difluoroethylpiperidinyl, N,N-dimethyl(piperidinyl)ethanamine, N,N-dimethyl(piperidinyl)propanamine, (2S,6S)-2,6-dimethylpiperidinyl, (2R,6S)-2,6-dimethylpiperidinyl, (2S,6S)-2,6-diethylpiperidinyl, (2S,6S)-(2,6-diethylmethyl)piperidinyl, (2S,6S)-1,2,6-trimethylpiperidinyl, (2R,6S)-1,2,6-trimethylpiperidinyl, (2S,4R,6R)-1,2,6-trimethylpiperidinyl, (2R,6R)ethyl-2,6-dimethylpiperidinyl, (2R,6S)-[1-(2-fluoroethyl)-2,6-dimethyl]piperidinyl, (ethylol)piperidinyl, methylpiperidinyl-ethanol, 3-(1H-pyrazolyl)propyl]piperidinyl, 3-(1H-benzimidazolyl)propyl]piperidinyl, 2-(1H-benzimidazolyl)ethyl]piperidinyl, 1-ethyl-1,2,3,6-tetrahydropyridinyl, 2,2,6,6-tetramethylpiperidinyl, 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl, (3R,5S)-3,5-dimethylpiperazinyl, 1-methylazepanyl, 1-ethylazepanyl, 2-fluoroethyl)azepanyl, azepanyl-ethanol, 4-methyl-1,4-diazepanyl, (3aS,6aS)methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aS,6aS)methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aR,6aR)methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)(propanyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)methyloctahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)ethyloctahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)methyloctahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridinyl, (7R,8aS)hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (1R,5S,6s)(dimethylamino)azabicyclo[3.1.0]hexyl, N,N-dimethylazabicyclo[3.1.0]hexanamine, )methylazabicyclo[3.2.1]octyl, 9-methylazabicyclo[3.3.1]nonyl, (3-exo)methylazabicyclo[3.3.1]nonyl, (1R,5S)methylazabicyclo[3.3.1]nonyl, -methyl-2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)methyl-2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)methyl-2,5-diazabicyclo[2.2.1]heptyl or (1S,4S)ethyl-2,5-diazabicyclo[2.2.1]heptyl.

Another aspect includes a compound of Formula (I), wherein R1 is substituted heterocyclyl selected from N,N-dimethylpyrrolidinamine, methylpiperidinamine, N,Ntrimethylpiperidinamine, 1-methylpiperidinyl, 1-ethyl-piperidinyl, 1-(propanyl)piperidinyl, 2-hydroxyethylpiperidinyl, 2-fluoroethylpiperidinyl, 2,2-difluoroethylpiperidinyl, N,N-dimethyl(piperidinyl)ethanamine, methyl(piperidinyl)propanamine, (2S,6S)-2,6-dimethylpiperidinyl, (2R,6S)-2,6-dimethylpiperidinyl, (2S,6S)-2,6-diethylpiperidinyl, (2S,6S)-2,6-diethylmethylpiperidinyl, (2S,6S)-1,2,6-trimethylpiperidinyl, (2R,6S)-1,2,6-trimethylpiperidinyl, (2S,4R,6R)-1,2,6-trimethylpiperidinyl, (2R,6R)ethyl-2,6-dimethylpiperidinyl, (2R,6S)(2-fluoroethyl)-2,6-dimethylpiperidinyl, piperidinyl-ethanol, 2,6-dimethylpiperidinyl-ethanol, pyrazolyl)propyl]piperidinyl, benzimidazolyl)propyl]piperidinyl, 2-(1H-benzimidazolyl)ethyl]piperidinyl, 1-ethyl-1,2,3,6-tetrahydropyridinyl, 2,2,6,6-tetramethylpiperidinyl, 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl, (3R,5S)-3,5-dimethylpiperazinyl, 1-methylazepanyl, 1-ethylazepanyl, 2-fluoroethylazepanyl, azepanyl-ethanol, N,N-dimethylazabicyclo[3.1.0]hexanamine, 5-methyl-2,5-diazabicyclo[2.2.1]heptan- 2-yl or (1S,4S)methyl-2,5-diazabicyclo[2.2.1]heptanyl.

One aspect includes a compound of Formula (I), wherein R1 is heterocyclyl-amino, wherein cyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or (1R,5S)azabicyclo[3.3.1]nonyl; and, wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

Another aspect includes a compound of Formula (I), wherein R1 is heterocyclyl-amino selected from azetidinyl-amino, pyrrolidinyl-amino, piperidinyl-amino, 9-azabicyclo[3.3.1]nonyl-amino, (1R,5S)azabicyclo[3.3.1]nonyl-amino, 9-methylazabicyclo[3.3.1]nonyl-amino, )methylazabicyclo[3.3.1]nonyl-amino or (1R,5S)methylazabicyclo[3.3.1]nonyl-amino; wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

One aspect es a compound of Formula (I), wherein R1 is (heterocyclyl)(C1-8alkyl)amino, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

Another aspect includes a compound of Formula (I), wherein R1 is (heterocyclyl)(C1-8alkyl)amino wherein heterocyclyl is piperidinyl.

Another aspect includes a nd of a (I), wherein R1 is (heterocyclyl)(C1-8alkyl)amino selected from (pyrrolidinyl)(methyl)amino or (piperidinyl)(methyl)amino; wherein, each instance of heterocyclyl is optionally tuted with R3 and R4 substituents.

One aspect includes a compound of Formula (I), wherein R3 is ed from cyano, halogen, hydroxy, oxo, C1-8alkyl, halo-C1-8alkyl, C1-8alkyl-carbonyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, koxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, kyl-amino-C1-8alkyl-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkyl-carbonyl-amino, koxy-carbonyl-amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino.

Another aspect es a compound of Formula (I), wherein R3 is selected from cyano, halogen, hydroxy, oxo, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, kyl-amino-C1-8alkyl, lkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkoxy-carbonyl-amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino.

Another aspect includes a compound of Formula (I), wherein R3 is kyl selected from methyl, ethyl, propyl, isopropyl or utyl.

Another aspect es a nd of Formula (I), R3 is C1-8alkyl selected from methyl, ethyl, propyl, pyl or tert-butyl.

Another aspect includes a compound of Formula (I), wherein R3 is halo-C1-8alkyl selected from trihalo-methyl, dihalo-methyl, ethyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

Another aspect includes a compound of Formula (I), wherein R3 is halo-C1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, trihalo-propyl or dihalo-propyl; wherein, halo is selected from , chloro, bromo or iodo.

Another aspect includes a compound of Formula (I), wherein R3 is hydroxy-C1-8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

Another aspect includes a compound of Formula (I), wherein R3 is hydroxy-C1-8alkyl ed from hydroxy-methyl, y-ethyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

Another aspect includes a compound of Formula (I), wherein R3 is C1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

Another aspect includes a compound of Formula (I), wherein R3 is halo-C1-8alkoxy selected from trihalo-methoxy, -methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.

Another aspect includes a nd of a (I), wherein R3 is C1-8alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

Another aspect includes a compound of Formula (I), wherein R4 is C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, C3-14cycloalkyl-amino, aryl-C1-8alkyl, aryl-C1-8alkoxy-carbonyl, ulfonyloxy-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl or heteroaryl; n, each instance of C3-14cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally tuted with one, two or three R5 substituents.

Another aspect includes a compound of Formula (I), wherein R5 is, in each instance, independently selected from halogen, y, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxy-C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl-thio or heteroaryl-C1-8alkyl.

One aspect includes a compound of a (I), wherein R2 is aryl, heteroaryl, heteroaryl-amino, (heteroaryl)(C1-8alkyl)amino or (heterocyclyl)(C1-8alkyl)amino.

Another aspect includes a compound of Formula (I), wherein R2 is aryl, heteroaryl, aryl-amino or (heteroaryl)(C1-8alkyl)amino.

Another aspect includes a compound of Formula (I), wherein R2 is aryl.

Another aspect includes a compound of Formula (I), wherein R2 is heteroaryl.

Another aspect includes a compound of Formula (I), wherein R2 is heteroaryl-amino.

Another aspect includes a compound of Formula (I), n R2 is (heteroaryl)(C1-8alkyl)amino. r aspect includes a compound of Formula (I), wherein R2 is (heterocyclyl)(C1-8alkyl)amino.

One aspect includes a compound of Formula (I), wherein R2 is heteroaryl selected from thienyl, azolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, zinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, [2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 2H- pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,3]oxazolo[4,5-c]pyridinyl, [1,3]thiazolo[4,5-c]pyridinyl, [1,3]thiazolo[5,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl or quinoxalinyl; n, each ce of aryl is optionally substituted with R6 and R7 substituents.

Another aspect includes a compound of Formula (I), wherein R2 is heteroaryl selected from thienyl, thienyl, 1H-pyrazolyl, azolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, 1H-indolyl, olyl, 1H-indolyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothienyl, 1H-benzimidazolyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzoxazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl, inyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[2,3-c]pyridin yl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, lo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, o[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,3]oxazolo[4,5-c]pyridinyl, [1,3]thiazolo[5,4-b]pyridinyl, [1,3]thiazolo[5,4-c]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, or quinoxalinyl; wherein, each ce of heteroaryl is ally substituted with R6 and R7 substituents.

One aspect includes a compound of Formula (I), wherein R6 is selected from halogen, y, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, y-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-C1-8alkoxy, (C1-8alkyl)2-amino-C1-8alkoxy, heteroaryl- C1-8alkoxy, aryl-oxy, (C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkyl-thio, C3-14cycloalkyl; wherein, halogen and halo is selected from fluoro, , bromo or iodo. r aspect includes a compound of Formula (I), wherein R6 is C1-8alkyl selected from , ethyl, propyl, isopropyl or tert-butyl.

Another aspect includes a compound of Formula (I), wherein R6 is C1-8alkyl selected from methyl, ethyl, , isopropyl or tert-butyl.

Another aspect includes a compound of Formula (I), n R6 is halo-C1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, -ethyl, thyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

Another aspect includes a compound of Formula (I), wherein R7 is C3-14cycloalkyl, C3-14cycloalkyl-oxy, aryl, cyclyl or heteroaryl.

One aspect includes a compound of Formula (I), wherein Ra is hydrogen or C1-8alkyl.

One aspect includes a compound of Formula (I), wherein Rb is hydrogen or C1-8alkyl.

Another aspect includes a compound of Formula (I), wherein Rb is halo.

One aspect of the compound of Formula (I) includes a compound selected from Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), a (Il), Formula (Im) or Formula (In): (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im) and (In), or a form thereof.

Another aspect of the compound of Formula (I) includes the compound selected from Formula (Ib), a (Ic), Formula (Ie), Formula (If), Formula (Ig), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Im) or Formula (In): (Ib), (Ic), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im) and (In), or a form thereof.

Another aspect of the compound of Formula (I) includes the compound selected from of Formula (Ia1), Formula (Ib1), Formula (Ic1), Formula (Id1), Formula (Ie1), Formula (If1), Formula (Ig1), Formula (Ih1), Formula (Ii1), a (Ij1), Formula (Ik1), Formula (Il1), a (Im1) or Formula (In1), respectively: (Ia1), (Ib1), (Ic1), (Id1), (Ie1), (If1), (Ig1) (Ih1) (Ii) (Ij1), (Ik1), (Il1), (Im1) and (In1), or a form thereof.

Another aspect of the compound of of Formula (I) es the compound selected from Formula (Ib1), Formula (Ic1), Formula (Ie1), Formula (If1), Formula (Ig1), Formula (Ii1), Formula (Ij1), Formula (Ik1), Formula (Il1), Formula (Im1) or Formula (In1), respectively: (Ib1), (Ic1), (Ie1), (If1), (Ig1) (Ii1), (Ij1), (Ik1), (Il1) (Im1) or (In1), or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ia1): (Ia1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ib1): (Ib1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ic1): (Ic1) or a form f.

Another aspect of the compound of Formula (I) includes the compound of Formula (Id1): (Id1) or a form thereof. r aspect of the compound of Formula (I) includes the compound of Formula (Ie1): (Ie1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (If1): (If1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ig1): (Ig1) or a form thereof.

Another aspect of the nd of Formula (I) includes the compound of Formula (Ih1): (Ih1) or a form thereof.

Another aspect of the compound of Formula (I) includes the nd of Formula (Ii1): (Ii1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ij1): (Ij1) or a form f.

Another aspect of the compound of Formula (I) includes the compound of Formula (Ik1): (Ik1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Il1): (Il1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (Im1): (Im1) or a form thereof.

Another aspect of the compound of Formula (I) includes the compound of Formula (In1): (In1) or a form thereof.

One aspect of the compound of Formula (I) or a form thereof includes a nd selected from the group consisting of: 1 2 3 4 5 6 7 9 10 11 12 13 14 15 16 17 18 19 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227, and 228; wherein the form of the nd is selected from the group consisting of a salt, prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

An aspect the compound of Formula (I) or a form thereof (wherein compound number (#1) indicates that the salt form was isolated) includes a compound selected from the group ting of: Cpd Name 11 ethyl-2H-indazolyl)(piperidinyl)quinoline 21 6-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline 31 6-(2-methyl-2H-indazolyl)(piperidinyl)quinolone 41 3-(2-methyl-2H-indazolyl)(1,2,3,6-tetrahydropyridinyl)cinnoline Cpd Name 51 4-methyl(2-methyl-2H-indazolyl)(piperidinyl)quinoline 61 6-(2-methyl-2H-indazolyl)(1-methylpiperidinyl)quinoline 7 2-(2-methyl-2H -indazolyl)(piperazinyl)quinoline 91 2-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline 101 2-(2-methyl-2H-indazolyl)(piperidinyl)quinazoline 11 6-(2,7-dimethyl-2H-indazolyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)quinolinamine 12 N-methyl(2-methyl-2H-indazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)quinolin- 2-amine 13 6-(2,7-dimethyl-2H-indazolyl)(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin- 4-yl)quinoline 14 6-(2,7-dimethyl-2H-indazolyl)(2,2,6,6-tetramethylpiperidinyl)quinoline -dimethyl-2H-indazolyl)(piperidinyl)quinoline 16 7-(2,7-dimethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 17 3-(2,7-dimethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 18 -dimethylimidazo[1,2-a]pyrazinyl)(piperidinyl)quinoline 19 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)quinoline 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinoline 23 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinazoline 241 6-[2-methyl(trifluoromethyl)-2H-indazolyl](piperidinyl)quinoxaline 251 3-(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 26 yl[7-(piperidinyl)-1,2,4-benzotriazinyl]-2H-indazolecarbonitrile 27 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)(piperidinyl)-1,2,4-benzotriazine 28 3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)(piperidinyl)-1,2,4-benzotriazine 29 3-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoline 7-(2,7-dimethyl-2H-indazolyl)(piperidinyl)isoquinoline 311 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoxaline 32 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 33 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine 341 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline 351 5-[8-fluoro(piperidinyl)quinazolinyl]methyl-2H-indazolecarbonitrile 361 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinazoline 371 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinazoline 381 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline 391 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline Cpd Name 40 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 41 ro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine 42 7-(2,7-dimethyl-2H-indazolyl)fluoro-N-methyl-N-(piperidinyl)- 1,2,4-benzotriazinamine 43 3-(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)-1,2,4-benzotriazine 44 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)-1,2,4-benzotriazine 451 -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoline 46 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 471 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)quinoline 481 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 8-fluoroquinoline 491 8-fluoro(7-methoxymethyl-2H-indazolyl)(piperidinyl)quinoline 501 8-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)quinoline 511 8-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)quinoline 52 3-(7-methoxymethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 531 8-fluoro[8-(2-methoxyethoxy)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)quinoline 541 6-[8-fluoro(piperidinyl)quinolinyl]-N-(2-methoxyethyl)- 2-methylimidazo[1,2-b]pyridazinamine 551 7-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline 561 7-(8-azabicyclo[3.2.1]octyl)(8-fluoromethylimidazo[1,2-a]pyridinyl)- 1,2,4-benzotriazine 571 -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 581 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine 591 7-(8-ethoxymethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 601 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 611 5-fluoro[2-methyl(trifluoromethyl)imidazo[1,2-a]pyridinyl](piperidinyl)- 1,2,4-benzotriazine 621 7-(2,4-dimethyl-1,3-benzoxazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine Cpd Name 631 7-(2,4-dimethyl-1H-benzimidazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine 641 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 651 7-(2,7-dimethylpyrazolo[1,5-a]pyridinyl)fluoro(piperidinyl)- benzotriazine 661 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 671 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 68 5-fluoro(4-fluoromethyl-1,3-benzoxazolyl)(piperidinyl)- 1,2,4-benzotriazine 691 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)-1,2,4-benzotriazine 70 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)fluoro- 1,2,4-benzotriazine 711 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)isoquinoline 721 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)isoquinoline 731 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline 741 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 75 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}ethanol 76 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- rocinnoline 77 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-propylpiperidin- 4-yl)cinnoline 78 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(propanyl)piperidin- 4-yl]cinnoline 79 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- innoline 801 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperazinyl)cinnoline 811 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(3R,5S)-3,5-dimethylpiperazinyl]- -fluorocinnoline 82 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoxaline 831 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)piperidin- 4-yl]cinnoline 841 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline 85 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)cinnoline Cpd Name 86 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]-N,N- dimethylpyrrolidinamine 871 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2S,6S)-2,6-dimethylpiperidinyl]- -fluorocinnoline 88 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N-dimethylpiperidinamine 89 -[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- methylpyrrolidinamine 90 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,4r,6S)-2,6-dimethylpiperidin- 4-yl]fluorocinnoline 911 5-fluoro(2-methylimidazo[1,2-a]pyrimidinyl)(piperidinyl)cinnoline 921 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 931 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-a]pyridine- 8-carbonitrile 941 5-fluoro(2-methyl[1,2,4]triazolo[1,5-a]pyridinyl)(piperidinyl)cinnoline 951 5-fluoro(2-methyl-2H-indazolyl)(piperidinyl)cinnoline 961 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 971 5-fluoro(6-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 981 3-[1-(2,2-difluoroethyl)piperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 991 5-fluoro(2-methylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline 1001 3-(1-ethylpiperidinyl)fluoro(2-methylimidazo[1,2-b]pyridazinyl)cinnoline 1011 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline 1021 3-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- 6-yl)cinnoline 1031 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)cinnoline 1041 5-[5-fluoro(piperidinyl)cinnolinyl]methyl-2H-indazolecarbonitrile 105 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 106 5-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline 107 {6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- ethanol 108 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazine- 8-carbonitrile 1091 5-fluoro(4-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 110 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 8-fluoroquinoxaline Cpd Name 111 3-(1-ethylpiperidinyl)fluoro(8-methoxymethylimidazo[1,2-b]pyridazin- 6-yl)cinnoline 112 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)cinnoline 113 {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]- ylimidazo[1,2-b]pyridazinyl}methanol 114 6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazine- 8-carbonitrile 1151 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- rocinnoline 116 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline 1171 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 118 7-(2,4-dimethyl-1,3-benzothiazolyl)fluoro(piperidinyl)cinnoline 119 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)(1-ethylpiperidinyl)fluorocinnoline 1201 7-(2,4-dimethyl-1,3-benzothiazolyl)(1-ethylpiperidinyl)fluorocinnoline 1211 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- -fluorocinnoline 1221 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline 1231 2-{4-[7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluorocinnolin- 3-yl]piperidinyl}ethanol 124 -dimethylimidazo[1,2-b]pyridazinyl)fluoro- 3-[(2S,6S)-1,2,6-trimethylpiperidinyl]cinnoline 125 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,6R)ethyl- 2,6-dimethylpiperidinyl]fluorocinnoline 126 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridinyl)fluoro(piperidinyl)cinnoline 1271 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylethanamine 1281 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 129 3-(azepanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 130 3-[(2S,6S)-2,6-diethylpiperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 131 3-[(2S,6S)-2,6-diethylmethylpiperidinyl](2,8-dimethylimidazo[1,2-b]pyridazin- 6-yl)fluorocinnoline 132 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 1331 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline Cpd Name 1341 5-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 1351 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 136 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)(1-ethylpiperidinyl)- rocinnoline 137 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluoro(piperidinyl)cinnoline 1381 2-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylethanamine 1391 3-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylpropanamine 1401 5-fluoro{2-methyl[2-(1H-pyrazolyl)ethoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 1411 5-fluoro{2-methyl[3-(1H-pyrazolyl)propoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 1421 5-fluoro{8-[3-(1H-imidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 143 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(pyrrolidinyl)cinnoline 144 7-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- 6-yl)cinnoline 1451 3-{1-[3-(1H-benzimidazolyl)propyl]piperidinyl}- 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 1461 7-(5,7-dimethylfuro[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline 147 -dimethyl[1,3]thiazolo[4,5-c]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 148 -dimethyl[1,3]oxazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline 149 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridinyl)fluoro(piperidinyl)cinnoline 1501 7-{8-[3-(1H-benzimidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- -fluoro(piperidinyl)cinnoline 1511 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 152 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 1531 7-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- -yl)cinnoline 154 7-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)cinnoline 155 2-{(2S,6S)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- 2,6-dimethylpiperidinyl}ethanol Cpd Name 1561 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 1571 -dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline 158 3-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylpropanamine 159 3-{1-[2-(1H-benzimidazolyl)ethyl]piperidinyl}- 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 160 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro{1-[3-(1H-pyrazol- 1-yl)propyl]piperidinyl}cinnoline 161 -dimethylimidazo[1,2-b]pyridazinyl)fluoro- 3-[(2R,6S)-1,2,6-trimethylpiperidinyl]cinnoline 162 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)cinnoline 1631 5-fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridinyl)(piperidin- 4-yl)cinnoline 164 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 1651 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinazoline 1661 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinoline 1671 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 168 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,6S)ethyl-2,6-dimethylpiperidin- 4-yl]fluorocinnoline 169 3-[(1R,3r,5S)azabicyclo[3.2.1]octanyl](2,8-dimethylimidazo[1,2-b]pyridazin- 6-yl)fluorocinnoline 170 -dimethylimidazo[1,2-b]pyridazinyl)fluoro[(2R,6S)(2-fluoroethyl)- 2,6-dimethylpiperidinyl]cinnoline 1711 5-fluoro(7-fluoromethyl-2H-benzotriazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 172 7-(7-ethylmethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidin- 4-yl)cinnoline 1731 3-(1-ethylpiperidinyl)fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridin- -yl)cinnoline 174 7-(7-ethylmethyl-2H-pyrazolo[4,3-b]pyridinyl)(1-ethylpiperidinyl)- -fluorocinnoline 1751 5-[5-fluoro(1,2,3,6-tetrahydropyridinyl)cinnolinyl]methyl-2H-indazole- 7-carbonitrile Cpd Name 1761 6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazine- 8-carbonitrile 1771 3-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline 1781 6-{5-fluoro[1-(2-hydroxyethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile 1791 6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile 180 {6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]- 2-methylimidazo[1,2-b]pyridazinyl}methanol 1811 2-(4-{5-fluoro[8-(hydroxymethyl)methylimidazo[1,2-b]pyridazinyl]cinnolin- 3-yl}piperidinyl)ethanol 1821 (6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinyl)methanol 183 3-(2,7-dimethyl-2H-indazolyl)(1-ethylpiperidinyl)fluorocinnoline 1841 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- -yl)quinoline 1851 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 186 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- -fluorocinnoline 187 {6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}acetonitrile 188 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylazepan- innoline 189 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylazepanyl)fluorocinnoline 190 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]azepan- 1-yl}ethanol 1911 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline 1921 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinoline 1931 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinoline 1941 5-fluoro[8-(1H-imidazolyl)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline 1951 5-fluoro(2-methylphenoxyimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline 1961 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridinyl)fluoro(piperidinyl)cinnoline 197 -dimethyl[1,3]thiazolo[5,4-c]pyridinyl)(1-ethylpiperidinyl)- rocinnoline 198 3-(2,7-dimethyl-2H-indazolyl)fluoro(2,3,6,7-tetrahydro-1H-azepin- 4-yl)cinnoline Cpd Name 199 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)azepan- innoline 200 3-(1-ethylpiperidinyl)fluoro(2-methylphenoxyimidazo[1,2-b]pyridazin- innoline 2011 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- -yl)quinazoline 2021 thylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinazoline 203 (3S,4S)[3-(2,7-dimethyl-2H-indazolyl)fluorocinnolinyl]piperidine-3,4-diol 204 5-fluoro(2-methylpropylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline 2051 {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}acetonitrile 206 2-{6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]- 2-methylimidazo[1,2-b]pyridazinyl}ethanol 207 2-{6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}ethanol 208 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridinyl)cinnoline 209 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(5-methyl- 2,5-diazabicyclo[2.2.1]heptanyl)cinnoline 2101 5-fluoro(2-methylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 211 5-fluoro[2-methyl(propanyl)imidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline 212 3-(1-ethylpiperidinyl)fluoro(2-methylpropylimidazo[1,2-b]pyridazin- 6-yl)cinnoline 213 2-{4-[7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluorocinnolinyl]piperidin- 1-yl}ethanol 214 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline 215 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[(1S,4S)methyl- 2,5-diazabicyclo[2.2.1]heptanyl]cinnoline 2161 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 2171 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 2181 3-(2,6-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 2191 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 2201 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline Cpd Name 2211 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline 222 3-(1-ethylpiperidinyl)fluoro[2-methyl(propanyl)imidazo[1,2-b]pyridazin- innoline 223 (1R,5S,6s)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N-dimethylazabicyclo[3.1.0]hexanamine 224 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N,4-trimethylpiperidinamine 2251 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 226 5-(5-fluoro((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinyl)- 2,7-dimethyloxazolo[5,4-b]pyridine 227 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro- ,4R,6R)-1,2,6-trimethylpiperidinyl)cinnoline and 228 7-(4,6-dimethyloxazolo[4,5-c]pyridinyl)fluoro ((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnoline; wherein the form of the compound is selected from the group consisting of a salt, prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

Another aspect of the compound of Formula (I) or a form thereof is a compound salt selected from the group consisting of: Cpd Name 1 ethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 2 thylpiperidinyl)(2-methyl-2H-indazolyl)quinoline hydrochloride 3 6-(2-methyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 4 3-(2-methyl-2H-indazolyl)(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 4-methyl(2-methyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 6 6-(2-methyl-2H-indazolyl)(1-methylpiperidinyl)quinoline hydrochloride 9 2-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline hydrochloride 2-(2-methyl-2H-indazolyl)(piperidinyl)quinazoline hydrochloride 24 ethyl(trifluoromethyl)-2H-indazolyl](piperidinyl)quinoxaline hloride 3-(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine dihydrochloride 31 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoxaline hydrochloride Cpd Name 34 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 5-[8-fluoro(piperidinyl)quinazolinyl]methyl-2H-indazolecarbonitrile ochloride 36 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinazoline ochloride 37 -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinazoline dihydrochloride 38 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 39 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 45 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoline hydrochloride 47 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)quinoline hydrochloride 48 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 8-fluoroquinoline hydrochloride 49 8-fluoro(7-methoxymethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 50 8-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)quinoline hydrochloride 51 8-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)quinoline hydrochloride 53 8-fluoro[8-(2-methoxyethoxy)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)quinoline hydrochloride 54 6-[8-fluoro(piperidinyl)quinolinyl]-N-(2-methoxyethyl)- 2-methylimidazo[1,2-b]pyridazinamine hydrochloride 55 7-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 56 zabicyclo[3.2.1]octyl)(8-fluoromethylimidazo[1,2-a]pyridinyl)- 1,2,4-benzotriazine hydrochloride 57 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 58 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine hydrochloride 59 7-(8-ethoxymethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride Cpd Name 60 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hloride 61 5-fluoro[2-methyl(trifluoromethyl)imidazo[1,2-a]pyridinyl](piperidinyl)- benzotriazine hydrochloride 62 -dimethyl-1,3-benzoxazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine hydrochloride 63 7-(2,4-dimethyl-1H-benzimidazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine hydrochloride 64 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)- benzotriazine hydrochloride 65 7-(2,7-dimethylpyrazolo[1,5-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 66 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine dihydrochloride 67 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine dihydrochloride 69 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidinyl)- 1,2,4-benzotriazine dihydrochloride 71 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)isoquinoline hydrochloride 72 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)isoquinoline hydrochloride 73 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline hydrochloride 74 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline dihydrochloride 80 -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperazinyl)cinnoline dihydrochloride 81 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(3R,5S)-3,5-dimethylpiperazinyl]- -fluorocinnoline dihydrochloride 83 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)piperidin- 4-yl]cinnoline dihydrochloride 84 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline dihydrochloride 87 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2S,6S)-2,6-dimethylpiperidinyl]- -fluorocinnoline hydrochloride 91 5-fluoro(2-methylimidazo[1,2-a]pyrimidinyl)(piperidinyl)cinnoline dihydrochloride 92 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline dihydrochloride Cpd Name 93 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-a]pyridine- 8-carbonitrile dihydrochloride 94 5-fluoro(2-methyl[1,2,4]triazolo[1,5-a]pyridinyl)(piperidinyl)cinnoline dihydrochloride 95 5-fluoro(2-methyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 96 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 97 5-fluoro(6-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hloride 98 3-[1-(2,2-difluoroethyl)piperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline dihydrochloride 99 5-fluoro(2-methylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline dihydrochloride 100 thylpiperidinyl)fluoro(2-methylimidazo[1,2-b]pyridazinyl)cinnoline dihydrochloride 101 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline dihydrochloride 102 3-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- innoline dihydrochloride 103 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)cinnoline dihydrochloride 104 5-[5-fluoro(piperidinyl)cinnolinyl]methyl-2H-indazolecarbonitrile hydrochloride 109 5-fluoro(4-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 115 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- -fluorocinnoline formate 117 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 120 7-(2,4-dimethyl-1,3-benzothiazolyl)(1-ethylpiperidinyl)fluorocinnoline formate 121 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- -fluorocinnoline dihydrochloride 122 thylmethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline dihydrochloride 123 2-{4-[7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluorocinnolin- 3-yl]piperidinyl}ethanol dihydrochloride 127 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylethanamine trihydrochloride Cpd Name 128 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline dihydrochloride 133 -dimethyl[1,3]thiazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline formate 134 5-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hloride 135 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- rocinnoline formate 138 2-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylethanamine trihydrochloride 139 3-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylpropanamine trihydrochloride 140 5-fluoro{2-methyl[2-(1H-pyrazolyl)ethoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline dihydrochloride 141 5-fluoro{2-methyl[3-(1H-pyrazolyl)propoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline trihydrochloride 142 5-fluoro{8-[3-(1H-imidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline trihydrochloride 145 3-{1-[3-(1H-benzimidazolyl)propyl]piperidinyl}- 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline trihydrochloride 146 -dimethylfuro[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline hydrochloride 150 7-{8-[3-(1H-benzimidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- -fluoro(piperidinyl)cinnoline trihydrochloride 151 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 153 7-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- innoline hydrochloride 156 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 157 3-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 163 5-fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridinyl)(piperidin- 4-yl)cinnoline formate 165 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinazoline hydrochloride 166 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinoline hydrochloride Cpd Name 167 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 171 5-fluoro(7-fluoromethyl-2H-benzotriazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 173 3-(1-ethylpiperidinyl)fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridin- -yl)cinnoline formate 175 5-[5-fluoro(1,2,3,6-tetrahydropyridinyl)cinnolinyl]methyl-2H-indazole- 7-carbonitrile hydrochloride 176 6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazine- onitrile trihydrochloride 177 3-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline hydrochloride 178 6-{5-fluoro[1-(2-hydroxyethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile trihydrochloride 179 6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile rochloride 181 2-(4-{5-fluoro[8-(hydroxymethyl)methylimidazo[1,2-b]pyridazinyl]cinnolin- 3-yl}piperidinyl)ethanol trihydrochloride 182 (6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinyl)methanol trihydrochloride 184 thyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- -yl)quinoline hydrochloride 185 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline hydrochloride 191 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline dihydrochloride 192 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 193 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinoline hydrochloride 194 5-fluoro[8-(1H-imidazolyl)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline formate 195 5-fluoro(2-methylphenoxyimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline e 196 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridinyl)fluoro(piperidinyl)cinnoline formate 201 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- -yl)quinazoline hydrochloride 202 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinazoline hydrochloride Cpd Name 205 {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}acetonitrile formate 210 5-fluoro(2-methylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline dihydrochloride 216 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline dihydrochloride 217 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline trihydrochloride 218 3-(2,6-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline rochloride 219 -diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline ditrifluoroacetate 220 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline ditrifluoroacetate 221 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline ditrifluoroacetate and 225 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline dihydrochloride; wherein the 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.

An aspect of the present description includes a method for preventing, treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present ption includes a method for treating or ameliorating HD in a subject in need thereof sing, administering to the subject an effective amount of a nd of Formula (I) or a form thereof.

Another aspect of the present description includes a method for ng or rating HD in a subject in need thereof sing, administering to the subject an effective amount of a compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a method for use of a nd of Formula (I) or a form or composition f for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or a form or composition thereof for ng or ameliorating HD in a subject in need thereof comprising, administering to the t an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need f comprising, administering to the subject an ive amount of the compound of Formula (I) or a form thereof.

Another aspect of the present description includes a use for a nd salt of Formula (I) or a form thereof for treating or rating HD in a subject in need thereof sing, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for 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 to the subject an effective amount of the medicament.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a t in need thereof comprising, administering to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in a combination product with one or more therapeutic agents for treating or rating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

Another aspect of the present ption es a use for a compound salt of Formula (I) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of a (I) or a form thereof in ation with an effective amount of the one or more agents.

CHEMICAL TIONS The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.

As used herein, the term “C1-8alkyl” generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), yl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl (also referred to as hexyl or hexanyl), n-heptyl (also referred to as heptyl or heptanyl), n-octyl and the like. In certain aspects, C1-8alkyl es, but is not limited to, C1-6alkyl, C1-4alkyl and the like. A C1-8alkyl radical is optionally substituted with substituent s as described herein where allowed by available valences.

As used herein, the term “C2-8alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl and the like. In certain aspects, C2-8alkenyl includes, but is not limited to, C2-6alkenyl, C2-4alkenyl and the like. A C2-8alkenyl l is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “C2-8alkynyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, ing, but not limited to, l, yl, butynyl and the like. In certain aspects, C2-8alkynyl es, but is not d to, C2-6alkynyl, C2-4alkynyl and the like. A C2-8alkynyl radical is optionally substituted with tuent species as bed herein where allowed by available es.

As used herein, the term “C1-8alkoxy” generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-C1-8alkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, poxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, xy and the like. In certain aspects, C1-8alkoxy includes, but is not limited to, C1-6alkoxy, C1-4alkoxy and the like. A koxy radical is optionally substituted with substituent s as described herein where allowed by available valences.

As used herein, the term “C3-14cycloalkyl” generally refers to a saturated or lly unsaturated monocyclic, bicyclic or polycyclic arbon radical, including, but not d to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In certain aspects, C3-14cycloalkyl es, but is not limited to, C3-8cycloalkyl, C5-8cycloalkyl, C3-10cycloalkyl and the like. A C3-14cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used , the term “heteroaryl” generally refers to 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 stability, with one or more atoms, such as an O, S or N atom, including, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, zolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, nyl, ,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, rolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, ]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and the like. A aryl radical is ally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

In certain aspects, the nomenclature for a heteroaryl radical may differ, such as in nonlimiting examples where furanyl may also be referred to as furyl, l may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl and 1,3-benzoxazolyl may also be referred to as 1,3-benzooxazolyl.

In certain other aspects, the term for a heteroaryl radical may also include other regioisomers, such as in non-limiting examples where the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and the like, the term pyrazolyl may also include azolyl and the like, the term olyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like, the term olyl may also e 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term indazolyl may also include azolyl, 2H-indazolyl and the like, the term benzoimidazolyl may also include zoimidazolyl and the term purinyl may also include 9H-purinyl and the like.

As used herein, the term “heterocyclyl” generally refers to a saturated or lly unsaturated monocyclic, ic or polycyclic carbon atom ring structure l in which one or more carbon atom ring s have been replaced, where allowed by structural stability, with a atom, such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, zinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, S)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, icyclo[3.3.1]nonyl, (1R,5S)azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl and the like. A heterocyclyl radical is ally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available es.

In certain aspects, the nomenclature for a heterocyclyl radical may differ, such as in nonlimiting examples where 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxolyl and hydro-1,4-benzodioxinyl may also be referred to as 2,3-dihydrobenzo[b][1,4]dioxinyl.

As used herein, the term “heteroaryl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-heteroaryl.

As used herein, the term “C1-8alkoxy-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-O-C1-8alkyl.

As used herein, the term “C1-8alkoxy-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-O-C1-8alkyl.

As used herein, the term alkoxy-C1-8alkyl)2-amino” refers to a radical of the formula: 8alkyl-O-C1-8alkyl)2.

As used herein, the term “C1-8alkoxy-C1-8alkyl-amino-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-NH-C1-8alkyl-O-C1-8alkyl.

As used herein, the term “(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-N(C1-8alkyl-O-C1-8alkyl)2.

As used herein, the term “(C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-O-C1-8alkyl).

As used herein, the term “C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-O-C1-8alkyl.

As used herein, the term “(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-O-C1-8alkyl)2.

As used herein, the term “(C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-O-C1-8alkyl).

As used herein, the term “C1-8alkoxy-carbonyl” refers to a radical of the a: -C(O)-O-C1-8alkyl.

As used herein, the term “C1-8alkoxy-carbonyl-C2-8alkenyl” refers to a radical of the formula: lkenyl-C(O)-O-C1-8alkyl.

As used herein, the term “C1-8alkoxy-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-O-C1-8alkyl.

As used herein, the term “heteroaryl-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-heteraryl.

As used herein, the term “C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl.

As used herein, the term “(C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl)2.

As used herein, the term “C1-8alkyl-amino-C2-8alkenyl” refers to a radical of the formula: -C2-8alkenyl-NH-C1-8alkyl.

As used herein, the term “(C1-8alkyl)2-amino-C2-8alkenyl” refers to a l of the formula: -C2-8alkenyl-N(C1-8alkyl)2.

As used herein, the term “C1-8alkyl-amino-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-NH-C1-8alkyl.

As used , the term “(C1-8alkyl)2-amino-C1-8alkoxy” refers to a l of the formula: -O-C1-8alkyl-N(C1-8alkyl)2.

As used herein, the term “C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl.

As used herein, the term “(C1-8alkyl)2-amino-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-N(C1-8alkyl)2.

As used herein, the term “C1-8alkyl-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH-C1-8alkyl.

As used herein, the term “(C1-8alkyl)2-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-N(C1-8alkyl)2.

As used herein, the term “(C1-8alkyl-amino-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-NH-C1-8alkyl)2.

As used herein, the term “[(C1-8alkyl)2-amino-C1-8alkyl]2-amino” refers to a radical of the formula: -N[C1-8alkyl-N(C1-8alkyl)2]2.

As used herein, the term “(C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-NH-C1-8alkyl).

As used herein, the term 8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)[C1-8alkyl-N(C1-8alkyl)2].

As used herein, the term lkyl-amino-C2-8alkynyl” refers to a radical of the formula: -C2-8alkynyl-NH-C1-8alkyl.

As used herein, the term “(C1-8alkyl)2-amino-C2-8alkynyl” refers to a radical of the formula: lkynyl-N(C1-8alkyl)2.

As used herein, the term “C1-8alkyl-carbonyl” refers to a radical of the formula: -C(O)-C1-8alkyl.

As used herein, the term “C1-8alkyl-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-C1-8alkyl.

As used , the term “C1-8alkyl-thio” refers to a radical of the a: -S-C1-8alkyl.

As used herein, the term “amino-C2-8alkenyl” refers to a radical of the formula: -C2-8alkenyl-NH2.

As used herein, the term -C1-8alkoxy” refers to a radical of the a: -O-C1-8alkyl-NH2.

As used herein, the term “amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH2.

As used herein, the term “amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH2.

As used herein, the term “(amino-C1-8alkyl)2-amino” refers to a radical of the formula: 8alkyl-NH2)2.

As used herein, the term “(amino-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-NH2).

As used herein, the term “amino-C2-8alkynyl” refers to a radical of the formula: -C2-8alkynyl-NH2.

As used herein, the term “aryl-C1-8alkoxy-carbonyl” refers to a radical of the formula: -C(O)-O-C1-8alkyl-aryl.

As used herein, the term “aryl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-aryl.

As used , the term “aryl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-aryl.

As used herein, the term “(aryl-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-aryl)2.

As used herein, the term “(aryl-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-aryl).

As used herein, the term “aryl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-aryl.

As used , the term “(aryl-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-aryl)2.

As used , the term “(aryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-aryl).

As used herein, the term “aryl-amino” refers to a radical of the formula: -NH-aryl.

As used herein, the term amino-carbonyl” refers to a radical of the formula: -C(O)-NH-aryl.

As used herein, the term “aryl-sulfonyloxy-C1-8alkyl” refers to a radical of the formula: lkyl-O-SO2-aryl.

As used herein, the term “benzoxy-carbonyl” refers to a l of the formula: O-CH2-phenyl.

As used herein, the term “C3-14cycloalkyl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-C3-14cycloalkyl.

As used herein, the term cycloalkyl-amino” refers to a radical of the formula: -NH-C3-14cycloalkyl.

As used herein, the term “C3-14cycloalkyl-oxy” refers to a radical of the formula: -O-C3-14cycloalkyl.

As used herein, the term “aryl-oxy” refers to a radical of the formula: -O-aryl.

As used herein, the term “halo” or “halogen” lly refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.

As used herein, the term “halo-C1-8alkoxy” refers to a l of the formula: -O-C1-8alkyl-halo, wherein kyl is partially or completely substituted with one or more halogen atoms where allowed by ble valences.

As used herein, the term “halo-C1-8alkyl” refers to a radical of the formula: lkyl-halo, wherein C1-8alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

As used , the term “halo-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-halo.

As used herein, the term “(halo-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-halo).

As used herein, the term “(halo-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-halo)2.

As used herein, the term “heteroaryl-C1-8alkoxy” refers to a radical of the formula: 8alkyl-heteroaryl.

As used herein, the term “heteroaryl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-heteroaryl.

As used herein, the term “heteroaryl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C1-8alkyl)2-amino” refers to a l of the formula: -N(C1-8alkyl-heteroaryl)2.

As used herein, the term “(heteroaryl-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-heteroaryl).

As used herein, the term “heteroaryl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-N(C1-8alkyl-heteroaryl)2.

As used herein, the term roaryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-heteroaryl).

As used herein, the term “heteroaryl-amino” refers to a radical of the formula: -NH-heteroaryl.

As used herein, the term “heterocyclyl-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-heterocyclyl)2.

As used herein, the term “(heterocyclyl-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: lkyl-NH-C1-8alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-N(C1-8alkyl-heterocyclyl)2.

As used herein, the term “(heterocyclyl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-amino” refers to a radical of the formula: -NH-heterocyclyl.

As used herein, the term “(heterocyclyl)(C1-8alkyl)amino” refers to a radical of the formula: 8alkyl)(heterocyclyl).

As used herein, the term “heterocyclyl-amino-C1-8alkyl” refers to a l of the formula: -C1-8alkyl-NH-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl” refers to a radical of the formula: -C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl-oxy” refers to a radical of the formula: -O-C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-oxy” refers to a radical of the formula: -O-heterocyclyl.

As used herein, the term “hydroxy” refers to a radical of the formula: -OH.

As used herein, the term “hydroxy-C1-8alkoxy-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-O-C1-8alkyl-OH.

As used herein, the term “hydroxy-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-OH, n C1-8alkyl is partially or completely substituted with one or more hydroxy radicals where allowed by available valences.

As used herein, the term “hydroxy-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-OH.

As used herein, the term “(hydroxy-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-OH)2.

As used , the term “(hydroxy-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-OH).

As used herein, the term xy-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-OH.

As used herein, the term “(hydroxy-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-OH)2.

As used herein, the term “(hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-OH).

As used herein, the term “hydroxy-C1-8alkyl-amino-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-NH-C1-8alkyl-OH.

As used herein, the term “(hydroxy-C1-8alkyl)2-amino-C1-8alkoxy” refers to a l of the formula: -O-C1-8alkyl-N(C1-8alkyl-OH)2.

As used , the term “(hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy” refers to a radical of the a: -O-C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-OH).

As used , the term “hydroxy-C1-8alkyl-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH-C1-8alkyl-OH.

As used herein, the term “(hydroxy-C1-8alkyl-amino-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-NH-C1-8alkyl-OH)2.

As used herein, the term “(hydroxy-C1-8alkyl)2-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-N(C1-8alkyl-OH)2.

As used herein, the term “(hydroxy-C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)(C1-8alkyl-NH-C1-8alkyl-OH).

As used , the term “[(hydroxy-C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)[C1-8alkyl-N(C1-8alkyl-OH)2].

As used herein, the term oxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl-amino” refers to a radical of the formula: -8alkyl-N(C1-8alkyl,C1-8alkyl-OH).

As used herein, the term “[(hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl](C1-8alkyl)amino” refers to a radical of the formula: -N(C1-8alkyl)[C1-8alkyl-N(C1-8alkyl)(C1-8alkyl-OH)].

As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated 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 combinations result in stable compounds. A person of ry 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 ces one or more substituents having a double bond (e.g., “oxo” or “=O”) 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 ment to the core ure of Formula (I). A person of ordinary 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 d in the art include, without limitation, isomers (including chain, branching or positional structural isomers), ion of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic 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 ed, and as appropriate, 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 n at any other occurrence.

Further, the use of a generic substituent le on any a or ure for a compound described herein is understood to include 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 naphthalenyl and the like, and that the ing compound is to be included within the scope of the compounds described herein.

As used herein, the terms “each instance of” or “in each ce, 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-C1-4alkyl,” are intended to refer to the C3-14cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.

As used herein, the term nally substituted” means optional substitution with the ied substituent variables, groups, radicals 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, racemate, enantiomer, diastereomer, stereoisomer, polymorph and er form thereof.

In certain s described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.

In n aspects described herein, the form of the compound of Formula (I) is a salt thereof.

In certain aspects described herein, the form of the compound of Formula (I) is an isotopologue thereof.

In n s described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

In certain aspects bed herein, the form of the nd of a (I) is a tautomer thereof.

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

In certain aspects described herein, the compound of a (I) or a form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination f according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques 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 thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable ting groups will be recognized by those with ordinary skill in the art as well as by nce to standard oks 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 carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., ldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, o and guanidino include xycarbonyl, oxycarbonyl, and the like. Suitable protecting groups for carboxylic 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. Protecting groups may be added or removed in accordance with standard techniques, which are well-known 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 compounds described herein may not possess pharmacological activity as such, they may be administered to a subject and thereafter lized in the body to form compounds described herein which are pharmacologically active.

Such tives may ore be described as "prodrugs". All prodrugs of compounds described herein are included within the scope of the use bed 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 (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by ysis and/or lism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T.

Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in ersible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In one example, 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 r 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 phosphonate ester and the like. In another e, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted yl. 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 , amino acid , phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood 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 able solvents such as water, ethanol, and the like, and the description herein is intended to e 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 nt g, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the l lattice of the lline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

As used herein, the term “hydrate” means a solvate wherein the solvent molecule is water.

The compounds of Formula (I) can form salts, which are intended to be ed 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 otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with nic 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 moiety, such as, without limitation an amine moiety, and an acidic , such as, but not limited to a ylic acid, zwitterions r salts") may be formed and are included within the term "salt(s)" as used herein.

The term "pharmaceutically acceptable )", as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of a (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.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Particular aspects of acid on 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, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, anate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain particular aspects of acid addition salts include chloride or dichloride.

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 of ceutical Salts. ties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of ceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of nal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, ium, 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 on, 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 further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or a form thereof as described herein.

The compounds of Formula (I) or a form f may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is ed to include all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.

The compounds described herein may e one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure omers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another particular aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure itions substantially sing 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 a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.

As used herein, the term “substantially pure” refers to compounds consisting ntially 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 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%.

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 “racemate” is any e of isometric forms that are not iomerically 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 Formula (I) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as es, are embraced within the scope of the description. Diastereomeric es can be separated into their dual diastereomers on the basis of their al chemical differences by methods well known to those skilled in the art, such as, for example, by tography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled 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), ting the diastereomers and converting (e.g., hydrolyzing) 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 nds (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), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for e, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a c mixture, as described supra.

The use of the terms "salt", "solvate", “ester”, "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

The term "isotopologue" refers to isotopically-enriched compounds 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 . Examples of es that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and ne, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 35Cl and 36Cl, respectively, each of which are also within the scope of this ption.

Certain ically-enriched compounds bed herein (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes 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 ity (e.g., increased in vivo ife or reduced dosage requirements) and hence may be preferred in some circumstances. rphic crystalline and amorphous 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 description.

COMPOUND USES In accordance with the ed scope of the present description, s of the present description include compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or ameliorating HD and have been provided for use for preventing, ng or ameliorating HD.

An aspect of the present description includes a method for preventing, treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a nd of Formula (I) or a form thereof.

An aspect of the present description includes a method 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.

An aspect of the present description includes a method for preventing HD in a subject in need thereof comprising, stering to the subject an effective amount of a compound of Formula (I) or a form thereof.

An aspect of the present ption includes a method for treating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of a (I) or a form thereof.

An aspect of the present description includes a method for ameliorating HD in a subject in need thereof sing, administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

Another aspect of the present ption includes a method for treating or ameliorating HD in a subject in need thereof comprising, stering to the t an effective amount of a compound salt of Formula (I) or a form f.

An aspect of the present description includes a method for use of a compound of a (I) or a form or composition thereof for treating or ameliorating HD in a subject in need f comprising, administering to the subject an effective amount of the compound of a (I) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description es a use for a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, stering to the subject an effective amount of the compound of Formula (I) or a form thereof.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof.

An aspect of the present description includes a use for 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 to the subject an effective amount of the medicament. r aspect of the present description includes a use for a compound salt 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 to the t an effective amount of the medicament.

An aspect of the t description includes in vitro or in vivo use of the compound of Formula (I) or a form thereof having activity toward HD.

An aspect of the present description includes a use of the compound of Formula (I) or a form thereof in a combination therapy to provide additive or synergistic activity, thus ng the development of a combination product for treating or ameliorating HD. r aspect of the present description es a combination therapy sing compounds bed herein in combination with one or more known drugs or one or more known therapies may be used to treat HD less of whether HD is responsive to the known drug.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in a combination product with one or more therapeutic agents for treating or rating HD in a subject in need thereof sing, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

Another aspect of the present description includes a use for a compound salt of Formula (I) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or a form thereof in combination with an effective amount of the one or more agents.

In an aspect of a use or method provided herein, compounds of Formula (I) or a form thereof used in ation with one or more additional agents can be administered to a t or ted with a subject or patient cell(s) prior to, concurrently with, or subsequent to administering to the subject or patient or contacting 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 aspect, a compound(s) of Formula (I) or a form thereof is used in combination with gene therapy to inhibit HTT expression (using, e.g., viral delivery s) or the administration of r small molecule HTT inhibitor. In another specific aspect, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using entiated non-mutant HTT stem cells. In another specific aspect, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated HTT stem cells.

In one aspect, provided herein is the use of compounds of Formula (I) or a form thereof in combination with supportive rd of care therapies, including palliative care.

An aspect of the present description includes a use for a compound of a (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of a (I) or a form thereof and instructions for administering an ive amount of the compound of Formula (I) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the nd of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form f; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents.

An aspect of the present description includes a use for a compound of Formula (I) or a form f in the preparation of a kit for treating or ameliorating HD in a t in need thereof sing, the compound of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form thereof; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents in a combination therapy with a standard of care supportive therapy, wherein the standard of care supportive therapy is palliative care.

In one respect, for each of such aspects, the subject is treatment naive. In another respect, for each of such aspects, the t is not treatment naive.

As used herein, the term “preventing” refers to keeping a disease, er 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.

As used herein, the term “treating” refers to ting the progression of a disease, disorder or condition in a subject y exhibiting the symptoms of the disease, disorder and/or condition, i.e., arresting the development of a disease, disorder and/or condition that has already affected the subject.

As used , the term “ameliorating” refers to relieving the symptoms of a disease, disorder or ion in a subject already exhibiting the ms of the disease, disorder and/or condition, i.e., causing regression of the e, disorder and/or condition that has y affected the subject.

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 es include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In certain aspects, the subject is a mammal or a warm-blooded rate animal. In other aspects, the subject is a human. As used herein, the term “patient” may be used interchangeably with “subject” and ”.

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 that achieves a target plasma concentration that is effective in ng or ameliorating HD as described herein and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a t in need thereof. In one aspect, the effective amount may be the amount required to treat HD in a subject or patient, more specifically, in a human.

In another , the concentration-biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration g from approximately 0.001 μg/mL to approximately 50 µg/mL, from approximately 0.01 µg/mL to approximately 20 µg/mL, from imately 0.05 µg/mL to approximately 10 µg/mL, or from approximately 0.1 µg/mL to approximately 5 µg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 1.0 ng to 10,000 mg.

In one aspect, the dose administered to achieve an effective target plasma concentration may be administered based upon subject or patient specific factors, wherein the doses administered on a weight basis may be in the 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 day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 day to about 200 mg/kg/day, or about 0.001 mg/kg/day to about 150 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 50 mg/kg/day, or about 0.001 mg/kg/day to about 25 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.001 mg/kg/day to about 5 mg/kg/day, or about 0.001 mg/kg/day to about 1 mg/kg/day, or about 0.001 day to about 0.5 mg/kg/day, or about 0.001 mg/kg/day to about 0.1 mg/kg/day, or from about 0.01 day to about 3500 mg/kg/day, or about 0.01 mg/kg/day to about 3000 mg/kg/day, or about 0.01 mg/kg/day to about 2500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 250 mg/kg/day, or about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.01 day to about 150 day, or about 0.01 mg/kg/day to about 100 mg/kg/day, or about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 50 mg/kg/day, or about 0.01 mg/kg/day to about 25 mg/kg/day, or about 0.01 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 5 mg/kg/day, or about 0.01 mg/kg/day to about 1 day, or about 0.01 mg/kg/day to about 0.5 day, or about 0.01 mg/kg/day to about 0.1 mg/kg/day, or from about 0.1 mg/kg/day to about 3500 mg/kg/day, or about 0.1 mg/kg/day to about 3000 mg/kg/day, or about 0.1 mg/kg/day to about 2500 mg/kg/day, or about 0.1 mg/kg/day to about 2000 mg/kg/day, or about 0.1 mg/kg/day to about 1500 mg/kg/day, or about 0.1 mg/kg/day to about 1000 mg/kg/day, or about 0.1 mg/kg/day to about 500 day, or about 0.1 mg/kg/day to about 250 mg/kg/day, or about 0.1 mg/kg/day to about 200 mg/kg/day, or about 0.1 mg/kg/day to about 150 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day, or about 0.1 day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 50 mg/kg/day, or about 0.1 mg/kg/day to about 25 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day, or about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1 mg/kg/day to about 1 mg/kg/day, or about 0.1 mg/kg/day to about 0.5 mg/kg/day.

Effective amounts for a given subject may be determined by routine experimentation that is within the skill and judgment of a clinician or a practitioner skilled in the art in light of s 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 genetic screening, ty of the disease state, status of disease progression, general health of the subject, ethnicity, age, weight, gender, diet, time of day and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerance/response to therapy.

The dose administered to achieve an effective target plasma concentration may be orally administered once (once in approximately a 24 hour period; i.e., “q.d.”), twice (once in imately a 12 hour period; i.e., “b.i.d.” or “q.12h”), thrice (once in imately 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.”, .” or “q.6h”) daily.

In certain aspects, the dose administered to achieve an effective target plasma concentration may also be administered in a single, divided, or continuous dose for a patient or subject 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, particularly children under 40 kg).

The typical adult subject is expected to have a median weight in a range of about 70 kg. Long - acting 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 ular formulation.

The nds and compositions bed herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples e oral, ocular, rectal, buccal, topical, nasal, gual, ermal, subcutaneous, intramuscular, intraveneous (bolus and on), intracerebral, and ary routes of administration.

In another aspect, the dose administered may be adjusted based upon a dosage form described herein 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, , 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg/day.

For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, guinea pig, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to ine 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 pharmaceutical procedures in cell es or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) 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 certain aspects, the effective amount is such tha t a large therapeutic index is achieved. In further particular aspects, 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 t, and the route of stration.

In one aspect, provided herein are methods for modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of Formula (I) or a form thereof.

In a specific aspect, provided herein are methods for ting the amount of HTT, comprising 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 vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In r specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, ing in a loss of HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In a specific aspect, provided herein is a method for enhancing the inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of Formula (I) or a form thereof. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, 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 l” HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another , the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In another aspect, ed herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a man animal model for HD a nd of Formula (I) or a form thereof. In a specific 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 a (I) or a form thereof.

In a specific aspect, the compound is a form of the compound of Formula (I).

In another aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a specific aspect, provided herein is a method for decreasing the amount of mutant HTT, sing contacting a human cell with a compound of Formula (I) that inhibits the ription of mutant HTT (huntingtin mRNA) from the Htt gene. In another ic aspect, provided herein is a method for decreasing the amount of HTT, comprising contacting a human cell with a compound of Formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, 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 on. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I).

In certain aspects, treating or ameliorating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or beneficial effect. In a specific aspect, 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 severity of HD; (ii) delays onset of HD; (iii) inhibits the progression of HD; (iv) reduces hospitalization of a subject; (v) s hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life for a subject; (viii) s 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 Another aspect included within the scope of the present description are the use of in vivo metabolic products of the nds 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 description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled isotopologue (e.g., 14C or 3H) of a nd described herein, administering the radio-labeled compound in a detectable dose (e.g., 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 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion ts are easily ed since they are “radiolabeled” by virtue of being isotopically-enriched (others are ed by the use of dies e of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR is. In l, analysis of metabolites may be done in the same way as conventional drug metabolism s well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they s no biological activity of their own.

PHARMACEUTICAL COMPOSITIONS In accordance with the intended scope of the present description, s of the present description include compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or rating HD and have been ed for use as one or more pharmaceutical compositions for preventing, treating or rating HD.

An aspect of the present description includes a use for a compound of Formula (I) or a form thereof in the preparation of a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof sing, administering to the subject an effective amount of the compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically able excipients.

An aspect of the t description includes a use for a pharmaceutical composition of the compound of Formula (I) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the pharmaceutical composition of the compound of Formula (I) or a form thereof and instructions for administering the pharmaceutical composition.

As used herein, the term “composition” means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical composition may be ated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In certain aspects, the pharmaceutical composition is formulated to e a pH of from about pH 3 to about pH 7. In other aspects, 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 stration of a pharmaceutical agent, such as the nds described 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.

Nonlimiting examples of pharmaceutically acceptable excipients e carriers, solvents, stabilizers, 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, ccharides, 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., hydroxypropylmethylcellulose, 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 included within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. le formulations for oral administration include solids, liquid solutions, emulsions and sions, while suitable inhalable formulations for pulmonary administration include liquids and s. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules ding micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.

Compositions ed for oral use may be prepared according to any method known to the art for the cture of ceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to e a palatable preparation.

Pharmaceutically acceptable ents suitable for use in conjunction with s e, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as rmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding , such as povidone, starch, gelatin or acacia; and ating 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 . For e, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

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 phosphate, or kaolin, or as soft gelatin capsules 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 aspects, pharmaceutical itions 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 excipients suitable for the manufacture of a suspension. In yet other aspects, pharmaceutical compositions described herein may be formulated as dispersible s and granules suitable for preparation of a suspension by the addition of one or more excipients.

Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a sation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a sation product of ethylene oxide with a long chain tic 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 eate); and thickening agents, such as carbomer, beeswax, hard paraffin, or cetyl alcohol. 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 ning agents such as sucrose or saccharin.

The pharmaceutical itions 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 naturallyoccurring 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 sation products of these l esters with ethylene oxide, such as yethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also n a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic erally acceptable diluent or t, such as a on in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile 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 compounds described herein may be substantially insoluble in water and sparingly soluble in most ceutically acceptable protic solvents and vegetable oils, but generally e in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of -chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or mical es which make them more suitable for ry (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In certain aspects, the compound described herein is formulated for oral stration in a lipid-based ition suitable for low solubility compounds. Lipid-based ations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or ene 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 ed to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

In other aspects, the ilability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of nanoparticles or nanosuspensions using techniques known to those d in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative aspects, 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 α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In certain aspects, the pharmaceutical ition further comprises HPBC in a range of from about 0.1% to about %, 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 GENERAL SYNTHETIC METHODS As disclosed herein, general methods for ing the compounds of Formula (I) or a form thereof as described herein are available via standard, well-known synthetic methodology.

Many of the starting materials are commercially available or, when not available, can be ed using the routes described below using techniques known to those skilled in the art. The synthetic schemes provided herein comprise multiple on steps, each of which is intended to stand on its own and can be carried out with or without any preceding or ding step(s). In other words, each of the individual on steps of the synthetic s provided herein in isolation is contemplated.

Scheme A: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems, may be prepared as bed in Scheme A below.

Compound A1 (where X1 and X2 are independently bromine, chlorine and the like) is converted to Compound A2 by a nucleophilic substitution with a primary or secondary amine in the presence of a suitable base (such as K2CO3 and the like) in a suitable solvent (such as DMF and the like). Alternatively, nd A1 is converted to Compound A2 via cross coupling with a primary or secondary amine (i.e., an R1 substituent base) in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and base (such as sodium tert-butoxide and the like) in an appropriate solvent (such as oxane and the like). Compound A2 is converted to Compound A3 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) (i.e., an R2 tuted-boronic acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a le solvent (such as 1,4-dioxane and the like).

Scheme B: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or aryl ring s, may be prepared as described in Scheme B below.

Following conditions described in Scheme A, but switching the order of steps 1 and 2, compound B1 can be converted to compound A3.

Scheme C: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems, may be prepared as described in Scheme C below.

Compound B1 (where X1 is bromine, chlorine and the like) is converted to Compound C1 by a Suzuki coupling with an optionally tuted and appropriately protected amino-containing cycloalkyl/cycloalkenyl pinacol boronic ester (where Y is hydrogen or an optionally substituted alkyl group and P is a protecting group such as Boc and the like) (i.e., an R1 substituted-boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a suitable t (such as 1,4-dioxane and the like). Alternatively, Compound B1 is converted to Compound C1 by a Negishi coupling with an optionally substituted and appropriately protected amino-containing cycloalkyl zinc halide (i.e., an R1 substituted-zinc halide) in the ce of a catalyst (such as Pd(dppf)Cl2 and the like) in a suitable t (such as 1,4-dioxane and the like). Upon treatment with a deprotecting agent appropriate for the protecting group (such as HCl in e for a Boc protecting group), Compound C1 is converted to nd C2. Compound C2 is converted to Compound C3 by reductive amination with a suitable aldehyde and reducing agent (such as NaBH(OAc)3 and the like) in a suitable solvent (such as 1,2-dichloroethane and the like). Alternatively, Compound C2 is converted to Compound C3 by alkylation with an alkyl halide (such as 2-iodopropane and the like) in the ce of an appropriate base (such as K2CO3 and the like). In cases where ration exists in the ring containing the basic amino group, the compound may be converted to the fully saturated analog under an atmosphere of H2 in a suitable solvent (such as methanol and the like) and in the presence of catalyst (such as 10% Pd/C and the like).

Scheme D: Compounds of Formula (I), wherein R1 and R2 are clic or ic heterocyclyl or heteroaryl ring systems, may be prepared as described in Scheme D below.

Following the general conditions described in Scheme C, compound D1 can be converted to compound D5.

Scheme E: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring s, may be prepared as described in Scheme E below.

Following the general conditions described in Scheme A and/or Scheme C, compound A1 can be converted to compound E1.

Scheme F: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring s, may be prepared as described in Scheme F below.

Compound F1 (where X is bromine, chlorine and the like) is converted to Compound F2 through a condensation with an optionally substituted N-Boc-piperidinealdehyde (where Y is hydrogen or an optionally substituted alkyl group and P is a protecting group such as Boc and the like) in a suitable solvent (such as EtOH and the like). Compound F2 is converted to Compound F3 by reducing the nitro group with H2 in the presence of a st (such as PtO2 and the like) in an appropriate solvent (such as EtOH and the like). Compound F3 is converted to Compound F4 through a cyclization/oxidation reaction with an riate oxidant (such as DDQ and the like) in an appropriate solvent (such as CH3CN and the like). Compound F4 is converted to Compound F5 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) (i.e., an R2 substituted-boronic acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a le solvent (such as 1,4-dioxane and the like). atively, Compound F4 is converted to nd F5 by treatment with pinacolatodiboron and a base (such as KOAc and the like) in the ce of a catalyst (such as Pd(dppf)Cl2 and the like) in an riate solvent (such as 1,4-dioxane and the like), followed by addition of an aryl- or heteroaryl-halide (i.e., an R2 tuted-halide). Compound F5 is converted to Compound F6 upon treatment with conditions appropriate to the removal of the protecting group (such as TFA or HCl in dioxane for a Boc protecting group). Additional modification to the basic amino group can be achieved according to methods described in Scheme Scheme G: Compounds of Formula (I), n R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems, may be prepared as described in Scheme G below.

Compound G1 (where X is bromine, chlorine and the like; Y is hydrogen or optionally substituted alkyl; and P is an appropriate protecting group) is converted to Compound G2 through a condensation/cyclization sequence in the presence of catalyst (such as CuI and the like), ligand (such as 1,10-phenanthroline and the like) and base (such as NaOt-Bu and the like) in an appropriate solvent (such as DMF and the like). Compound G2 is converted to Compound G3 by treatment with strong acid (conc. HCl and the like) in the presence of oxygen. Compound G3 is converted to Compound G4 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol c ester) (i.e., an R2 substituted-boronic acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a le solvent (such as 1,4-dioxane and the like). Alternatively, Compound G3 is converted to Compound G4 by ent with latodiboron and a base (such as KOAc and the like) in the presence of a st (such as Pd(dppf)Cl2 and the like) in an appropriate solvent (such as 1,4- dioxane and the like), followed by addition of an aryl- or heteroaryl-halide (i.e., an R2 tuted-halide). Compound G4 is converted to Compound G5 upon treatment with conditions appropriate to the l of the protecting group (such as TFA or HCl in dioxane for a Boc protecting group). Additional cation to the basic amino group can be achieved according to methods described in Scheme C.

Scheme H: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic cyclyl or heteroaryl ring s, may be prepared as described in Scheme H below.

Compound H1 (where X2 is bromine, chlorine and the like; and P is a protecting group such as tert-butyl and the like) is converted to Compound H2 by a Suzuki coupling with an arylor heteroaryl-boronic acid or ester (i.e., an R2 substituted-boronic acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a le solvent (such as 1,4-dioxane and the like). Upon treatment with acid (such as TFA or HCl in dioxane and the like) Compound H2 is converted to Compound H3. Compound H3 is converted to Compound B1 (where X1 is te and the like) by treatment with an activated triflate (such as Tf2O or Tf2NPh and the like) in the presence of base (such as K2CO3 or NaH and the like) in an appropriate solvent (such as THF or DMF and the like). Alternatively, Compound H3 can be converted to Compound B1 (where X1 is Cl and the like) by treatment with a dehydrative halogenating agent (such as POCl3 and the like). Additional modification to the basic amino group can be achieved according to methods described in Scheme C.

Scheme I: Compounds of Formula (I), wherein R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems, may be prepared as described in Scheme I below.

Compound I1 (where X1 is bromine, chlorine and the like; and P is a protecting group such as methyl and the like) is converted to Compound I2 by a Suzuki coupling with an optionally substituted and appropriately ted containing cycloalkyl/cycloalkenyl pinacol boronic ester (where Y is hydrogen or an optionally substituted alkyl group and P is a protecting group such as Boc and the like) (i.e., an R1 substituted-boronic ester) in the presence of a catalyst (such as f)Cl2 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound I2 is converted to Compound E2 (where X2 is triflate and the like) by ent with an activated triflate (such as Tf2O or Tf2NPh and the like) in the presence of base (such as K2CO3 or NaH and the like) in an appropriate t (such as THF or DMF and the like). onal modification to the basic amino group can be achieved according to methods described in Scheme C.

SPECIFIC SYNTHETIC EXAMPLES To describe in more detail and assist in understanding, the following miting examples are offered to more fully illustrate the scope of compounds described herein and are not to be construed as specifically limiting the scope thereof. Such variations of the compounds described herein that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the nds as described herein and hereinafter d. These examples illustrate the ation of certain compounds. Those of skill in the art will understand that the techniques described in these examples represent techniques, as described by those of ordinary skill in the art, that function well in synthetic practice, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific methods that are sed and still obtain a like or similar result without departing from the spirit and scope of the present ption.

Other than in the ing examples of the embodied compounds, unless indicated to the contrary, all numbers expressing quantities of ingredients, reaction conditions, experimental data, and so forth used in the specification and claims are to be understood as being modified by the term ”. 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 mental conditions. Therefore, within an expected range of experimental reproducibility, the term ” in the context of the resulting data, refers to a range for data provided that may vary according 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 ued in light of the number of significant digits and rounding techniques used by those of skill in the art.

While the numerical ranges and ters setting forth the broad scope of the present description are approximations, the numerical values set forth in the examples set forth below are reported as precisely as le. Any numerical value, however, inherently contains n errors necessarily resulting from the standard deviation found in their respective testing measurements.

COMPOUND EXAMPLES As used above, and throughout the present description, the following iations, unless otherwise indicated, shall be understood to have the following meanings: Abbreviation Meaning  heating (chemistry) or deletion (biology) AcOH or HOAc acetic acid Ac2O acetic anhydride Ag2SO4 silver sulfate Ar argon ACN or CH3CN acetonitrile Abbreviation g atm atmosphere(s) B2pin2 bis(pinacolato)diboron Boc tert-butoxy-carbonyl Boc2O di-tert-butyl dicarbonate Br2 bromine nBuLi n-butyl lithium iBuNO isobutyl nitrite BuOH n-butanol l Tributylchlorostannane or tributyltin chloride oC degrees Centigrade Celite® or Celite diatomaceous earth CO2Cl2 oxalyl chloride Cs2CO3 cesium carbonate CuI copper (I) iodide d/h/hr/hrs/min/s day(d)/hour(h, hr or hrs)/minute(min)/second(s) DCM or CH2Cl2 romethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIEA or DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine or N,N-dimethylpyridin amine DMF dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol Et2O diethyl ether Fe(acac)32 iron(III) acetylacetonate H2 hydrogen HCl hydrochloric acid HI hydriodic acid H2SO4 sulfuric acid K2CO3 potassium carbonate KOAc potassium acetate Abbreviation Meaning KOtBu Potassium t-butoxide KOH potassium hydroxide K2OsO4·2H20 potassium osmate(VI) dihydrate LAH or LiAlH4 lithium aluminum e Lawesson’s reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane- 2,4-disulfide LC/MS, LCMS or liquid chromatographic mass spectroscopy LC-MS LiOH lithium ide MeOH methanol MeSO3H methanesulfonic acid MgSO4 magnesium sulfate MnO2 manganese dioxide MS mass spectroscopy MsCl methanesulfonyl chloride NBS N-bromosuccinimide NEt3 triethylamine NH4Cl ammonium chloride NH4OAc ammonium acetate NaBH4 sodium borohydride NaBH(OAc)3 sodium triacetoxyborohydride NaH sodium hydride NaHCO3 sodium bicarbonate NaHMDS sodium bis(trimethylsilyl)amide or sodium hexamethyldisilazide NaH sodium hydride NaOH sodium hydroxide NaOMe sodium ide NaNO2 sodium nitrite Na2SO4 sodium sulfate N2 nitrogen NH4Cl uim chloride NMO ylmoropholine N-oxide Abbreviation g NMP methylpyrrolidone NMR nuclear magnetic resonance NOBF4 nitrosonium tetrafluoroborate or nitrosyl tetrafluoroborate Pb(OAc)4 lead(IV) acetate or lead tetracetate Pd palladium Pd/C palladium on carbon Pd(dppf)Cl2 or [1,1'- Pd(dppf)Cl2-CH2Cl2 bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PHBu3BF4 or tBu3PHBF4 tri-tert-butylphosphonium tetrafluoroborate PhCH3 e PhI iodobenzene PhI(OTFA)2 [bis(trifluoroacetoxy)iodo]benzene PhMe toluene f)2 or PhN(Tf)2 N-phenyl triflimide, also referred to as N-phenylbis uoromethanesulfonimide) POBr3 phosphoryl e or phosphorous(V) oxybromide P2O5 phosphorous pentoxide or phosphorous(V) oxide POCl3 phosphoryl chloride or phosphorous(V) oxychloride PhMe toluene Psi pounds per square inch pressure Pt2O Platinum(IV) oxide Rt or rt room ature SEMCl 2-(trimethylsilyl)ethoxymethyl chloride SnCl2 tin(II) chloride or stannous chloride SOCl2 thionly chloride S-Phos, SPhos or Sphos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G2 chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) TBAF tetrabutylamonium fluoride TBSCl tert-butyldimetylsilyl chloride TEA, Et3N or NEt3 triethylamine TFA trifluoroacetic acid Abbreviation Meaning THF tetrahydrofuran TIPS tiisopropylsilane TLC thin layer chromatography TMEDA tetramethylethylenediamine TMS trimethylsilyl TMSCCH trimethylsilylacetylene t-Bu tert-butyl Zn(CN)2 zinc cyanide ZnMe2 dimethyl zinc Example 1 Preparation of Compound 11 Step A: ochloro-quinoline (121 mg, 0.5 mmol) was ed with N,2,2,6,6- pentamethylpiperidinamine (170 mg, 0.95 mmol) and Cs2CO3 (325 mg, 1.0 mmol) in DMF (2 mL) and the mixture was stirred at 100 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and trated.

The residue was chromatographed on silica gel, eluting with 0-5% MeOH in CH2Cl2 to yield 6- bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)quinolinamine (480 mg, 65%). MS m/z 375.9, 377.9 [M+H]+.

Step B: 6-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidinyl)quinolinamine (40 mg, 0.11 mmol), 2,7-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2H-indazole (51 mg, 0.15 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (8 mg, 0.01 mmol) were combined with s 1 M K2CO3 (0.5 mL, 0.5 mmol) and 1,4-dioxane (1 mL). The mixture was stirred at 80 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0- % MeOH (2 N NH3) in CH2Cl2 to yield 6-(2,7-dimethyl-2H-indazolyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidinyl)quinolinamine (40 mg, 85%) as an off white solid.

MS m/z 442.1 ; 1H NMR (DMSO-d 6) δ: 8.35 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 8.01 (m, 1H), 7.89 (dd, J = 9.0, 1.5 Hz, 1H), 7.83 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.13 (d, J = 8.9 Hz, 1H), 5.24 (br, 1H), 4.20 (s, 3H), 2.99 (s, 3H), 2.59 (s, 3H), 1.69-1.01 (m, 16 H).

Using the procedure described for Example 1, above, additional compounds described herein were prepared by substituting the appropriate boronic acid in Step B, suitable ts and reaction conditions, obtaining compounds such as those selected from: Cpd Data 12 MS m/z 428.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.39 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 8.00 – 8.05 (m, 2H), 7.91 (dd, J = 9.0, 1.5 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.59 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 5.24 (br, 1H), 4.20 (s, 3H), 2.99 (s, 3H), 1.69- 1.01 (m, 16 H).

Example 2 Preparation of Compound 15 Step A: 6-Bromochloro-quinoline (242 mg, 1.0 mmol) was combined with 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (45 mg, 0.05 mmol), methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2H-indazole (350 mg, 1.0 mmol), 1,4-dioxane (5 mL) and aqueous 1 M K2CO3 (2.5 mL, 2.5 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 10-100% EtOAc in hexanes to yield 2-chloro(2,7- dimethyl-2H-indazolyl)quinoline (150 mg, 49%). MS m/z 308.0, 310.0 .

Step B: 2-Chloro(2,7-dimethyl-2H-indazolyl)quinoline (135 mg, 0.30 mmol) was combined with N-Boc-1,2,5,6-tetrahydropyridineboronic acid pinacol ester (193 mg, 0.61 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.05 mmol), 1,4-dioxane (2.5 mL), and aqueous 1 M K2CO3 (1.2 mL, 1.2 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and trated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in EtOAc to yield tert-butyl 4-[6-(2,7- dimethylindazolyl)quinolyl]-3,6-dihydro-2H-pyridinecarboxylate (135 mg, 61%). MS m/z 455.1 [M+H]+.

Step C: tert-Butyl 4-[6-(2,7-dimethylindazolyl)quinolyl]-3,6-dihydro-2H-pyridine carboxylate (35 mg, 0.08 mmol) was combined with 10% Pd/C (10 mg) in MeOH (3 mL). The mixture was d under H2 (1 atm) for 18 h. The mixture was filtered over Celite®. The filtrate was concentrated to yield tert-butyl 4-[6-(2,7-dimethylindazolyl)quinolyl]piperidine carboxylate (35 mg, 99%). MS m/z 457.2 [M+H]+.

Step D: tert-Butyl 4-[6-(2,7-dimethylindazolyl)quinolyl]piperidinecarboxylate from Step C (35 mg, 0.077 mmol) was combined with TFA (1 mL). The solution stood for 20 min before the volatiles were removed with a stream of N2. The residue was partitioned between EtOAc and aqueous 1 M aqueous K2CO3. The c layer was collected and concentrated to yield 6-(2,7- dimethyl-2H-indazolyl)(piperidinyl)quinoline (25 mg, 91%).

MS m/z 357.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.40 (s, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.8, 2.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.93 - 7.97 (m, 1H), 7.50 - 7.57 (m, 1H), 7.48 (d, J = 8.5 Hz, 1H), 4.21 (s, 3H), 3.05 - 3.11 (m, 2H), 2.92 - 2.99 (m, 1H), 2.61 - 2.68 (m, 2H), 2.61 (s, 3H), 1.81 - 1.88 (m, 2H), 1.69 - 1.79 (m, 2H), NH proton not ed.

Using the procedure described for Example 2, above, additional compounds described herein were prepared by substituting the appropriate starting al, suitable reagents and reaction conditions, ing compounds such as those selected from: Cpd Data 3 MS m/z 343.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.29 (br s, 1H), 9.19 (br s, 1H), 8.81 (br s, 1H), 8.47 - 8.52 (m, 2H), 8.33 - 8.40 (m, 2H), 8.21 (m, 1H), 7.73 - 7.80 (m, 3H), 4.22 (s, 3H), 3.54 (br s, 1H), 3.41 - 3.48 (m, 2H), 3.02 - 3.12 (m, 2H), 2.14 - 2.25 (m, Example 3 Preparation of Compound 13 Step A: 2,2,6,6-Tetramethylpiperidinone (3.1 g, 20 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. NaHMDS (21 mL, 21 mmol, 1.0 M in THF) was added to the solution. The mixture was stirred for 15 min at -78 °C. N,N-bis(trifluoromethylsulfonyl)aniline (7.8 g, 22 mmol) was added to the mixture as a solid. The mixture was allowed to warm to room temperature before being quenched with aqueous saturated NaHCO3. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with aqueous 2 M KOH, dried over Na2SO4, filtered and concentrated to yield 6-tetramethyl-1,2,3,6-tetrahydropyridinyl trifluoromethanesulfonate (6.0 g, 100%). 1H NMR (acetone-d 6) δ: 10.28 (br s, 1H), 6.13 (s, 1H), 2.85 (br s, 2H), 1.76 (s, 6H), 1.68 (s, 6H).

Step B: ,6-Tetramethyl-1,3-dihydropyridinyl) trifluoromethanesulfonate (100 mg, 0.35 mmol) was combined with nacolato)diboron (125 mg, 0.50 mmol), potassium acetate (100 mg, 1.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride romethane complex (12 mg, 0.015 mmol) and 1,4-dioxane (2.4 mL). The mixture was stirred at 90 °C for 2 h. The mixture was cooled to room temperature. To the mixture was added aqueous 1 M K2CO3 (1 mL, 1 mmol), 2-chloro(2,7-dimethylindazolyl)quinoline (100 mg, 0.30 mmol, prepared according to Example 2, Step A) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (12 mg, 0.015 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, g with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 6-(2,7- dimethyl-2H-indazolyl)(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl)quinoline (90 mg, 46%).

MS m/z 411.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.41 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.8, 2.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.93 - 7.97 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 1.6 Hz, 1H), 6.78 - 6.82 (m, 1H), 4.21 (s, 3H), 2.61 (s, 3H), 2.50 (m, 2H), 1.49 (s, 1H), 1.26 (s, 6H), 1.17 (s, 6H).

Example 4 Preparation of Compound 14 6-(2,7-Dimethylindazolyl)(2,2,6,6-tetramethyl-1,3-dihydropyridinyl)quinoline (20 mg, 0.05 mmol) was ed with 10 % Pd/C (10 mg) in MeOH (2 mL). The mixture was stirred under H2 (1 atm) at room temperature for 6 h. The mixture was then filtered over Celite. The filtrate was trated to yield 6-(2,7-dimethyl-2H-indazolyl)(2,2,6,6- tetramethylpiperidinyl)quinoline (20 mg, 99%).

MS m/z 413.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.40 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.8, 2.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.93 - 7.95 (m, 1H), 7.49 - 7.53 (m, 2H), 4.21 (s, 3H), 2.61 (s, 3H), 1.73 - 1.79 (m, 2H), 1.47 - 1.55 (m, 2H), 1.27 (s, 6H), 1.11 (s, 6H), NH proton not observed.

Example 5 Preparation of Compound 20 Step A: ochlorofluoro-quinoline (52 mg, 0.2 mmol) was combined with 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol), 2,7-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)indazole (54 mg, 0.2 mmol), 1,4-dioxane (1 mL) and aqueous 1 M K2CO3 (0.5 mL, 0.5 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 10-100% EtOAc in hexanes to yield 2-chloro(2,7-dimethyl-2H-indazol- 8-fluoroquinoline (25 mg, 38%). MS m/z 326.2, 328.2 [M+H]+.

Step B: Zinc powder (5 g, 76 mmol) was suspended in N,N-dimethylacetamide (10 mL) under argon. A mixture of 1,2-dibromoethane (520 μL, 6.02 mmol) and trimethylsilane (730 μL, .74 mmol) was added se over 10 min. Over the course of the addition the internal temperature rose to 50 °C. The reaction mixture was allowed to cool to room temperature. A on of tert-butyl 4-iodopiperidinecarboxylate (16.5 g, 53.0 mmol) in N,N- dimethylacetamide (26 mL) was added dropwise over 20 min. The reaction mixture was filtered through Celite in a Schlenk filter to yield roughly 50 mL of ~1M (1-tert-butoxycarbonyl piperidyl)-iodo-zinc solution. 2-Chloro(2,7-dimethyl-2H-indazolyl)fluoroquinoline (25 mg, 0.077 mmol) was combined with the -butoxycarbonylpiperidinylzinc iodide on (0.25 mL, 0.25 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino- 1,1'-biphenylyl) palladium(II) (4 mg, 0.005 mmol) and oxane (1 mL). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and H2O. The c layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in EtOAc to yield tert-butyl 4-[6-(2,7-dimethylindazolyl)fluoroquinolyl]piperidine carboxylate (30 mg, 82%). MS m/z 475.4 [M+H]+.

Step C: tert-Butyl 4-[6-(2,7-dimethylindazolyl)fluoroquinolyl]piperidinecarboxylate (30 mg, 0.06 mmol) was combined with TFA (1 mL). After 10 min, the volatiles were removed.

The mixture was partitioned between CH2Cl2 and aqueous 1 M K2CO3. The organic layer was loaded onto silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 6-(2,7-dimethyl- 2H-indazolyl)fluoro(piperidinyl)quinoline (20 mg, 85%).

MS m/z 375.3 [M+H]+; 1H NMR (acetone-d 6) δ: 8.22 (dd, J = 8.7, 1.7 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.79 - 7.81 (m, 1H), 7.70 (dd, J = 12.5, 2.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.36 - 7.40 (m, 1H), 4.12 (s, 3H), 2.99 - 3.06 (m, 2H), 2.87 - 2.93 (m, 1H), 2.58 - 2.65 (m, 2H), 2.52 (s, 3H), 1.67 - 1.81 (m, 4H), NH proton not observed.

Using the procedure described for Example 5, above, additional compounds bed herein were prepared by substituting the indicated starting material in Step A, suitable reagents and reaction conditions, ing compounds such as those selected from: Cpd Starting Material and Data 23 Starting material: 6-bromochloroquinazoline MS m/z 358.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.59 (s, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.98 - 8.02 (m, 2H), 7.54 (s, 1H), 4.22 (s, 3H), 3.29 - 3.35 (m, 2H), 2.86 - 2.94 (m, 1H), 3.01 - 3.09 (m, 2H), 2.61 (s, 3H), 1.90 - 1.96 (m, 2H), 1.75 - 1.84 (m, 2H), NH proton not observed.

Cpd Starting Material and Data Starting material: ochloroisoquinoline MS m/z 357.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.32 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.13 (dd, J = 8.5, 1.9 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.96 - 7.97 (m, 1H), 7.64 (s, 1H), 7.54 (t, J = 1.6 Hz, 1H), 4.21 (s, 3H), 3.09 - 3.15 (m, 2H), 2.86 - 2.94 (m, 1H), 2.66 - 2.74 (m, 2H), 2.61 (s, 3H), 1.87 - 1.93 (m, 2H), 1.69 - 1.78 (m, 2H), NH proton not observed.

Example 6 Preparation of Compound 72 Step A: Methyl cyanoacetate (5.71 g, 57.6 mmol) was added to a e of DMSO (30 mL) and NaH (60 mass %) in mineral oil (2.3 g, 57.6 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min. 5-Chloro-2,3-difluoro-benzonitrile (5.0 g, 28.8 mmol) in DMSO (5 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min and then heated to 90 °C for 4 h.

The mixture was cooled to room temperature and diluted with H2O (200 mL), brine (100 mL) and EtOAc (200 mL). A precipitate formed and was collected by vacuum filtration. The solid was washed with H2O and dried to yield methyl 2-(4-chlorocyanofluoro-phenyl)cyano-acetate (6 g, 82%) as a tan powder. MS m/z 251.1, 253.1 .

Step B: Methyl 2-(4-chlorocyanofluoro-phenyl)cyano-acetate (5.5 g, 22 mmol) was combined with s concentrated HCl (40 mL) and 1,4-dioxane (20 mL). The mixture was heated at 80 °C for 4 h. The mixture was cooled to room temperature and filtered. The solid was washed with H2O and CH3CN, and then dried to yield rofluoro-4H-isoquinoline-1,3- dione (3.0 g, 65%) as an off white solid. MS m/z 214.1, 216.1 [M+H]+.

Step C: 7-Chlorofluoro-4H-isoquinoline-1,3-dione (3.0 g, 14.0 mmol) was combined with POCl3 (20 mL, 212 mmol). The mixture was heated at 110 °C for 2 h and then 90 °C overnight.

The mixture was cooled to room temperature and then poured onto ice with vigorous stirring. The solid material was collected by vacuum filtration, dried, and chromatographed on silica gel, eluting with CH2Cl2 to afford 1,3,7-trichlorofluoro-isoquinoline (1.3 g, 37%) as a white powder. MS m/z 250.2, 252.2, 254.2 [M+H]+.

Step D: 1,3,7-Trichlorofluoro-isoquinoline (1.3 g, 5.2 mmol) was combined with [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (210 mg, 0.26 mmol), TMEDA (0.77 mL, 5.2 mmol) and THF (20 mL). To the e was added sodium borohydride (378 mg, 10 mmol). The mixture was stirred at room temperature for 30 min, and then was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and trated. The residue was chromatographed on silica gel, eluting with 0-10% EtOAc in CH2Cl2 to yield 3,7-dichlorofluoro-isoquinoline (870 mg, 78%) as a white solid.

MS m/z 216.2, 218.2, 220.2 [M+H]+; 1H NMR (acetone-d6) δ: 9.26 (m, 1H), 8.16 (m, 1H), 8.00 (s, 1H), 7.72 (dd, J = 9.8, 1.9 Hz, 1H).

Step E: 3,7-Dichlorofluoro-isoquinoline (432 mg, 2.0 mmol) was combined with N-Boc- 1,2,5,6-tetrahydropyridineboronic acid pinacol ester (610 mg, 2.4 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane x (50 mg, 0.06 mmol), 1,4-dioxane (6 mL) and aqueous 1 M K2CO3 (4 mL, 4 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to yield tert-butyl 4-(7-chlorofluoroisoquinolyl)-3,6-dihydro-2H-pyridine carboxylate (370 mg, 51%) as an off-white solid. MS m/z 362.2, 364.2 .

Step F: 6-Chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine hydrochloride (62 mg, 0.28 mmol, prepared according to the procedure in Example 11) was combined with KOAc (83 mg, 0.85 mmol), 1,1'-bis(diphenylphosphino) ene-palladium(II)dichloride dichloromethane x (23 mg, 0.03 mmol), bis(pinacolato)diboron (91 mg, 0.36 mmol) and 1,4-dioxane (1.5 mL). The e was stirred under N2 at 100 °C for 2 h. To the mixture was added 1 M K2CO3 (aq) (0.75 mL, 0.75 mmol), followed by is(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane x (11 mg, 0.014 mmol) and tert-butyl 4-(7-chlorofluoro isoquinolyl)-3,6-dihydro-2H-pyridinecarboxylate (100 mg, 0.28 mmol). The mixture was stirred under N2 for 1 h at 80 °C. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 10- 100% EtOAc in CH2Cl2 then 5% MeOH in EtOAc to yield tert-butyl 4-[7-(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluoroisoquinolyl]-3,6-dihydro-2H-pyridine carboxylate (90 mg, 69%) as a white solid. MS m/z 474.5 [M+H]+.

Step G: tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoroisoquinolyl]-3,6- dihydro-2H-pyridinecarboxylate (90 mg, 0.19 mmol) was combined with 10% Pd/C (20 mg) in MeOH (3 mL). The mixture was stirred under H2 (1 atm) for 2 h at 40 °C. The e was filtered through a syringe filter. The filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 40-100% EtOAc in hexanes to yield tert-butyl 4-[7-(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluoroisoquinolyl]piperidinecarboxylate (52 mg, 57%) as an off-white solid. MS m/z 476.3 .

Step H: tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro isoquinolyl]piperidinecarboxylate (52 mg, 0.11 mmol) was combined with 4 N HCl in 1,4- dioxane (2 mL, 8 mmol). The mixture was stirred and sonicated and room temperature. After 1 h, the volatiles were removed. The residue was suspended in CH3CN, sonicated and filtered. The solid was dried to give 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(4- piperidyl)isoquinoline hydrochloride (36 mg, 46%) as a yellow solid.

MS m/z 376.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.58 (s, 1H), 9.14 - 9.22 (br, 1H), 8.96 - 9.05 (br, 1H), 8.89 (s, 1H), 8.48 - 8.53 (m, 2H), 8.34 (dd, J = 11.6, 1.5 Hz, 1H), 7.84 (s, 1H), 3.39 - 3.45 (m, 2H), 3.25 - 3.31 (m, 1H), 3.02 - 3.12 (m, 2H), 2.79 (s, 3H), 2.60 (s, 3H), 2.07 - 2.17 (m, 4H).

Using the procedure described for e 6, above, additional nds described herein were prepared by substituting the appropriate boronic acid in Step F, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 71 MS m/z 375.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.56 (s, 1H), 9.12 - 9.20 (br, 1H), 8.89 - 8.98 (br, 1H), 8.89 (s, 1H), 8.43 - 8.48 (m, 2H), 8.34 (d, J = 12.2 Hz, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 4.22 (s, 3H), 3.39 - 3.46 (m, 2H), 3.27 - 3.34 (m, 1H), 3.02 - 3.12 (m, 2H), 2.61 (s, 3H), 2.05 - 2.20 (m, 4H).

Using the ure bed for Example 6, Steps E-H, above, additional compounds described herein were prepared by substituting the appropriate starting material in Step E, appropriate boronic acid in Step F, suitable ts and reaction conditions, obtaining compounds such as those selected from: Cpd Starting Material and Data 1 Starting material: 6-bromochloroquinoline MS m/z 343.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.75 - 8.80 (br, 2H), 8.64 (s, 1H), 8.54 (s, 1H), 8.47 - 8.50 (m, 1H), 8.22 - 8.26 (m, 2H), 8.07 - 8.10 (m, 1H), 7.83 (s, 1H), 7.70 - 7.76 (m, 2H), 4.22 (s, 3H), 3.42 - 3.48 (m, 2H), 3.05 - 3.14 (m, 3H), 2.07 - 2.12 (m, 2H), 1.87 - 1.95 (m, 2H).

Starting material: 6-bromochloroquinazoline MS m/z 344.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.67 (s, 1H), 9.03 - 9.12 (br s, 2H), 9.00 (s, 1H), 8.55 (s, 1H), 8.44 - 8.47 (m, 1H), 8.02 - 8.05 (m, 1H), 7.91 - 7.96 (m, 2H), 7.71 - 7.74 (m, 1H), 4.21 (s, 3H), 3.40 - 3.44 (m, 2H), 3.03 - 3.11 (m, 3H), 1.98 - 2.09 (m, 4H).

Preparation of Compound 74 Step A: 1,2-Difluoronitro-benzene (23 g, 145 mmol) was combined with Ag2SO4 (45.2 g, 145 mmol) in H2SO4 (150 mL). The mixture was stirred for 5 min at room temperature. To the mixture was added Br2 (11.2 mL, 217 mmol). The mixture was d at room temperature for 16 h, and then was poured into ice water (800 mL). The mixture was extracted with Et2O (3 X 500 mL). The combined organics were dried, filtered and concentrated. The residue was tographed on silica gel, eluting with 10-30% CH2Cl2 in hexanes to yield 5-bromo-1,2- difluoronitro-benzene (18.8 g, 55%) as a white crystalline solid. 1H NMR (acetone-d 6) δ: 8.20 (ddd, J = 5.8, 2.4, 2.2 Hz, 1H), 8.12 (ddd, J = 9.2, 6.5, 2.2 Hz, 1H).

Step B: 5-Bromo-1,2-difluoronitro-benzene (15 g, 63 mmol), dimethyl malonate (12.5 g, 95 mmol), Cs2CO3 (41.1 g, 126 mmol), and DMF (63 mL) were stirred at rt for 6 h. The reaction mixture was ioned between aqueous 1 M HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was combined with AcOH (30 mL) and conc. HCl (30 mL) and heated at 110 °C for 16 h. The mixture was diluted with H2O to form a itate. The solid was collected by vacuum filtration, washed with H2O, washed with 1:1 hexane/ether and dried to afford 2-(4-bromofluoronitro-phenyl)acetic acid (14.5 g, 83%) as a white solid. 1H NMR (acetone-d 6) δ: 11.28 (br s, 1H), 8.16 (t, J = 1.5 Hz, 1H), 7.92 (dd, J = 9.0, 1.5 Hz, 1H), 4.06 (s, 2H).

Step C: 2-(4-Bromofluoronitro-phenyl)acetic acid (14.5 g, 52 mmol) was suspended in CH2Cl2 (250 mL). Oxalyl chloride (7 mL, 79 mmol) was added to the mixture followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room ature for 1 h, and then added dropwise to MeOH at 0 °C. The volatiles were removed under vacuum to yield methyl 2-(4-bromo fluoronitro-phenyl)acetate (15 g, 98%) as an off-white solid. 1H NMR (acetone-d 6) δ: 8.16 (t, J = 1.5 Hz, 1H), 7.93 (dd, J = 9.0, 1.5 Hz, 1H), 4.05 (s, 2H), 3.71 (s, 3H).

Step D: Methyl 2-(4-bromofluoronitro-phenyl)acetate (15 g, 51 mmol) was suspended in a mixture of MeOH (200 mL) and NH4Cl (55 g, 1.03 mol) at 0 °C. Zinc powder (16.8 g, 257 mmol) was added in one portion. The mixture was stirred at room temperature for 4 h, and then was filtered through Celite. The filtrate was trated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to yield methyl 2-(2-aminobromofluoro-phenyl)acetate (12.6 g, 94%) as a white solid. MS m/z 262.0, 264.0 [M+H]+.

Step E: Methyl 2-(2-aminobromofluoro-phenyl)acetate (12.6 g, 48 mmol) was suspended in CH2Cl2 (150 mL) at 0 °C. Nitrosonium tetrafluoroborate (8.4 g, 72 mmol) was added in one portion to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was added directly to a usly stirred mixture of SnCl2 dihydrate (43.8 g, 194 mmol) in conc. HCl (200 mL) at 0 °C. The mixture was allowed to slowly warm to room temperature with stirring. After 24 h, the mixture was filtered. The solid was washed with H2O and ether, and then dried to yield o- ofluoro-indolinone (9.0 g, 76%) as a white solid. MS m/z 244.9, 246.9 [M+H]+.

Step F: 1-Aminobromofluoro-indolinone (9.0 g, 37 mmol) was suspended in CH2Cl2 (500 mL) at 0 °C. Pb(OAc)4 (22.8 g, 51.4 mmol) was added to the mixture in one portion. The mixture was stirred at room temperature for 16 h. MeOH (50 mL) was added to the mixture, and the e was eluted h a pad of silica gel. The filtrate was concentrated and chromatographed on silica gel, eluting with 0-100% EtOAc in CH2Cl2 to yield ofluorocinnolinol (3.5 g, 39%) as a yellow . MS m/z 241.1, 243.1 [M-H]-.

Step G: 7-Bromofluoro-cinnolinol (3.5 g, 14 mmol) was suspended in POCl3 (28 mL, 300 mmol). The mixture was stirred at 100 °C for 4 h in a sealed tube. The mixture was cooled to room temperature and quenched onto ice. The ice water was extracted with CH2Cl2 (2X). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% EtOAc in CH2Cl2 to yield 7-bromo chlorofluorocinnoline (2.6 g, 69%) as an off white powder. MS m/z 261.1, 263.1, 265.1 [M+H]+.

Step H: 7-Bromochlorofluoro-cinnoline (785 mg, 3.00 mmol) was combined with (2,8- dimethylimidazo[1,2-b]pyridazinyl)boronic acid (3.6 mmol, prepared according to the procedure in Example 11), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'- amino-1,1'-biphenylyl) palladium(II) (108 mg, 0.15 mmol), oxane and aqueous 1 M K2CO3 (10 mL, 10 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was partitioned between EtOAc and H2O, then filtered through Celite. The organic layer was trated. The residue was chromatographed on silica gel, eluting with 40-100% EtOAc in hexanes followed by % MeOH in EtOAc to yield 3-chloro(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline (605 mg, 62%) as a tan solid. MS m/z 328.2, 330.2 [M+H]+.

Step I: 3-Chloro(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnoline (400 mg, 1.2 mmol) was combined with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (50 mg, 0.06 mmol), N-Boc-1,2,5,6-tetrahydropyridineboronic acid pinacol ester (462 mg, 1.47 mmol), 1,4-dioxane (6 mL) and aqueous 1 M K2CO3 (3 mL, 3.0 mmol). The e was d at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 40-100% EtOAc in hexanes, then 5% MeOH in EtOAc to yield tert-butyl 4-[7-(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]-3,6-dihydro-2H-pyridine carboxylate (430 mg, 74%) as a tan solid. MS m/z 475.5 [M+H]+.

Step J: tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]-3,6- dihydro-2H-pyridinecarboxylate (430 mg, 0.91 mmol) was combined with 10% Pd/C (500 mg) in MeOH:EtOAc (1:1) (25 mL). The mixture was stirred under H2 (1 atm) for 3 h at 40 °C. The mixture was filtered through a syringe filter and the filtrate was concentrated. The residue was dissolved in CH2Cl2 (2 mL). MnO2 (20 equiv.) was added to the on. The mixture was stirred at room temperature for 30 min and then filtered through Celite. The filtrate was concentrated.

The residue was chromatographed on silica gel, eluting with 40-100% EtOAc in hexanes to yield tert-butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]piperidine carboxylate (200 mg, 46%) as an off-white solid. MS m/z 477.5 .

Step K: tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolin yl]piperidinecarboxylate (200 mg, 0.42 mmol) was ed with 4 N HCl in 1,4-dioxane (1 mL, 4 mmol). The mixture was stirred at room temperature for 1 h. The volatiles were removed with a stream of N2. The e was ded in CH3CN, sonicated and filtered. The solid was dried to give 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(4-piperidyl)cinnoline hloride (190 mg, quant.) as an off white solid.

MS m/z 377.3 [M+H]+; 1H NMR (DMSO-d6) δ: 9.13 (s, 1H), 8.84 (br, 1H), 8.58 (br, 1H), 8.32 - 8.41 (m, 3H), 8.20 (s, 1H), 3.55 - 3.62 (m, 1H), 3.47 - 3.53 (m, 2H), 3.11 - 3.20 (m, 2H), 2.71 (s, 3H), 2.52 (s, 3H), 2.16 - 2.30 (m, 4H).

Using the procedure described for Example 7, above, additional compounds described herein were prepared by substituting the appropriate boronic acid or boronic acid equivalent in Step H or I, suitable ts and reaction conditions, obtaining compounds such as those selected from: Cpd Data 73 MS m/z 376.4 ; 1H NMR (DMSO-d 6) δ: 9.02 - 9.10 (br, 1H), 8.75 - 8.84 (br, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.34 (dd, J = 11.4, 1.4 Hz, 1H), 8.16 - 8.19 (m, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 4.23 (s, 3H), 3.51 - 3.59 (m, 1H), 3.43 - 3.50 (m, 2H), 3.08 - 3.18 (m, 2H), 2.62 (s, 3H), 2.18 - 2.28 (m, 4H). 84 MS m/z 359.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.26 (s, 1H), 8.71 (dd, J = 8.5, 1.5 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 3.61 - 3.69 (m, 3H), 2.45 - 2.55 (m, 2H – overlaps with al t peak), 2.88 (s, 3H), 2.72 (s, 3H), 2.30 - 2.50 (m, 4H). NH proton not observed. 87 MS m/z 405.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.13 (s, 1H), 8.59 (s, 1H), 8.40-8.45 (m, 2H), 8.32 (s, 1H), 4.04 (m, 1H), 3.91 (t, J = 12.5 Hz, 1H), 3.79 (br s, 1H), 2.87 (s, 3H), 2.70 (s, 3H), 2.38 - 2.50 (m, 2H), 2.24 (d, J = 14 Hz, 1H), 2.06 (q, J = 14 Hz, 1H), 1.65 (d, J = 7 Hz, 3H), 1.45 (d, J = 6 Hz, 3H). NH and HCl protons not observed. 90 MS m/z 405.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.88 (s, 1H), 8.28 (d, J = 10 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 3.48 (tt, J = 10, 3 Hz, 1H), 2.98 - 3.04 (m, 2H), 2.71 (s, 3H), 2.51 (s, 3H), 2.13 (d, J = 15 Hz, 2H), 1.55 (q, J = 12 Hz, 2H), 1.26 (d, J = 7 Hz, 6H). NH proton not observed. 129 MS m/z 391.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.96 (s, 1H), 8.36 (dd, J = 11 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 3.60 - 3.71 (m, 2H), 3.37 - 3.52 (m, 3H), 2.74 (s, 3H), 2.42 - 2.55 (m, 5H), 2.30 - 2.40 (m, 1H), 2.05 - 2.30 (m, 3H), NH proton not observed. 130 MS m/z 433.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.91 (s, 1H), 8.30 (dd, J = 11, 1.5 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.62 - 3.71 (m, 1H), 3.16 - 3.20 (m, 1H), 2.95 - 3.02 (m, 1H), 2.73 (s, 3H), 2.51 (s, 3H), 2.21 (d, J = 12.5 Hz, 1H), 2.07 - 2.16 (m, 2H), 1.89 (pentet, J = 7.5 Hz, 2H), 1.46 - 1.60 (m, 3H), 1.00 - 1.08 (m, 6H).

NH proton not observed. 143 MS m/z 363.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.00 (s, 1H), 8.39 (d, J = 11 Hz, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 4.24 (septet, J = 7.5 Hz, 1H), 3.91 (d, J = 7.5 Hz, 2H), 3.68 - 3.75 (m, 1H), 3.54 - 3.61 (m, 1H), 2.70 - 2.78 (m, 4H), 2.53 (s, 3H), 2.45 - 2.52 (m, 1H), NH proton not observed. 169 MS m/z 403.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.13 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.40 (m, 2H), 4.18 (br s, 2H), 3.87 (m, 1H), 3.12 (d, J = 15 Hz, 2H), 2.85 (s, 3H), 2.60 - 2.70 (m, 5H), 1.96 (m, 2H), 1.80 - 1.84 (m, 2H). 210 MS m/z 362.3 [M+H]+; 1H NMR (methanol-d4) δ: 9.76 (s, 1H), 8.88 (s, 1H), 8.83 - 8.86 (m, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 3.61 - 3.64 (m, 2H), 3.23 - 3.31 (m, 3H), 2.63 (s, 3H), 2.28 - 2.35 (m, 2H), 2.07 - 2.18 (m, 2H), NH and HCl protons not observed. 216 MS m/z 377.3 [M+H]+; 1H NMR (methanol-d) δ 9.15 (s, 1 H), 8.55 (s, 1 H), 8.44 (br d, J = 10.8 Hz, 1 H), 8.41 (s, 1 H), 8.39 (s, 1 H), 3.83 - 3.45 (m, 5 H), 2.86 (s, 3 H) 2.69 (s, 3 H) 2.33 - 2.42 (m, 1 H) 2.02 - 2.19 (m, 3 H), NH and HCl protons not observed.

Boronic acid or bornic acid equivalents for use in Step H or I were ed ing to the following procedures: Example 7-1 rac-(2R,6R)Benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridinyl trifluoromethanesulfonate and rac-(2S,6R)benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridinyl trifluoromethanesulfonate Step A: 3-Oxopentanedioic acid (20.5 g, 140 mmol) and acetaldehyde (15.7 mL, 279 mmol) were suspended in H2O (50 mL). The mixture was stirred with a strong stir bar at room temperature for min. The mixture was then cooled in an ice bath. Benzylamine (15.3 mL, 140 mmol) was added dropwise. The mixture became thick. Stirring was ued at room temperature for 5 days. s 6N HCl was added. The mixture was stirred at room temperature for 1 h. The mixture was then made basic with aqueous K2CO3 and washed 3 times with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (10-20% EtOAc in hexanes) yielded 6.6 g (17% total yield) of a mixture of rac- )benzyl-2,6-dimethylpiperidinone and (2S,6R)benzyl-2,6-dimethylpiperidin one. These two components readily interconvert one to the other.

Step B: A roughly 2:3 ratio of rac-(2R,6R)benzyl-2,6-dimethylpiperidinone and (2S,6R) benzyl-2,6-dimethylpiperidinone (4.45 g, 18.4 mmol) was dissolved in THF (12.8 mL) at −78 °C. NaHMDS (2M in THF, 13.1 mL, 26.2 mmol) was added dropwise. The mixture was stirred at −78 °C for 3 h. N,N-Bis(trifluoromethylsulfonyl)aniline (9.25 g, 25.9 mmol) was added to the mixture in one portion. The mixture was slowly warmed to room temperature over 15 h. THF was removed from the e under vacuum. The product mixture was diluted with CH2Cl2 and was filtered through a plug of silica to remove solid impurities. The filtrate was concentrated under vacuum. The residue was dissolved in EtOAc. This on was washed with dilute aqueous NaOH (ca. 800 mL) and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under . The residue was purified by silica gel chromatography (50-100% CH2Cl2 in hexanes) yielding trans-isomer rac-(2R,6R)benzyl-2,6-dimethyl-1,2,3,6- tetrahydropyridinyl trifluoromethanesulfonate (1.5 g, 23%) as the higher Rf component. 1H NMR (acetone-d4) δ: 7.37 - 7.40 (m, 2H), 7.30 - 7.35 (m, 2H), 7.22 - 7.27 (m, 1H), 5.87 (s, 1H), 3.76 (d, J = 14.5 Hz, 1H), 3.58 (d, J = 14.5 Hz, 1H), 3.30 - 3.42 (m, 2H), 2.41 - 2.50 (m, 1H), 2.24 - 2.30 (m, 1H), 1.20 - 1.25 (m, 6H). The cis-isomer rac-(2S,6R)benzyl-2,6-dimethyl-1,2,3,6- tetrahydropyridinyl trifluoromethanesulfonate (2.1 g, 33%) was collected as the lower Rf component. 1H NMR (acetone-d 4) δ: 7.37 - 7.40 (m, 2H), 7.30 - 7.35 (m, 2H), 7.20 - 7.25 (m, 1H), 5.85 (s, 1H), 3.87 (d, J = 16 Hz, 1H), 3.82 (d, J = 16 Hz, 1H), 3.50 - 3.57 (m, 1H), 3.16 - 3.22 (m, 1H), 2.49 - 2.57 (m, 1H), 2.24 - 2.30 (m, 1H), 1.22 (d, J = 7 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H).

Example 7-2 (2R,6R)Benzyl-2,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,2,3,6-tetrahydropyridine Potassium acetate (1.8 g, 18 mmol) was dried under Ar at 180 °C for 30 min and then cooled to room temperature. To the solid was added rac-(2S,6R)benzyl-2,6-dimethyl-1,2,3,6- tetrahydropyridinyl trifluoromethanesulfonate (1.5 g, 4.3 mmol, prepared according to Example 36), Pd(dppf)Cl2 (146 mg, 0.175 mmol), dppf (110 mg, 0.19 mmol), bis(pinacolato)diboron (1.2 g, 4.7 mmol), and 1,4-dioxane (14.5 mL). The mixture was heated at 80 °C for 15 h. The reaction mixture was then diluted in EtOAc and ed through . The filtrate was trated under . The residue was dissolved in EtOAc and washed with 800 mL of dilute s NaHCO3 and brine. The organic layer was dried over MgSO4, ed, and concentrated under vacuum. The residue was dissolved in ether and filtered through Celite to remove brown insoluble impurities. The filtrate was concentrated to afford (2S,6R)benzyl-2,6- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-tetrahydropyridine (1.43 g, 80% pure, 81% yield) as a crude black oil. 1H NMR (acetone-d 4) δ: 7.40 - 7.45 (m, 2H), 7.25 - 7.32 (m, 2H), 7.16 - 7.21 (m, 1H), 6.31 (s, 1H), 3.80 (m, 2H), 3.20 - 3.28 (m, 1H), 2.73 - 2.79 (m, 1H), 2.12 - 2.19 (m, 1H), 1.90 - 1.98 (m, 1H), 1.35 (s, 12H), 1.22 (d, J = 5.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H).

Example 7-3 (2R,6R)Benzyl-2,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,2,3,6-tetrahydropyridine was prepared from rac-(2R,6R)benzyl-2,6-dimethyl-1,2,3,6- tetrahydropyridinyl trifluoromethanesulfonate according to Example 7-2. 1H NMR (acetone-d 4) δ: 7.40 - 7.45 (m, 2H), 7.25 - 7.32 (m, 2H), 7.16 - 7.21 (m, 1H), 6.38 (s, 1H), 3.62 (m, 2H), 3.12 - 3.21 (br s, 1H), 3.00 - 3.08 (m, 1H), 2.12 - 2.21 (m, 1H), 1.90 - 1.98 (m, 1H), 1.27 (s, 12H), 1.22 (m, 6H).

Example 7-4 (2R,6R)Benzyl-2,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,2,3,6-tetrahydropyridine was prepared by substituting the appropriate acetaldehyde in Step A of Example 7-1. 1H NMR (acetone-d 4) δ: 7.40 - 7.45 (m, 2H), 7.25 - 7.32 (m, 2H), 7.16 - 7.21 (m, 1H), 6.38 (s, 1H), 3.62 (m, 2H), 3.12 - 3.21 (br s, 1H), 3.00 - 3.08 (m, 1H), 2.12 - 2.21 (m, 1H), 1.90 - 1.98 (m, 1H), 1.27 (s, 12H), 1.22 (m, 6H).

Example 8 Preparation of Compound 34 Step A: 2-Aminobromofluoro-benzoic acid (1.0 g, 4.27 mmol) was dissolved in THF (20 mL). To the solution was added LAH (8.5 mL, 8.5 mmol, 1.0 M in THF) at 0 °C. The mixture was warmed to room temperature. After 1 h, the e was quenched with aqueous 2 N NaOH at 0 °C. After vigorous ng for 30 min, the mixture was filtered over Celite. The filter cake was washed with THF and MeOH. The combined filtrate was concentrated to yield no bromofluoro-phenyl)methanol (900 mg, 96%). MS m/z 220.2, 222.2 [M+H]+.

Step B: (2-Aminobromofluoro-phenyl)methanol (900 mg, 4.09 mmol) was combined with MnO2 (6.9 g, 79 mmol) in CH2Cl2 (20 mL). The e was stirred at room temperature for 1 h.

The mixture was filtered over Celite. The filtrate was trated to yield 2-aminobromo fluoro-benzaldehyde (650 mg, 73%). MS m/z 218.1, 220.1 .

Step C: 2-Aminobromofluoro-benzaldehyde (650 mg, 3.0 mmol) was combined with urea (3.6 g, 60 mmol) and DMSO (3 mL). The mixture was stirred at 180 °C for 2 h. The mixture was cooled to room temperature, upon which H2O (10 mL) was added. The precipitate was collected, washed with H2O and dried to yield 6-bromofluoro-quinazolinol (615 mg, 85%). MS m/z 243.1, 245.1 [M+H]+.

Step D: 6-Bromofluoro-quinazolinol (615 mg, 2.53 mmol) was combined with POCl3 (5 mL, 53 mmol). The mixture was stirred at 110 °C for 2 h. The mixture was cooled to room temperature and poured over ice. After vigorously stirring for 15 min, the solid was collected, dried and chromatographed on silica gel, eluting with 0-20% EtOAc in CH2Cl2 to yield 6-bromo- rofluoroquinazoline (345 mg, 52%). MS m/z 261.1, 263.1, 265.1 [M+H]+.

Steps E-G: Following a procedure r to that found in Example 5 (Steps A-C), 6-bromo chlorofluoroquinazoline was converted to 6-(2,7-dimethyl-2H-indazolyl)fluoro (piperidinyl)quinazoline hydrochloride.

MS m/z 376.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.70 (s, 1H), 8.86 - 8.93 (br, 1H), 8.54 - 8.63 (br, 1H), 8.46 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 12.10, 1.9 Hz, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 4.22 (s, 3H), 3.36 - 3.44 (m, 3H), 3.08 - 3.16 (m, 2H), 2.61 (s, 3H), 2.22 - 2.28 (m, 2H), 2.08 - 2.15 (m, 2H).

Using the procedure described for e 8, above, additional compounds described herein were prepared by substituting the appropriate boronic acid in Step E, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data MS m/z 387.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.69 (d, J = 1.6 Hz, 1H), 8.79 - 8.85 (br, 1H), 8.78 (s, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.49 - 8.55 (br, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.43 (dd, J = 12.2, 1.8 Hz, 1H), 4.30 (s, 3H), 3.37 - 3.46 (m, 3H), 3.07 - 3.17 (m, 2H), 2.22 - 2.28 (m, 2H), 2.07 - 2.16 (m, 2H).

Cpd Data 36 MS m/z 380.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.69 (s, 1H), 8.73 - 8.79 (br, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.43 - 8.52 (br, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.37 (dd, J = 12.3, 1.8 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 12.2, 1.9 Hz, 1H), 4.25 (s, 3H), 3.37 - 3.46 (m, 3H), 3.08 - 3.18 (m, 2H), 2.22 - 2.28 (m, 2H), 2.05 - 2.14 (m, 37 MS m/z 377.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.83 (s, 1H), 8.85 - 8.91 (br, 1H), 8.83 (d, J = 1.9 Hz, 1H), 8.59 - 8.64 (br, 1H), 8.56 (dd, J = 12.3, 1.8 Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 3.58 (s, 3H), 3.39 - 3.47 (m, 3H), 3.08 - 3.18 (m, 2H), 2.74 (s, 3H), 2.23 - 2.30 (m, 2H), 2.07 - 2.15 (m, 2H).

Using the ure bed for Example 8, above, additional compounds described herein were prepared by substituting the indicated starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Starting Material and Data 38 ng material: 6-aminobromofluorobenzoic acid MS m/z 376.4 [M+H]+; 1H NMR (methanol-d4) δ: 8.70 (s, 1H), 7.94 (s, 1H), 7.81 - 7.86 (m, 1H), 7.58 - 7.61 (m, 1H), 7.47 (d, J = 8.5 Hz, 1H), 6.37 (s, 1H), 4.40 (s, 3H), 3.63 - 3.70 (m, 3H), 3.21 - 3.29 (m, 2H), 2.69 (s, 3H), 2.29 - 2.40 (m, 4H) NH proton not observed. 39 Starting material: 2-aminobromofluorobenzoic acid MS m/z 376.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.77 (s, 1H), 7.98 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.63 - 7.68 (m, 1H), 7.43 (d, J = 10.4 Hz, 1H), 6.27 (s, 1H), 4.42 (s, 3H), 3.63 - 3.70 (m, 3H), 3.24 - 3.31 (m, 2H), 2.69 (s, 3H), 2.28 - 2.45 (m, 4H), NH proton not observed.

Example 9 Preparation of Compound 17 Step A: onitroaniline (3.7 g, 17 mmol), cyanamide (5.72 g, 135 mmol) and Et2O (3 mL) were combined in a 75 mL tube. The mixture was stirred at 100 °C for 30 min. The mixture was cooled to 50 °C. To the mixture was slowly added s concentrated HCl (7.2 mL). The resulting mixture was stirred for 1 h at 110 °C. The reaction mixture was again cooled to 50 °C, before adding aqueous 7.5 M NaOH (16 mL). The mixture was again heated to 110 °C for 1 h.

After cooling to room temperature, 20 mL of H2O was added to the mixture. The solid material was collected, washed with H2O and dried to yield 7-bromooxido-1,2,4-benzotriazinium amine (3.2 g, 79%). MS m/z 240.8, 242.8 [M+H]+.

Step B: To a solution of 7-bromooxido-1,2,4-benzotriaziniumamine (3.2 g, 13 mmol) and TFA (25 mL) was added NaNO2 (2.76 g, 40.0 mmol) in small portions at room temperature. The mixture d at room temperature for 30 min. To the mixture was added H2O (75 mL) to form a white precipitate. The solid was collected, washed with H2O and dried. The solid was combined with POCl3 (30 mL, 318.6 mmol). The e was stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was poured onto ice with vigorous ng. After stirring for 10 min, CH2Cl2 (400 mL) was added. The organic phase was collected and dried over , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% EtOAc in CH2Cl2 to yield 7-bromochlorooxido-1,2,4-benzotriazinium (2.37 g, 54%). MS m/z 259.9, 261.9, 264.0 [M+H]+.

Step C: 7-Bromochlorooxido-1,2,4-benzotriazinium (520 mg, 2.0 mmol) was ed with 1,2,5,6-tetrahydropyridineboronic acid pinacol ester (773 mg, 2.45 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (80 mg, 0.10 mmol), 1,4-dioxane (10 mL), and aqueous 1 M K2CO3 (5 mL, 5.0 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 10-100% EtOAc in hexanes to yield tert-butyl 4-(3- chlorooxido-1,2,4-benzotriaziniumyl)-3,6-dihydro-2H-pyridinecarboxylate (540 mg, 75%). MS m/z 307.1, 309.1 [M+H-tBu]+ (molecule ionizes as M+H minus tBu).

Step D: tert-Butyl 4-(3-chlorooxido-1,2,4-benzotriaziniumyl)-3,6-dihydro-2H-pyridine- 1-carboxylate (72 mg, 0.20 mmol) was combined with 2,7-dimethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)indazole (80 mg, 0.30 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane complex (8 mg, 0.01 mmol), 1,4-dioxane (1 mL), and aqueous 1 M K2CO3 (0.5 mL, 0.5 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with % MeOH in EtOAc to yield tert-butyl 4-[3-(2,7-dimethylindazolyl)oxido-1,2,4- benzotriaziniumyl]-3,6-dihydro-2H-pyridinecarboxylate (72 mg, 77%). MS m/z 473.4 [M+H]+.

Step E: tert-Butyl 4-[3-(2,7-dimethylindazolyl)oxido-1,2,4-benzotriaziniumyl]-3,6- dihydro-2H-pyridinecarboxylate (60 mg, 0.13 mmol) was combined with 10% Pd/C (10 mg) and MeOH (3 mL). The mixture was stirred under H2 (1 atm) for 2 h at 30 °C. The e was filtered through a 0.2 µm syringe filter to yield tert-butyl 4-[3-(2,7-dimethylindazolyl)-1,2,4- benzotriazinyl]piperidinecarboxylate (58 mg, 99%). MS m/z 459.4 [M+H]+.

Step F: utyl 4-[3-(2,7-dimethylindazolyl)-1,2,4-benzotriazinyl]piperidine carboxylate (58 mg, 0.13 mmol) was ved in TFA (1 mL). After 20 min, the volatiles were removed from the mixture. The residue was partitioned between EtOAc and aqueous 1 M K2CO3.

The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 3-(2,7-dimethyl-2H-indazolyl)(piperidinyl)benzo[e][1,2,4]triazine (20 mg, 44%).

MS m/z 359.3 [M+H]+; 1H NMR d 6) δ: 9.01 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.06 - 8.12 (m, 2H), 4.24 (s, 3H), 3.11 - 3.19 (m, 2H), 2.94 - 3.01 (m, 1H), 2.68 - 2.76 (m, 2H), 2.64 (s, 3H), 1.88 - 1.94 (m, 2H), 1.66 - 1.76 (m, 2H), NH proton not observed.

Using the procedure described for Example 9, above, additional compounds described herein were prepared by substituting the appropriate boronic acid in Steps B and/or C, suitable reagents and on conditions, obtaining nds such as those selected from: Cpd Data MS m/z 363.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.03 (s, 1H), 8.76 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H), 8.16 (dd, J = 13.0, 1.2 Hz, 1H), 8.10 - 8.14 (m, 2H), 4.24 (s, 3H), 3.14 - 3.20 (m, 2H), 2.97 - 3.05 (m, 1H), 2.71 - 2.79 (m, 2H), 1.90 - 1.97 (m, 2H), 1.69 - 1.79 (m, 2H), NH proton not observed. 26 MS m/z 370.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.48 (d, J = 1.6 Hz, 1H), 9.05 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.09 - 8.17 (m, 2H), 4.36 (s, 3H), 3.35 - 3.42 (m, 2H), 3.11 - 3.20 (m, 1H), 2.97 - 3.05 (m, 2H), 2.11 - 2.19 (m, 2H), 1.89 - 1.99 (m, 2H), NH proton not observed. 27 MS m/z 359.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.52 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.01 - 8.07 (m, 2H), 7.73 (s, 1H), 3.27 - 3.32 (m, 2H), 3.03 - 3.10 (m, 1H), 2.88 - 2.94 (m, 2H), 2.63 (s, 3H), 2.45 (s, 3H), 2.04 - 2.09 (m, 2H), 1.81 - 1.91 (m, 2H), NH proton not observed. 43 MS m/z 363.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.78 (s, 1H), 8.36 (s, 1H), 8.10 - 8.17 (m, 3H), 8.04 (dd, J = 12.2, 1.3 Hz, 1H), 3.09 - 3.15 (m, 2H), 2.94 - 3.01 (m, 1H), 2.66 - 2.72 (m, 2H), 2.42 (s, 3H), 1.87 - 1.93 (m, 2H), 1.64 - 1.74 (m, 2H), NH proton not observed.

Cpd Data 52 MS m/z 375.4 [M+H]+; 1H NMR d 6) δ: 8.78 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.07 - 8.12 (m, 2H), 7.82 (s, 1H), 4.21 (s, 3H), 4.07 (s, 3H), 3.10 - 3.17 (m, 2H), 2.93 - 2.99 (m, 1H), 2.66 - 2.73 (m, 2H), 1.87 - 1.93 (m, 2H), 1.65 - 1.75 (m, 2H), NH proton not observed. 56 MS m/z 389.2 [M+H]+; 1H NMR (methanol-d 4) δ: 10.01 (s, 1H), 8.88 - 8.92 (m, 1H), 8.75 (s, 1H), 8.36 (dd, J = 9.0, 2.2 Hz, 1H), 8.30 - 8.33 (m, 1H), 8.24 - 8.27 (m, 1H), 4.18 - 4.28 (m, 2H), 3.61 - 3.69 (m, 1H), 2.58 - 2.74 (m, 5H), 2.20 - 2.33 (m, 4H), 2.08 - 2.13 (m, 2H), NH proton not observed.

Example 10 Preparation of Compound 28 Step A: 1-(1H-Pyrrolyl)ethanone (1.09 g, 10.0 mmol) was dissolved in 50 mL CH2Cl2 and cooled to -78 °C. A solution of Br2 (620 μL, 12.1 mmol) in 12 mL of CH2Cl2 was added dropwise to the solution. The reaction mixture was poured onto ice. The organic layer was washed with aqueous 1M NaOH, dried over MgSO4, ed and concentrated to yield 1-(4-bromo-1H-pyrrol- 2-yl)ethanone (1.42 g, 76%). 1H NMR ne-d 6) δ: 11.08 (br s, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 2.34 (s, 3H).

Step B: romo-1H-pyrrolyl)ethanone (1.36 g, 7.2 mmol) was dissolved in DMF (15 mL) and cooled to 0 °C. To the solution was added NaH (60 mass% in l oil) (316 mg, 7.9 mmol). The e was warmed to room temperature for 30 min. Chloroacetone (0.6 mL, 7 mmol) was added dropwise. The mixture was stirred at room temperature for 16 h. The mixture was partitioned between H2O and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 30% EtOAc in hexanes to yield 1-(2-acetylbromo-pyrrolyl)propanone (1.2 g, 68%) as a white solid. 1H NMR (acetone-d 6) δ: 7.13 (d, J = 2 Hz, 1H), 7.10 (d, J = 2 Hz, 1H), 5.17 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H).

Step C: 1-(2-Acetylbromo-pyrrolyl)propanone (1.15 g, 4.7 mmol), acetic acid (40 mL) and ammonium acetate (7.2 g, 93 mmol) were heated at 120 °C for 16 h. The les were removed under reduced pressure. The residue was partitioned between s 1 M NaOH and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 10-50% EtOAc in CH2Cl2 to yield 7-bromo-1,3- yl-pyrrolo[1,2-a]pyrazine (975 mg, 92%). 1H NMR (acetone-d 6) δ: 7.86 (s, 1H), 7.63 (s, 1H), 6.84 (s, 1H), 2.56 (s, 3H), 2.31 (s, 3H).

Step D: 7-Bromo-1,3-dimethylpyrrolo[1,2-a]pyrazine (2.0 g, 8.9 mmol) was dissolved in THF (90 mL). The solution was cooled to -78 °C, upon which n-butyllithium was added (6.7 mL, 13.3 mmol, 2 M solution in cyclohexane). The mixture was stirred at -78 °C for 30 min. To the mixture was added tributylchlorostannane. The mixture was allowed to slowly warm to 0 °C. The excess reagent was quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield tributyl-(1,3- dimethylpyrrolo[1,2-a]pyrazinyl)stannane (1.3 g, 30%). 1H NMR (chloroform-d ) δ: 7.53 (s, 1H), 7.20 (s, 1H), 6.72 (s, 1H), 2.65 (s, 3H), 2.37 (s, 3H), 1.52 - 1.58 (m, 6H), 1.30 - 1.38 (m, 6H), 1.04 - 1.08 (m, 6H), 0.88 - 0.94 (m, 9H).

Step E: tert-Butyl 4-(3-chlorooxido-1,2,4-benzotriaziniumyl)-3,6-dihydro-2H-pyridine- 1-carboxylate (72 mg, 0.20 mmol, prepared according to the procedure in e 9, Step C) was combined with yl-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)stannane (140 mg, 0.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.015 mmol), 1,4-dioxane (1.5 mL) and aqueous 1 M K2CO3 (0.75 mL, 0.75 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was tographed on silica gel, eluting with 50-100% EtOAc in CH2Cl2, then EtOAc containing % MeOH to yield tert-butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)oxido-1,2,4- benzotriaziniumyl]-3,6-dihydro-2H-pyridinecarboxylate (50 mg, 53%). MS m/z 473.5 [M+H]+.

Step F: tert-Butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)oxido-1,2,4-benzotriazin iumyl]-3,6-dihydro-2H-pyridinecarboxylate (30 mg, 0.06 mmol) was combined with 10% Pd/C (10 mg) in MeOH (1:1, 2 mL). The mixture was stirred under H2 (1 atm) for 2 h at 40 °C. The mixture was filtered through a 2 µm syringe filter. The filtrate was concentrated to yield tert-butyl 4-(3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)benzo[e][1,2,4]triazinyl)-3,6- opyridine-1(2H)-carboxylate (25 mg, 86%). MS m/z 457.5 .

Step G: tert-Butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)-1,2,4-benzotriazin yl]piperidinecarboxylate (25 mg, 0.05 mmol) was dissolved in TFA (1 mL). After 15 min, the volatiles were removed. The residue was partitioned between CH2Cl2 and aqueous 1 M K2CO3.

The organic layer was loaded on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)(1,2,3,6-tetrahydropyridin yl)benzo[e][1,2,4]triazine (8 mg, 43%). 1H NMR (DMSO-d 6) δ: 8.34 (s, 1H), 8.25 (s, 1H), 8.23 (dd, J = 9.0, 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 6.62 (s, 1H), 3.58 - 3.62 (m, 2H), 3.15 - 3.19 (m, 2H), 2.64 - 2.70 (m, 5H), 2.35 (s, 3H), NH proton not observed.

Example 11 Preparation of Compound 44 Step A: 4-Bromochloro-pyridazinamine (5.2 g, 25 mmol) was combined with tetrakis(triphenylphosphine)palladium(0) (700 mg, 0.61 mmol) and DMF (50 mL). To the e was added dimethylzinc in heptane (50 mL, 50 mmol, 1.0 M) at room temperature. The mixture was heated at 50 °C for 2 h then 70 °C for 1 h. The mixture was cooled to 0 °C and excess reagent was quenched by the addition of H2O. The mixture was filtered over Celite and trated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in CH2Cl2. MS m/z 144.2, 146.2 [M+H]+.

Step B: 6-Chloromethyl-pyridazinamine (3.5 g, 24 mmol) was combined with ethanol (40 mL), ylamine (8.7 mL, 62 mmol) and chloroacetone (4 mL, 49 mmol) in a 100 mL high pressure flask. The flask was sealed and heated behind a blast shield at 150 °C for 45 min. The mixture was concentrated and chromatographed on silica gel, eluting with 30-80% EtOAc in CH2Cl2 to yield 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (2.2 g, 49%). MS m/z 182.3, 184.3 .

Step C: 6-Chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (54 mg, 0.30 mmol) was combined with potassium acetate (87 mg, 0.89 mmol), is(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane complex (12 mg, 0.015 mmol), and bis(pinacolato)diboron (94 mg, 0.37 mmol) in 1,4-dioxane (1 mL). The mixture was stirred under N2 at 95 °C for 2 h to yield imethylimidazo[1,2-b]pyridazinyl)boronic acid. MS m/z 192.4 [M+H]+. The crude mixture was used directly in the next step.

Step D: To the crude mixture from Step C was added aqueous 1 M K2CO3 (0.75 mL, 0.75 mmol), tert-butyl 4-(3-chlorooxido-1,2,4-benzotriaziniumyl)-3,6-dihydro-2H-pyridine carboxylate (72 mg, 0.20 mmol, prepared according to the procedure in Example 9, Step C), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-80% EtOAc in CH2Cl2 to yield tert-butyl 4-[3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)oxido-1,2,4- benzotriaziniumyl]-3,6-dihydro-2H-pyridinecarboxylate (69 mg, 73%). MS m/z 474.4 [M+H]+.

Step E: tert-Butyl 4-[3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)oxido-1,2,4-benzotriazin iumyl]-3,6-dihydro-2H-pyridinecarboxylate (69 mg, 0.15 mmol) was combined with 10% Pd/C (20 mg) in MeOH (2 mL). The mixture was stirred under H2 (1 atm) for 2 h at 40 °C. The mixture was filtered. The te was concentrated and chromatographed on silica gel, eluting with 20-100% EtOAc in hexanes to yield tert-butyl 4-[3-(2,8-dimethylimidazo[1,2-b]pyridazin yl)oxido-1,2,4-benzotriaziniumyl]-3,6-dihydro-2H-pyridinecarboxylate (69 mg, 97%).

MS m/z 460.4 [M+H]+.

Step F: utyl 4-[3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)oxido-1,2,4-benzotriazin yl]-3,6-dihydro-2H-pyridinecarboxylate (69 mg, 0.15 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol). The volatiles were removed after 30 min. The residue was partitioned between CH2Cl2 and aqueous 1 M K2CO3. The c layer was concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)benzo[e][1,2,4]triazine.

MS m/z 360.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.47 (s, 1H), 8.32 (s, 1H), 8.18 - 8.25 (m, 2H), 8.10 (s, 1H), 3.35 - 3.40 (m, 2H), 3.15 - 3.22 (m, 1H), 2.96 - 3.04 (m, 2H), 2.78 (s, 3H), 2.56 (s, 3H), 2.12 - 2.18 (m, 2H), 1.89 - 1.99 (m, 2H), NH proton not observed.

Example 12 Preparation of Compound 16 Step A: ochlorooxido-1,2,4-benzotriazinium (260 mg, 1.0 mmol, prepared in Example 9 Step B) was combined with 2,7-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -indazole (360 mg, 1.06 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane complex (45 mg, 0.05 mmol), 1,4-dioxane (5 mL) and aqueous 1 M K2CO3 (2.5 mL). The mixture was stirred at 70 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over , filtered and concentrated. The residue was chromatographed on silica gel, eluting with -90% EtOAc in hexanes to yield 3-chloro(2,7-dimethyl-2H-indazol yl)benzo[e][1,2,4]triazineoxide (200 mg, 54%). MS m/z 326.0, 328.0 [M+H]+.

Step B: 3-Chloro(2,7-dimethyl-2H-indazolyl)benzo[e][1,2,4]triazineoxide (200 mg, 0.54 mmol) was combined with N-Boc-1,2,5,6-tetrahydropyridineboronic acid pinacol ester (250 mg, 0.80 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.05 mmol), 1,4-dioxane (3 mL) and aqueous 1 M K2CO3 (1.5 mL, 1.5 mmol).

The mixture was stirred at 80 °C for 2 h. The e was partitioned between EtOAc and H2O.

The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 10-100% EtOAc in hexanes to yield tyl 4-[7-(2,7-dimethylindazolyl)oxido-1,2,4-benzotriaziniumyl]-3,6-dihydro-2H- pyridinecarboxylate (200 mg, 78%). MS m/z 473.1 [M+H]+.

Step C: tert-Butyl 4-[7-(2,7-dimethylindazolyl)oxido-1,2,4-benzotriaziniumyl]-3,6- dihydro-2H-pyridinecarboxylate (200 mg, 0.085 mmol) was ed with 10% Pd/C (40 mg) in MeOH (5 mL). The mixture was stirred under H2 (1 atm) for 2 h at 40 °C. The mixture was ed through a 2 µm syringe filter. The filtrate was concentrated and chromatographed on silica gel, eluting with 10-100% EtOAc in CH2Cl2 to yield utyl 4-[7-(2,7-dimethylindazolyl)- benzotriazinyl]piperidinecarboxylate (100 mg, 50%). MS m/z 459.1 [M+H]+.

Step D: tert-Butyl 4-[7-(2,7-dimethylindazolyl)-1,2,4-benzotriazinyl]piperidine ylate (50 mg, 0.11 mmol) was dissolved in TFA (1 mL). After 20 min, the volatiles were removed from the reaction mixture. The residue was partitioned between CH2Cl2 and aqueous 1 M K2CO3. The organic layer was loaded directly to silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 7-(2,7-dimethyl-2H-indazolyl)(piperidin yl)benzo[e][1,2,4]triazine (30 mg, 77%).

MS m/z 359.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.77 (d, J = 2.5 Hz, 1H), 8.56 (dd, J = 9.0, 1.9 Hz, 1H), 8.47 (s, 1H), 8.12 - 8.18 (m, 2H), 7.66 (s, 1H), 4.23 (s, 3H), 3.40 - 3.47 (m, 1H), 3.08 - 3.15 (m, 2H), 2.69 - 2.76 (m, 2H), 2.63 (s, 3H), 2.00 - 2.07 (m, 2H), 1.83 - 1.92 (m, 2H), NH proton not observed.

Preparation of Compound 46 Step A: 5-Bromo-1,3-difluoronitro-benzene (9.52 g, 40.0 mmol) was dissolved in EtOH (50 mL). To the solution was added ine monohydrate (16.6 mL, 160 mmol). The on was stirred at room ature for 24 h. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to yield (5-bromofluoronitrophenyl)hydrazine (8.5 g, 85%).

MS m/z 250.2, 252.2 [M+H]+.

Step B: (5-Bromofluoronitrophenyl)hydrazine (1.25 g, 5.0 mmol) and tert-butyl 4- formylpiperidinecarboxylate (3.2 g, 15 mmol) were combined in EtOH (25 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure.

The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in CH2Cl2 to yield tert-butyl (E)((2-(5-bromofluoronitrophenyl)hydrazono)methyl)piperidinecarboxylate (2.2 g, 99%) MS m/z 443.1, 445.4 [M-H]-.

Step C: tert-Butyl (E)((2-(5-bromofluoronitrophenyl)hydrazono) methyl)piperidine carboxylate (2.2 g, 4.9 mmol) was suspended in EtOH (50 mL) with PtO2 (100 mg, 0.4402 mmol). The mixture was stirred under H2 (1 atm, balloon) at room temperature for 3 h. The reaction mixture was filtered over Celite. The filtrate was concentrated under reduced pressure to yield tert-butyl (E)((2-(2-aminobromofluorophenyl)hydrazono)methyl)piperidine carboxylate (2.03 g, 98%). MS m/z 413.3, 415.3 [M-H]-.

Step D: tert-Butyl 4-(7-bromofluoro-1,2,3,4-tetrahydro-1,2,4-benzotriazinyl)piperidine ylate (2.03 g, 4.9 mmol) was dissolved in CH3CN (40 mL, 765 mmol). To the mixture was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.41 g, 15.0 mmol). The e was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The e was suspended in CH2Cl2 and filtered. The filtrate was trated and chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to yield tert-butyl 4-(7-bromo fluorobenzo[e][1,2,4]triazinyl)piperidinecarboxylate (805 mg, 39%). MS m/z 411.2, 413.2 [M+H]+.

Step E: tert-Butyl 4-(7-bromofluorobenzo[e][1,2,4]triazinyl)piperidinecarboxylate (500 mg, 1.22 mmol) was combined with KOAc (358 mg, 3.65 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with romethane (100 mg, 0.12 mmol), bis(pinacolato)diboron (386 mg, 1.52 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 100 °C for 2 h. After cooling the mixture to room temperature, aqueous 1 M K2CO3 (1.5 mL, 1.5 mmol), 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (270 mg, 1.22 mmol, prepared according the ure in Example 11), and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (100 mg, 0.12 mmol) were added. The mixture was stirred at 80 °C for 2 h. The e was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 20-80% EtOAc in hexanes to yield tert-butyl 4-(7-(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluorobenzo[e][1,2,4]triazinyl)piperidinecarboxylate (550 mg, 94%). MS m/z 478.6 [M+H]+.

Step F: tert-Butyl 4-(7-(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluorobenzo[e][1,2,4]triazinyl)piperidinecarboxylate (67 mg, 0.14 mmol) was suspended in 4 N HCl in 1,4-dioxane (2 mL, 8 mmol). The mixture was d vigorously for 1 h. The solid was collected, washed with CH3CN, and dried to afford 7-(2,8-dimethylimidazo[1,2-b]pyridazin- 6-yl)fluoro(piperidinyl)benzo[e][1,2,4]triazine hydrochloride (46 mg, 73%).

MS m/z 378.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.24 (s, 1H), 8.68 (d, J = 10.6 Hz, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 3.91 (m, 1H), 3.59 - 3.67 (m, 2H), 3.34 - 3.42 (m, 2H), 2.87 (s, 3H), 2.70 (s, 3H), 2.53 - 2.61 (m, 2H), 2.32 - 2.43 (m, 2H), NH proton not observed.

Using the procedure described for Example 13, above, additional compounds described herein were prepared by substituting the appropriate aryl halide in Step E, suitable reagents and reaction conditions, obtaining nds such as those selected from: Cpd Data 32 MS m/z 381.1 [M+H]+; 1H NMR (methanol-d 4) δ: 8.67 - 8.69 (m, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.34 (dd, J = 11.0, 1.9 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 12.6, 1.6 Hz, 1H), 4.31 (s, 3H), 3.83 - 3.90 (m, 1H), 3.60 - 3.67 (m, 2H), 3.32 - 3.38 (m, 2H), 2.52 - 2.59 (m, 2H), 2.32 - 2.42 (m, 2H), NH proton not observed. 33 MS m/z 377.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.69 (d, J = 1.9 Hz, 1H), 8.47 - 8.52 (m, 2H), 8.20 - 8.23 (m, 1H), 7.69 - 7.71 (m, 1H), 4.23 (s, 3H), 3.44 - 3.51 (m, 1H), 3.10 - 3.15 (m, 2H), 2.69 - 2.77 (m, 2H), 2.62 (s, 3H), 2.03 - 2.08 (m, 2H), 1.83 - 1.92 (m, 2H), NH proton not ed. 58 MS m/z 381.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.42 (s, 1H), 9.02 - 9.09 (br, 1H), 8.95 (s, 1H), 8.74 - 8.82 (br, 1H), 8.58 (dd, J = 13.0, 1.2 Hz, 1H), 8.30 - 8.37 (m, 1H), 8.07 (s, 1H), 3.77 - 3.84 (m, 1H), 3.43 - 3.49 (m, 2H), 3.14 - 3.24 (m, 2H), 2.51 (s, 3H), 2.33 - 2.39 (m, 2H), 2.17 - 2.27 (m, 2H). 59 MS m/z 408.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.35 (s, 1H), 8.94 - 9.01 (br, 1H), 8.65 - 8.75 (m, 2H), 8.26 (s, 1H), 7.82 (s, 1H), 4.64 (q, J = 7.3 Hz, 2H), 3.78 - 3.86 (m, 1H), 3.43 - 3.50 (m, 2H), 3.15 - 3.25 (m, 2H), 2.46 (s, 3H), 2.34 - 2.41 (m, 2H), 2.18 - 2.27 (m, 2H), 1.54 (t, J = 6.9 Hz, 3H). 60 MS m/z 377.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.23 (s, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 10.5, 1.5 Hz, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 3.88 - 3.93 (m, 1H), 3.68 - 3.61 (m, 2H), 3.32 - 3.39 (m, 2H), 2.78 (s, 3H), 2.65 (s, 3H), 2.54 - 2.60 (m, 2H), 2.34 - 2.43 (m, 2H), NH proton not observed. 61 MS m/z 431.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.61 (s, 1H), 9.02 (br, 1H), 8.98 (s, 1H), 8.72 (br, 1H), 8.63 (dd, J = 11.8, 2.0 Hz, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 3.77 - 3.83 (m, 1H), 3.42 - 3.49 (m, 2H), 3.15 - 3.24 (m, 2H), 2.47 (s, 3H), 2.33 - 2.39 (m, 2H), 2.16 - 2.27 (m, 2H).

Cpd Data 62 MS m/z 378.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.84 (s, 1H), 8.56 (dd, J = 11.6, 1.9 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 3.75 - 3.82 (m, 1H), 3.44 - 3.49 (m, 2H), 3.16 - 3.23 (m, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H), NH proton not observed. 63 MS m/z 377.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 14.98 (br, 1H), 9.05 (br, 1H), 8.87 (s, 1H), 8.77 (br, 1H), 8.60 (dd, J = 11.5, 1.9 Hz, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 3.77 - 3.83 (m, 1H), 3.44 - 3.49 (m, 2H), 3.16 - 3.23 (m, 2H), 2.85 (s, 3H), 2.70 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 64 MS m/z 377.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.89 - 8.92 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 10.7, 1.9 Hz, 1H), 8.37 - 8.42 (m, 2H), 3.85 - 3.91 (m, 1H), 3.61 - 3.67 (m, 2H), 3.35 - 3.39 (m, 2H), 3.05 (s, 3H), 2.53 - 2.60 (m, 5H), 2.33 - 2.44 (m, 2H), NH proton not observed. 65 MS m/z 377.3 [M+H]+; 1H NMR (DMSO-d6) δ: 8.95 (br, 1H), 8.90 (s, 1H), 8.59 - 8.66 (m, 2H), 8.26 (s, 1H), 7.53 (s, 1H), 6.60 (s, 1H), 3.77 - 3.83 (m, 1H), 3.44 - 3.49 (m, 2H), 3.16 - 3.23 (m, 2H), 2.77 (s, 3H), 2.48 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 66 MS m/z 378.3 ; 1H NMR (DMSO-d 6) δ: 9.17 (s, 1H), 9.08 (br, 1H), 8.82 (dd, J = 11.5, 1.9 Hz, 1H), 8.78 (s, 1H), 8.76 (br, 1H), 8.21 (s, 1H), 4.28 (s, 3H), 3.75 - 3.83 (m, 1H), 3.43 - 3.49 (m, 2H), 3.15 - 3.23 (m, 2H), 2.69 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 67 MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.17 (s, 1H), 8.79 - 8.86 (m, 2H), 8.64 (s, 1H), 8.58 (s, 1H), 8.52 (br, 1H), 4.31 (s, 3H), 3.77 - 3.83 (m, 1H), 3.44 - 3.51 (m, 2H), 3.15 - 3.23 (m, 2H), 2.89 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 68 MS m/z 382.0 [M+H]+; 1H NMR (methanol-d 4) δ: 8.68 (s, 1H), 8.27 (d, J = 13.0, 1H), 8.01 (s, 1H), 7.72 (d, J = 13.0, 1H), 3.58 - 3.67 (m, 1H), 3.26 - 3.30 (m, 2H), 2.87 - 2.96 (m, 2H), 2.72 (s, 3H), 2.20 - 2.28 (m, 2H), 2.05 - 2.16 (m, 2H), NH proton not observed.

Example 14 Preparation of Compound 57 Step A: 5-Bromo-1,2-difluoronitro-benzene (11.7 g, 49 mmol, prepared according to the procedure in Example 7, Step A) was combined with guanidine hydrochloride (23.5 g, 246 mmol), K2CO3 (34 g, 246 mmol) and DMSO (75 mL). The mixture was vigorously stirred at 120 °C for 30 min. The mixture was cooled to room temperature. To the mixture was added aqueous 7.5 N NaOH (100 mL). The mixture was d at 60 °C for 30 min. To the mixture was added AcOH (75 mL) and H2O (400 mL). The mixture was ed. The collected solid was dried to yield 7-bromofluorooxido-1,2,4-benzotriaziniumamine (9.6 g, 76%). MS m/z 259.1, 261.1 [M+H]+.

Step B: 7-Bromofluorooxido-1,2,4-benzotriaziniumamine (9.6 g, 37 mmol) was dissolved in TFA (66 mL). To the mixture was added NaNO2 (13.1 g, 190 mmol) in small portions at 0 °C. The mixture was stirred at room temperature for 20 min, and then cooled to 0 °C.

Ice water was slowly added to the mixture (20 mL). A solid formed and was collected, washed with H2O and dried. The solid was suspended in CH3CN, collected by filtration and dried to yield ofluorooxido-1,2,4-benzotriaziniumol (5.3 g, 55%). MS m/z 260.1, 262.1 [M+H]+.

Step C: 7-Bromofluorooxido-1,2,4-benzotriaziniumol (2.9 g, 11 mmol) was combined with POCl3 (30 mL, 320 mmol). The e was stirred at 110 °C for 2 h. The mixture was cooled to room temperature and then added to ice. The mixture was partitioned in CH2Cl2 and H2O. The organic layer was collected and loaded onto silica gel, eluting with 0-10% EtOAc in CH2Cl2 to yield 7-(2,7-dimethyl-2H-indazolyl)fluoro-N-methyl-N-(piperidin yl)benzo[e][1,2,4]triazinamine (490 mg, 16%). MS m/z 277.9, 279.9, 281.9 [M+H]+.

Step D: 7-Bromochlorofluorooxido-1,2,4-benzotriazinium (78 mg, 0.28 mmol) was combined with (2,8-dimethylimidazo[1,2-b]pyridazinyl)boronic acid (53 mg, 0.28 mmol, prepared according to the procedure in Example 11), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride romethane complex (11 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and aqueous 1 M K2CO3 (0.75 mL). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with 0- 100% EtOAc in CH2Cl2 to yield 7-bromo(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro- 1-(λ1-oxidanyl)-1λ4-benzo[e][1,2,4]triazine (69 mg, 63%). MS m/z 389.0, 391.0 [M+H]+.

Step E: 7-Bromo(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(λ1-oxidanyl)-1λ4- benzo[e][1,2,4]triazine (20 mg, 0.051 mmol) was combined with N-Boc-1,2,5,6- tetrahydropyridineboronic acid pinacol ester (19 mg, 0.062 mmol), 1,1'- phenylphosphino)ferrocene-palladium(II)dichloride dichloromethane x (4 mg, 0.005 mmol), 1,4-dioxane (1 mL) and aqueous 1 M K2CO3 (0.5 mL). The mixture was heated at 80 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 10-100% EtOAc in CH2Cl2 to yield tert-butyl 4-(3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(λ1- yl)-1λ4-benzo[e][1,2,4]triazinyl)-3,6-dihydropyridine-1(2H)-carboxylate (20 mg, 79%).

MS m/z 492.3 [M+H]+.

Step F: tert-Butyl 4-(3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(λ1-oxidanyl)-1λ4- benzo[e][1,2,4]triazinyl)-3,6-dihydropyridine-1(2H)-carboxylate (20 mg, 0.04 mmol) was combined with 10% Pd/C (5 mg) in MeOH (2 mL). The mixture was stirred under H2 (1 atm) for 2 h at 40 °C. The mixture was filtered over Celite. The filtrate was concentrated and chromatographed on a reversed phase C18 , eluting with 40-100% CH3CN in H2O to yield tert-butyl 4-(3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorobenzo[e][1,2,4]triazin yl)piperidinecarboxylate (17 mg, 87%). MS m/z 478.5 [M+H]+.

Step G: tert-Butyl 4-(3-(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluorobenzo[e][1,2,4]triazinyl)piperidinecarboxylate (17 mg, 0.036 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol HCl). The volatiles were removed from the mixture after min. The residue was suspended in CH3CN. The solid was collected and dried to yield - ylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)benzo[e][1,2,4]triazine hydrochloride (8 mg, 54%). 1H NMR nol-d 4) δ: 8.89 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 1.3 Hz, 1H), 8.08 (dd, J = 10.6, 1.7 Hz, 1H), 3.61 - 3.67 (m, 2H), 3.35 - 3.43 (m, 1H), 3.25 - 3.33 (m, 2H), 2.92 (s, 3H), 2.73 (s, 3H), 2.32 - 2.38 (m, 2H), 2.09 - 2.19 (m, 2H), NH protons not observed.

Using the procedure described for Example 14, above, additional compounds described herein were prepared by substituting the appropriate aryl boronic acid in Step D, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 40 MS m/z 377.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.84 - 8.86 (m, 1H), 8.64 - 8.67 (m, 1H), 8.25 (dd, J = 11.0, 1.9 Hz, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 3.63 - 3.70 (m, 1H), 3.32 - 3.38 (m, 2H), 2.94 - 3.02 (m, 2H), 2.66 (s, 3H), 2.48 (s, 3H), 2.25 - 2.32 (m, 2H), 2.10 - 2.19 (m, 2H), NH proton not observed. 41 Starting material: 2-aminobromofluorobenzoic acid MS m/z 381.4 [M+H]+; 1H NMR d 6) δ: 8.89 (d, J = 1.6 Hz, 1H), 8.65 - 8.68 (m, 1H), 8.25 (dd, J = 10.8, 1.9 Hz, 1H), 7.83 (dd, J = 2.8, 0.6 Hz, 1H), 7.70 (dd, J = 12.0, 1.6 Hz, 1H), 3.60 - 3.68 (m, 1H), 3.27 - 3.32 (m, 2H), 2.89 - 2.97 (m, 2H), 2.48 (s, 3H), 2.21 - 2.29 (m, 2H), 2.06 - 2.16 (m, 2H), NH proton not observed.

Example 15 Preparation of Compound 4 Step A: ochlorofluorooxido-1,2,4-benzotriazinium (60 mg, 0.22 mmol, prepared according to the procedure in Example 14, Step C) was combined with Cs2CO3 (104 mg, 0.32 mmol) and 1-Bocmethylaminopiperidine (56 mg, 0.26 mmol) in DMF (2 mL). The e was stirred at 60 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, ed and concentrated. The residue was chromatographed on silica gel, eluting with 10-80% EtOAc in CH2Cl2 to 7-bromo((1-(tertbutoxycarbonyl )piperidinyl)(methyl)amino)fluorobenzo[e][1,2,4]triazine 1-oxide (64 mg, 65%). MS m/z 356.2, 358.2 [M+H-Boc]+.

Step B: 7-bromo((1-(tert-butoxycarbonyl)piperidinyl)(methyl)amino) fluorobenzo[e][1,2,4]triazine 1-oxide (64 mg, 0.14 mmol) and 2,7-dimethyl(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)indazole (46 mg, 0.17 mmol) were combined with 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.05 equiv., 0.007 mmol) and 1,4-dioxane (1 mL). To the mixture was added aqueous 1 M K2CO3 (0.5 mL).

The mixture was stirred at 80 °C for 2 h. The mixture was partitioned between EtOAc and H2O.

The organic layer was concentrated. The residue was chromatographed on silica gel, g with -90% EtOAc in CH2Cl2 to yield (tert-butoxycarbonyl)piperidinyl)(methyl)amino) (2,7-dimethyl-2H-indazolyl)fluorobenzo[e][1,2,4]triazine 1-oxide (74 mg, 100%). MS m/z 522.4 [M+H]+.

Step C: 3-((1-(tert-butoxycarbonyl)piperidinyl)(methyl)amino)(2,7-dimethyl-2H-indazol yl)fluorobenzo[e][1,2,4]triazine e (74 mg, 0.14 mmol) was combined with 10% Pd/C (20 mg) in MeOH (2 mL). The mixture was stirred under H2 (1 atm) at rt for 1 h. The e was filtered over . The filtrate was concentrated to yield tert-butyl 4-[[7-(2,7-dimethylindazol yl)fluoro-1,2,4-benzotriazinyl]-methyl-amino]piperidinecarboxylate (70 mg, 97%). MS m/z 506.3 [M+H]+.

Step D: tert-Butyl 4-[[7-(2,7-dimethylindazolyl)fluoro-1,2,4-benzotriazinyl]-methylamino ]piperidinecarboxylate (70 mg, 0.14 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol HCl). The mixture was stirred at room temperature for 1 h. The volatiles were removed from the reaction mixture with a stream of N2. The residue was partitioned in CH2Cl2 and aqueous 1 M K2CO3. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 7-(2,7-dimethyl-2H- indazolyl)fluoro-N-methyl-N-(piperidinyl)benzo[e][1,2,4]triazinamine (43 mg, 77%).

MS m/z 406.4 [M+H]+; 1H NMR (DMSO-d6) δ: 8.42 (s, 1H), 8.37 (s, 1H), 8.15 - 8.19 (m, 1H), 8.04 - 8.07 (m, 1H), 7.60 (s, 1H), 4.24 - 4.30 (m, 1H), 4.21 (s, 3H), 3.22 (br s, 3H), 3.06 - 3.11 (m, 2H), 2.61 - 2.66 (m, 2H), 2.60 (s, 3H), 1.72 - 1.81 (m, 2H), 1.64 - 1.70 (m, 2H), NH proton not observed.

Example 17 Preparation of Compound 50 Step A: 6-Bromochlorofluoro-quinoline (260 mg, 1.0 mmol) was combined with 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (80 mg, 0.10 mmol) and 1,4-dioxane (4 mL). To the mixture was added a solution of butoxycarbonylpiperidinylzinc iodide in N,N-dimethylacetamide (2 mL, 2 mmol, prepared according to the procedure in Example 5, Step B) at room temperature. The mixture was stirred at 70 °C for 1 h. The volatiles were d from the mixture with a stream of N2. The residue was tographed on silica gel, eluting with 0-30% EtOAc in hexanes to yield tert-butyl 4-(6- bromofluoroquinolyl)piperidinecarboxylate (235 mg, 58%). 1H NMR (DMSO-d 6) δ: 8.36 (dd, J = 8.8, 1.6 Hz, 1H), 8.10 - 8.14 (m, 1H), 7.85 (dd, J = 10.3, 2.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 4.04 - 4.16 (m, 2H), 3.07 - 3.14 (m, 1H), 2.89 (br s, 2H), 1.88 - 1.96 (m, 2H), 1.64 - 1.74 (m, 2H), 1.44 (s, 9H).

Step B: tert-Butyl 4-(6-bromofluoroquinolyl)piperidinecarboxylate (40 mg, 0.10 mmol) was combined with (8-fluoromethyl-imidazo[1,2-a]pyridinyl)boronic acid (40 mg, 0.21 mmol), is(diphenylphosphino)ferrocene-palladium(II)dichloride romethane complex (4 mg, 0.005 mmol), 1,4-dioxane (1.5 mL) and aqueous 1 M K2CO3 (0.75 mL). The mixture was stirred at 80 °C for 1 h. The e was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-80% EtOAc in CH2Cl2 to yield tert-butyl 4-[8- fluoro(8-fluoromethyl-imidazo[1,2-a]pyridinyl)quinolyl]piperidinecarboxylate (45 mg, 96%). MS m/z 479.4 [M+H]+.

Step C: utyl 4-[8-fluoro(8-fluoromethyl-imidazo[1,2-a]pyridinyl) quinolyl]piperidinecarboxylate (45 mg, 0.09 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol HCl). The volatiles were removed from the reaction mixture after 30 min. The residue was partitioned between CH2Cl2 and s 1 M K2CO3. The organic layer was concentrated and chromatographed on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2.

The collected material was dissolved in 1.25 M HCl in MeOH. The volatiles were removed to yield 8-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)quinoline hydrochloride (35 mg, 90%).

MS m/z 379.3 [M+H]+; 1H NMR (DMSO-d6) δ: 9.36 - 9.39 (m, 1H), 9.16 (br, 1H), 8.88 (br, 1H), 8.46 - 8.50 (m, 1H), 8.41 (d, J = 11.8 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.13 (dd, J = 12.1, 1.9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 3.39 - 3.46 (m, 2H), 3.27 - 3.35 (m, 1H), 3.03 - 3.12 (m, 2H), 2.54 (s, 3H), 2.04 - 2.18 (m, 4H).

Using the procedure described for Example 17, above, additional nds described herein were prepared by substituting the indicated starting material in Step A, the appropriate boronic acid Step B, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Starting Material and Data 29 Starting al: 7-bromochloroquinoline MS m/z 357.4 [M+H]+; 1 H NMR (DMSO-d6) δ: 9.26 (d, J = 2.5 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.43 (s, 1H), 8.01 - 8.03 (m, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.81 - 7.83 (m, 1H), 7.53 - 7.58 (m, 2H), 4.22 (s, 3H), 3.06 - 3.11 (m, 2H), 2.79 - 2.86 (m, 1H), 2.63 - 2.69 (m, 2H), 2.61 (s, 3H), 1.80 - 1.86 (m, 2H), 1.59 - 1.69 (m, 2H), NH proton not observed.

Cpd Starting Material and Data 45 Starting material: 6-bromochlorofluoro-quinoline MS m/z 376.1 [M+H]+; 1H NMR (methanol-d 4) δ: 8.63 - 8.68 (m, 2H), 8.48 (s, 1H), 8.38 (s, 1H), 8.35 (d, J = 11.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 3.60 - 3.65 (m, 2H), 3.46 - 3.50 (m, 1H), 3.25 - 3.33 (m, 2H), 2.86 (s, 3H), 2.70 (s, 3H), 2.27 - 2.33 (m, 4H), NH proton not observed. 49 Starting material: 6-bromochlorofluoro-quinoline MS m/z 391.4 [M+H]+; 1H NMR d 6) δ: 9.11 (br, 1H), 8.77 (br, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.17 - 8.20 (m, 1H), 8.05 (dd, J = 12.7, 2.1, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.06 - 7.08 (m, 1H), 4.18 (s, 3H), 4.05 (s, 3H), 3.39 - 3.45 (m, 2H), 3.24 - 3.31 (m, 1H), 3.02 - 3.12 (m, 2H), 2.04 - 2.18 (m, Example 18 Preparation of Compound 51 Step A: 8-Bromochloromethyl-imidazo[1,2-b]pyridazine (250 mg, 1.01 mmol) was combined with Cs2CO3 (700 mg, 2.15 mmol) in CH3CN (5 mL). To the mixture was added MeOH (0.2 mL). The mixture was stirred at room ature for 4 h. The volatiles were removed from the on mixture. The residue was partitioned between EtOAc and H2O. The organic layer was collected, concentrated and chromatographed on silica gel, eluting with 20- 100% EtOAc in hexanes to yield 6-chloromethoxymethyl-imidazo[1,2-b]pyridazine (180 mg, 90%). MS m/z 198.2, 202.2 [M+H]+.

Step B: 6-Chloromethoxymethyl-imidazo[1,2-b]pyridazine (39 mg, 0.20 mmol) was combined with KOAc (59 mg, 0.60 mmol), is(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane x (8 mg, 0.01 mmol), and bis(pinacolato)diboron (63 mg, 0.25 mmol) in 1,4-dioxane (1 mL). The mixture was stirred under N2 at 95 °C for 1 h. To the e was added aqueous 1 M K2CO3 (0.75 mL), tert-butyl 4-(6-bromofluoro quinolyl)piperidinecarboxylate (40 mg, 0.10 mmol, obtained in Example 17, Step A) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4 mg, 0.005 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-80% EtOAc in CH2Cl2 to yield tertbutyl 4-[8-fluoro(8-methoxymethyl-imidazo[1,2-b]pyridazinyl)quinolyl]piperidine carboxylate (38 mg, 79%). MS m/z 492.4 [M+H]+.

Step C: tert-Butyl luoro(8-methoxymethyl-imidazo[1,2-b]pyridazinyl) quinolyl]piperidinecarboxylate (38 mg, 0.08 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol HCl). The volatiles were removed from the reaction mixture with a stream of N2 after 30 min. The residue was ded in CH3CN, collected by filtration and dried to yield 8- fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidinyl)quinoline hydrochloride (26 mg, 79%).

MS m/z 392.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.22 (br, 1H), 8.95 (br, 1H), 8.77 - 8.80 (m, 1H), 8.60 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H), 8.37 (dd, J = 12.0, 2.0 Hz, 1H), 7.99 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 4.35 (s, 3H), 3.39 - 3.45 (m, 2H), 3.29 - 3.37 (m, 1H), 3.02 - 3.12 (m, 2H), 2.53 (s, 3H), 2.06 - 2.20 (m, 4H).

Using the procedure bed for Example 18, above, additional compounds described herein were prepared by substituting the appropriate reagent in Step A, suitable ts and reaction conditions, obtaining compounds such as those ed from: Cpd Data 53 MS m/z 436.3 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.97 (br, 1H), 8.71 (br, 1H), 8.68 (s, 1H), 8.57 (d, J = 8.6 Hz, 1H), 8.28 - 8.35 (m, 2H), 7.76 (br s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 4.70 - 4.74 (m, 2H), 3.84 - 3.88 (m, 2H), 3.42 - 3.47 (m, 2H), 3.39 (s, 3H), 3.29 - 3.37 (m, 1H), 3.05 - 3.14 (m, 2H), 2.48 (s, 3H), 2.06 - 2.20 (m, 4H). 54 MS m/z 435.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.59 - 8.64 (m, 2H), 8.30 (dd, J = 12.0, 1.7 Hz, 1H), 8.18 (d, J = 1.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 3.78 - 3.84 (m, 4H), 3.60 - 3.65 (m, 2H), 3.49 (s, 3H), 3.43 - 3.49 (m, 1H), 3.24 - 3.31 (m, 2H), 2.64 (s, 3H), 2.24 - 2.36 (m, 4H), NH s not observed.

Example 19 Preparation of Compound 70 7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro(4-piperidyl)-1,2,4-benzotriazine dihydrochloride (36 mg, 0.08 mmol, prepared according to the procedure in Example 13) was combined with 1,2-dichloroethane (1 mL), EtOH (0.2 mL) and triethylamine (22 uL, 0.16 mmol).

To the mixture was added acetaldehyde (18 µL, 0.32 mmol). The mixture became homogeneous.

The mixture was stirred for 5 min. To the mixture was added sodium toxyborohydride (36 mg, 0.16 mmol). After 20 min of stirring at room temperature, the mixture was loaded directly to silica gel and chromatographed, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to afford 7-(2,8- dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)fluorobenzo[e][1,2,4]triazine (32 mg, 84%) as a yellow powder.

MS m/z 406.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.06 (s, 1H), 8.62 (dd, J = 10.9 Hz, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 3.69 - 3.77 (m, 1H), 3.48 - 3.56 (m, 2H), 2.98 (q, J = 7.2 Hz, 2H), 2.84 - 2.92 (m, 2H), 2.75 (s, 3H), 2.54 (s, 3H), 2.45 - 2.52 (m, 2H), 2.32 - 2.42 (m, 2H), 1.34 (t, J = 7.3 Hz, 3H).

Using the reductive ion procedure described for Example 19, above, additional compounds bed herein were prepared by substituting the indicated starting materials, aldehyde, le reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Starting Material and Data 2 Starting material: 2-(2-methyl-2H-indazolyl)(piperidinyl)quinoline (prepared according to the procedure in Example 6) and acetaldehyde MS m/z 371.1 [M+H]+; 1H NMR (methanol-d4) δ: 8.99 (br s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.34 - 8.40 (m, 2H), 8.15 - 8.20 (m, 1H), 8.04 - 8.10 (m, 2H), 7.19 (d, J = 9.5 Hz, 1H), 4.33 (s, 3H), 3.76 - 3.82 (m, 2H), 3.49 - 3.56 (m, 1H), 3.26 (q, J = 7.5 Hz, 2H), 3.19 - 3.24 (m, 2H), 2.31 - 2.36 (m, 2H), 2.18 - 2.23 (m, 2H), 1.44 (t, J = 7.5 Hz, 6 ng material: 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)quinoline (prepared according to the ure in e 17) and formaldehyde MS m/z 357.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.95 (br s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 8.44 - 8.50 (m, 2H), 8.24 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.76 - 7.78 (m, 2H), 4.22 (s, 3H), 4.00 - 4.07 (m, 2H), 3.22 - 3.28 (m, 1H), 3.14 - 3.20 (m, 2H), 2.81 (s, 3H), 2.27 - 2.33 (m, 4H). 9 Starting material: 6-(2-methyl-2H-indazolyl)(piperidinyl)quinoline (prepared according to the procedure in Example 2) and acetaldehyde MS m/z 371.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.11 (d, J = 8.5 Hz, 1H), 8.58 - 8.64 (m, 2H), 8.48 - 8.54 (m, 2H), 8.23 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.74 - 7.78 (m, 2H), 4.23 (s, 3H), 3.75 - 3.80 (m, 1H), 3.63 - 3.67 (m, 2H), 3.08 - 3.18 (m, 4H), 2.32 - 2.46 (m, 4H), 1.32 (t, J = 7.5 Hz, 3H). 47 Starting material: 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)quinoline (prepared according to the procedure in e 17) and formaldehyde MS m/z 390.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.67 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.27 (d, J = 12.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 3.54 - 3.57 (m, 1H), 3.14 - 3.25 (m, 4H), 2.80 (s, 3H), 2.76 (s, 3H), 2.58 (s, 3H), 2.20 - 2.25 (m, 4H). 48 Starting material: 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)quinoline (prepared according to the procedure in Example 17) and acetaldehyde MS m/z 404.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.67 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.27 (d, J = 12.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 3.60 - 3.64 (m, 1H), 3.27 - 3.32 (m, 2H), 3.07 - 3.16 (m, 4H), 2.77 (s, 3H), 2.59 (s, 3H), 2.22 - 2.26 (m, 4H), 1.30 (t, J = 7.5 Hz, 3H).

Cpd Starting Material and Data 69 Starting material: 7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro(4- piperidyl)-1,2,4-benzotriazine (prepared according to the procedure in Example 13) and formaldehyde MS m/z 392.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.27 (s, 1H), 8.70 (dd, J = 11.0, 1.7 Hz, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 3.70 - 3.77 (m, 1H), 3.59 - 3.65 (m, 2H), 3.21 - 3.30 (m, 2H), 2.84 (d, J = 4.7 Hz, 3H), 2.76 (s, 3H), 2.56 (s, 3H), 2.41 - 2.47 (m, 2H), 2.25 - 2.35 (m, 2H). 75 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)cinnoline (prepared according to the procedure in Example 7) and 1,4-dioxane- 2,5-diol MS m/z 421.5 [M+H]+; 1H NMR (methanol-d4) δ: : 9.17 (s, 1H), 8.61 (d, J = 1.0 Hz, 1H), 8.42 - 8.47 (m, 2H), 8.35 (s, 1H), 3.98 - 4.01 (m, 2H), 3.88 - 3.94 (m, 2H), 3.63 - 3.70 (m, 1H), 3.35 - 3.42 (m, 4H), 2.88 (s, 3H), 2.71 (s, 3H), 2.44 - 2.52 (m, 4H), OH proton not observed. 76 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)cinnoline and dehyde (prepared according to the procedure in Example 7) MS m/z 405.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.17 (s, 1H), 8.60 (d, J = 1.0 Hz, 1H), 8.42 - 8.47 (m, 2H), 8.35 (s, 1H), 3.81 - 3.87 (m, 2H), 3.63 - 3.70 (m, 1H), 3.25 - 3.38 (m, 4H), 2.88 (s, 3H), 2.71 (s, 3H), 2.38 - 2.52 (m, 4H), 1.47 (t, J = 7.4 Hz, 3H). 77 ng al: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)cinnoline dihydrochloride (prepared according to the procedure in Example 7) MS m/z 419.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.02 (s, 1H), 8.32 (dd, J = 11.0, 1.3 Hz, 1H), 8.15 (s, 1H), 8.14 (d, J = 0.6 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 3.10 - 3.22 (m, 3H), 2.94 - 3.07 (m, 2H), 2.65 (d, J = 0.9 Hz, 3H), 2.43 (d, J = 0.6 Hz, 3H), 2.02 - 2.14 (m, 4H), 1.52 - 1.61 (m, 2H), 1.12 - 1.18 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), HCl protons not observed. 79 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- innoline dihydrochloride (prepared according to the procedure in Example 7) MS m/z 391.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.05 (s, 1H), 8.36 (dd, J = 10.9, 1.4 Hz, 1H), 8.19 (s, 1H), 8.15 (d, J = 0.6 Hz, 1H), 8.07 (d, J = 0.9 Hz, 1H), 3.36 - 3.48 (m, 3H), 2.80 - 2.94 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.44 (d, J = 0.6 Hz, 3H), 2.18 - 2.28 (m, 4H), HCl protons not ed. 85 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidin yl)cinnoline (prepared according to the ure in Example 7) MS m/z 387.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.01 (s, 1H), 8.57 (dd, J = 9, 1.5 Hz, 1H), 8.13 (m, 2H), 8.00 (s, 1H), 7.85 (s, 1H), 3.26 - 3.33 (m, 3H), 2.74 (s, 3H), 2.65 (q, J = 7.5 Hz, 2H), 2.52 (s, 3H), 2.35 - 2.41 (m, 2H), 2.20 - 2.24 (m, 2H), 2.06 - 2.18 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H).

Cpd ng Material and Data 100 ng material: 5-fluoro(2-methylimidazo[1,2-b]pyridazinyl)(piperidin yl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 391.5 [M+H]+; 1H NMR nol-d 4) δ: 9.14 (s, 1H), 8.58 (d, J = 9.5 Hz, 1H), 8.43 - 8.48 (m, 2H), 8.40 (s, 1H), 8.32 (s, 1H), 3.82 - 3.86 (m, 2H), 3.61 - 3.68 (m, 1H), 3.24 - 3.33 (m, 4H), 2.67 (s, 3H), 2.38 - 2.52 (m, 4H), 1.46 (t, J = 7.6 Hz, 3H), HCl protons not observed. 102 Starting material: 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl) (piperidinyl)cinnoline hydrochloride (prepared according to the procedure in Example 29) MS m/z 408.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.28 (d, J = 1.2 Hz, 1H), 8.78 (s, 1H), 8.47 (dd, J = 11.0, 1.2 Hz, 1H), 8.33 (s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.12 (dd, J = 10.5, 1.7 Hz, 1H), 3.84 (br d, J = 12.5 Hz, 2H), 3.61 - 3.69 (m, 1H), 3.24 - 3.35 (m, 4H), 2.66 (d, J = 0.9 Hz, 3H), 2.38 - 2.51 (m, 4H), 1.46 (t, J = 7.3 Hz, 3H), HCl protons not observed. 110 Starting material: 6-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidin yl)quinoxaline hydrochloride (prepared according to the procedure in Example 38) MS m/z 405.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.88 (s, 1H), 8.26 (d, J = 0.9 Hz, 1H), 8.03 (dd, J = 11.3, 1.8 Hz, 1H), 7.81 (s, 1H), 7.57 (d, J = 1.2 Hz, 1H), 3.17 (d, J = 11.3 Hz, 2H), 3.06 (spt, J = 4.9 Hz, 1H), 2.59-2.61 (m, 1H), 2.60 (s, 2H), 2.54 (q, J = 7.3 Hz, 2H), 2.60 (s, 3H), 2.21 (td, J = 11.3, 3.7 Hz, 2H), 2.03-2.12 (m, 4H), 1.18 (t, J = 7.3 Hz, 3H). 111 Starting material: 5-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl) (piperidinyl)cinnoline dihydrochloride (prepared ing to the procedure in Example 29) MS m/z 421.0 [M+H]+; 1H NMR (chloroform-d) δ: 8.80 (s, 1H), 8.21 (d, J = 12 Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.00 (s, 1H), 4.23 (s, 3H), 3.37 - 3.42 (m, 1H), 3.21 (d, J = 11.3 Hz, 2H), 2.52 - 2.55 (m, 5H), 2.19 - 2.25 (m, 4H), 2.01 - 2.09 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). 113 Starting material: (6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinyl)methanol dihydrochloride (prepared ing to the procedure in Example 29) MS m/z 421.5 ; 1H NMR (methanol-d 4) δ: 9.13 (s, 1H), 8.61 (s, 1H), 8.46 (d, J = 0.9 Hz, 1H), 8.43 (dd, J = 10.6, 1.3 Hz, 1H), 8.33 (s, 1H), 5.17 (d, J = 1.1 Hz, 2H), 3.82 (br d, J = 12.2 Hz, 2H), 3.61 - 3.70 (m, 1H), 3.23 - 3.30 (m, 4H), 2.69 (s, 3H), 2.39 - 2.50 (m, 4H), 1.45 (t, J = 7.3 Hz, 3H), HCl and OH protons not observed.

Cpd Starting Material and Data 114 Starting material: 6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinecarbonitrile dihydrochloride (prepared according to the procedure in Example 29) MS m/z 416.0 ; 1H NMR (chloroform-d) δ: 8.53 (s, 1H), 8.23 (dd, J = 10.8, 1.5 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 0.4 Hz, 1H), 7.95 (s, 1H), 3.36 - 3.43 (m, 1H), 3.19 (br d, J = 11 Hz, 2H), 2.64 (s, 3H), 2.52 - 2.54 (m, 2H), 2.21 - 2.23 (m, 4H), 1.98 - 2.08 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). 115 Starting material: yclopropylmethylimidazo[1,2-b]pyridazinyl)fluoro- 3-(piperidinyl)cinnoline (prepared according to the procedure in Example 29) MS m/z 431.1 ; 1H NMR (chloroform-d) δ: 8.78 (s, 1H), 8.19 (d, J = 12 Hz, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 3.28 - 3.42 (m, 1H), 3.29 (br d, J = 12 Hz, 2H), 2.60 - 2.72 (m, 3H), 2.56 (s, 3H), 2.24 - 2.27 (m, 2H), 2.09 - 2.13 (m, 4H), 1.33 - 1.37 (m, 2H), 1.19 - 1.25 (m, 5H). 119 Starting material: 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)fluoro(piperidin yl)cinnoline (prepared according to the procedure in Example 41) MS m/z 405.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.86 (s, 1H), 8.56 (s, 1H), 8.21 (m, 3H), 4.59 (s, 1H), 3.28 (s, 2H), 2.90 (s, 3H), 2.65 (dd, J = 14.4, 7.1 Hz, 2H), 2.48 (s, 3H), 2.39 (t, J = 11.8 Hz, 2H), 2.27 - 2.06 (m, 4H), 1.23 (t, J = 7.2 Hz, 3H). 120 ng material: 6-(5-fluoro(piperidinyl)cinnolinyl)-2,4- dimethylbenzo[d]thiazole (prepared according to the procedure in Example 29) MS m/z 421.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.58 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.90 (s, 1H), 7.71 (dd, J = 10.6, 1.2 Hz, 1H), 7.63 (d, J = 0.8 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.20 (d, J = 11.2 Hz, 2H), 2.89 (s, 3H), 2.83 (s, 3H), 2.51 - 2.56 (m, 2H), 2.08 - 2.24 (m, 4H), 2.01 - 2.05 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). 121 Starting material: 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro (piperidinyl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 419.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.18 (s, 1H), 8.54 (s, 1H), 8.40 - 8.50 (m, 2H), 8.33 (s, 1H), 3.84 (br d, J = 12.5 Hz, 2H), 3.61 - 3.70 (m, 1H), 3.16 - 3.31 (m, 6H), 2.71 (s, 3H), 2.38 - 2.52 (m, 4H), 1.58 (t, J = 7.6 Hz, 3H), 1.46 (t, J = 7.6 Hz, 3H), HCl protons not observed. 122 Starting al: 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro (piperidinyl)cinnoline dihydrochloride red according to the procedure in Example 29) MS m/z 405.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.16 (s, 1H), 8.47 (s, 1H), 8.45 (d, J = 10.4 Hz, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 3.75 - 3.80 (m, 2H), 3.59 - 3.69 (m, 1H), 3.32 - 3.38 (m, 2H), 3.23 (q, J = 7.5 Hz, 2H), 3.02 (s, 3H), 2.69 (s, 3H), 2.37 - 2.49 (m, 4H), 1.57 (t, J = 7.5 Hz, 3H) HCl protons not observed.

Cpd Starting Material and Data 123 Starting material: 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro idinyl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 435.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.17 (s, 1H), 8.50 (s, 1H), 8.45 (d, J = 10.7 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 3.98 - 4.02 (m, 2H), 3.88 - 3.94 (m, 2H), 3.62 - 3.68 (m, 1H), 3.35 - 3.42 (m, 4H), 3.23 (q, J = 7.5 Hz, 2H), 2.70 (s, 3H), 2.44 - 2.51 (m, 4H), 1.58 (t, J = 7.5 Hz, 3H), HCl and OH protons not observed. 124 Starting material: rac(2,8-dimethylimidazo[1,2-b]pyridazinyl)((2R,6R)-2,6- dimethylpiperidinyl)fluorocinnoline dihydrochloride (prepared ing to the procedure in Example 7) MS m/z 419.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.92 (s, 1H), 8.32 (d, J = 10 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.76 (tt, J = 12.5, 3.5 Hz, 1H), 3.43 (m, 1H), 3.00 (m, 1H), 2.73 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 2.30 - 2.36 (dd, J = 13, 5 Hz, 1H), 2.05 - 2.15 (m, 2H), 1.8 (q, J = 12.5 Hz, 1H), 1.32 (d, J = 7 Hz, 3H), 1.23 (d, J = 6 Hz, 3H). 125 Starting material: rac(2,8-dimethylimidazo[1,2-b]pyridazinyl)((2R,6R)-2,6- ylpiperidinyl)fluorocinnoline hydrochloride (prepared ing to the procedure in Example 7) MS m/z 433.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.91 (s, 1H), 8.31 (d, J = 11 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 3.65 - 3.80 (m, 2H), 3.13 - 3.27 (m, 2H), 2.73 (s, 3H), 2.64 (m, 1H), 2.51 (s, 3H), 2.31 (m, 1H), 2.13 (t, J = 13.5 Hz, 2H), 1.90 (q, J = 12.5 Hz, 1H), 1.34 (d, J = 6.5 Hz, 3H), 1.21 - 1.30 (m, 6H). 131 Starting material: rac((2R,6R)-2,6-diethylpiperidinyl)(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline (prepared according to the procedure in Example 7) MS m/z 447.6 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (s, 1H), 8.33 (d, J = 11 Hz, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 3.71 (m, 1H), 3.32 (m, 1H), 3.18 (br s, 1H), 2.73 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H), 2.28 - 2.35 (m, 1H), .23 (m, 2H), 1.80 - 2.00 (m, 4H), 1.51 (m, 1H), 1.08 (t, J = 7.5 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H). 132 Starting material: 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridinyl)fluoro idinyl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 405.2 [M+H]+; 1H NMR (chloroform-d) δ: 9.30 (s, 1H), 8.50 (d, J = 12 Hz, 1H), 7.99 (s, 1H), 7.37 (s, 1H), 3.37 (t, J = 13.2, 1H), 3.20 (d, J = 11.2, 2H), 2.93 (s, 3H), 2.69 (s, 3H), 2.56 - 2.51 (m, 2H), 2.22 - 2.04 (m, 6H), 1.17 (t, J = 8 Hz, 3H), NH proton not observed.

Cpd Starting Material and Data 135 Starting material: 5-(5-fluoro(piperidinyl)cinnolinyl)-2,7- dimethylthiazolo[5,4-b]pyridine dihydrochloride (prepared ing to the ure in Example 29) MS m/z 422.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.90 (s, 1H), 8.34 (dd, J = 11, 1.2 Hz, 1H), 7.93 (s, 2H), 3.42 (m, 1H), 3.33 (d, J = 12.4 Hz, 2H), 2.90 (s, 3H), 2.84 (s, 3H), 2.65 - 2.71 (m, 2H), 2.37 - 2.39 (m, 2H), 2.24 - 2.29 (m, 2H), 2.13 - 2.20 (m, 2H), 1.23 (t, J = 7.4 Hz, 3H). 136 Starting material: 2-(5-fluoro(piperidinyl)cinnolinyl)-4,6- dimethyloxazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure in Example 29) MS m/z 406.2 [M+H]+; 1H NMR (methanol-d 4) δ: 9.11 (s, 1H), 8.35 (dd, J = 9.9, 1.2 Hz, 1H), 8.25 (s, 1H), 7.57 (s, 1H), 3.41 - 3.56 (m, 1H), 3.28 - 3.25 (m, 2H), 2.86 (s, 3H), 2.69 (s, 3H), 2.61 (q, J = 7.2 Hz, 2H), 2.34 (td, J = 11.6, 2.1 Hz, 2H), 2.24 - 2.10 (m, 4H), 1.22 (t, J = 7.3 Hz, 3H). 147 Starting material: 2-(5-fluoro(piperidinyl)cinnolinyl)-4,6- dimethylthiazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure in Example 29) MS m/z 422.3 ; 1H NMR (chloroform-d) δ: 8.89 (s, 1H), 8.32 (dd, J = 10,1.2 Hz, 1H), 7.94 (s, 1H), 7.59 (s, 1H), 3.40 (m, 1H), 3.22 (d, J = 12.4 Hz, 2H), 3.04 (s, 3H), 2.68 (s, 3H), 2.54 - 2.57 (m, 2H), 2.21 - 2.25 (br s, 4H), 2.04 - 2.11 (m, 2H), 1.18 (t, J = 14.4 Hz, 3H). 152 Starting material: 5-(5-fluoro(piperidinyl)cinnolinyl)-2,7- dimethyloxazolo[5,4-b]pyridine dihydrochloride (prepared according to the procedure in Example 29) MS m/z 406.2 [M+H]+; 1H NMR (chloroform-d) δ: 8.89 (s, 1H), 8.29 (dd, J = 10.6, 1.6 Hz, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 3.35 - 3.39 (m, 1H), 3.21 (d, J = 10.4 Hz, 2H), 2.70 (s, 6H), 2.55 (d, J = 6.8 Hz, 2H), 2.18 - 2.21 (m, 4H), 2.03 - 2.07 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H). 155 Starting material: rac(2,8-dimethylimidazo[1,2-b]pyridazinyl)((2R,6R)-2,6- dimethylpiperidinyl)fluorocinnoline hydrochloride (prepared ing to the procedure in Example 7) MS m/z 449.5 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.96 (s, 1H), 8.26 (d, J = 11.5 Hz, 1H), 8.06 (m, 2H), 7.88 (s, 1H), 3.68 (m, 1H), 3.52 (t, J = 6.5 Hz, 2H), 3.43 (m, 1H), 3.09 (br s, 1H), 2.83 (m, 1H), 2.60 - 2.70 (m, 4H), 2.47 (s, 3H), 2.22 (td, J = 12.5, 5.5 Hz, 1H), 1.98 (d, J = 12 Hz, 1H), 1.90 (d, J = 11.5 Hz, 1H), 1.70 (q, J = 12.5 Hz, 1H), 1.26 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H), OH proton not observed.

Cpd Starting Material and Data 161 Starting material: -dimethylimidazo[1,2-b]pyridazinyl)((2S,4r,6R)-2,6- dimethylpiperidinyl)fluorocinnoline dihydrochloride (prepared according to the procedure in Example 7) MS m/z 419.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.92 (s, 1H), 8.32 (d, J = 11 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.51 (m, 1H), 2.8 (br s, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 2.52 (s, 3H), 2.20 (d, J = 11.5 Hz, 2H), 1.96 (q, J = 12.5 Hz, 2H), 1.37 (d, J = 6.5 Hz, 6H). 164 Starting material: 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro (piperidinyl)cinnoline dihydrochloride (prepared according to the ure in Example 29) MS m/z 405.2 [M+H]+; 1H NMR (chloroform-d) δ: 8.88 (s, 1H), 8.38 (dd, J = 10.8, 1.2 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.78 (d, J = 0.8 Hz, 1H), 4.32 (s, 3H), 3.32 - 3.44 (m, 3H), 2.86 (s, 3H), 2.66 - 2.71 (m, 2H), 2.25 - 2.29 (m, 4H), 2.20 (s, 3H), 1.25 - 1.29 (m, 2H). 173 Starting material: ro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridinyl)- 3-(piperidinyl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 421.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.84 (s, 1H), 8.37 (dd, J = 10.8, 1.2 Hz, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.29 (s, 1H), 4.29 (s, 3H), 4.22 (s, 3H), 3.34 - 3.41 (m, 1H), 3.20 (br d, J = 12 Hz, 2H), 2.50 - 2.55 (m, 2H), 2.17 - 2.23 (m, 4H), 1.98 - 2.08 (m, 2H) 1.21 (t, J = 6.4 Hz, 3H). 174 ng material: 7-(7-ethylmethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro (piperidinyl)cinnoline (prepared according to the procedure in Example 29) MS m/z 419.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.89 (s, 1H), 8.38 (dd, J = 10.9, 1.3 Hz, 1H), 8.24 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 4.31 (s, 3H), 3.39 (t, J = 11.9 Hz, 1H), 3.27 - 3.13 (m, 4H), 2.56 (dd, J = 14.0, 7.5 Hz, 2H), 2.24 (d, J = 10.5 Hz, 4H), 2.07 (dd, J = 24.6, 12.5 Hz, 2H), 1.52 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H). 176 Starting material: 6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinecarbonitrile dihydrochloride (prepared according to the ure in Example 29) MS m/z 402.4 [M+H]+; 1H NMR (methanol-d4) δ: 9.22 (s, 1H), 9.17 (s, 1H), 8.58 (s, 1H), 8.43 (dd, J = 10.8, 0.9 Hz, 1H), 8.37 (s, 1H), 3.76 (br d, J = 12.5 Hz, 2H), 3.64 (tt, J = 10.6, 6.2 Hz, 1H), 3.35 (dd, J = 12.0, 4.4 Hz, 2H), 3.00 (s, 3H), 2.71 (s, 3H), 2.49 - 2.34 (m, 4H), HCl protons not observed.

Cpd Starting al and Data 178 Starting material: 6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinecarbonitrile dihydrochloride (prepared according to the procedure in Example 29) MS m/z 432.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.16 (s, 2H), 8.55 (s, 1H), 8.43 (br d, J = 10.22 Hz, 1H), 8.34 (s, 1H), 3.96 - 4.02 (m, 2H), 3.89 (br d, J = 12.51 Hz, 2H), 3.58 - 3.71 (m, 2H), 3.35 - 3.40 (m, 3H), 2.69 (s, 3H), 2.41 - 2.51 (m, 4H), OH and HCl s not observed. 179 Starting material: 6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinecarbonitrile (prepared according to the procedure in Example 29) MS m/z 434.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.16 (s, 1H), 9.14 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 10.0 Hz, 1H), 8.35 (s, 1H), 4.98 - 5.02 (m, 1H), 4.89 - 4.93 (m, 1H), 3.90 (br d, J = 12.5 Hz, 2H), 3.62 - 3.71 (m, 3H), 3.39 - 3.50 (m, 2H), 2.69 (s, 3H), 2.44 - 2.52 (m, 4H), HCl protons not observed. 180 ng material: (6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinyl)methanol (prepared according to the procedure in e 29) MS m/z 407.5 [M+H]+; 1H NMR (methanol-d4) δ: 8.94 (s, 1H), 8.33 - 8.39 (m, 1H), 8.25 (s, 1H), 8.04 (d, J = 1.98 Hz, 2H), 5.10 (s, 2H), 3.48 - 3.63 (m, 3H), 3.11 (br s, 2H), 2.87 (s, 3H), 2.50 (s, 3H), 2.31 - 2.40 (m, 4H), OH proton not observed. 181 Starting material: (6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinyl)methanol dihydrochloride (prepared according to the procedure in Example 29) MS m/z 437.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.14 (s, 1 H), 8.62 (s, 1 H), 8.46 (s, 1 H), 8.44 (d, J = 10.1 Hz, 1 H), 8.36 (s, 1 H), 5.17 (s, 2 H), 3.96 - 4.01 (m, 2 H), 3.89 (br d, J = 12.7 Hz, 2 H), 3.35 - 3.40 (m, 3 H), 3.20 - 3.27 (m, 2 H), 2.69 (s, 3 H), 2.43 - 2.50 (m, 4 H), OH and HCl protons not observed. 182 Starting material: (6-(5-fluoro(piperidinyl)cinnolinyl)methylimidazo[1,2- b]pyridazinyl)methanol ochloride MS m/z 439.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.14 (s, 1H), 8.62 (s, 1H), 8.45 - 8.49 (m, 1H), 8.43 (d, J = 10 Hz, 1H), 8.33 - 8.37 (m, 1H), 5.17 (s, 2H), 4.91 - 5.06 (m, 2H), 3.90 (br d, J = 12.21 Hz, 2H), 3.61 - 3.72 (m, 3H), 3.37 - 3.47 (m, 2H), 2.69 (s, 3H), 2.43 - 2.54 (m, 4H), OH and HCl protons not observed. 188 Starting al: 3-(azepanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluorocinnoline dihydrochloride (prepared according to the ure in Example 7) MS m/z 405.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.92 (s, 1H), 8.32 (d, J = 11.5 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 3.62 (septet, J = 5 Hz, 1H), 3.03 - 3.09 (m, 1H), 2.85 - 2.92 (m, 3H), 2.73 (s, 3H), 2.52 (s, 3H), 2.51 (s, 3H), 2.28 - 2.40 (m, 1H), 2.20 - 2.28 (m, 2H), 2.03-2.20 (m, 2H), 1.90 - 1.99 (m, 1H).

Cpd Starting Material and Data 189 Starting material: (azepanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline (prepared according to the procedure in Example 7) MS m/z 419.3 ; 1H NMR (methanol-d 4) δ: 8.87 (s, 1H), 8.27 (d, J = 11 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 3.60 (septet, J = 5 Hz, 1H), 3.09 - 3.15 (m, 1H), 2.83 - 3.00 (m, 3H), 2.75 (q, J = 7 Hz, 2H), 2.71 (s, 3H), 2.51 (s, 3H), 2.20 - 2.35 (m, 3H), 2.00 - 2.20 (m, 2H), 1.90 - 1.98 (m, 1H), 1.20 (t, J = 7 Hz, 3H). 190 Starting material: rac(azepanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluorocinnoline red according to the procedure in e 7) MS m/z 435.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.91 (s, 1H), 8.31 (d, J = 11 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 3.76 (t, J = 6 Hz, 2H), 3.60 (m, 1H), 3.17 - 3.21 (m, 1H), 2.99-3.07 (m, 3H), 2.88 (t, J = 6 Hz, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.00 - 2.34 (m, 5 H), 1.91-1.98 (m, 1H), OH proton not observed. 197 Starting material: 2-(5-fluoro(piperidinyl)cinnolinyl)-4,6- dimethylthiazolo[5,4-c]pyridine (prepared according to the procedure in Example 29) MS m/z 422.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.93 (s, 1H), 8.21 (dd, J = 9.9, 1.4 Hz, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 3.38 - 3.29 (m, 1H), 3.16 (d, J = 11.2 Hz, 2H), 2.79 (s, 3H), 2.64 (s, 3H), 2.49 (q, J = 7.2 Hz, 2H), 2.25 - 2.09 (m, 4H), 2.06 - 1.93 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). 200 Starting al: 5-fluoro(2-methylphenoxyimidazo[1,2-b]pyridazinyl) (piperidinyl)cinnoline (prepared according to the procedure in Example 29) MS m/z 483.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.59 (s, 1H), 8.25 (dd, J = 10.8, 1.2 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.61 - 7.65 (m, 2H), 7.42 - 7.49 (m, 3H), 6.95 (s, 1H), 3.33 - 3.34 (m, 1H), 3.23 - 3.32 (m, 2H), 2.54 - 2.62 (m, 2H), 2.54 (s, 3H), 2.28 - 2.34 (m, 2H) , 2.07 - 2.19 (m, 4H), 1.20 (t, J = 7.2 Hz, 3H). 205 Starting material: 2-(6-(5-fluoro(piperidinyl)cinnolinyl) methylimidazo[1,2-b]pyridazinyl)acetonitrile dihydrochloride (prepared according to the procedure in Example 29) MS m/z 430.2 [M+H]+; 1H NMR (methanol-d 4) δ: 9.00 (s, 1H), 8.39 (dd, J = 11, 1.6 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 3.49 - 3.52 (m, 3H), 2.91 - 2.94 (m, 2H), 2.70 - 2.79 (br s, 2H), 2.56 (s, 3H), 2.22 - 2.35 (m, 6H), 1.32 (t, J = 7.2 Hz, 3H). 206 Starting material: 2-(6-(5-fluoro(piperidinyl)cinnolinyl) imidazo[1,2-b]pyridazinyl)ethanol dihydrochloride (prepared according to the procedure in Example 29) MS m/z 435.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.96 (s, 1H), 8.36 (dd, J = 11.6, 1.2 Hz, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.34 - 3.37 (br s, 3H), 3.25 - 3.28 (m, 2H), 2.61 - 2.63 (m, 2H), 2.53 (s, 3H), 2.34 (m, 2H), 2.14 - 2.20 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H), OH proton not observed.

Cpd Starting Material and Data 212 Starting material: 5-fluoro(2-methylpropylimidazo[1,2-b]pyridazinyl) (piperidinyl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 433.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.84 (s, 1H), 8.22 (dd, J = 10.4 Hz, 1.2 Hz, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 3.43 (t, J = 12 Hz, 1H), 3.26 (d, J = 10.8 Hz, 2H), 3.12 (t, J = 7.6, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.56 (s, 3H), 2.27 - 1.91 (m, 8H), 1.21 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H). 213 ng al: 2-(5-fluoro(piperidinyl)cinnolinyl)-4,6- dimethyloxazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure in Example 29) MS m/z 422.1[M+H]+; 1H NMR (chloroform-d) δ: 9.11 (s, 1H), 8.22 (dd, J = 9.6, 1.2 Hz, 1H), 7.90 (s, 1H), 7.25 (s, 1H), 3.80 - 3.66 (m, 2H), 3.46 - 3.27 (m, 3H), 2.87 - 2.70 (m, 5H), 2.64 - 2.50 (m, 5H), 2.30 - 2.18 (m, 4H), OH proton not observed. 214 Starting al: 2-(5-fluoro(piperidinyl)cinnolinyl)-4,6- yloxazolo[4,5-c]pyridine (prepared according to the procedure in Example 29) MS m/z 392.1 [M+H]+; 1H NMR (chloroform-d) δ: 9.17 (s, 1H), 8.26 (dd, J = 9.7, 1.3 Hz, 1H), 7.93 (s, 1H), 7.32 (s, 1H), 3.40 - 3.29 (m, 1H), 3.10 (d, J = 11.7 Hz, 2H), 2.89 (s, 3H), 2.71 (s, 3H), 2.39 (s, 3H), 2.30 - 2.15 (m, 4H), 2.11 - 1.98 (m, 2H). 222 Starting material: 5-fluoro(8-isopropylmethylimidazo[1,2-b]pyridazinyl) (piperidinyl)cinnoline (prepared according to the procedure in Example 29) MS m/z 433.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.97 (s, 1H), 8.36 (dd, J = 10.9, 1.3 Hz, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 3.76 - 3.69 (m, 1H), 3.39 (d, J = 11.7 Hz, 2H), 3.28 (s, 1H), 2.65 (dd, J = 14.4, 7.2 Hz, 2H), 2.54 (s, 3H), 2.38 (t, J = 11.0 Hz, 2H), 2.27 - 2.10 (m, 4H), 1.54 (d, J = 6.9 Hz, 6H), 1.23 (t, J = 7.3 Hz, 3H).

Example 20 Preparation of nd 18 Step A: 6-Bromochloro-quinoline (300 mg, 1.2 mmol) was dissolved in THF (7.5 mL). To the solution was added a solution of KOtBu in THF (2.5 mL, 2.5 mmol, 1.0 M). The mixture was heated at 40 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The c layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, g with 0-20% EtOAc in hexanes to yield 6-bromotertbutoxy-quinoline (310 mg, 89%). MS m/z 224.2, 226.2 [M+H-tBu]+.

Step B: 6-Bromotert-butoxy-quinoline (310 mg, 1.11 mmol) was combined with bis(pinacolato)diboron (375 mg, 1.46 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane complex (40 mg, 0.048 mmol), KOAc (300 mg, 3.03 mmol) and 1,4-dioxane (4 mL). The mixture was stirred at 90 °C for 2 h to yield 2-tert-butoxy ,5-tetramethyl-1,3,2-dioxaborolanyl)quinoline as a crude mixture that was used t purification. MS m/z 272.3 [M+H-tBu]+. 6-Bromo-2,8-dimethyl-imidazo[1,2-a]pyrazine (100 mg, 0.44 mmol) and 2-tert-butoxy (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)quinoline (164 mg, 0.50 mmol, prepared above) were combined with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.024 mmol), 1,4-dioxane (2.5 mL) and aqueous 1 M K2CO3 (1.5 mL). The mixture was heated at 80 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and trated.

The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in hexanes to yield 2- tert-butoxy(2,8-dimethylimidazo[1,2-a]pyrazinyl)quinoline (140 mg, 73%). MS m/z 347.3 [M+H]+.

Step C: 2-tert-Butoxy(2,8-dimethylimidazo[1,2-a]pyrazinyl)quinoline (130 mg, 0.38 mmol) was suspended in 4 N HCl in 1,4-dioxane (1 mL, 4 mmol). The e was stirred at room temperature for 1 h. The volatiles were removed. The residue was suspended in DMF (1 mL) with Cs2CO3 (325 mg, 1.0 mmol). To the mixture was added N,N-bis(trifluoromethylsulfonyl)aniline (107 mg, 0.30 mmol). The mixture was stirred at room temperature for 2 h. The mixture was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with -100% EtOAc in hexanes to yield 8-dimethylimidazo[1,2-a]pyrazinyl)quinolyl] trifluoromethanesulfonate (90 mg, 56%). MS m/z 423.3 [M+H]+.

Step D: [6-(2,8-Dimethylimidazo[1,2-a]pyrazinyl)quinolyl] trifluoromethanesulfonate (90 mg, 0.21 mmol) was combined with 1-tert-butoxycarbonylpiperidinylzinc iodide (0.25 mL, 0.25 mmol, prepared according to the ure in e 5, Step B), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol), 1,4-dioxane (2 mL). The mixture was heated at 80 °C for 20 min. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with -100% EtOAc in hexanes, followed by 5% MeOH in EtOAc to yield tert-butyl 4-[6-(2,8- dimethylimidazo[1,2-a]pyrazinyl)quinolyl]piperidinecarboxylate (60 mg, 62%). MS m/z 458.4 [M+H]+.

Step E: tert-Butyl 2,8-dimethylimidazo[1,2-a]pyrazinyl)quinolyl]piperidine carboxylate (60 mg, 0.1311 mmol) was ved in TFA (1 mL). After 20 min, the volatiles were removed. The residue was partitioned between CH2Cl2 and aqueous 1 M K2CO3. The organic layer was loaded directly onto silica gel, eluting with 0-20% MeOH (2 M NH3) in CH2Cl2 to yield 6-(2,8-dimethylimidazo[1,2-a]pyrazinyl)(piperidinyl)quinoline as white powder (15 mg, 32%).

MS m/z 358.4 [M+H]+. 1H NMR (DMSO-d6) δ: 9.17 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 3.11 - 3.17 (m, 2H), 2.98 - 3.05 (m, 1H), 2.83 (s, 3H), 2.69 -2.77 (m, 2H), 2.44 (s, 3H), 1.87 - 1.95 (m, 2H), 1.75 - 1.85 (m, 2H).

Using the procedure bed for Example 20, above, additional compounds described herein were prepared by substituting the appropriate aryl boronic acid in Step B, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 19 MS m/z 358.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.67 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.42 (dd, J = 8.8, 2.0 Hz, 1H), 8.11 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 3.24 - 3.30 (m, 2H), 3.09 - 3.15 (m, 1H), 2.84 -2.91 (m, 2H), 2.65 (s, 3H), 2.43 (s, 3H), 1.87 - 1.95 (m, 2H), 1.75 - 1.85 (m, Example 21 Preparation of Compound 55 tert-Butyl 4-(7-(2,7-dimethyl-2H-indazolyl)fluorocinnolinyl)-3,6-dihydropyridine-1(2H)- carboxylate (25 mg, 0.053 mmol, prepared ing to Example 7, Step I) was stirred in the presence of HCl in e (4M, 1 mL, 4 mmol) for 1 h. The reaction mixture was filtered, and the solids were washed with ether, then 9:1 CH2Cl2:MeOH to yield 7-(2,7-dimethyl-2H-indazol- -yl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride (19 mg, 88%).

MS m/z 374.4 [M+H]+; 1H NMR (DMSO-d6) δ: 9.30 - 9.40 (br s, 2H), 8.66 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 8.24 (dd, J = 11.5, 1 Hz, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 7.21 (br s, 1H), 4.23 (s, 3H), 3.94 (br s, 2H), 3.40 - 3.50 (m, 2H), 3.05 (br s, 2H), 2.64 (s, 3H).

Using the procedure described for Example 2, above, additional compounds described herein were prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 225 MS m/z 375.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.70 (s, 1H), 8.08 (dd, J = 10.7, 1.0 Hz, 1H), 7.86 (s, 1H), 7.73 - 7.67 (m, 1H), 7.40 (s, 1H), 7.11 (br s, 1H), 4.23 (dd, J = 6.8, 2.2 Hz, 2H), 3.73 (dd, J = 5.2 Hz, 2H), 2.79 (br s, 2H), 2.69 (s, 3H), 2.48 (s, 3H), NH and HCl s not observed. 208 MS m/z 431.5 [M+H]+; 1H NMR (chloroform-d) δ: 8.81 - 8.89 (m, 1H), 8.21 (d, J = .1 Hz, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.54 (d, J = 0.9 Hz, 1H), 7.13 (br s, 1H), 2.78 (s, 3H), 2.59 - 2.73 (br m, 2H), 2.53 - 2.57 (m, 3H), 1.43 (br s, 12H).

Preparation of Compound 4 Step A: 7-Bromocinnolinol (100 mg, 0.44 mmol, prepared according to the procedure used for 7-Bromofluoro-cinnolinol in e 7), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.65 mmol), Pd(dppf)Cl2- CH2Cl2 (50 mg, 0.061 mmol), DMF (2.5 mL), and aqueous K2CO3 (2M, 0.825 mL, 1.65 mmol) were heated at 80 °C for 1 hour. The mixture was then partitioned between H2O and EtOAc. The organic layer was washed with H2O and then brine. The c layer was dried over MgSO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (5% MeOH in ), followed by ether trituration, yielded tert-butyl 4-(3-hydroxycinnolinyl)-3,6- dihydropyridine-1(2H)-carboxylate (110 mg) as a yellow solid. MS m/z 328.0 [M+H]+.

Step B: tert-Butyl 4-(3-hydroxycinnolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (108 mg, 0.33 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (143 mg, 0.4 mmol), Cs2CO3 (175 mg, 0.54 mmol) and DMF (1 mL) were stirred at room temperature for min. The mixture was partitioned between H2O and EtOAc. The c layer was washed with H2O and brine. The organic layer was dried over MgSO4, filtered, and concentrated under . Purification by silica gel chromatography (0-5% EtOAc in CH2Cl2) yielded tert-butyl 4- trifluoromethyl)sulfonyl)oxy)cinnolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (109 mg, 54% over two steps) as a white solid. 1H NMR (acetone-d 6) δ: 8.53 (s, 1H), 8.43 (s, 1H), 8.28 (dd, J = 9 Hz, 2 Hz, 1H), 8.23 (d, J = 9 Hz, 1H), 6.69 (br s, 1H), 4.22 (s, 2H), 3.75 (m, 2H), 2.79 (m, 2H), 1.51 (s, 9H).

Step C: A mixture of tert-butyl 4-(3-(((trifluoromethyl)sulfonyl)oxy)cinnolinyl)-3,6- dihydropyridine-1(2H)-carboxylate (85 mg, 0.18 mmol), (2-methyl-2H-indazolyl)boronic acid (51 mg, 0.29 mmol), Pd(dppf)Cl2-CH2Cl2 (40 mg, 0.05 mmol), dioxane (1.05 mL), and aqueous K2CO3 (2M, 220 µL, 0.44 mmol) were heated at 80 °C for 90 min. The mixture was partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The e was purified by silica gel chromatography (20% acetone in CH2Cl2, followed by 5% MeOH in CH2Cl2). The material obtained was triturated with 2:1 hexanes:CH2Cl2. The solid material was collected and dried yielding tert-butyl 4-(3-(2-methyl- 2H-indazolyl)cinnolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (51 mg, 64%) as a yellow solid. 1H NMR d 6) δ: 8.72 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.21 (dd, J = 9 Hz, 2 Hz, 1H), 8.11 (dd, J = 9 Hz, 2 Hz, 1H), 8.06 (d, J = 9 Hz, 1H), 7.80 (d, J = 9 Hz, 1H), 6.61 (br s, 1H), 4.23 (s, 3H), 4.13 (s, 2H), 3.64 (t, J = 5.5 Hz, 2H), 2.72 (s, 2H), 1.46 (s, 9H).

Step D: A solution of tert-butyl 4-(3-(2-methyl-2H-indazolyl)cinnolinyl)-3,6- dihydropyridine-1(2H)-carboxylate (51 mg, 0.12 mmol) in CH2Cl2 (1 mL) and TFA (0.3 mL) was stirred at room temperature for 1 h. The volatiles were removed by a N2 stream. The solid material was triturated with 1 N HCl in ether for 1 h and the volatiles were d by a N2 stream. The residue was washed with 4:1 CH2Cl2:MeOH and dried to yield 3-(2-methyl-2H- indazolyl)(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride (42 mg, 100%) as a light tan solid.

MS m/z 342.0 [M+H]+; 1H NMR (DMSO-d6) δ: 9.25 (br s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.22 (dd, J = 9 Hz, 1.5 Hz, 1H), 8.14 (dd, J = 9 Hz, 2 Hz, 1H), 8.10 (d, J = 9 Hz, 1H), 7.81 (d, J = 9 Hz, 1H), 6.65 (br s, 1H), 4.24 (s, 3H), 3.88 (s, 2H), 3.41 (m, 2H), 2.95 (s, Preparation of Compound 24 Step A: alinol (2.0 g, 13.7 mmol), concentrated H2SO4 (14 mL), Ag2SO4 (2.12 g, 6.8 mmol), and Br2 (0.7 mL, 13.6 mmol) were stirred at room temperature for 15 h. The mixture was filtered to remove AgBr. The solid was washed with sulfuric acid. The combined filtrate was poured onto ice. A white solid was collected by filtration, washed with H2O, EtOH, and ether, and then dried to yield 6-bromoquinoxalinol (2.7 g, 87%) as a light tan solid containing 10% unreacted starting material. 1H NMR (DMSO-d 6) δ: 12.54 (br s, 1H), 8.21 (s, 1H), 7.99 (d, J = 2 Hz, 1H), 7.73 (dd, J = 9 Hz, 2 Hz, 1H), 7.27 (d, J = 9 Hz, 1H).

Step B: 6-Bromoquinoxalinol (200 mg, 0.88 mmol), 2-methyl(4,4,5,5-tetramethyl-1,3,2- orolanyl)(trifluoromethyl)-2H-indazole (300 mg, 1.09 mmol), Pd(dppf)Cl2-CH2Cl2 (50 mg, 0.061 mmol), DMF (5 mL), and aqueous K2CO3 (2M, 1.65 mL, 3.3 mmol) were heated at 90 °C for 2 h. To the mixture was added dilute aqueous HCl. The solid material was collected by filtration, washed with H2O, EtOH and ether, and then dried to yield crude 6-(2-methyl (trifluoromethyl)-2H-indazolyl)quinoxalinol (231 mg). MS m/z 345.2 [M+H]+.

Step C: 6-(2-Methyl(trifluoromethyl)-2H-indazolyl)quinoxalinol (231 mg, 0.67 mmol), CH3CN (3 mL) and POBr3 (1.2 g, 4.18 mmol) were heated at 90 °C for 15 h. The mixture was diluted in ether and filtered. The solid material was washed with . The e was dissolved in CH2Cl2:MeOH and was filtered through a silica plug to remove baseline impurities.

The filtrate was concentrated under vacuum. The residue was purified by silica gel tography (30% EtOAc in CH2Cl2). The product was triturated with CH2Cl2. The solid was collected and dried to yield 2-bromo(2-methyl(trifluoromethyl)-2H-indazol noxaline (117 mg, 32% over two steps) as an off-white solid. 1H NMR (acetone-d 6) δ: 9.02 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.46 (d, J = 2 Hz, 1H), 8.37 (dd, J = 8.5 Hz, 2 Hz, 1H), 8.14-8.17 (m, 2H), 4.36 (s, 3H).

Step D: 2-Bromo(2-methyl(trifluoromethyl)-2H-indazolyl)quinoxaline (85 mg, 0.21 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- yl)]palladium(II) (10 mg, 0.013 mmol), 1,4-dioxane (0.5 mL), and (1-(tertbutoxycarbonyl )piperidinyl)zinc(II) iodide (1M in DMA, 0.5 mL, 0.5 mmol, prepared according to Example 5) were heated at 80 °C for 2 h. The mixture was partitioned between EtOAc and aqueous saturated NH4Cl. The organic layer was dried over MgSO4, filtered and concentrated under . The residue was purified by silica gel chromatography (1:1 CH2Cl2:EtOAc, followed by 20% e in CH2Cl2). The collected material was triturated with 1:1 hexanes:ether. The solid material was collected by vacuum filtration and dried to yield tertbutyl 4-(6-(2-methyl(trifluoromethyl)-2H-indazolyl)quinoxalinyl)piperidine carboxylate (41 mg, 38%) as a pink solid. 1H NMR (acetone-d 6) δ: 8.97 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.39 (d, J = 2 Hz, 1H), 8.26 (dd, J = 8.5 Hz, 2 Hz, 1H), 8.14 - 8.17 (m, 2H), 4.36 (s, 3H), 4.25 - 4.34 (m, 2H), 3.42 (m, 1H), 2.90 - 3.15 (br s, 2H), 2.05 - 2.10 (m, 2H), 1.91 (qd, J = 12.5 Hz, 4 Hz, 2H), 1.50 (s, 9H).

Step E: tert-Butyl 4-(6-(2-methyl(trifluoromethyl)-2H-indazolyl)quinoxalin yl)piperidine1-carboxylate (25 mg, 0.049 mmol) and 4 N HCl in dioxane (1 mL, 4 mmol) were heated at 80 °C for 1 h. The mixture was diluted in ether. The solid al was collected by vacuum filtration and dried to yield 6-(2-methyl(trifluoromethyl)-2H-indazolyl) (piperidinyl)quinoxaline hydrochloride as a yellow solid (20 mg, 91%).

MS m/z 412.1 ; 1H NMR (methanol-d 4) δ: 8.97 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 2 Hz, 1H), 8.27 (dd, J = 9 Hz, 2 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 4.34 (s, 3H), 3.59 - 3.66 (m, 2H), 3.45 - 3.54 (m, 1H), 3.24 - 3.33 (m, 2H), 2.33 - 2.40 (m, 2H), 2.22 - 2.33 (m, 2H), NH proton not observed.

Using the procedure described for Example 23, above, additional compounds described herein were prepared by substituting the appropriate boronic acid in Step B, suitable reagents and reaction conditions, ing compounds such as those selected from: Cpd Data 31 MS m/z 358.2 [M+H]+; 1H NMR nol-d4) δ: 8.98 (s, 1H), 8.86 (s, 1H), 8.39 (d, J = 2 Hz, 1H), 8.27 (dd, J = 9 Hz, 2 Hz, 1H), 8.23 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 4.46 (s, 3H), 3.60 -3.69 (m, 2H), 3.46 - 3.54 (m, 1H), 3.24 - 3.33 (m, 2H), 2.75 (s, 3H), 2.33 - 2.40 (m, 2H), 2.21 - 2.31 (m, 2H), NH proton not observed.

Example 24 Preparation of Compound 5 Step A: oaniline (5.0 g, 29.1 mmol) was dissolved in EtOAc (60 mL) and Et3N (5.25 mL, 37.5 mmol) at 0 °C. Methyl 3-chlorooxopropanoate (3.95 mL, 31.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned n EtOAc and dilute aqueous HCl. The organic layer was washed with aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The e was triturated with 2:1 hexane:ether. The solid material was collected by vacuum filtration and dried to yield ethyl 3-((4-bromophenyl)amino) oxopropanoate (6.23 g, 75%) as a white solid. 1H NMR (acetone-d 6) δ: 9.50 (br s, 1H), 7.64 (m, 2H), 7.49 (m, 2H), 4.19 (q, J = 7 Hz, 2H), 3.48 (s, 2H), 1.26 (t, J = 7 Hz, 3H).

Step B: Ethyl 3-((4-bromophenyl)amino)oxopropanoate (6.23 g, 22.1 mmol) was dissolved in THF (60 mL) and MeOH (15 mL) at 0 °C. Aqueous 2 N NaOH (15 mL, 30 mmol) was added dropwise to the e. The mixture was stirred at 0 °C for 1 h, upon which excess reagent was quenched with aqueous 6 N HCl (7.5 mL). The mixture was concentrated under vacuum. The residue was suspended in H2O. The solid material was collected by vacuum filtration and dried to yield 3-((4-bromophenyl)amino)oxopropanoic acid (5.7 g, 100%) as a white solid. 1H NMR ne-d 6) δ: 9.63 (br s, 1H), 7.64 (m, 2H), 7.49 (m, 2H), 3.50 (s, 2H), CO2H proton not ed.

Step C: Methanesulfonic acid (28 mL), 3-((4-bromophenyl)amino)oxopropanoic acid (5.7 g, 22.1 mmol), and P2O5 (9 g, 63.4 mmol) were combined and heated at 80 °C for 6 h. The mixture was poured onto ice, and the resulting solid material was collected by vacuum filtration. The solid material was washed with EtOH and ether, and dried to yield 6-bromohydroxyquinolin-4(1H)- one (3.48 g, 65%) as a tan solid. MS m/z 240.0, 242.0 [M+H]+.

Step D: 6-Bromohydroxyquinolin-4(1H)-one (3.48 g, 14.5 mmol) and POCl3 (25 mL) were heated at 100 °C for 15 h. The mixture was poured into ter. The ing mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (30% hexanes in ) to yield 6-bromo-2,4-dichloroquinoline (2.9 g, 72%) as a white solid. 1H NMR (acetone-d 6) δ: 8.42 (d, J = 2 Hz, 1H), 8.06 (dd, J = 9 Hz, 2 Hz, 1H), 7.98 (d, J = 9 Hz, 1H), 7.85 (s, 1H).

Step E: 6-Bromo-2,4-dichloroquinoline (2.82 g, 10.2 mmol) and 0.5 M NaOMe in MeOH (21.2 mL, 10.6 mmol) were combined and heated at reflux for 2 h. The mixture was partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was ed by silica gel chromatography (50-70% CH2Cl2 in hexanes) to yield 6-bromochloromethoxyquinoline (1.02 g, 37%). 1H NMR (acetone-d 6) δ: 8.25 (d, J = 2 Hz, 1H), 7.88 (dd, J = 9, 2 Hz, 1H), 7.80 (d, J = 9 Hz, 1H), 7.22 (s, 1H), 4.06 (s, 3H).

Step F: 6-Bromochloromethoxyquinoline (210 mg, 0.77 mmol), (2-methyl-2H-indazol yl)boronic acid (161 mg, 0.91 mmol), Pd(PPh3)4 (90 mg, 0.078 mmol), 2 M aqueous K2CO3 (1.4 mL, 2.8 mmol) and 1,4-dioxane (4.2 mL) were combined and heated at 80 °C for 1 h. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (30% EtOAc in CH2Cl2). The collected product was triturated in ether. The solid material was ted by vacuum filtration and dried to yield romethoxy(2-methyl- 2H-indazolyl)quinoline (182 mg, 73%) as a white solid. 1H NMR (acetone-d 6) δ: 8.37 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J = 9 Hz, 2 Hz, 1H), 8.11 (m, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.76 - 7.80 (m, 1H), 7.72 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.20 (s, 1H), 4.27 (s, 3H), 4.08 (s, 3H).

Step G: 4-Chloromethoxy(2-methyl-2H-indazolyl)quinoline (120 mg, 0.37 mmol) was combined with Pd(dppf)Cl2-CH2Cl2 (35 mg, 0.043 mmol) in 1,4-dioxane (0.5 mL). To the mixture was added dimethylzinc (1.2 M in toluene, 1 mL, 1.2 mmol). The mixture was heated at 80 °C for 4 h. The on mixture was cooled to room temperature, upon which excess t was carefully quenched with MeOH. The mixture was partitioned between NH4OH and CH2Cl2.

The organic layer was dried over MgSO4, filtered and concentrated under vacuum. Purification by silica gel chromatography (30% EtOAc in CH2Cl2), followed by ether trituration, yielded 2- methoxymethyl(2-methyl-2H-indazolyl)quinoline (102 mg, 91%) as a white solid. 1H NMR (acetone-d 6) δ: 8.31 (s, 1H), 8.23 (d, J = 2 Hz, 1H), 8.08 (t, J = 1.5 Hz, 1H), 8.02 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.89 (d, J = 9 Hz, 1H), 7.74 (m, 2H), 6.88 (s, 1H), 4.27 (s, 3H), 4.03 (s, 3H), 2.76 (s, 3H).

Step H: 2-Methoxymethyl(2-methyl-2H-indazolyl)quinoline (100 mg, 0.33 mmol) and 4 N HCl in oxane (1.5 mL, 6 mmol) were heated at 110 °C for 3 h. The mixture was diluted in ether and was filtered. The solid was dried, yielding 4-methyl(2-methyl-2H-indazol yl)quinolinol (82 mg, 84%) as a light tan solid. MS m/z 289.9 [M+H]+.

Step I: 4-Methyl(2-methyl-2H-indazolyl)quinolinol (82 mg, 0.28 mmol) and POCl3 (1.5 mL) were heated at 120 °C for 2 h. The mixture was poured onto ice. Aqueous saturated NaHCO3 was added to the ice to neutralize the mixture. The aqueous mixture was washed with .

The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was ed by silica gel chromatography (5% MeOH in CH2Cl2). The collected product was triturated with 1:1 acetone:CH2Cl2. The solid was collected and dried to yield 2-chloromethyl- ethyl-2H-indazolyl)quinoline (84 mg, 100%) as an orange solid. 1H NMR (DMSO-d 6) δ: 8.46 (s, 1H), 8.32 (d, J = 2 Hz, 1H), 8.17 - 8.23 (m, 2H), 8.01 (d, J = 9 Hz, 1H), 7.79 (dd, J = 9 Hz, 1.5 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.52 (s, 1H), 4.22 (s, 3H), 2.80 (s, 3H).

Step J: 2-Chloromethyl(2-methyl-2H-indazolyl)quinoline (75 mg, 0.24 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6-dihydropyridine-1(2H)-carboxylate (93 mg, 0.3 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) (10 mg, 0.014 mmol), aqueous 2 M K2CO3 (0.45 mL, 0.9 mmol) and DMF (1.35 mL) were combined and heated at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (30-50% EtOAc in ). The collected product was triturated with ether. The solid was collected and dried to yield tert-butyl 4- (4-methyl(2-methyl-2H-indazolyl)quinolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (73 mg, 67%) as a white solid. 1H NMR (acetone-d 6) δ: 8.32 (s, 1H), 8.31 (s, 1H), 8.14 (t, J = 1.5 Hz, 1H), 8.06 - 8.12 (m, 2H), 7.75 - 7.80 (m, 2H), 7.73 (s, 1H), 6.86 (br s, 1H), 4.27 (s, 3H), 4.20 (s, 2H), 3.69 (t, J = 5.5 Hz, 2H), 2.88 (m, 2H), 2.83 (s, 3H), 1.51 (s, 9H).

Step K: tert-Butyl 4-(4-methyl(2-methyl-2H-indazolyl)quinolinyl)-3,6-dihydropyridine- 1(2H)-carboxylate (70 mg, 0.15 mmol) was combined with 4:1 CH2Cl2:MeOH (1.5 mL) and 10% Pd/C (35 mg). The mixture was stirred at room temperature under H2 (1 atm) for 4 h. The mixture was filtered through Celite. The te was concentrated under vacuum. The residue was purified by silica gel chromatography (1:1 CH2Cl2:EtOAc, followed by 20% acetone in CH2Cl2). The collected material was triturated in ether. The solid was ted and dried to yield tert-butyl 4- (4-methyl(2-methyl-2H-indazolyl)quinolinyl)piperidinecarboxylate (55 mg, 79%) as a white solid. 1H NMR (acetone-d 6) δ: 8.32 (s, 1H), 8.30 (s, 1H), 8.12 (t, J = 1.5 Hz, 1H), 8.04 - 8.11 (m, 2H), 7.73 - 7.78 (m, 2H), 7.37 (s, 1H), 4.27 (m, 5H), 3.03 - 3.14 (m, 1H), 2.85-3.01 (m, 2H), 2.82 (s, 3H), 1.95 - 2.03 (m, 2H), 1.82 - 1.92 (m, 2H), 1.49 (s, 9H).

Step L: tert-Butyl 4-(4-methyl(2-methyl-2H-indazolyl)quinolinyl)piperidine carboxylate (53 mg, 0.12 mmol) and 4 N HCl in 1,4-dioxane (1 mL, 4 mmol) were combined and heated at 50 °C for 1 h. The mixture was diluted with ether. The solid material was collected by vacuum filtration, washed with 9:1 CH2Cl2:MeOH and dried to yield 4-methyl(2-methyl-2H- indazolyl)(piperidinyl)quinoline hydrochloride (46 mg, 100%) as a yellow solid.

MS m/z 357.0 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.11 - 9.23 (br s, 1H), 8.95 - 9.10 (br s, 1H), 8.38 - 8.53 (m, 4H), 8.28 (s, 1H), 7.83 (dd, J = 9 Hz, 1.5 Hz, 1H), 7.72 - 7.80 (m, 2H), 4.23 (s, 3H), 3.50 - 3.60 (m, 1H), 3.41 - 3.49 (m, 2H), 3.09 (m, 2H), 3.00 (s, 3H), 2.20 - 2.38 (m, 4H).

Example 25 Preparation of Compound 7 Step A: 6-Bromoquinolinol (670 mg, 3.0 mmol) was combined with zine (504 mg, 6.0 mmol), potassium tert-butoxide (840 mg, 7.5 mmol), 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl (280 mg, 0.6 mmol) and tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.3 mmol) in 1,4-dioxane (10 mL). The mixture was heated at 100 °C for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with 0- % MeOH in CH2Cl2 to yield 6-(piperazinyl)quinolinol (575 mg, 84%). MS m/z 230.1 Step B: erazinyl)quinolinol (575 mg, 2.5 mmol) was suspended in POCl3 (4.6 mL, 50 mmol). The mixture was heated at 100 °C for 16 h. The mixture was slowly added to a vigorously d mixture of CH2Cl2 (100 mL), H2O (100 mL), and 10 g of (NaHCO3). The organic layer was collected and concentrated. The residue was tographed on silica gel, eluting with 0- % MeOH in CH2Cl2 to yield 2-chloro(piperazinyl)quinoline (280 mg, 45%). MS m/z 248.1, 250.1 [M+H]+.

Step C: ro(piperazinyl)quinoline (280 mg, 1.1 mmol) was ed with 2- methylindazoleboronic acid (387 mg, 1.5 mmol), 1,1'-bis(diphenylphosphino) ferrocenepalladium (II)dichloride dichloromethane complex (80 mg, 0.10 mmol), 1,4-dioxane (10 mL), and aqueous 1 M K2CO3 (5 mL, 5 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0- % MeOH in CH2Cl2 to yield 2-(2-methyl-2H-indazolyl)(piperazinyl)quinoline (51 mg, %).

MS m/z 344.1 [M+H]+; 1H NMR (DMSO-d6) δ: 8.52 (s, 1H), 8.46 (s, 1H), 8.18 - 8.22 (m, 2H), 8.05 (d, J = 8.5 Hz), 7.88 (d, J = 9.0 Hz), 7.69 (d, J = 9.0 Hz), 7.60 (d, J = 8.5 Hz), 7.18 (s, 1H), 4.20 (s, 3H), 3.19 - 3.22 (m, 4H), 2.88 - 2.91 (m, 4H), NH proton not observed.

Example 26 Preparation of Compound 117 Step A: A mixture of 7-bromochlorofluorocinnoline (120 mg, 0.46 mmol, prepared according to Example 7), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6- dihydropyridine-1(2H)-carboxylate (153 mg, 0.49 mmol), and (2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) (25 mg, 0.034 mmol) in 1,4-dioxane (3.5 mL) and aqueous 2 M K2CO3 (0.7 mL, 1.4 mmol) was heated to 80 ºC for 2 h.

The crude reaction mixture was cooled to room temperature, filtered over celite, and concentrated.

The residue was chromatographed on silica gel, eluting with 10-50% EtOAc in hexanes to yield tert-butyl 4-(3-chlorofluorocinnolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 72%) as a tan solid. MS m/z 364.4, 366.4 [M+H]+.

Step B: A mixture of 8-fluoromethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)imidazo[1,2-a]pyridine (69 mg, 0.25 mmol), tert-butyl 4-(3-chlorofluorocinnolinyl)-3,6- dihydropyridine-1(2H)-carboxylate (60 mg, 0.16 mmol), and chloro(2-dicyclohexylphosphino- dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) (12 mg, 0.016 mmol) in 1,4-dioxane (1.5 mL) and aqueous 2 M K2CO3 (0.25 mL, 0.5 mmol) was heated to 90 ºC for 2 h.

The mixture was cooled to room temperature, filtered over celite, and concentrated. The residue was chromatographed on silica gel, eluting with 5-10% MeOH in CH2Cl2 to yield tert-butyl 4-(5- (8-fluoromethylimidazo[1,2-a]pyridinyl)cinnolinyl)-3,6-dihydropyridine-1(2H)- carboxylate (54 mg, 69%) as a brown solid. MS m/z 478.5 .

Step C: To a solution of tert-butyl 4-(5-fluoro(8-fluoromethylimidazo[1,2-a]pyridin yl)cinnolinyl)-3,6-dihydropyridine-1(2H)-carboxylate (54 mg, 0.11 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction was stirred at room temperature for 15 minutes, then concentrated. The residue was dissolved in HCl in MeOH (1.25 M) and concentrated. This procedure was repeated once more to afford 5-fluoro(8-fluoro methylimidazo[1,2-a]pyridinyl)(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride (26 mg, 56%) as a yellow solid.

MS m/z 378.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.82 (s, 1H), 9.35 - 9.42 (br s, 2H), 8.92 (s, 1H), 8.64 (d, J = 11.9 Hz, 1H), 8.43 (s, 1H), 8.21 - 8.25 (br s, 1H), 8.13 (d, J = 11.6 Hz, 1H), 6.74 - 6.77 (br s, 1H), 3.87 - 3.92 (br s, 2H), 3.39 - 3.44 (m, 2H), 2.92 - 2.97 (m, 2H), 2.53 (s, 3H).

Using the procedure described for Example 26, above, additional compounds bed herein were prepared by substituting the riate boronic acid in Step B, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 134 MS m/z 378.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.21 - 9.26 (br s, 2H), 8.77 (s, 1H), 8.65 - 8.74 (m, 2H), 8.38 (s, 1H), 8.12 (d, J = 13.4 Hz, 1H), 8.06 (d, J = 11.9 Hz, 1H), 6.70 - 6.74 (br s, 1H), 4.27 (s, 3H), 3.85 - 3.90 (m, 2H), 3.35 - 3.44 (m, 2H), 2.90 - Cpd Data 2.95 (m, 2H). 156 MS m/z 374.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.65 (s, 1H), 8.89 (d, J = 1.0 Hz, 1H), 8.69 (t, J = 1.2 Hz, 1H), 8.46 (s, 1H), 8.14 (d, J = 0.9 Hz, 1H), 8.00 (dd, J = 11.1, 1.4 Hz, 1H), 6.67 (dt, J = 3.4, 1.8 Hz, 1H), 4.02 (d, J = 3.1 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 3.01 - 3.11 (m, 2H), 2.81 (s, 3H), 2.65 (s, 3H), NH and HCl protons not observed. 157 MS m/z 374.4 [M+H]+; 1H NMR nol-d 4) δ: 8.82 (s, 1H), 8.58 - 8.61 (m, 2H), 8.38 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 10.4 Hz, 1H), 6.64 - 6.67 (m, 1H), 4.36 (s, 3H), 4.01 - 4.03 (m, 2H), 3.60 (t, J = 6.1 Hz, 2H), 3.04 - 3.08 (m, 2H), 2.75 (s, 3H), NH and HCl protons not observed. 165 MS m/z 378.4 ; 1H NMR (methanol-d 4) δ: 8.73 (d, J = 2.4 Hz, 1H), 8.37 (s, 1H), 7.66 - 7.72 (m, 1H), 7.62 (s, 1H), 7.50 (d, J = 11.4 Hz, 1H), 6.37 - 6.43 (m, 1H), 6.24 - 6.28 (m, 1H), 4.34 - 4.39 (s, 3H), 3.92 - 3.97 (m, 2H), 3.51 - 3.55 (m, 2H), 2.84 - 2.93 (m, 2H), NH and HCl protons not observed. 166 MS m/z 377.4 [M+H]+; 1H NMR (methanol-d4) δ: 8.70 (d, J = 9.8 Hz, 1H), 8.57 (dd, J = 2.4, 1.4 Hz, 1H), 8.44 (s, 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.99 (s, 1H), 7.94 (m, 2H), 6.52 (br s, 1H), 4.29 - 4.36 (m, 3H), 3.98 (d, J = 2.1 Hz, 2H), 3.58 (dd, J = 7.8, 6.1 Hz, 2H), 2.96 - 3.04 (m, 2H), NH and HCl protons not observed. 167 MS m/z 375.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.08 (s, 1H), 8.86 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.91 (d, J = 11.0 Hz, 1H), 6.57 - 6.59 (br s, 1H), 3.87 - 3.95 (m, 2H), 3.49 (t, J = 6.1 Hz, 2H), 2.94 - 2.98 (m, 2H), 2.78 (s, 3H), 2.59 (s, 3H), NH protons not observed. 171 MS m/z 379.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.20 - 9.25 (br s, 2H), 8.96 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.36 (d, J = 12.5 Hz, 1H), 8.11 (d, J = 11.6 Hz, 1H), 6.73 - 6.76 (br s, 1H), 4.62 (s, 3H), 3.87 - 3.91 (m, 2H), 3.39 - 3.44 (m, 2H), 2.92 - 2.97 (m, 175 MS m/z 385.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.25 (s, 1H), 9.05 - 9.10 (br s, 2H), 8.90 (s, 1H), 8.94 (s, 1H), 8.84 (s, 1H), 8.41 (s, 1H), 8.09 (d, J = 11.0 Hz, 1H), 6.72 - 6.75 (m, 1H), 4.32 (s, 3H), 3.88 - 3.92 (m, 2H), 3.40 - 3.45 (m, 2H), 2.91 - 2.96 (m, 198 MS m/z 388.3 [M+H]+. 1H NMR (DMSO-d 6) δ: 8.67 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.86-7.88 (d, J = 11 Hz, 1H), 6.45 (t, J = 6.5 Hz, 1H), 4.34 (s, 3H), 3.97 (m, 2H), 3.00 (m, 2H), 2.65 (s, 3H), 2.37 (m, 2H), 2.02, (m, 2H).

NH proton not observed.

Example 27 Preparation of Compound 128 A suspension of 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(1,2,3,6- tetrahydropyridinyl)cinnoline hydrochloride (22 mg, 0.05 mmol) and Pd/C (20 mg) in MeOH (2 mL) was stirred under H2 (1 atm) at room temperature for 12 h. The mixture was ed over celite and concentrated. The residue was dissolved in DMF (1 mL). To the solution was added MnO2 (45 mg, 0.5 mmol). The on was stirred at room temperature for 1h, then filtered over celite. The filtrate was concentrated. The residue was dissolved in 1.25 M HCl in MeOH.

Concentration afforded 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidin yl)cinnoline hydrochloride (15 mg, 62%) as a yellow solid.

MS m/z 380.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.69 (s, 1H), 8.93 (s, 1H), 8.79 (d, J = 11.0 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.74 (d, J = 10.7 Hz, 1H), 3.61 (d, J = 12.5 Hz, 2H), 3.21 - 3.35 (m, 3H), 2.65 (s, 3H), 2.31 (d, J = 14.0 Hz, 2H), 2.00 - 2.18 (m, 2H), NH and HCl s not observed.

Using the procedure described for Example 27, above, additional nds described herein were prepared by substituting le reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 151 MS m/z 380.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.71 (s, 1H), 8.47 - 8.57 (m, 2H), 8.23 (s, 1H), 8.02 (d, J = 12.2 Hz, 1H), 7.64 (d, J = 10.1 Hz, 1H), 4.31 (s, 3H), 3.62 (d, J = 11.6 Hz, 2H), 3.21 - 3.29 (m, 3H), 2.32 (d, J = 13.4 Hz, 2H), 1.97 - 2.15 (m, 2H), NH and HCl protons not observed. 177 MS m/z 376.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.00 - 9.07 (br s, 1H), 8.87 - 8.95 (br s, 1H), 8.60 - 8.66 (m, 2H), 8.51 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.68 (d, J = 10.5 Hz, 1H), 4.23 (s, 3H), 3.46 - 3.55 (m, 1H), 3.15 - 3.22 (m, 2H), 3.01 - 3.10 (br s, 2H), 2.64 (s, 3H), 2.12 - 2.19 (m, 2H), 1.98 - 2.07 (m, 2H). 185 MS m/z 377.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.21 (s, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.78 (d, J = 9.5 Hz, 1H), 3.63 (d, J = 12.5 Hz, 2H), 3.23 - 3.40 (m, 3H), 2.90 (s, 3H), 2.71 (s, 3H), 2.34 (d, J = 14.0 Hz, 2H), 2.06 - 2.17 (m, 2H), NH and Cpd Data HCl protons not observed. 192 MS m/z 379.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.46 (d, J = 2.4 Hz, 1H), 8.35 - 8.40 (m, 2H), 8.16 (d, J = 8.9 Hz, 1H), 8.03 (dd, J = 13.2, 1.1 Hz, 1H), 7.61 (s, 1H), 7.48 (dd, J = 11.9, 1.5 Hz, 1H), 4.29 (s, 3H), 3.30 (br s, 2H), 2.88 - 3.01 (m, 3H), 2.04 (d, J = 12.5 Hz, 2H), 1.80 - 1.90 (m, 2H), NH proton not observed.

Example 28 Preparation of Compound 144 To a suspension of 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidin yl)cinnoline hloride (175 mg, 0.42 mmol) and sodium triacetoxyborohydride (900 mg, 4.2 mmol) in CH2Cl2 (4 mL) and EtOH (1 mL) was added a solution of acetaldehyde (0.25 mL, 4.4 mmol) in EtOH (1 mL). The reaction was stirred at room temperature for 1h, then quenched with saturated aqueous K2CO3. The mixture was ioned between CH2Cl2 and H2O. The aqueous layer was extracted once with CH2Cl2. The combined cs were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% 1.4 N NH3/MeOH in CH2Cl2 to yield 7-(1-ethylpiperidinyl)fluoro(8-fluoro methylimidazo[1,2-a]pyridinyl)cinnoline (120 mg, 70%) as a light orange solid.

MS m/z 408.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.29 (d, J = 1.2 Hz, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 8.01 (dd, J = 12.2, 1.2 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 10.7 Hz, 1H), 3.36 - 3.39 (m, 2H), 2.98 - 3.09 (m, 1H), 2.76 (q, J = 7.2 Hz, 2H), 2.44 - 2.55 (m, 5H), 2.16 (d, J = 13.1 Hz, 2H), 1.95 - 2.03 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H).

Using the procedure described for Example 28 above, onal compounds bed herein were prepared by substituting suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 153 MS m/z 406.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.83 (s, 1H), 8.55 (d, J = 1.5 Hz, 2H), 8.38 (s, 1H), 8.01 (dd, J = 12.8, 1.2 Hz, 1H), 7.97 (dd, J = 11.3, 1.2 Hz, 1H), 6.63 - 6.67 (br s, 1H), 4.32 (s, 3H), 4.25 (d, J = 13.1 Hz, 1H), 3.88 - 4.01 (m, 2H), 3.38 - 3.50 (m, 3H), 3.10-3.18 (m, 2H), 1.49 (t, J = 7.3 Hz, 3H), HCl proton not observed. 154 MS m/z 408.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.66 - 8.71 (m, 1H), 8.48 - 8.54 (m, 2H), 8.21 (s, 1H), 8.01 (dd, J = 12.8, 1.2 Hz, 1H), 7.63 (d, J = 10.7 Hz, 1H), 4.31 (s, 3H), 3.42 - 3.55 (m, 2H), 3.12 (t, J = 12.4 Hz, 1H), 2.91 - 2.97 (m, 2H), 2.70 - 2.78 (m, 2H), 2.23 (d, J = 13.1 Hz, 2H), 1.98 - 2.14 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H). 183 MS m/z 404.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.63 (d, J = 6.4 Hz, 2H), 8.51 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.74 (d, J = 10.4 Hz, 1H), 4.23 (s, 3H), 3.12 - 3.25 (m, 3H), 2.86 - 2.96 (m, 2H), 2.64 (s, 3H), 2.45 - 2.55 (m, 2H), 1.97 - 2.05 (m, 2H), 1.84 - 1.91 (m, 2H), 1.06 - 1.17 (m, 3H). 184 MS m/z 405.5 [M+H]+; 1H NMR nol-d4) δ: 8.83 (d, J = 9.5 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 8.02 (d, J = 11.7 Hz, 1H), 7.91 (d, J = 12.4 Hz, 1H), 6.54 (br s, 1H), 4.33 (s, 3H), 4.22 (d, J = 15.4 Hz, 1H), 3.81 - 3.99 (m, 2H), 3.37 - 3.49 (m, 3H), 3.04 - 3.15 (m, 2H), 1.48 (t, J = 7.2 Hz, 186 MS m/z 405.3 [M+H]+; 1H NMR (methanol-d4) δ: 9.04 (d, J = 0.9 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.66 - 7.73 (m, 1H), 3.47 (d, J = 11.9 Hz, 2H), 3.07 - 3.17 (m, 1H), 2.90 (q, J = 7.2 Hz, 2H), 2.76 (d, J = 0.9 Hz, 3H), 2.69 (t, J = 11.6 Hz, 2H), 2.54 (s, 3H), 2.23 (d, J = 13.7 Hz, 2H), 2.04 (qd, J = 12.9, 3.5 Hz, 2H), 1.32 (t, J = 7.3 Hz, 3H). 193 MS m/z 407.5 [M+H]+;1H NMR (methanol-d4) δ: 8.47 (d, J = 2.4 Hz, 1H), 8.37 - 8.41 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 13.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J = 12.2 Hz, 1H), 4.30 (s, 3H), 3.42 - 3.52 (m, 2H), 2.87 - 3.01 (m, 3H), 2.59 - 2.76 (m, 2H), 2.15 (d, J = 16.6 Hz, 2H), 2.00 (m, 2H), 1.32 (t, J = 7.3 Hz, 3H). 201 MS m/z 406.3 [M+H]+; 1H NMR (methanol-d4) δ: 9.58 (s, 1H), 8.89 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 14.3 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.91 (s, 1H), 6.50 (br s, 1H), 4.29 (s, 3H), 2.92 (t, J = 6.7 Hz, 2H), 2.77 - 2.83 (m, 2H), 2.70 (d, J = 7.3 Hz, 2H), 1.31 (br s, 2H), 1.25 (t, J = 7.2 Hz, 3H).

Cpd Data 202 MS m/z 408.3 [M+H]+; 1H NMR nol-d 4) δ: 9.59 (br s, 1H), 8.91 (br s, 1H), 8.51 (br s, 1H), 8.25 (d, J = 13.1 Hz, 1H), 7.82 (br s, 1H), 7.74 (d, J = 12.4 Hz, 1H), 4.30 (br s, 3H), 3.68 (d, J = 9.3 Hz, 2H), 3.20 (br s, 3H), 3.08 (br s, 2H), 2.28 (d, J = 14.8 Hz, 2H), 1.99 - 2.12 (m, 2H), 1.35 - 1.44 (t, J = 7.2 Hz, 3H).

Example 29 Preparation of Compound 108 Step A: 1-Bromo-2,3-difluoronitrobenzene (10.0 g, 42.0 mmol, prepared in Example 7, Step A) was combined with tert-butyl 4-(3-ethoxyoxo-propanoyl)piperidinecarboxylate (13.8 g, 46.2 mmol) in DMF (100 mL). To the solution was added Cs2CO3 (27.4 g, 84.0 mmol). The mixture turned dark red upon addition. The mixture was stirred at 60 °C for 4 h. The mixture was ioned between EtOAc and aqueous 0.5 M HCl. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-[2-(2-bromofluoronitro- phenyl)ethoxyoxo-propanoyl]piperidinecarboxylate (21.5 g) as a crude oil. MS m/z 515.5, 517.5 [M-H]-.

Step B: The crude material from Step A was suspended in AcOH (40 mL) and conc. aqueous HCl (37 mass%, 40 mL). The mixture was heated at 120 °C for 4 h, then 100 °C for 16 h. Volatiles were removed under reduced pressure. The residue was dissolved in MeOH (100 mL) and triethylamine (23.4 mL, 168.0 mmol). To the e was added di-tert-butyl dicarbonate (13.7 g, 63.0 mmol). The mixture was stirred at room temperature for 30 min. The volatile material was removed from the mixture under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in CH2Cl2 to yield tert-butyl 4-[2-(2-bromofluoronitrophenyl )acetyl]piperidinecarboxylate (10.2 g, 55%). MS m/z 443.5, 445.5 [M-H]-.

Step C: tert-Butyl 4-[2-(2-bromofluoronitro-phenyl)acetyl]piperidinecarboxylate (10 g, 22.5 mmol) was combined with Zn (73.2, 112 mmol), NH4Cl (24.1 g, 450 mmol) and MeOH (100 mL). The mixture was stirred at 40 °C for 3 h. The mixture was diluted with EtOAc and ed through . The filtrate was concentrated to yield tert-butyl 4-[2-(4-aminobromofluorophenyl )acetyl]piperidinecarboxylate (9.5 g, 100%). MS m/z 315.2, 317.2 [M-Boc+H]+.

Step D: tert-Butyl 4-aminobromofluoro-phenyl)acetyl]piperidinecarboxylate (9.5 g, 23 mmol) was combined with CuCl (4.6 g, 46 mmol), CuCl2 (9.3 g, 69 mmol) and CH3CN (100 mL). To the mixture was added l nitrite (9.3 mL, 69 mmol) dropwise at 0 °C. The mixture was stirred at 60 °C for 2 h. The e was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-40% EtOAc in hexanes to yield tert-butyl 4-[2-(2- bromochlorofluoro-phenyl)acetyl]piperidinecarboxylate (7.5 g, 75% Yield). 1H NMR ne-d6) : 7.56 (t, J = 1.7 Hz, 1H), 7.34 (dd, J = 9.1, 1.9 Hz, 1H), 4.15 (d, J = 1.9 Hz, 2H), 4.11 (br d, J = 12.0 Hz, 2H), 2.78 - 2.96 (m, 3H), 1.98 (br d, J = 12.3 Hz, 2H), 1.48 - 1.58 (m, 2H), 1.46 (s, 9H).

Step E: tert-Butyl 4-[2-(2-bromochlorofluoro-phenyl)acetyl]piperidinecarboxylate (7.5 g, 17 mmol) was combined benzoyl hydrazide (3.6 g, 26 mmol), CuI (0.32 g, 1.7 mmol), 1,10- phenanthroline (0.31 g, 1.7 mmol) and sodium tert-butoxide (3.36 g, 35 mmol) in DMF (50 mL).

The mixture was stirred under N2 at 70 °C for 1 h. The mixture was ioned between EtOAc and 0.25 M HCl (aq). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was tographed on silica gel, eluting with 0-40% EtOAc in hexanes to yield tert-butyl 4-(1-benzoylchlorofluoro-2H-cinnolinyl)piperidine carboxylate (6.4 g, 79%). MS m/z 470.6, 472.6 [M-H]-.

Step F: tert-Butyl 4-(1-benzoylchlorofluoro-2H-cinnolinyl)piperidinecarboxylate (6.2 g, 13 mmol) was suspended in conc. aqueous HCl (37 mass%, 30 mL) and EtOH (20 mL). The mixture was heated at 100 °C for 24 h. The mixture was cooled to 60 °C. Air was bubbled through the mixture for 5 h. The volatile material was removed with a stream of N2. To the crude residue was added MeOH (50 mL), triethylamine (7.4 mL, 53 mmol) and then di-tert-butyl dicarbonate (5.7 g, 26 mmol). The mixture was stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-60% EtOAc in hexanes to yield tert-butyl 4-(7-chlorofluoro-cinnolin eridinecarboxylate (3.0 g, 62%).

MS m/z 310.2, 312.2 [M-tBu+H]+. 1H NMR (acetone-d6) δ: 8.38 (s, 1H), 8.09 (s, 1H), 7.71 (dd, J = 9.5, 1.9 Hz, 1H), 4.26 - 4.38 (m, 2H), 3.49 (tt, J = 12.0, 3.7 Hz, 1H), 3.00 (br s, 2H), 2.10 - 2.15 (m, 2H) 1.95 (qd, J = 12.6, 4.4 Hz, 2H), 1.49 (s, 9H).

Step G: Powdered tert-butyl 4-(7-chlorofluoro-cinnolinyl)piperidinecarboxylate (1.00 g, 2.73 mmol) was weighed into a 50-mL screw-cap tube, followed by ous 1,4-dioxane (27 mL), followed by 2 (0.76 g, 3.0 mmol), SPhos Pd G2 pre-catalyst (0.20 g, 0.27 mmol), and ed potassium acetate (1.02 g, 10.4 mmol) last. The yellow mixture was then sparged for 2 minutes with argon, the ace was purged, and the vial was capped and sealed tightly. The vial was placed in an aluminum heating block and d vigorously at 90 C for 3 h. After this time, the reaction mixture was cooled to room temperature. The dark-brown reaction mixture was filtered through . The Celite was washed with EtOAc (60 mL). The brown filtrate was then washed with water (60 mL), 50% aq. NaHCO3 (2 x 60 mL), and brine (60 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-[5- fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cinnolinyl]piperidinecarboxylate as a crude, dark brown powder without further purification.

MS m/z 490.5 [M+MeOH+H]+; 1H NMR (chloroform-d) δ: ppm 8.84 (s, 1H), 7.87 (s, 1H), 7.72 (d, J = 9.5 Hz, 1H), 4.37 (br s, 2H), 3.45 (tt, 1H), 2.98 (br s, 2H), 2.16 (br d, J = 13.6 Hz, 2H), 1.93 (qd, J = 12.6, 4.0, 2H), 1.52 (s, 12H), 1.42 (s, 9H).

Step H: A screw-top vial was charged with solid 6-chloromethyl-imidazo[1,2-b]pyridazine carbonitrile (0.14 g, 0.72 mmol) and anhydrous 1,4-dioxane (6.56 mL), followed by tert-butyl 4- [5-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cinnolinyl]piperidinecarboxylate (0.30 g, 0.66 mmol), SPhos Pd G2 pre-catalyst (0.047 g, 0.065 mmol), granular K2CO3 (0.27 g, 1.96 mmol), and water (0.33 mL). The brown e was sparged with argon for 5 s, then sealed with a screw cap. The reaction mixture was stirred vigorously at 90 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water (2 x 100 mL) and brine (100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The dark-brown, crude material was purified by silica gel column tography (hexanes/EtOAc gradient elution) to afford tert-butyl 4-[7-(8-cyano methyl-imidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]piperidinecarboxylate (0.182 g, 57%) as a yellow powder.

MS m/z 488.5 [M+H]+; 1H NMR (chloroform-d) δ: 8.87 (s, 1 H), 8.18 (d, J = 10.2 Hz, 1 H), 8.03 (s, 1 H), 8.00 (s, 1 H), 7.91 (s, 1 H), 4.37 (br d, J = 5.6 Hz, 2 H), 3.49 (tt, J = 12.0, 3.4 Hz, 1 H), 2.98 (br t, J = 12.2 Hz, 2 H), 2.63 (s, 3 H), 2.16 (br d, J = 12.5 Hz, 2 H), 1.93 (qd, J = 12.6, 4.0 Hz, 2 H), 1.50 (s, 9 H).

Step I: tert-Butyl 4-[7-(8-cyanomethyl-imidazo[1,2-b]pyridazinyl)fluoro-cinnolin yl]piperidinecarboxylate (0.060 g, 0.12 mmol) was dissolved in anhydrous 1,4-dioxane (4 mL), and a 4.0 M solution of HCl in 1,4-dioxane (0.15 mL, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, after which time the reaction mixture was concentrated on a rotovap. The crude product was triturated in Et2O (5 mL), then dried under high vacuum to afford luoro(4-piperidyl)cinnolinyl]methyl-imidazo[1,2-b]pyridazine carbonitrile hydrochloride (0.060 g, 100%) as a tan solid.

MS m/z 388.4 [M+H]+; 1H NMR (methanol-d4) δ: 9.11 (s, 1 H), 8.81 (s, 1 H), 8.42 (d, J = 11.3 Hz, 1 H), 8.37 (s, 1 H), 8.30 (s, 1 H), 3.58 - 3.77 (m, 5 H), 2.63 (s, 3 H), 2.21 - 2.47 (m, 4 H).

Using the procedure described for Example 29, above, additional compounds described herein were prepared by substituting the appropriate aryl halide in Step H, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 91 MS m/z 363.4 [M+H]+; 1H NMR (methanol-d4) δ: 9.77 (d, J = 2.4 Hz, 1H), 9.54 (d, J = 2.1 Hz, 1H), 8.84 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.08 (s, 1H), 3.61 - 3.70 (m, 3H), 3.28 - 3.37 (m, 2H), 2.67 (s, 3H), 2.31 - 2.44 (m, 4H), NH and HCl s not observed. 92 MS m/z 380.4 ; 1H NMR (methanol-d 4) δ: 9.27 (d, J = 1.2 Hz, 1H), 8.78 (s, 1H), 8.46 (dd, J = 11.0, 1.2 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.12 (dd, J = 10.4, 1.5 Cpd Data Hz, 1H), 3.59 - 3.69 (m, 3H), 3.27 - 3.37 (m, 2H), 2.66 (d, J = 0.9 Hz, 3H), 2.32 - 2.45 (m, 4H), NH and HCl protons not observed. 93 MS m/z 387.5 [M+H]+; 1H NMR nol-d4) δ: 9.61 (d, J = 1.5 Hz, 1H), 9.01 (d, J = 1.5 Hz, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.13 (dd, J = 10.5, 1.7 Hz, 1H), 3.60 - 3.70 (m, 3H), 3.28 - 3.36 (m, 2H), 2.66 (d, J = 0.9 Hz, 3H), 2.31 - 2.45 (m, 4H), NH and HCl protons not ed. 94 MS m/z 363.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.47 (s, 1H), 8.75 (s, 1H), 8.44 (br d, J = 9.5 Hz, 1H), 8.29 (s, 1H), 8.15 (dd, J = 10.7, 1.5 Hz, 1H), 7.99 (d, J = 9.5 Hz, 1H), 3.60 - 3.69 (m, 3H), 3.25 - 3.37 (m, 2H), 2.69 (s, 3H), 2.30 - 2.44 (m, 4H), NH and HCl protons not observed. 95 MS m/z 362.4 [M+H]+; 1H NMR nol-d 4) δ: 8.61 (s, 2H), 8.47 (s, 1H), 8.40 (s, 1H), 8.19 (dd, J = 10.7, 1.2 Hz, 1H), 8.03 (dd, J = 9.0, 1.7 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 4.36 (s, 3H), 3.62 - 3.70 (m, 3H), 2.39 - 2.46 (m, 2H), 2.28 - 2.39 (m, 2H), NH and HCl protons not observed; CH2 obscured by solvent peak. 96 MS m/z 380.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.99 (s, 1H), 8.51 (d, J = 17.4 Hz, 2H), 8.32 (d, J = 10.7 Hz, 1H), 8.18 (s, 1H), 7.59 (d, J = 12.2 Hz, 1H), 4.25 (s, 3H), 3.72 (t, J = 10.1 Hz, 1H), 3.61 (d, J = 12.2 Hz, 2H), 3.28-3.32 (m, 2H), 2.22-2.47 (m, 4H), NH and HCl protons not observed. 97 MS m/z 380.4 ; 1H NMR (methanol-d 4) δ: 9.06 (s, 1H), 8.84 (s, 1H), 8.60 (s, 1H), 8.41 (br d, J = 7.0 Hz, 1H), 8.22 (br d, J = 10.1 Hz, 1H), 7.66 (d, J = 11.3 Hz, 1H), 4.40 (s, 3H), 3.82 (t, J = 10.4 Hz, 1H), 3.68 (d, J = 12.5 Hz, 2H), 3.35-3.42 (m, 2H), 2.47 (d, J = 11.9 Hz, 2H), 2.33-2.44 (m, 2H), NH and HCl protons not observed. 99 MS m/z 363.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.14 (s, 1H), 8.59 (d, J = 9.8 Hz, 1H), 8.47 (d, J = 10.1 Hz, 1H), 8.44 (dd, J = 10.7, 1.5 Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 3.60 - 3.70 (m, 3H), 3.30 - 3.35 (m, 2H), 2.67 (d, J = 0.9 Hz, 3H), 2.31 - 2.43 (m, 4H), NH and HCl protons not observed. 101 MS m/z 376.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.84 (d, J = 1.2 Hz, 1H), 8.81 (s, 1H), 8.39 (s, 2H), 8.29 (s, 1H), 8.21 (dd, J = 10.4, 1.2 Hz, 1H), 3.62 - 3.67 (m, 3H), 3.28 - 3.33 (m, 2H), 3.04 (s, 3H), 2.55 (s, 3H), 2.30 - 2.43 (m, 4H), NH and HCl protons not observed. 103 MS m/z 376.5 [M+H]+; 1H NMR (methanol-d4) δ: 9.21 (s, 1H), 8.75 (s, 1H), 8.27 - 8.39 (m, 2H), 8.12 (d, J = 10.6 Hz, 1H), 8.08 (s, 1H), 3.62 - 3.69 (m, 3H), 3.29 - 3.36 (m, 2H), 2.78 (s, 3H), 2.65 (s, 3H), 2.30 - 2.45 (m, 4H), NH and HCl protons not observed. 104 MS m/z 387.4 [M+H]+; 1H NMR (methanol-d 4) δ: 8.67 (d, J = 1.5 Hz, 1H), 8.64 (s, 1H), 8.64 (br s, 1H), 8.63 (br s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.25 (br d, J = 10.1 Hz, 1H), 4.36 (s, 3H), 3.69 - 3.75 (m, 1H), 3.66 (d, J = 12.8 Hz, 2H), 2.42 (d, J = 12.5 Hz, 2H), 2.35 (qd, J = 12.8, 3.4 Hz, 2H), NH and HCl protons not observed, CH2 obscured by solvent peak.

Cpd Data 105 MS m/z 391.2 [M+H]+; 1H NMR (chloroform-d) δ: 8.86 (s, 1H), 8.23 (dd, J = 10.8, 1.5 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.53 (s, 1H), 3.42 - 3.52 (m, 1H), 3.33 (br d, J = 12.2 Hz, 2H), 3.20 (q, J = 7.6 Hz, 2H), 2.87 - 2.96 (m, 2H), 2.56 (s, 3H), 2.14 - 2.22 (m, 2H), 1.92 (dq, J = 11.2, 4.2 Hz, 2H), 1.51 (t, J = 7.6 Hz, 3H), NH proton not ed. 106 MS m/z 393.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.18 (s, 1H), 8.39 (dd, J = 11, 1.5 Hz, 1H), 8.16 (s, 1H), 8.09 (d, J = 0.7 Hz, 1H), 7.56 (s, 1H), 4.22 (s, 3H), 3.47-3.56 (m, 3H), 3.01 - 3.09 (m, 2H), 2.39 (s, 3H), 2.07 - 2.24 (m, 4H), NH proton not observed. 107 MS m/z 393.1 [M+H]+; 1H NMR (DMSO-d 6) δ: 8.93 (s, 1H), 8.32 (d, J = 11 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 5.77 (br s, 1H), 4.99 (s, 2H), 3.12 - 3.20 (m, 3H), 2.71 - 2.80 (m, 2H), 2.43 (s, 3H), 1.96 - 2.03 (m, 2H), 1.82 - 1.96 (m, 2H), NH proton not observed. 109 MS m/z 380.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.22 (s, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.31 (d, J = 10.4 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 4.37 (s, 3H), 3.85 (t, J = 11.3 Hz, 1H), 3.68 (d, J = 12.2 Hz, 2H), 3.34 - 3.42 (m, 2H), 2.48 (d, J = 12.8 Hz, 2H), 2.39 (q, J = 11.8 Hz, 2H), NH and HCl protons not observed. 112 MS m/z 403.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.78 (s, 1H), 8.22 (d, J = 12Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.10 (s, 1H), 3.33 - 3.49 (m, 1H), 3.31 (d, J = 12.4 Hz, 2H), 2.90 (t, J = 12.2 Hz, 2H), 2.70 - 2.74 (m, 1H), 2.56 (s, 3H), 2.17 (d, J = 12.4 Hz, 2H), 1.85 - 1.92 (m, 2H), 1.25 - 1.38 (m, 2H), 1.22 - 1.25 (m, 2H), NH proton not observed. 118 MS m/z 393.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.59 (s, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J = 10.4, 1.2 Hz, 1H), 7.63 (s, 1H), 3.43 - 3.50 (m, 3H), 3.01 (t, J = 12 Hz, 2H), 2.90 (s, 3H), 2.83 (s, 3H), 2.25 (d, J = 13.2 Hz, 2H), 2.03 - 2.06 (m, 2H), NH proton not observed. 126 MS m/z 377.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.13 (s, 1H), 8.41 (d, J = 10.5 Hz, 1H), 8.11 (s, 1H), 7.33 (s, 1H), 3.43 (s, 2H), 3.24 (s, 1H), 3.16 (d, J = 12.0 Hz, 2H), 2.78 (s, 3H), 2.55 (s, 3H), 2.05 - 1.82 (m, 4H), NH protons not ed. 133 MS m/z 394.1 [M+H]+; 1H NMR (methanol-d 4) δ: 9.03 (s, 1H), 8.47 (dd, J = 11.2, 1.6Hz, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 3.59 - 3.63 (m, 3H) ,3.24 - 3.28 (m, 2H), 2.92 (s, 3H), 2.85 (s, 3H), 2.29 - 2.37 (m, 4H), NH proton observed. 137 MS m/z 378.0 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.00 (s, 1H), 8.29 (d, J = 9.8 Hz, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 3.22 - 3.31 (m, 1H), 3.14 (d, J = 11.9 Hz, 2H), 2.76 (s, 3H), 2.71 (d, J = 11.0 Hz, 2H), 2.60 (s, 3H), 1.97 - 2.00 (m, 2H), 1.82 - 1.93 (m, 2H). 148 MS m/z 378.1 [M+H]+; 1H NMR oform-d) δ: 8.91 (s, 1H), 8.54 (dd, J = 11, 1.6 Hz, 1H), 7.89 (s, 2H), 3.42 - 3.48 (m, 1H), 3.33 (br d, J = 12 Hz, 2H), 2.89 - 2.95 (m, 2H), 2.73 (s, 6H), 2.16 - 2.19 (m, 2H), 1.92 - 1.96 (m, 2H), NH proton not observed. 148 MS m/z 394.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.89 (s, 1H), 8.33 (dd, J = 10, 1.2 Hz, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 3.44 - 3.50 (m, 1H), 3.33 (d, J = 12.4 Hz, 2H), Cpd Data 3.04 (s, 3H), 2.89 - 2.95 (m, 2H), 2.68 (s, 3H), 2.18 (d, J = 12.4 Hz, 2H), 1.90 - 1.94 (m, 2H), NH proton not observed. 162 MS m/z 377.1 [M+H]+; 1H NMR oform-d) δ: 8.89 (s, 1H), 8.38 (dd, J = 9.6, 1.2 Hz, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 4.32 (s, 3H), 3.38 - 3.51 (m, 3H), 2.94 - 3.00 (m, 2H), 2.78 (s, 3H), 2.21 - 2.24 (m, 2H), 1.97 - 2.07 (m, 2H), NH proton not observed. 163 MS m/z 393.1 [M+H]+; 1H NMR (chloroform-d) δ: 8.88 (s, 1H), 8.42 (dd, J = 10.8, 1.2 Hz, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.31 (s, 1H), 4.29 (s, 3H), 4.23 (s, 3H), 3.57 - 3.62 (m, 3H), 3.05 - 3.15 (m, 4H), 2.31 - 2.36 (m, 2H), NH proton not observed. 172 MS m/z 391.2 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.06 (s, 1H), 8.74 (s, 1H), 8.44 - 8.57 (m, 1H), 8.08 (d, J = 12.9 Hz, 2H), 4.26 (s, 3H), 3.03 - 3.20 (m, 4H), 2.95 (d, J = 7.9 Hz, 1H), 2.71 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 11.9 Hz, 2H), 1.85 (qd, J = 12.3, 3.9 Hz, 2H), 1.44 (t, J = 7.6 Hz, 3H). 187 MS m/z 402.2 [M+H]+; 1H NMR (chloroform-d) δ: 8.94 (s, 1H), 8.62 (br s, 1H); 8.23 (dd, J = 10.4, 1.2 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 4.32 (s, 2H), 3.56 - 3.60 (m, 3H), 3.11 (br s, 2H), 2.56 (s, 3H), 2.26 - 2.35 (m, 4H). 194 MS m/z 429.1 ; 1H NMR (methanol-d 4) δ: 9.29 (s, 1H), 9.15 (s, 1H) 8.55 (br s, 2H), 8.27 - 8.28 (m, 2H), 8.19 (s, 1H), 7.33 (s, 1H), 3.60 - 3.64 (m, 3H), 3.25 - 3.29 (m, 2H), 2.58 (s, 3H), 2.30 - 2.41 (m, 4H), NH proton not observed. 195 MS m/z 455.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.59 (s, 1H), 8.25 (dd, J = 10.8, 1.2 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.61 - 7.65 (m, 2H), 7.42 - 7.49 (m, 3H), 6.96 (s, 1H), 3.59 - 3.63 (m, 3H), 3.25 - 3.28 (m, 2H), 2.55 (s, 3H), 2.27 - 2.38 (m, 4H), NH proton not observed. 196 MS m/z 394.0 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.00 (s, 1H), 8.30 - 8.48 (m, 2H), 8.17 (s, 1H), 7.80 (s, 1H), 3.44 - 3.51 (m, 1H), 3.33 (d, J = 10.2 Hz, 2H), 2.89 - 3.00 (m, 2H), 2.75 (s, 3H), 2.60 (s, 3H), 2.00 - 2.17 (m, 4H). 204 MS m/z 405.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.93 (s, 1H), 8.33 (dd, J = 10.9, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J = 0.6 Hz, 1H), 7.86 (s, 1H), 3.43 - 3.50 (m, 2H), 3.26 - 3.31 (m, 1H), 3.09 (t, J = 8 Hz, 2H), 2.91 - 2.98 (m, 2H), 2.53 (s, 3H), 2.17 (d, J = 12.2 Hz, 2H), 1.90 - 2.08 (m, 4H), 1.12 (t, J = 7.4 Hz, 3H), NH proton not observed. 207 MS m/z 407.2 [M+H]+; 1H NMR (methanol-d 4) δ: 9.05 (s, 1H), 8.42 (dd, J = 10.8, 1.2 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 4.10 (t, J = 6 Hz, 2H), 3.63 - 3.66 (br s, 3H), 3.35 - 3.36 (m, 2H), 3.28 - 3.32 (m, 2H), 2.58 (s, 3H), 2.32 - 2.42 (m, 4H), NH and OH protons not observed. 211 MS m/z 405.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (s, 1H), 8.33 (dd, J = 10.9, 1.3 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.82 (s, 1H), 3.74 - 3.67 (m, 1H), 3.48 - 3.44 (m, 1H), 3.36 (s, 2H), 2.97 (td, J = 12.5, 2.6 Hz, 2H), 2.53 (s, 3H), 2.19 (d, J = 12.7 Hz, 2H), 3.01 - 2.94 (m, 2H), 1.53 (d, J = 6.9 Hz, 6H). NH proton not observed.

Halides for use in Step H were prepared according to the following procedures: Example 29-1 ert-Butyldimethylsilyl)oxy)methyl)chloromethylimidazo[1,2- b]pyridazine Step A: To ethyl 3-aminochloropyridazinecarboxylate (4.0 g, 19.9 mmol) in dry THF (1 mL) was slowly added LiAlH4 (2.42 g, 64 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Excess reagent was quenched carefully with water (1 mL), then 15% aqueous NaOH (1 mL) was added. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield (3-aminochloropyridazin yl) methanol (1.0 g, 32%). MS m/z 160.1, 162.1 [M+H]+.

Step B: (3-Aminochloropyridazinyl)methanol (1.0 g, 6.3 mmol) was combined with DIEA (2.44 g, 18.8 mmol) and 1-bromopropanone (860 mg, 6.3 mmol) in isopropyl alcohol (10 mL).

The reaction vessel was ed and then charged with nitrogen three times. The mixture was d at 80 °C for 16 h. The mixture was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-50% EtOAc in petroleum ether to yield (6-chloro methylimidazo [1,2-b]pyridazinyl)methanol (0.9 g, 73%). MS m/z 198.2, 200.2 [M+H]+.

Step C: (6-chloromethylimidazo[1,2-b]pyridazinyl)methanol (900 mg, 4.5 mmol) was combined with TBS-Cl (1.72 g, 9.1 mmol) and imidazole (1.24 g,14.6 mmol) in CH2Cl2 (15 mL).

The mixture was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, g with 0-20% EtOAc in petroleum ether to yield8-(((tert-butyldimethylsilyl)oxy)methyl)chloromethylimidazo[1,2- b]pyridazine (500 mg, 35.2% yield). MS m/z 312.1, 314.1 [M+H]+.

Example 29-2 6-Chloroethylmethylimidazo[1,2-b]pyridazine Step A: 6-Chloropyridazinamine (50 g, 388 mmol) and NaHCO3 (65 g, 775 mmol) were combined in MeOH (500 mL). To the mixture was added Br2 (30 mL, 580 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. One half of the volume of solvent was removed under d pressure. The remaining was poured into ice water. The solid formed was collected and dried to yield 4-bromochloropyridazinamine (80 g, 99%). MS m/z 207.9 [M+H]+.

Step B: 4-Bromochloropyridazinamine (20 g, 97 mmol), Na2CO3 (10.2 g, 97 mmol) and 1- bromopropanone (9.7 mL, 116 mmol) were added into isopropyl alcohol (200 mL). The reaction vessel was degassed and then d with nitrogen three times. The mixture was stirred at 90 °C for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in petroleum ether to yield 8-bromo chloromethylimidazo[1,2-b]pyridazine (8.1 g, 34%). MS m/z 245.9, 247.9 [M+H]+.

Step C: 8-Bromochloromethylimidazo[1,2-b]pyridazine (200 mg, 0.82 mmol) was combined with triethylborane (1M in THF, 2 mL, 2 mmol), K2CO3 (283 mg, 2.05 mmol) and 3)4 (92 mg, 0.08 mmol ) in DMF (3 mL). The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 100 °C for 5 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over , ed and concentrated. The residue was chromatographed on silica gel, g with 0- % EtOAc in petroleum ether to yield 6-chloroethylmethylimidazo[1,2-b]pyridazine (80 mg, 50%). MS m/z 196.0, 198.0 [M+H]+.

Example 29-3 6-Chlorocyclopropylmethylimidazo[1,2-b]pyridazine A mixture of 8-bromochloromethylimidazo[1,2-b]pyridazine (1.2 g, 4.9 mmol), cyclopropylboronic acid (843 mg, 9.8 mmol), Pd(dppf)Cl2 (359 mg, 0.49 mmol) and Na2CO3 (1.56 g, 14.7 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was stirred at 90 °C under N2 for 48 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, ed and concentrated. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield 6-chlorocyclopropyl methylimidazo[1,2-b]pyridazine (405 mg, 40%). MS m/z 208.0, 210.0 [M+H]+.

Example 29-4 romethylimidazo[1,2-b]pyridazinecarbonitrile 8-Bromochloromethylimidazo[1,2-b]pyridazine (1.2 g, 4.9 mmol) was combined with Zn(CN)2 (850 mg, 7.3 mmol) and Pd(PPh3)4 (570 mg, 0.49 mmol ) in DMF (20 mL). The reaction vessel was degassed and then charged with en three times. The mixture was stirred at 100 °C for 1 h under µwave irradiation. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, ed and concentrated. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield 6- chloromethylimidazo [1,2-b]pyridazinecarbonitrile (0.5 g, 53%). MS m/z 193.0, 195.0 [M+H]+.

Example 29-5 6-bromo-2,4-dimethylbenzo[d]thiazole Step A: 2,4-Dibromomethylaniline (3.8 g, 14.5 mmol) was ed with KOAc (1.56 g, 15.9 mmol) and acetic anhydride (5.5 mL, 58 mmol) in toluene (40 mL). The mixture was stirred at room temperature for 16 h. The t was removed in vacuo. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield N-(2,4-dibromo methylphenyl)acetamide (3.9 g, 82%). MS m/z 305.9, 308.0 [M+H]+.

Step B: N-(2,4-Dibromomethylphenyl)acetamide (4.0 g, 13 mmol) was combined with Lawesson’s reagent (10.6 g, 26 mmol) in toluene (40 mL). The mixture was stirred at 110 °C for 16 h. The solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield N-(2,4-dibromomethylphenyl)ethanethioamide (3.9 g, 93%). MS m/z 322.9, 324.9 [M+H]+.

Step C: -Dibromomethylphenyl)ethanethioamide (3.8 g, 11.8 mmol) was ved in NMP (40 mL). To the solution was added NaH (94.7 mg, 2.4 mmol) in portions at room temperature. The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 120 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, ed and trated. The residue was chromatographed on silica gel, eluting with 0-25% EtOAc in petroleum ether to yield 6- bromo-2,4-dimethylbenzo[d]thiazole (369 mg, 12%). MS m/z 241.9, 243.9 [M+H]+.

Example 29-6 5-Chloro-2,7-dimethyl((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- b]pyridine Step A: 6-Chloromethylnitropyridinamine (187 mg, 1 mmol), iron powder (56 mg, 10 mmol) in AcOH (3 mL) was stirred at 100 °C for 16 h. The mixture was concentrated. To the residue was added aqueous NaOH (2 N) until pH >9. The mixture was filtered through .

The filtrate was extracted with EtOAc (50 mL X 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine, which was used without r cation (154 mg crude, 85% crude). MS m/z 182.0, 184.0 [M+H]+.

Step B: 5-Chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.1 g, 6.07 mmol) was dissolved in THF (30 mL). To the mixture was added NaH (310 mg, 7.9 mmol) in portions at 0 °C. After stirring the mixture at 0 °C for 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 6.69 mmol) was added. The resulting mixture was stirred at room ature for 2 h. MeOH (10 mL) was added to the solution, after which all volatile material was removed under reduced pressure.

The residue was chromatographed on silica gel, eluting with 25% EtOAc in petroleum ether to afford a mixture of N-alkylated products, which was used without separation (900 mg, 76%). MS m/z 312.0, 314.0 [M+H]+.

Example 29-7 5-Chloro-2,7-dimethyloxazolo[5,4-b]pyridine Step A: A solution of 2,6-dichloromethylnicotinonitrile (3 g, 16 mmol) in H2SO4 (15 mL) was stirred at 80 °C for 4 h. The mixture was cooled to room temperature, and then poured into ice water (100 mL). The suspension was filtered. The filter cake was washed with water to afford 2,6- dichloromethylnicotinamide (3.2 g, 91%) as a yellow solid. MS m/z 204.9, 206.9 [M+H]+.

Step B: To a solution of NaOH (3.7 g, 93 mmol) in H2O (100 mL) was added Br2 (4.7g, 29.4 mmol) se at 0 °C. The mixture was stirred at 0 °C for 1 h before adding 2,6-dichloro methylnicotinamide (5 g, 24.5 mmol). The mixture was allowed to warm to room temperature gradually over 1 h. The mixture was then heated to 75 °C for 1h. The resulting suspension was cooled to room temperature with stirring overnight. The suspension was filtered. The collected solid material was washed with water to afford 2,6-dichloromethylpyridinamine (3.3 g, 76%). MS m/z 176.9, 178.9 [M+H]+.

Step C: To a solution of 2,6-dichloromethylpyridinamine (3 g, 17 mmol) in toluene (50 mL) was added KOAc (2 g, 20.4 mmol) and Ac2O (6.9 g, 68 mmol). The mixture was stirred at 70 ° C for 48 h. The mixture was cooled to room temperature, and then poured into ice water (100 mL). The water was extracted with EtOAc (60 mL X 3). The combined c phases were concentrated under reduced pressure. The residue was tographed on silica gel eluting with % EtOAc in petroleum ether to afford N-(2,6-dichloromethylpyridinyl) ide (842 mg, 22%) as a yellow solid. MS m/z 219.0, 221.0 [M+H]+.

Step D: To a solution of N-(2,6-dichloromethylpyridinyl)acetamide (700 mg, 3.2 mmol) in NMP (10 mL) was added NaH (128 mg, 3.2 mmol) in ns at room temperature. The reaction vessel was degassed and then d with nitrogen three times. The mixture was stirred at 120 °C for 2 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-25% EtOAc in petroleum ether to yield 5-chloro-2,7- dimethyloxazolo[5,4-b]pyridine (400 mg, 68%). MS m/z 183.1, 185.1 [M+H]+.

Example 29-8 5-Chloro-2,7-dimethylthiazolo[5,4-b]pyridine N-(2,6-dichloromethylpyridinyl)acetamide (1.6 g, 7.3 mmol) was combined with Lawesson’s reagent (5.93 g, 14.7 mmol) in toluene (20 mL). The mixture was d at 110 °C for 16 h. The solvent was removed under d pressure. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield 5-chloro-2,7- dimethylthiazolo[5,4-b]pyridine (500 mg, 34.4% yield). MS m/z 199.0, 201.0 [M+H]+.

Example 29-9 2-Bromo-4,6-dimethyloxazolo[4,5-c]pyridine Step A: 2,6-Dimethylpyridinol (3 g, 24.3 mmol) was added in portions to conc. HNO3 (11 mL). Conc. H2SO4 (16 mL) was then added slowly while keeping the temperature below 20 °C.

The mixture was stirred at room temperature for 3 h. The mixture was then slowly poured onto ice and neutralized with K2CO3. The mixture was extracted with CH2Cl2. The organic phases were concentrated under reduced pressure. The residue was chromatographed on silica gel, g with 10-20% MeOH in CH2Cl2 to afford 2,6-dimethylnitropyridinol as a white solid (3.69 g, 90%). MS m/z 169.1 .

Step B: A mixture of 2,6-dimethylnitropyridinol (1.68 g, 10 mmol) and 10% Pd/C (106 mg, 0.1 mmol) in MeOH (16 mL) was stirred under H2 for 16 h. The e was filtered over Celite to afford 3-amino-2,6-dimethylpyridinol as a white solid (1.3 g, 95%). MS m/z 139.0 [M+H]+.

Step C: To a solution of 3-amino-2,6-dimethylpyridinol (1.38 g, 10 mmol) in EtOH (10 mL) was added cyanogen bromide (1.16 g, 11 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. A precipitate was formed and collected by filtration. The solid material was dried to afford 4,6-dimethyloxazolo[4,5-c]pyridinamine as a white solid (1.2 g, 75%). MS m/z 164.1 [M+H]+.

Step D: To a mixture of 4,6-dimethyloxazolo[4,5-c]pyridinamine (600 mg, 3.7 mmol) and CuBr2 (2.5 g, 11.1 mmol) in CH3CN (6 mL) was added t-butylnitrite (1.3 mL, 11.1 mmol) at 0 °C.

The mixture was stirred at 0 °C for 10 min and then stirred at 55 °C for 2 h. The reaction mixture was made basic with sat. NaHCO3 and then extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting 10-20% EtOAc in petroleum ether to afford 2-bromo-4,6- yloxazolo[4,5-c]pyridine as a white solid (416 mg, 50% yield). MS m/z 227.0, 229.0 [M+H]+.

Example 29-10 2-Bromo-4,6-dimethylthiazolo[4,5-c]pyridine Step A: 4-Chloro-2,6-dimethylnitropyridine (4.7 g, 25 mmol) was combined with Fe powder (4.24 mg, 75 mmol) in AcOH (40 mL). The mixture was stirred at 70 °C for 2 h. The volatile material was removed under reduced pressure. The e was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-80% EtOAc in petroleum ether to yield ro-2,6-dimethylpyridinamine (4.0 g, 99%). MS m/z 157.2, 159.2 [M+H]+.

Step B: 4-Chloro-2,6-dimethylpyridinamine (3.8 g, 24 mmol) was ed with benzoyl isothiocyanate (4.77 g, 29 mmol) in acetone (40 mL) and the mixture was stirred at 56 °C for 2 h.

The solvent was removed under reduced pressure. The residue was chromatographed on silica gel, g with 0-50% EtOAc in petroleum ether to yield N-(4,6-dimethylthiazolo[4,5-c]pyridin yl)benzamide (6.5 g, 95%). MS m/z 284.2 [M+H]+.

Step C: N-(4,6-Dimethylthiazolo[4,5-c]pyridinyl)benzamide (4.5 g ,16 mmol) was combined with NaOH (1.27 g, 32 mmol) in H2O (10 mL) and MeOH (30 mL). The mixture was stirred at 100 °C for 1 h under µwave irradiation. The volatile material was removed under d pressure. The residue was chromatographed on silica gel, eluting with 0-60% EtOAc in petroleum ether to yield 4,6-dimethylthiazolo[4,5-c]pyridinamine (2.7 g, 95%). MS m/z 180.0 [M+H]+.

Step D: 4,6-Dimethylthiazolo[4,5-c]pyridinamine (2.7 g, 15 mmol) was ed with isobutyl nitrite (4.67 g, 45 mmol) and CuBr2 (16.8 g, 75 mmol) in CH3CN (30 mL). The mixture was stirred at 50 °C for 0.5 h. The volatile material was removed under reduced pressure. The residue was tographed on silica gel, eluting with 0-50 % EtOAc in petroleum ether to yield 2-bromo-4,6-dimethylthiazolo[4,5-c]pyridine (1.0 g, 27%). MS m/z 242.9, 245 [M+H]+.

Example 29-11 5-Chloro-2,7-dimethyl-2H-pyrazolo[4,3-b]pyridine Step A: 6-Chloromethylpyridinamine (40 g, 282 mmol) was combined with AcOH (32 mL) in MeOH (400 mL). To the solution was added Br2 (26 mL, 507 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. The volatile material was removed under d pressure. The residual reagent was quenched by the addition of aqueous NaHSO3. The aqueous solution was lized with aqueous sat’d NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in petroleum ether to yield 4- bromochloromethylpyridinamine (60 g, 97%). MS m/z 220.9, 222.9 [M+H]+.

Step B: 4-Bromochloromethylpyridinamine (13 g, 59 mmol) was combined with isobutyl nitrite (9.13 g, 89 mmol), KOAc (13.3 g, 136 mmol) and AcOH (34 ml, 590 mmol) in toluene (130 mL). The mixture was d at 60 °C for 10 h. The volatile material was removed under reduced pressure. The residue was treated with aqueous sat’d NaHCO3. The e was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0- % EtOAc in petroleum ether to yield 7-bromochloro-2H-pyrazolo[4,3-b]pyridine (3.7 g, 27%). MS m/z 232.0, 234.0 [M+H]+.

Step C: 7-Bromochloro-2H-pyrazolo[4,3-b]pyridine (3.7 g, 16 mmol) was combined with K2CO3 (4.4 g, 32 mmol) and iodomethane (2.7 g, 19 mmol) in DMF (40 mL). The mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and trated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in petroleum ether to yield 7- bromochloromethyl-2H-pyrazolo[4,3-b]pyridine (1.5 g, 38%). MS m/z 245.9, 247.9 [M+H]+.

Step D: 7-Bromochloromethyl-2H-pyrazolo[4,3-b]pyridine (3.0 g, 12 mmol) was combined with trimethyl-1,3,5,2,4,6-trioxatriborinane (5.2 mL, 18 mmol), K2CO3 (6.7 g, 49 mmol) and Pd(PPh3)4 (707 mg, 0.6 mmol) in DMF (30 mL). The reaction mixture was degassed and then charged with nitrogen three times. The mixture was stirred at 100 °C for 5 h. The mixture was ioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was tographed on silica gel, eluting with 0- % EtOAc in petroleum ether to yield 5-chloro-2,7-dimethyl-2H-pyrazolo[4,3-b]pyridine (1.2 g, 54%). MS m/z 182.0, 184.0 [M+H]+.

Example 29-12 5-Chloromethoxymethyl-2H-pyrazolo[4,3-b]pyridine 7-Bromochloromethyl-2H-pyrazolo[4,3-b]pyridine (250 mg, 1.0 mmol) was combined with MeOH (0.2 mL, 5 mmol) and K2CO3 (296.7 mg, 2.15 mmol) in CH3CN (5 mL). The mixture was stirred at room temperature for 16 h. The e was partitioned between EtOAc and H2O. The c layer was washed with brine, dried over Na2SO4, filtered and trated. The residue was chromatographed on silica gel, eluting with 0-25 % EtOAc in petroleum ether to yield (190 mg, 80%). MS m/z 198.0, 200.0 [M+H]+.

Example 29-13 5-Chloroethylmethyl-2H-pyrazolo[4,3-b]pyridine 7-Bromochloromethyl-2H-pyrazolo[4,3-b]pyridine (200 mg, 0.8 mmol) was combined with triethylborane (1 M in THF, 1.95 mL, 1.95 mmol), K2CO3 (441.6 g, 3.2 mmol) and Pd(PPh3)4 (30 mg, 0.04 mmol) in DMF (3 mL). The reaction mixture was degassed and then charged with nitrogen three times. The mixture was d at 100 °C for 5 h. The mixture was ioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield 5-chloroethylmethyl-2H-pyrazolo[4,3-b]pyridine (72 mg, 45%).

MS m/z 196.0, 198.0 [M+H]+. e 29-14 2-Bromo-4,6-dimethylthiazolo[5,4-c]pyridine Step A: A mixture of 2,6-dimethylpyridinamine (0.5 g, 4.07 mmol) and e (0.21 mL, 4.07 mmol) in acetic acid (1 mL) was stirred at room temperature for 2 h. The mixture was treated with s 20% sodium hydroxide (10 mL) and extracted with 30 mL CH2Cl2. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was suspended in hot heptanes. The solid material was collected and dried to yield 3-bromo-2,6- dimethylpyridinamine (0.43 g, 52%). MS m/z 201.1, 203.1 [M+H]+.

Step B: A mixture of 3-bromo-2,6-dimethylpyridinamine (400 mg, 2 mmol) and benzoyl isothiocyanate (296 µL, 2.2 mmol) in THF (4 mL) was stirred at 45 °C for 2 h. The mixture was concentrated and the residue was chromatographed on silica gel, eluting with 17% EtOAc in petroleum ether to afford N-((3-bromo-2,6-dimethylpyridinyl)carbamothioyl)benzamide as a light-yellow solid (363 mg, 50%). MS m/z 364.0, 366.0 [M+H]+.

Step C: A mixture of N-((3-bromo-2,6-dimethylpyridinyl)carbamothioyl)benzamide (181 mg, 0.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and Cs2CO3 (326 mg, 1 mmol) in DME (5 mL) was stirred at 100 °C under N2 for 3 h. After completion, the on mixture was cooled to room temperature and partitioned n EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4 and trated. The residue was tographed on silica gel, eluting 30-100% EtOAc in petroleum ether to afford N-(4,6-dimethylthiazolo[5,4- c]pyridinyl)benzamide as a light-yellow solid (92 mg, 65%). MS m/z 284.1 [M+H]+.

Step D: A mixture of N-(4,6-dimethylthiazolo[5,4-c]pyridinyl)benzamide (2 g, 7.1 mmol) and NaOH (1.42 g, 36 mmol) in MeOH (45 mL) and water (15 mL) was stirred in a sealed tube at 85 °C for 24 h. The mixture was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting 50-100% EtOAc in CH2Cl2 to afford 4,6-dimethylthiazolo[5,4-c]pyridin amine as a yellow solid (0.88 g, 70%). MS m/z 180.1 [M+H]+.

Step E: To a e of 4,6-dimethylthiazolo[5,4-c]pyridinamine (880 mg, 4.9 mmol) and CuBr2 (3.25 g, 14.7 mmol) in MeCN (10 mL) was added tert-butyl nitrite (1.74 mL, 14.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and then 55 °C for 1 h. To the reaction mixture was added aqueous sat’d NaHCO3. The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting 20% EtOAc in petroleum ether to afford 2-bromo-4,6- dimethylthiazolo[5,4-c]pyridine as a white solid (595 mg, 50%). MS m/z 242.9, 245.0 [M+H]+. e 29-15 2-(6-Chloromethylimidazo[1,2-b]pyridazinyl)ethanol Step A: A dry three-necked round-bottomed flask at −78°C under inert atmosphere was charged with anhydrous THF (20 mL). A solution of n-butyllithium (2.5 M in hexane, 26.1 mL, 65.3 mmol) was added dropwise, followed by addition of anhydrous acetonitrile (4 mL, 65.3 mmol).

The internal temperature was maintained below −70 °C during the entire addition process. After ng 30 min at −78 °C, a solution of 8-bromochloromethylimidazo[1,2-b]pyridazine (2.0 g, 8.2 mmol, prepared according to Example 43) in anhydrous THF (20 mL) was added dropwise.

The mixture was d for 2 h at −78 °C. The excess reagent was quenched carefully with sat’d aqueous NH4Cl. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with 0-35% EtOAc in petroleum ether to yield 2-(6-chloro- 2-methylimidazo[1,2-b]pyridazinyl)acetonitrile (1.2 g, 71%). MS m/z 207.1, 209.1 [M+H]+.

Step B: 2-(6-Chloromethylimidazo[1,2-b]pyridazinyl)acetonitrile (500 mg, 2.4 mmol) was ed with MeOH (0.97 mL, 24 mmol) in conc. H2SO4 (2 mL). The mixture was stirred at 60 °C for 16 h. The mixture was ioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in petroleum ether to yield methyl 2-(6-chloro methylimidazo[1,2-b]pyridazinyl)acetate (500 mg, 86%). MS m/z 240.1, 242.1 [M+H]+.

Step C: To methyl 2-(6-chloromethylimidazo[1,2-b]pyridazinyl)acetate (500 mg, 2.1 mmol) in dry THF (5 mL) was added LiAlH4 (183 mg, 5.2 mmol) in small portions at 0 °C. The mixture was stirred at 0 °C for 20 min. The reaction was quenched carefully with water (1 mL), followed by aqueous 15% NaOH (1 mL). The mixture was ioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-35% EtOAc in eum ether to yield 2-(6- chloromethylimidazo[1,2-b]pyridazinyl)ethanol (144 mg, 33%). MS m/z 212.1, 214.1 [M+H]+.

Example 29-16 6-Chloro(1H-imidazolyl)methylimidazo[1,2-b]pyridazine 8-Bromochloromethylimidazo[1,2-b]pyridazine (500 mg, 2.0 mmol, prepared according to Example 43) was combined with K2CO3 (550 mg, 4.0 mmol) and 1H-imidazole (250 mg, 0.36 mmol) in NMP (5 mL). The mixture was stirred at 120 °C for 16 h. The mixture was ioned between EtOAc and H2O. The organic layer was washed with brine, dried over , filtered and concentrated. The residue was chromatographed on silica gel, g with 0-30% EtOAc in petroleum ether to yield 6-chloro(1H-imidazolyl)methylimidazo[1,2-b]pyridazine (228 mg, 48%). MS m/z 234.0, 236.0 [M+H]+.

Example 29-17 6-Chloromethylphenoxyimidazo[1,2-b]pyridazine 8-Bromochloromethylimidazo[1,2-b]pyridazine (1.0 g, 4.0 mmol) was combined with K2CO3 (1.1 g, 8 mmol) and phenol (0.6 g, 6.0 mmol) in NMP (10 mL). The mixture was stirred at 60 °C for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in petroleum ether to yield 6-chloro methylphenoxyimidazo[1,2-b]pyridazine (560 mg, 53%). MS m/z 260.0, 262.0 [M+H]+.

Example 29-18 6-Chloroisopropylmethylimidazo[1,2-b]pyridazine Step A: ochloromethylimidazo[1,2-b]pyridazine (500 mg, 2.05 mmol, prepared according to example 43) was combined with vinylboronic acid pinacol ester (0.43 mL, 2.3 mmol), Pd(dppf)Cl2 (150 mg, 0.21 mmol) and K2CO3 (850 mg, 6.15 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL). The mixture was stirred at 90 °C for 2 h under N2. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with -20% EtOAc in petroleum ether to yield 6-chloromethyl(propenyl)imidazo[1,2- b]pyridazine (300 mg, 77%). MS m/z 208.0, 210.0 .

Step B: 6-Chloromethyl(propenyl)imidazo[1,2-b]pyridazine (250 mg, 1.21 mmol) was combined with PtO2 (30 mg, 0.13 mmol) in EtOAc (10 mL). The mixture was stirred at room temperature for 3 h under an atmosphere of H2. The mixture was filtered over Celite, and the filtrate was removed under reduce pressure. The residue was chromatographed on silica gel, eluting with 20-35% EtOAc in petroleum ether to yield 6-chloroisopropyl methylimidazo[1,2-b]pyridazine (200 mg, 80%). MS m/z 210.0, 212.0 [M+H]+.

Example 29-19 6-Chloromethylpropylimidazo[1,2-b]pyridazine 8-Bromochloromethylimidazo[1,2-b]pyridazine (1 g, 4.1 mmol, ed according to Example 43) was ed with propylmagnesiumbromide (660 mg, 4.5 mmol) and iron(III) 2,4- pentanedionate (140 mg, 0.4 mmol) in dry THF (30 mL). The mixture was stirred at 50 °C for 1 h under N2. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The e was tographed on silica gel, eluting with 20-30% EtOAc in eum ether to yield 6-chloromethyl imidazo[1,2-b]pyridazine (230 mg, 27%). MS m/z 210.0, 212.0 [M+H]+.

Example 30 Preparation of Compound 78 7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro(4-piperidyl)cinnoline dihydrochloride (55 mg, 0.13 mmol, prepared in Example 7) was combined with Cs2CO3 (85 mg, 0.26 mmol), 2- iodopropane (26 µL, 0.26 mmol) and DMF (1 mL). The mixture was stirred at 60 °C for 4 h. The mixture was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to yield 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)- -fluoro(1-isopropylpiperidyl)cinnoline (6 mg, 11%).

MS m/z 419.4 [M+H]+; 1H NMR nol-d 4) δ: 8.92 (s, 1H), 8.32 (dd, J = 11.0, 1.5 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.91 - 4.02 (m, 2H), 3.61 - 3.68 (m, 1H), 3.24 - 3.33 (m, 2H), 2.73 (s, 3H), 2.56 - 2.62 (m, 1H), 2.52 (s, 3H), 2.20 - 2.26 (m, 2H), 2.06 - 2.16 (m, 2H), 1.21 (d, J = 7.2 Hz, 6H).

Using the procedure bed for Example 30, above, additional compounds described herein were prepared by substituting the appropriate aryl halide, suitable reagents and reaction conditions, obtaining compounds such as those ed from: Cpd Data 83 MS m/z 423.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.17 (s, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.43 - 8.47 (m, 2H), 8.35 (s, 1H), 4.98 (ddd, J = 47, 5.1, 3.7 Hz, 2H), 3.89 - 3.95 (m, 2H), 3.63 - 3.73 (m, 3H), 3.40 - 3.48 (m, 2H), 2.88 (d, J = 0.9 Hz, 3H), 2.71 (d, J = 0.9 Hz, 3H), 2.46 - 2.53 (m, 4H), HCl protons not observed. 98 MS m/z 441.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.15 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.44 (dd, J = 10.7, 1.5 Hz, 1H), 8.41 (d, J = 0.9 Hz, 1H), 8.34 (s, 1H), 6.53 (tt, J = 53.7, 3.5 Hz, 1H), 3.82 - 3.96 (m, 4H), 3.64 - 3.71 (m, 1H), 3.49 - 3.59 (m, 2H), 2.87 (d, J = 1.2 Hz, 3H), 2.69 (d, J = 0.9 Hz, 3H), 2.46 - 2.57 (m, 4H), HCl protons not observed. 168 MS m/z 433.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.92 (s, 1H), 8.32 (d, J = 11 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.60 (m, 1H), 3.30 (br s, 4H), 2.73 (s, 3H), 2.52 (s, 3H), 2.26 - 2.32 (m, 2H), 2.01 (m, 2H), 1.41 (d, J = 6 Hz, 6H), 1.21 (m, Cpd Data 170 MS m/z 451.6 [M+H]+; 1H NMR nol-d 4) δ: 8.90 (s, 1H), 8.30 (d, J = 10.5 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 4.64 (dd, J = 50, 5.0 Hz, 2H), 3.51 (m, 1H), 3.15-3.32 (m, 2H), 3.07 (br s, 2H), 2.73 (s, 3H), 2.52 (s, 3H), 2.13 (d, J = 12.5 Hz, 2H), 1.85 (q, J = 12 Hz, 2H), 1.32 (d, J = 6 Hz, 6H). 199 MS m/z 437.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.90 (s, 1H), 8.29 (d, J = 10 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 4.64 (dd, J = 50, 5.0 Hz, 2H), 3.60 (m, 1H), 3.13 - 3.19 (m, 1H), 2.95 - 3.08 (m, 5H), 2.72 (s, 3H), 2.52 (s, 3H), 2.00 - 2.30 (m, 5H), 1.90 - 2.00 (m, 1H).

Example 31 Preparation of Compound 158 Step A: A solution of oxalyl chloride (105 µL, 1.2 mmol) in CH2Cl2 (1.4 mL) was cooled to −78 °C. To the solution was added DMSO (150 µL, 2.1 mmol) in CH2Cl2 (0.5 mL). The solution was stirred at −78 °C for 30 min. To the solution was added 3-(dimethylamino)propanol (55 mg, 0.53 mmol) in CH2Cl2 (1 mL). The solution was stirred for 30 min at −78 °C. ylamine (42 µL, 0.30 mmol) was added to the solution. The mixture was allowed to slowly warm to 0 °C over ~30 min. The excess reagent was quenched by the addition of aqueous saturated NaHCO3. The organic layer was removed and dried over Na2SO4, filtered and trated. The crude product was used directly in the next step without additional purification.

Step B: 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(4-piperidyl)cinnoline dihydrochloride (45 mg, 0.10 mmol, prepared in Example 7) was combined with CH2Cl2 (2 mL), triethylamine (42 µL, 0.30 mmol), and EtOH (0.2 mL). To the mixture was added 3- (dimethylamino)propanal (53 mg, 0.52 mmol, from Step A) in CH2Cl2 (0.5 mL). The mixture was stirred at room temperature until homogeneous, and then sodium triacetoxyborohydride (64, 0.30 mmol) was added. After stirring for 20 min at room temperature, the e was concentrated.

The e was dissolved in TFA and CH2Cl2 and was dried onto Celite. The dry material was chromatographed on a reverse phase C18 , eluting with 5-60% CH3CN (0.1% TFA) in H2O (0.1% TFA). The collected fractions were concentrated. The residue was ioned in CH2Cl2 and aqueous 1 M K2CO3. The organic layer was loaded onto silica gel, eluting with 0- % MeOH (2 N NH3) in CH2Cl2 to afford 3-[4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluoro-cinnolinyl]piperidyl]-N,N-dimethyl-propanamine (7 mg, 15%).

MS m/z 462.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.96 (s, 1H), 8.36 (dd, J = 11.0, 1.5 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 3.54 - 3.60 (m, 2H), 3.46 - 3.53 (m, 1H), 3.20 - 3.26 (m, 2H), 2.99 - 3.08 (m, 2H), 2.92 (s, 6H), 2.81 - 2.90 (m, 2H), 2.74 (d, J = 0.9 Hz, 3H), 2.53 (s, 3H), 2.26 - 2.37 (m, 4H), 2.14 (quin, J = 7.2 Hz, 2H).

Using the procedure described for Example 31, above, additional compounds described herein were prepared by substituting the appropriate alcohol in Step A, suitable reagents and reaction ions, obtaining compounds such as those ed from: Cpd Data 145 MS m/z 535.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.91 (s, 1H), 8.31 (dd, J = 10.8, 1.4 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 4.45 (t, J = 6.6 Hz, 2H), 3.23 -3.31 (m, 1H), 3.12 (br d, J = 11.3 Hz, 2H), 2.73 (s, 3H), 2.52 (s, 3H), 2.47 (t, J = 6.6 Hz, 2H), 2.16 - 2.28 (m, 4H), 2.01 - 2.15 (m, 4H), HCl protons not observed. 159 MS m/z 521.2 [M+H]+; 1H NMR (methanol-d 4) δ: 8.94 (s, 1H), 8.34 (dd, J = 10.7, 1.3 Hz, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.51 (t, J = 6.4 Hz, 2H), 3.24 - 3.31 (m, 1H), 3.18 (br d, J = 11.3 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.75 (s, 3H), 2.53 (s, 3H), 2.39 - 2.46 (m, 2H), 2.02 - 2.20 (m, 4H). 160 MS m/z 485.5 [M+H]+; 1H NMR (methanol-d 4) δ: 8.89 (s, 1H), 8.29 (dd, J = 11.0, 1.2 Hz, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 6.32 (t, J = 2.1 Hz, 1H), 4.29 (m, 2H), 3.26 - 3.31 (m, 1H), 3.20 (br d, J = 11.6 Hz, 2H), 2.72 (d, J = 0.9 Hz, 3H), 2.51 (s, 3H), 2.46 - 2.50 (m, 2H), 2.28 - 2.36 (m, 2H), 2.07 - 2.21 (m, 6H).

Example 32 Preparation of Compound 127 Step A: 2-[4-[7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl] piperidyl]ethanol dihydrochloride (200 mg, 0.41 mmol, ed in Example 19) was combined with CH2Cl2 (4 mL) and triethylamine (0.22 mL, 1.6 mmol). To the mixture was added methanesulfonyl chloride (137 µL, 0.81 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was washed with aqueous 1 M K2CO3. The organic layer was Loaded onto silica gel, eluting with 0-10% MeOH (2 N NH3) in CH2Cl2 to provide 2- [4-[7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]piperidyl]ethyl methanesulfonate. MS m/z 499.4 [M+H]+.

Step B: 2-[4-[7-(2,8-Dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl] piperidyl]ethyl methanesulfonate (30 mg, 0.06 mmol) was combined with N,N- diisopropylethylamine (105 µL, 0.60 mmol), DMF (1 mL) and dimethylamine hydrochloride (55 mg, 0.60 mmol). The mixture was heated at 40 °C for 18 h. The volatile material was removed.

The residue was dissolved in TFA and CH2Cl2 and was dried onto Celite. The dry material was chromatographed on a reverse phase C18 column, eluting with 5-65% CH3CN (0.1% TFA) in H2O (0.1% TFA). The collected al was concentrated. The residue was dissolved in 1.25 M HCl in MeOH. The volatiles were d. The residue was ded in CH3CN, sonicated, ted by filtration and dried yielding 2-[4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl) fluoro-cinnolinyl]piperidyl]-N,N-dimethyl-ethanamine trihydrochloride (13 mg, 39%).

MS m/z 448.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.15 (s, 1H), 8.56 (m, 1H), 8.43 (d, J = 9.5 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 3.93 (br s, 2H), 3.68 - 3.83 (m, 5H), 3.46 (br d, J = 10.4 Hz, 2H), 3.07 (s, 6H), 2.87 (s, 3H), 2.70 (s, 3H), 2.48 - 2.63 (m, 4H), HCl protons not observed.

Example 33 Preparation of nd 141 Step A: 8-Bromochloromethyl-imidazo[1,2-b]pyridazine (124 mg, 0.50 mmol) was combined with 3-(1H-pyrazolyl)propanol (252 mg, 2.0 mmol) and cesium carbonate (650 mg, 2.0 mmol) in CH3CN (4 mL). The mixture was stirred at 40 °C for 16 h. To the mixture was added EtOAc (10 mL). The mixture was filtered over Celite. The filtrate was trated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in EtOAc to yield 6- chloromethyl(3-pyrazolylpropoxy)imidazo[1,2-b]pyridazine (70 mg, 48%). MS m/z 292.3 [M+H]+.

Step B: tert-Butyl 4-(7-chlorofluoro-cinnolinyl)piperidinecarboxylate (73 mg, 0.20 mmol, prepared in Example 29) was combined with bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (59 mg, 0.60 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'- amino-1,1'-biphenylyl) ium(II) (14 mg, 0.02 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 90 °C for 1 h. To the mixture was added aqueous 1 M K2CO3 (1 mL), followed by another n of chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- biphenyl)(2'-amino-1,1'-biphenylyl) palladium(II) (14 mg, 0.02 mmol) and 6-chloromethyl- 8-(3-pyrazolylpropoxy)imidazo[1,2-b]pyridazine (70 mg, 0.24 mmol) (in 1 mL of 1,4- dioxane). The e was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in EtOAc to yield tert-butyl 4-[5-fluoro[2-methyl(3-pyrazol ylpropoxy)imidazo[1,2-b]pyridazinyl]cinnolinyl]piperidinecarboxylate (110 mg, 94%).

MS m/z 587.3 [M+H]+.

Step C: tert-Butyl 4-[5-fluoro[2-methyl(3-pyrazolylpropoxy)imidazo[1,2-b]pyridazin yl]cinnolinyl]piperidinecarboxylate (110 mg, 0.18 mmol) was dissolved in trifluoroacetic acid (1 mL) and 1 mL CH2Cl2. The solution was dried onto Celite. The dry material was chromatographed on a reverse phase C18 column, eluting with 5-65% CH3CN (0.1% TFA) in H2O (0.1% TFA). The desired fractions were concentrated. The residue was ved in 1.25 M HCl in MeOH. The volatiles were removed. The residue was suspended in CH3CN, sonicated, filtered and dried to yield 5-fluoro[2-methyl(3-pyrazolylpropoxy)imidazo[1,2- dazinyl](4-piperidyl)cinnoline dihydrochloride (66 mg, 63%) as a pale yellow solid.

MS m/z 487.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.18 (s, 1H), 8.44 (d, J = 10.7 Hz, 1H), 8.40 (d, J = 0.6 Hz, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 6.41 (t, J = 2.3 Hz, 1H), 4.67 (t, J = 6.7 Hz, 2H), 4.58 (t, J = 6.7 Hz, 2H), 3.63 - 3.70 (m, 3H), 3.29 - 3.35 (m, 2H), 2.70 (s, 3H), 2.59 (quin, J = 6.3 Hz, 2H), 2.33 - 2.45 (m, 4H), NH and HCl protons not observed.

Using the procedure described for Example 33, above, additional compounds described herein were ed by substituting the appropriate alcohol in Step A, suitable ts and reaction conditions, obtaining compounds such as those ed from: Cpd Data 138 MS m/z 450.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.20 (s, 1H), 8.46 (dd, J = 10.7, 1.2 Hz, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 5.06 (t, J = 5.0 Hz, 2H), 3.90 (t, J = .0 Hz, 2H), 3.63 - 3.71 (m, 3H), 3.29 - 3.37 (m, 2H), 3.12 (s, 6H), 2.69 (s, 3H), 2.32 - 2.46 (m, 4H), NH and HCl protons not observed. 139 MS m/z 464.5 [M+H]+; 1H NMR nol-d 4) δ: 9.19 (s, 1H), 8.45 (dd, J = 10.5, 1.4 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 4.82 (t, J = 6.1 Hz, 2H), 3.63 - 3.70 (m, 3H), 3.55 - 3.60 (m, 2H), 3.28 - 3.37 (m, 2H), 3.03 (s, 6H), 2.70 (s, 3H), 2.49 - 2.56 (m, 2H), 2.31 - 2.45 (m, 4H), NH and HCl protons not observed. 140 MS m/z 473.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.16 (s, 1H), 8.42 (d, J = 10.4 Hz, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.63 (s, 1H), 6.40 (t, J = 2.1 Hz, 1H), 5.01 - 5.06 (m, 2H), 4.85 - 4.90 (m, 2H), 3.63 - 3.71 (m, 3H), 3.29 - 3.37 (m, 2H), 2.69 (s, 3H), 2.32 - 2.46 (m, 4H), NH and HCl protons not Cpd Data 142 MS m/z 487.4 [M+H]+; 1H NMR (methanol-d 4) δ: 9.19 (s, 2H), 8.45 (dd, J = 10.5, 1.4 Hz, 1H), 8.41 (d, J = 0.9 Hz, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 4.77 (t, J = 5.8 Hz, 2H), 4.71 (t, J = 7.3 Hz, 2H), 3.62 - 3.71 (m, 3H), 3.29 - 3.37 (m, 2H), 2.71 (s, 3H), 2.65 - 2.70 (m, 2H), 2.32 - 2.45 (m, 4H), NH and HCl s not observed. 150 MS m/z 537.4 [M+H]+; 1H NMR (methanol-d4) δ: 9.72 (s, 1H), 9.16 (s, 1H), 8.44 (d, J = 10.6 Hz, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.11-8.16 (m, 1H), 8.08 (s, 1H), 7.89 - 7.95 (m, 1H), 7.68 - 7.77 (m, 2H), 5.00 (t, J = x Hz, 2H), 4.83 (t, J = x Hz, 2H), 3.63 - 3.70 (m, 3H), 3.28 - 3.37 (m, 2H), 2.80 (dt, J = 13.4, 6.4 Hz, 2H), 2.72 (d, J = 0.9 Hz, 3H), 2.31 - 2.45 (m, 4H), NH proton not observed.

Example 34 Preparation of nd 223 Step A: A screw-cap tube was charged with 3-chloro(2,8-dimethylimidazo[1,2-b]pyridazin yl)fluoro-cinnoline (0.037 g, 0.11 mmol), tert-butyl N-[(1S*,5R*)azabicyclo[3.1.0]hexan yl]carbamate (0.034 g, 0.17 mmol), ar cesium carbonate (0.110 g, 0.338 mmol), and RuPhos Pd G4 pre-catalyst (0.0011 g, 0.0013 mmol). Anhydrous 1,4-dioxane (5 mL) was added last, and the mixture was sparged with argon for 10 minutes. The vial was tightly capped with a screw-cap, placed on a pre-heated aluminum block, and stirred vigorously at 100 C for 2 h. After this time, the reaction mixture was cooled to room temperature. The brown, heterogeneous reaction mixture was diluted with sat. aq. Na2CO3 (20 mL) and extracted with CH2Cl2 (2 x 30 mL). The combined CH2Cl2 extracts were diluted with more CH2Cl2 (30 mL) and washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.

The brown, crude t was ed by silica gel column tography (CH2Cl2/methanolic ammonia (1.0M) gradient elution) to afford the desired tert-butyl N-[(1S*,5R*)[7-(2,8- ylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]azabicyclo[3.1.0]hexan yl]carbamate (0.048 g, 87%) as a yellow solid.

MS m/z 490.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.54 (s, 1H), 7.97 (dd, J = 11.3, 1.2 Hz, 1H), 7.97 (d, J = 1.3 Hz, 1H), 7.47 (s, 1H), 6.76 (s, 1H), 4.83 (br s, 1H), 4.07 (br d, J = 9.6 Hz, 2H), 3.72 (br d, J = 9.9 Hz, 2H), 2.76 (s, 3H), 2.55 (s, 3H), 2.46 (br s, 1H), 2.00 (br s, 2H), 1.47 (m, Step B: tert-Butyl *,5R*)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl ]azabicyclo[3.1.0]hexanyl]carbamate (0.048 g, 0.098 mmol) was dissolved in CH2Cl2 (5 mL), and trifluoroacetic acid (0.10 mL, 1.3 mmol) was added dropwise to the yellow solution, resulting in instantaneous color change to a wine red. The reaction mixture was capped and allowed to sit at room temperature for 17 h. After this time, the wine-red solution was concentrated on a rotovap. The red, crude oil was purified by C18 e-phase column chromatography (H2O:MeCN (0.1% TFA) gradient elution) to afford (1S*,5R*)[7-(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]azabicyclo[3.1.0]hexanamine tetra(trifluoroacetic acid) (0.054 g, 65%) as a dark red oil. MS m/z 390.3 [M+H]+.

Step C: (1S*,5R*)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl] azabicyclo[3.1.0]hexanamine tetra(trifluoroacetic acid) (0.050 g, 0.059 mmol), was dissolved in CH2Cl2 (3 mL) in a screw-top vial. A 37% aqueous solution of formaldehyde (0.018 mL, 0.24 mmol) was added, followed by anhydrous MgSO4 (0.021 g, 0.17 mmol), triethylamine (0.025 mL, 0.18 mmol), and NaBH(OAc)3 (0.031 g, 0.15 mmol). The vial was sealed with a screw-cap, and the reaction mixture was stirred vigorously at room temperature for 5 days. After this time, the on mixture was diluted with CH2Cl2 (30 mL), washed with sat. aq. Rochelle’s salt (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4, decanted, and concentrated on a rotovap to afford a dark yellow solid/oil mixture. The crude product was purified by silica gel column chromatography (CH2Cl2/methanolic ammonia (1.0 M) gradient) to afford the desired (1S*,5R*)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-cinnolinyl]-N,N- dimethylazabicyclo[3.1.0]hexanamine (0.021 g, 85%) as a yellow solid.

MS m/z 418.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.54 (s, 1H), 7.98 (dd, J = 11.3, 1.3 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 6.76 (s, 1H), 3.83 (ABq, J = 126.7, 9.6 Hz, 4H), 2.74 (s, 3H), 2.54 (s, 3H), 2.40 (s, 6H), 1.93 (s, 2H), 1.57 (s, 1H).

Using the procedure described for Example 34, above, additional compounds bed herein were prepared by substituting the appropriate amine in Step A, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data 80 MS m/z 378.4 [M+H]+; 1H NMR d 6) δ: 9.29 (br s, 2H), 8.94 (s, 1H), 8.44 (br s, 1H), 8.39 (br s, 1H), 8.19 (dd, J = 11.3, 1.3 Hz, 1H), 7.60 (s, 1H), 4.06 - 4.20 (m, 4H), 3.26 - 3.35 (m, 4H), 2.73 (s, 3H), 2.54 (s, 3H). 81 MS m/z 406.4 [M+H]+; 1H NMR (DMSO-d 6) δ: 9.53 (br s, 1H), 9.11 (br s, 1H), 8.93 (s, 1H), 8.45 (br s, 1H), 8.39 (br s, 1H), 8.19 (d, J = 11.3 Hz, 1H), 7.67 (s, 1H), 4.87 (br d, J = 12.0 Hz, 2H), 3.45 (br s, 2H), 3.12 (dd, J = 14.2, 11.7 Hz, 2H), 2.73 (s, 3H), 2.54 (m, 3H), 1.39 (d, J = 6.3 Hz, 6H). 86 MS m/z 406.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.44 (s, 1H), 7.84 - 7.94 (m, 2H), 7.66 (s, 1H), 6.90 (s, 1H), 3.92 - 4.00 (m, 1H), 3.83 - 3.90 (m, 1H), 3.54 - 3.62 (m, 1H), 3.35 - 3.46 (m, 2H), 2.99 - 3.08 (m, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.42 (s, 6H), 1.99 - 2.09 (m, 1H). 88 MS m/z 420.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.50 (s, 1H), 7.96 (dd, J = 11.4, 1.4 Hz, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 4.64 - 4.73 (m, 2H), 3.02 - 3.13 (m, 2H), 2.67 (s, 3H), 2.57 (tt, J = 11.3, 3.8 Hz, 1H), 2.48 (s, 3H), 2.37 (s, 6H), 2.10 (br d, J = 12.2 Hz, 2H), 1.60 (qd, J = 12.2, 4.0 Hz, 2H). 89 MS m/z 406.3 [M+H]+; 1H NMR nol-d 4) δ: 8.49 (s, 1H), 7.95 (dd, J = 11.6, 1.5 Hz, 1H), 7.89 (d, J = 0.6 Hz, 1H), 7.70 (d, J = 0.9 Hz, 1H), 6.94 (s, 1H), 3.95 - 4.02 (m, 1H), 3.85 - 3.92 (m, 1H), 3.60 (td, J = 10.1, 7.0 Hz, 1H), 3.40 - 3.47 (m, 1H), 2.99 - 3.07 (m, 1H), 2.68 (d, J = 0.9 Hz, 3H), 2.48 (s, 3H), 2.38 - 2.45 (m, 7H), 1.99 - 2.08 (m, 1H). 209 MS m/z 404.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.55 (s, 1H), 7.99 (dd, J = 11.3, 1.4 Hz, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 5.13 (bs, 1H), 3.74 (d, J = 9.3 Hz, 1H), 3.69 (s, 1H), 3.57 (dd, J = 9.7, 1.7 Hz, 1H), 3.09 (dd, J = 9.9, 1.4 Hz, 1H), 2.80 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 2.48 (s, 3H), 2.15 (d, J = 9.6 Hz, 1H), 1.99 (d, J = 9.7 Hz, 1H). 215 MS m/z 404.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.55 (s, 1H), 7.99 (dd, J = 11.3, 1.3 Hz, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 5.13 (bs, 1H), 3.73 (bs, 1H), 3.68 (bs, 1H), 3.57 (d, J = 9.0 Hz, 1H), 3.09 (d, J = 9.3 Hz, 1H), 2.80 (bs, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 2.48 (s, 3H), 2.15 (d, J = 9.5 Hz, 1H), 2.00 (d, J = 9.5 Hz, 1H). 217 MS m/z 404.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.77 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 10.7 Hz, 1H), 7.58 (s, 1H), 4.48 (ABq, J = 36.1, 9.0 Hz, 4H), 3.68 (s, 2H), 3.47 (dd, J = 7.4 Hz, 2H), 2.84 (s, 3H), 2.68 (s, 3H), 2.50 (dd, J = 7.3 Hz, 2H), Cpd Data NH and HCl protons not observed. 218 MS m/z 418.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.82 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.18 (d, J = 10.8 Hz, 1H), 7.28 (s, 1H), 4.21 (ABq, J = 59.7, 8.7 Hz, 4H), 3.53 (s, 2H), 3.23 - 3.18 (m, 2H), 2.83 (s, 3H), 2.68 (s, 3H), 2.14 - 2.06 (m, 2H), 1.97 - 1.90 (m, 2H), NH and HCl protons not observed. 219 MS m/z 418.3 [M+H]+; 1H NMR (methanol-d4) δ: 8.43 (s, 1H), 7.90 (dd, J = 11.5, 1.3 Hz, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.25 (s, 1H), 3.98 (s, 4H), 3.81 (ddd, J = 7.5, 3.7, 1.9 Hz, 4H), 2.61 (s, 3H), 2.45 (s, 3H), 2.04 (ddd, J = 7.4, 3.7, 1.9 Hz, 4H), NH and TFA protons not observed. 220 MS m/z 404.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.63 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.00 (dd, J = 11.2, 1.0 Hz, 1H), 6.99 (s, 1H), 4.23 (ABq, J = 51.2, 11.5 Hz, 4H), 4.00 (s, 2H), 3.74 (dd, J = 6.9 Hz, 2H), 2.74 (s, 3H), 2.59 (s, 3H), 2.51 (dd, J = 7.0 Hz, 2H), NH and TFA protons not ed. 221 MS m/z 418.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.73 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.08 (d, J = 11.2 Hz, 1H), 7.04 (s, 1H), 4.13 (s, 4H), 3.28 (dd, J = 7.3, 5.7 Hz, 4H), 2.77 (s, 3H), 2.62 (s, 3H), 2.18 (dd, J = 7.3, 5.6 Hz, 4H), NH and TFA protons not observed. 224 MS m/z 434.3 [M+H]+; 1H NMR (chloroform-d) δ: 8.56 (s, 1H), 7.98 (dd, J = 11.3, 1.3 Hz, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.09 (s, 1H), 3.92 - 3.79 (m, 4H), 2.74 (s, 3H), 2.54 (s, 3H), 2.29 (s, 6H), 2.00 (dd, J = 13.7, 5.9 Hz, 2H), 1.67 (dt, J = 12.9, 5.9 Hz, 2H), 1.03 (s, 3H).

Example 35 Preparation of Compound 203 Step A: A culture tube was charged with tert-butyl 4-[3-(2,7-dimethylindazolyl)fluorocinnolinyl ]-3,6-dihydro-2h-pyridinecarboxylate (20 mg, 0.0422 mmol, potassium osmate(VI) dihydrate (2.00 mg, 0.00543 mmol), 4-methylmorpholine N-oxide (11.0 mg, 0.0911 mmol), e (0.2 ml) and water (0.053 ml, 2.9 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by the dropwise addition of sat’d aqueous NaHSO3, with ng for 5 min. The resulting black sion was extracted with EtOAc. The combined organic extracts were washed with water, dried and concentrated to furnish tert-butyl 4-[3-(2,7-dimethylindazolyl)fluoro-cinnolinyl]-3,4-dihydroxy-piperidine carboxylate (cis-diol, racemate) (14.0 mg, 0.0276 mmol, 65.3% yield) as a yellow solid. MS m/z 508.2 [M+H]+.

Step B: A vial was charged with tert-butyl 2,7-dimethylindazolyl)fluoro-cinnolin yl]-3,4-dihydroxy-piperidinecarboxylate (7.00 mg, 0.0138 mmol), trifluoroacetic acid (0.22 ml, 2.9 mmol) and romethane (0.5 ml). The mixture was stirred at room temperature for 1h.

The mixture was concentrated. To the mixture was added 1.25 N HCl in methanol (1 mL). The e concentrated (this step was repeated three . The solid was washed with ethyl acetate, ether and hexanes in a fritted funnel and then freeze dried to give 4-(3-(2,7-dimethyl-2H- indazolyl)fluorocinnolinyl)piperidine-3,4-diol hydrogen chloride (cis-diol, racemate) (7.3 mg, 0.018 mmol, 100% yield).

MS m/z 408.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.69 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 11 Hz, 1H), 4.35 (dd, J = 5, 1.5 Hz, 1H), 4.30 (s, 3H), 3.40 (m, 6H), 2.70 (s, 3H). NH and OH protons not observed.

Example 36 Preparation of nd 146 Step A: 2,6-Dimethylpyridinol (996 mg, 8.1 mmol) was dissolved in aqueous sodium hydroxide (2.0 M, 4.1 mL) while ng at room temperature. To this stirred solution was added iodine (2.65 g, 10.4 mmol). The mixture was warmed to 50 °C and stirred for 3 h. The mixture was neutralized with aqueous hydrochloric acid (6 M), then quenched with saturated aqueous sodium thiosulfate solution. MeOH (5 mL) was added to the mixture, and then the reaction mixture was concentrated. CH2Cl2 (90 mL) and MeOH (10 mL) were added, the reaction was stirred for 10 min, then ed. The filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield 4-iodo-2,6-dimethyl-pyridinol (564.6 mg, 28%).

MS m/z 250.1 [M+H]+; 1H NMR (methanol-d 4) δ: 7.61 (s, 1H), 2.47 (s, 3H), 2.39 (s, 3H), OH proton not observed.

Step B: tert-Butyl 4-(7-chlorofluoro-cinnolinyl)piperidinecarboxylate (500 mg, 1.37 mmol), sodium tert-butoxide (198 mg, 2.06 mmol), and chloro(2-dicyclohexylphosphino-2’,6’- dimethoxy-1,1’-biphenyl)[2-2’-amino-1,1’-biphenyl)]palladium(II) (103 mg, 0.14 mmol), 1,4- dioxane (10 mL), and diphenylmethanimine (260 uL, 1.55 mmol) were combined, argon degassed, and heated to 100 °C for 16 h. After cooling the reaction mixture to room temperature, hydroxylamine hloride (445 mg, 6.4 mmol), potassium acetate (815 mg, 8.3 mmol) and methanol (30 mL) were added. The reaction mixture was stirred at room temperature for 7 h. The mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was tographed on silica gel, eluting with 0-10% MeOH in CH2Cl2 to yield tert-butyl 4-(7-aminofluoro-cinnolin- 3-yl)piperidinecarboxylate (337 mg, 71%).

MS m/z 347.3 ; 1H NMR nol-d 4) δ: 7.87 (s, 1H), 7.14 (s, 1H), 7.06 (dd, J = 11.6, 1.8 Hz, 1H), 4.30 (d, J = 13.7 Hz, 2H), 3.29 (tt, J = 12.2, 3.7 Hz, 1H), 2.92-3.11 (m, 2H), 2.04 (d, J = 12.2 Hz, 2H), 1.87 (qd, J = 12.6, 4.3 Hz, 2H), 1.51 (s, 9H), NH2 protons not observed.

Step C: utyl 4-(7-aminofluoro-cinnolinyl)piperidinecarboxylate (187 mg, 0.54 mmol) was ved in trifluoroacetic acid (4.0 mL) and stirred at room temperature for 5 min.

Sodium nitrite (43 mg, 0.63 mmol) was added to the mixture, which was stirred at room temperature for 10 min. The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (4.0 mL) and water (1.0 mL). To this stirred solution at room temperature was added potassium iodide (394 mg, 2.37 mmol) portion wise. The mixture was d for 20 min at room temperature. Diisopropylethylamine (1.4 mL, 8.0 mmol) and di-tert-butyl dicarbonate (800 uL, 3.35 mmol) were added to the mixture. The mixture was stirred at room ature for 18 h. The mixture was concentrated, and the residue was chromatographed on silica gel, eluting with 0-100% EtOAc in s to yield tert-butyl 4-(5-fluoroiodocinnolin yl)piperidinecarboxylate (119 mg, 48%).

MS m/z 402.3 [M+H-tBu]+; 1H NMR (CDCl 3) δ: 8.82 (s, 1H), 7.84 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 4.36 (br s, 2H), 3.45 (tt, J = 12.2, 3.7 Hz, 1H), 2.97 (t, J = 11.0 Hz, 2H), 2.15 (br d, J = 13.1 Hz, 2H), 1.91 (qd, J = 12.5, 4.3 Hz, 2H), 1.50 - 1.54 (m, 9H).

Step D: tert-butyl 4-(5-fluoroiodocinnolinyl)piperidinecarboxylate, curprous iodide (1.0 mg, 0.0053 mmol), and bis(triphenylphosphine)palladium(II) dichloride (6.2 mg, 0.0088 mmol) were combined under a nitrogen atmosphere, followed by the addition of CH3CN (2.0 mL). The solution was argon degassed for 30 s, followed by the addition of trimethylamine (40 uL, 0.29 mmol). The solution was argon degassed for 3 min, followed by the addition of trimethylsilylacetylene (20 uL, 0.14 mmol). This mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The e was trated, and the residue was chromatographed on silica gel, eluting with 0-100% EtOAc in s to yield tert-butyl 4-(5- fluoro((trimethylsilyl)ethynyl)cinnolinyl)piperidinecarboxylate (24.5 mg, 72%). MS m/z 372.5 [M+H-t-Bu]+.

Step E: utyl 4-(5-fluoro((trimethylsilyl)ethynyl)cinnolinyl)piperidinecarboxylate (25 mg, 0.057 mmol) was dissolved in MeOH (2.0 mL). The stirred solution was cooled to 0 °C.

Potassium carbonate (17.9 mg, 0.130 mmol) was added and the reaction mixture continued stirring at 0 °C for 1 h. The reaction was quenched with sat’d aqueous NH4Cl (8.0 mL). The mixture was ioned between CH2Cl2 and H2O. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-(7-ethynylfluoro-cinnolinyl)piperidinecarboxylate as a crude mixture that was used without cation. MS m/z 300.0 [M+H-t-Bu]+. utyl 4-(7-ethynylfluorocinnolinyl )piperidinecarboxylate (20 mg, 0.057 mmol), s iodide (0.3 mg, 0.002 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.4 mg, 0.0063 mmol), and 4-iodo-2,6- dimethyl-pyridinol (15.8 mg, 0.063 mmol) were combined under a nitrogen atmosphere, followed by the addition of N,N-dimethylformamide (1.0 mL). The solution was argon degassed for 30 s, followed by the addition of trimethylamine (50.0 uL, 0.36 mmol). This solution was argon degassed for 5 min, then d at 45 °C under an argon atmosphere for 20 h. The mixture was concentrated, and the residue was chromatographed on silica gel, g with 0-30% MeOH in CH2Cl2 to yield tert-butyl 4-[7-(5,7-dimethylfuro[2,3-c]pyridinyl)fluoro-cinnolin yl]piperidinecarboxylate (10.3 mg, 38%). MS m/z 477.5 [M+H]+.

Step F: tert-Butyl 4-[7-(5,7-dimethylfuro[2,3-c]pyridinyl)fluoro-cinnolinyl]piperidine carboxylate (10.3 mg, 0.022 mmol) was dissolved in trifluoroacetic acid (2 mL). After 15 minutes, the volatile material was removed. The residue was chromatographed on a reversed phase C18 column, eluting with 0-100% CH3CN in H2O (0.1% v/v TFA ve). The collected fractions were concentrated. The residue was dissolved in 1.25 M HCl in MeOH. The volatile material was removed to yield 2-[5-fluoro(4-piperidyl)cinnolinyl]-5,7-dimethyl-furo[2,3- c]pyridine hydrochloride (8.3 mg, 93%).

MS m/z 377.5 [M+H]+; 1H NMR (methanol-d 4) δ: 9.11 (s, 1H), 8.48 (s, 1H), 8.40 (br d, J = 10.1 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 3.69 - 3.77 (m, 1H), 3.66 (br d, J = 12.8 Hz, 2H), 3.34 - 3.39 (m, 2H), 3.12 (s, 3H), 2.84 (s, 3H), 2.27 - 2.50 (m, 4H), NH and HCl protons not observed.

Example 37 Preparation of Compound 191 Step A: 4-Chloro-2,6-dimethylnitro-pyridine (1.1054 g, 5.9239 mmol), acetonitrile (4.0 mL), and aqueous hydroiodic acid (concentrated, 57%, 4.0 mL) were combined and heated to 70 °C for h. The mixture was ioned between , aqueous sat’d Na2CO3, and aqueous NaOH (1 M). The s layer was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated. The e was chromatographed on silica gel, eluting with 0- 100% EtOAc in hexanes to yield 4-iodo-2,6-dimethylnitro-pyridine (1.48 g, 90%). MS m/z 279.1 [M+H]+.

Step B: 4-Iodo-2,6-dimethylnitro-pyridine (1.004 g, 3.611 mmol), stannous chloride dihydrate (3.32 g, 14.7 mmol) and EtOAc (5.0 mL) were combined and heated to 60 °C for 10 min. The mixture was partitioned between EtOAc, aqueous sat’d Na2CO3 and aqueous NaOH (1 M). The aqueous layer was extracted with EtOAc. The combined organic phases were dried over , filtered and concentrated to yield -2,6-dimethyl-pyridinamine (723.7 mg, 81%). MS m/z 249.1 [M+H]+.

Step C: 4-Iodo-2,6-dimethyl-pyridinamine (724 mg, 2.92 mmol), di-tert-butyl dicarbonate (2.2 mL, 9.2 mmol), 4-dimethylaminopyridine (42 mg, 0.34 mmol) and CH2Cl2 (5.0 mL) were combined and stirred at 40 °C for 17 h. The e was concentrated, and the residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield tert-butyl N-tertbutoxycarbonyl-N- (4-iodo-2,6-dimethylpyridyl)carbamate (489 mg, 37%). MS m/z 449.4 [M+H]+.

Step D: tert-Butyl N-tert-butoxycarbonyl-N-(4-iodo-2,6-dimethylpyridyl)carbamate (489 mg, 1.1 mmol), s NaOH (1 M, 4.0 mL), and MeOH (4.0 mL) were combined and stirred at 70 °C for 7 h. The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted twice with MeOH/CH2Cl2 (1:9) and the ed organic phases were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0- 100% EtOAc in hexanes to yield tert-butyl N-(4-iodo-2,6-dimethylpyridyl)carbamate (278 mg, 73%). MS m/z 349.1 [M+H]+; 1H NMR (CDCl 7.54 (s, 1H), 6.00 (br d, J = 2.7 Hz, 1H), 2.57 3) δ: (s, 3H), 2.48 (s, 3H), 1.53 (s, 9H).

Step E: tert-Butyl 4-(5-fluoro((trimethylsilyl)ethynyl)cinnolinyl)piperidinecarboxylate (from Example 38, 104 mg, 0.24 mmol) was dissolved in ol (2.0 mL). The stirred solution was cooled to 0 °C. Potassium carbonate (50.6 mg, 0.366 mmol) was added and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with sat’d aqueous NH4Cl (8.0 mL).

The e was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated to yield utyl 4-(7-ethynylfluoro-cinnolinyl)piperidinecarboxylate as a crude mixture that was used without purification. MS m/z 300.0 [M+H-tBu]+. tert-Butyl 4-(7-ethynylfluorocinnolinyl )piperidinecarboxylate (86 mg, 0.24 mmol) was dissolved in DMF (1.0 mL). The vessel was purged with argon. ylamine (135 uL, 0.97 mmol) was added. The vessel was again purged with argon. This solution was added to a mixture of cuprous iodide (1.4 mg, 0.0073 mmol), bis(triphenylphosphine) palladium(II) dichloride (10.2 mg, 0.0146 mmol), and tert-butyl N-(4-iodo-2,6-dimethylpyridyl)carbamate (93 mg, 0.27 mmol) under an argon atmosphere. The solution was stirred at 50 °C for 17 h. The mixture was concentrated, and the residue partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated to yield utyl 4-[7-[2-[3-(tertbutoxycarbonylamino )-2,6-dimethylpyridyl]ethynyl]fluoro-cinnolinyl]piperidine carboxylate as a crude e that was used without purification. MS m/z 576.5 [M+H]+.

Step F: utyl 4-[7-[2-[3-(tert-butoxycarbonylamino)-2,6-dimethylpyridyl]ethynyl] fluoro-cinnolinyl]piperidinecarboxylate (140 mg, 0.24 mmol), tetrahydrofuran (4.0 mL), and tetrabutylammonium fluoride (1.0 M in THF, 730 uL, 0.73 mmol) were combined and d at 65 °C for 2 h. The on was concentrated and the e was chromatographed on silica gel, eluting with 0-30% MeOH in CH2Cl2 to yield tert-butyl 4-[7-(5,7-dimethyl-1H-pyrrolo[2,3- c]pyridinyl)fluoro-cinnolinyl]piperidinecarboxylate (34.2 mg, 30%). MS m/z 476.5 [M+H]+.

Step G: tert-Butyl 4-[7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro-cinnolin yl]piperidinecarboxylate (34.2 mg, 0.0719 mmol) was dissolved in trifluoroacetic acid (1 mL).

After 1 min, the volatile material was removed. The residue was chromatographed on a reversed phase C18 column, eluting with 0-100% CH3CN in H2O (0.1% v/v TFA additive), and subsequently chromatographed on silica gel, eluting with 0-100% MeOH (2.5% v/v NH4OH additive) in CH2Cl2, to yield 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro (piperidinyl)cinnoline hydrochloride.

MS m/z 376.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.95 (s, 1H), 8.23 (s, 1H), 8.22 (dd, J = 10.7, 1.2 Hz, 1H), 7.67 (s, 1H), 7.41 (s, 1H), 3.50 - 3.61 (m, 3H), 3.17 - 3.26 (m, 2H), 2.99 (s, 3H), 2.64 (s, 3H), 2.18 - 2.34 (m, 4H), NH and HCl protons not observed.

Example 38 Preparation of Compound 82 Step A: 5-Bromofluoro-benzene-1,2-diamine (1.07 g, 5.2 mmol), tert-butyl 4-(2- bromoacetyl)piperidinecarboxylate (1.60 g, 5.2 mmol), and DMF (80 mL) were combined and stirred at room temperature for 16 h, 50 °C for 24 h, and 70 °C for 24 h. After cooling to room temperature, potassium carbonate (1.08 g, 7.84 mmol) and t-butyl onate (1.4 mL, 6.3 mmol) were added. The reaction mixture was stirred at room ature for 2 h. The mixture was partitioned between EtOAc and brine. The organic layer was washed twice with brine, dried over , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield tert-butyl 4-(6-bromofluoro-quinoxalin yl)piperidinecarboxylate and tert-butyl 4-(7-bromofluoroquinoxalinyl)piperidine carboxylate as an approximate 1:1 mixture (labeled distinguishable peaks as compounds A and B in 1H NMR; labeled overlapping peaks as apparent peaks “apt”) (1.23 g, 58%).

MS m/z 310.2 [M+H-CO2-t-Bu]+; 1H NMR ) δ: 8.84 (s, 1H, A), 8.82 (s, 1H, B), 8.12 (t, J = 1.7 Hz, 1H, A), 8.09 (t, J = 1.7 Hz, 1H, B), 7.61 (dd, J = 9.2, 2.1 Hz, 1H, A), 7.58 (dd, J = 9.0, 2.0 Hz, 1H, B), 4.34 (apt d, J = 12.2 Hz, 4H), 3.17 (apt qt, J = 11.9, 3.7 Hz, 2H), 2.94 (apt br tt, J = 13.1, 2.8 Hz, 4H), 1.99 - 2.06 (m, 4H), 1.93 (apt quint J = 11.6, 4.0 Hz, 4H), 1.51 (apt d, J = 1.8 Hz, 18H).

Step B: A 1:1 mixture of tert-butyl 4-(6-bromofluoro-quinoxalinyl)piperidinecarboxylate and tert-butyl 4-(7-bromofluoroquinoxalinyl)piperidinecarboxylate was combined with sodium tert-butoxide (760 mg, 7.9 mmol), tris(dibenzylideneacetone) dipalladium(0) (74 mg, 0.08 mmol), racemic is(diphenylphosphino)-1,1’-binaphthyl (144 mg, 0.23 g), toluene (13.0 mL) and benzophenone imine (500 uL, 3.6 mmol) were combined under a nitrogen here. The vessel was argon purged for 6 min, then warmed to 80 °C for 20 h. Hydroxylamine hydrochloride (1.37 g, 19.6 mmol), potassium acetate (2.47 g, 25.2 mmol), and MeOH (65 mL) were added to the mixture. The mixture was stirred at room temperature for 24 h and then was concentrated. The e was partitioned between sat’d aqueous Na2CO3, brine, and CH2Cl2. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield tert-butyl minofluoro-quinoxalinyl)piperidinecarboxylate (340.0 mg, 38%).

MS m/z 291.3 [M+H-t-Bu]+; 1H NMR (DMSO-d 6) δ: 8.69 (s, 1H), 7.01 (dd, J = 12.5, 2.1 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.11 (s, 2H), 4.03 - 4.21 (m, 2H), 3.06 (tt, J = 11.5, 3.4 Hz, 1H), 2.89 (br s, 2H), 1.86 - 1.93 (m, 2H), 1.66 (qd, J = 12.6, 4.4 Hz, 2H), 1.43 (s, 9H).

Step C: Sodium nitrite (23.9 mg, 0.346 mmol) was added to a stirred solution of tert-butyl 4-(6- 8-fluoro-quinoxalinyl)piperidinecarboxylate in trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 1 min. The mixture was concentrated and oped twice with MeCN. The e was dissolved in acetonitrile (1.4 mL) and cooled to 0 °C. This solution was added dropwise to a solution of copper(I) chloride (47 mg, 0.47 mmol) and copper(II) chloride (95 mg, 0.71 mmol) in acetonitrile (1.2 mL) at 0 °C. After stirring for 1 min at 0 °C, the reaction mixture was partitioned between EtOAc, aqueous sat’d Na2CO3, and aqueous NaOH (1 M). The aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to yield 6-chlorofluoro(4- dyl)quinoxaline (130.0 mg) as a crude mixture that was used without purification. MS m/z 266.3 [M+H]+. 6-Chlorofluoro(4-piperidyl)quinoxaline (61 mg, 0.23 mmol), CH2Cl2 (3.0 mL), N,N-diisopropylethylamine (400 uL, 2.3 mmol), and di-tert-butyl dicarbonate (230 uL, 0.96 mmol) were combined and stirred at room temperature for 18 h. The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted twice with . The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-40% EtOAc in s to yield tert-butyl 4-(6- chlorofluoroquinoxalinyl)piperidinecarboxylate (52.7 mg, 50%).

MS m/z 310.3 [M+H-t-Bu]+; 1H NMR (CDCl 3) δ: 8.84 (s, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.48 (dd, J = 9.5, 2.1 Hz, 1H), 4.26 - 4.44 (m, 2H), 3.19 (tt, J = 11.7, 3.8 Hz, 1H), 2.94 (br t, J = 12.2 Hz, 2H), 2.04 (d, J = 11.9 Hz, 2H), 1.94 (qd, J = 12.2, 4.3 Hz, 2H), 1.52 (s, 9H).

Step D: 6-Chloro-2,8-dimethyl-imidazol[1,2-b]pyridazine (50.0 mg, 0.275 mmol), 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (15 mg, 0.019 mmol), bis(pinacolato)diboron (96 mg, 0.37 mmol), and potassium e (dried at 250 °C under vacuum immediately prior to using, 89 mg, 0.89 mmol), and 1,4-dioxane (1.5 mL) were combined. The mixture stirred under argon at 95 °C for 2 h. tert-Butyl 4-(6-chlorofluoro-quinoxalin eridinecarboxylate (65.8 mg, 0.180 mmol), chloro(2-dicyclohexylphosphino-2’6’- dimethoxy-1,1’-biphenyl)(2’-amino-1,1’-biphenylyl) palladium(II) (6.6 mg, 0.0091 mmol), and aqueous K2CO3 (1 M, 750 uL) were added to the mixture. The e was argon flushed, and then was stirred at 80 °C for 16 h. The reaction was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to yield tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoroquinoxalinyl ]piperidinecarboxylate (44 mg, 52%). MS m/z 477.6 [M+H]+.

Step E: tert-Butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro-quinoxalin yl]piperidinecarboxylate (45 mg, 0.094 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL). After 10 min, the volatile material was removed. The residue was dissolved in methanolic hydrogen de (1.25 M) and concentrated to yield 6-(2,8-dimethylimidazo[1,2-b]pyridazin fluoro(4-piperidyl)quinoxaline hydrochloride (47 mg, quant.).

MS m/z 377.3 [M+H]+; 1H NMR nol-d 4) δ: 9.11 (s, 1H), 8.75 (s, 1H), 8.51 (d, J = 0.9 Hz, 1H), 8.35 - 8.46 (m, 2H), 3.64 (dt, J = 12.9, 3.2 Hz, 2H), 3.58 (tt, J = 11.0, 3.8 Hz, 1H), 3.24 - 3.32 (m, 2H), 2.87 (s, 3H), 2.71 (s, 3H), 2.35 - 2.42 (m, 2H), 2.26 - 2.34 (m, 2H), NH and HCl protons not observed.

Example 39 Preparation of Compound 116 Step A: tert-Butyl 4-(7-chlorofluorocinnolinyl)piperidinecarboxylate (500 mg, 1.4 mmol) was combined with tri-butyl(1-ethoxyvinyl)tin (0.52 mL, 1.54 mmol) and CsF (470 mg, 3.08 mmol) in 1,4-dioxane (16 mL). The mixture was stirred at 90 °C for 2 h under N2. The mixture was partitioned n EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with -20% EtOAc in petroleum ether to yield tert-butyl 1-ethoxyvinyl)fluorocinnolin yl)piperidinecarboxylate (500 mg, 90%). MS m/z 402.7 [M+H]+.

Step B: tert-Butyl 4-(7-(1-ethoxyvinyl)fluorocinnolinyl)piperidinecarboxylate (480 mg, 1.2 mmol) was combined with NBS (235 mg, 1.32 mmol) in THF (20 mL) and H2O (10 mL). The mixture was stirred at room temperature for 10 min. The THF was removed under reduce pressure. The solution was filtered. The solid was dried to yield tert-butyl 4-(7-(2-bromoacetyl)- rocinnolinyl)piperidinecarboxylate (500 mg, 92%). MS m/z 474.0, 476.0 [M+Na]+.

Step C: tert-Butyl 4-(7-(2-bromoacetyl)fluorocinnolinyl)piperidinecarboxylate (477 mg, 1.06 mmol) was combined with 3, 5-dimethylpyrazinamine (234 mg, 1.9 mmol) in EtOH (20 mL). The mixture was stirred at 90 °C for 4 h. Then the mixture was cooled to room temperature, and the solvent was removed under d pressure. The residue was chromatographed on silica gel, eluting with 30-50% EtOAc in CH2Cl2 to yield tert-butyl 4-(7-(6,8-dimethylimidazo[1,2- a]pyrazinyl)fluorocinnolinyl)piperidinecarboxylate (270 mg, 53%). MS m/z 477.2 [M+H]+.

Step D: tert-Butyl 4-(7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)fluorocinnolin yl)piperidinecarboxylate (230 mg, 0.48 mmol) was into TFA (2 mL). The mixture was stirred at room temperature for 1 h. The volatile material was removed under reduced pressure. The residue was purified by prep-HPLC to yield 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)fluoro- 3-(piperidinyl)cinnoline hydrochloride (86 mg, 45% .

MS m/z 377.2 ; 1H NMR (DMSO-d 6) δ: 8.93 (s, 1H), 8.83 (s, 1H), 8.29 - 8.38 (m, 2H), 8.11 (s, 1H), 3.82 (s, 1H), 3.12 (dd, J = 12.5, 9.5 Hz, 4H), 2.82 (d, J = 13.2 Hz, 3H), 2.41 (s, 3H), 2.10 - 2.28 (m, 4H), NH proton not observed Example 40 Preparation of Compound 226 Step A: KOAc (6.6 g, 67 mmol) was dried under sweeping argon at 180 °C for 30 min. The mixture was cooled to room temperature. 7-Bromochlorofluorocinnoline (90% purity, 3 g, .3 mmol) was added, along with nacolato)diboron (3 g, 11.8 mmol), SPhos Pd G2 (300 mg, 0.41 mmol) and 1,4-dioxane (40 mL). The mixture was heated at 80 °C for 15 h. The mixture was diluted in EtOAc and was ed through Celite. The filtrate was concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 20-50% EtOAc in CH2Cl2 to yield crude boronic acid. This material was suspended in 100 mL of 1:1 acetone:H2O at 0 °C.

Oxone (20 g, 32.3 mmol) was added. The mixture was d at 0 °C for 15 min. The reaction mixture was diluted in 600 mL H2O and then filtered. The collected material was dried to yield 3- chlorofluorocinnolinol (1.92 g, 84%) as a dark yellow solid. 1H NMR (DMSO-d 6) δ: 11.34 (s, 1H), 8.39 (s, 1H), 7.49 (s, 1H), 7.40 (dd, J = 11, 2 Hz, 1H).

Step B: 3-Chlorofluorocinnolinol (1.9 g, 8.6 mmol, 90% purity) was dissolved in DMF (37 mL). K2CO3 (3.8 g, 27 mmol) was added to the solution. The mixture was stirred at room temperature for 30 min. Iodomethane (1.9 mL, 31 mmol) was added to the e. The reaction mixture was stirred at room ature for 2 h. The e was partitioned between H2O and EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 20% EtOAc in hexanes to yield 3-chlorofluoromethoxycinnoline (1.04 g, 57%) as a white solid. 1H NMR (acetone-d 4) δ: 8.26 (s, 1H), 7.69 (s, 1H), 7.37 (dd, J = 10.5, 2 Hz, 1H), 4.13 (s, 3H).

Step C: 3-Chlorofluoromethoxycinnoline (990 mg, 4.65 mmol), (2R,6S)benzyl-2,6- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6-tetrahydropyridine (80% purity, 2.14 g, 5.24 mmol), Pd(dppf)Cl2-CH2Cl2 (190 mg, 0.23 mmol), 1,4-dioxane (26 mL), and aqueous K2CO3 (2.0 M, 13 mL, 26 mmol) were heated at 90 °C for 4 h. The mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 10-20% e in CH2Cl2 to yield 3-((2R,6S)benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridinyl) fluoromethoxycinnoline (1.28 g, 73%) as an off-white solid. 1H NMR (acetone-d 4) δ: 8.07 (s, 1H), 7.67 (s, 1H), 7.47 - 7.51 (m, 2H), 7.30 - 7.36 (m, 2H), 7.20 - 7.27 (m, 2H), 7.00 (s, 1H), 4.11 (s, 3H), 3.97 (d, J = 16 Hz, 1H), 3.91 (d, J = 16 Hz, 1H), 3.53 - 3.60 (m, 1H), 3.10 - 3.15 (m, 1H), 2.86 - 2.92 (m, 1H), 2.54 - 2.62 (m, 1H), 1.32 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H).

Step D: 3-((2R,6S)Benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridinyl)fluoro methoxycinnoline (1.28 g, 3.39 mmol) was ved in 140 mL of 1:1 :MeOH. 10% Pd/C (300 mg) and 20% 2/C (300 mg) were added. The mixture was stirred under H2 (50 psi) for 2 d. The reaction mixture was filtered over Celite, washing with CH2Cl2:MeOH. The filtrate was concentrated under vacuum. The residue was partitioned between aqueous NaOH and CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in CH2Cl2 (20 mL). To the on was added MnO2 (5 g, 57.5 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was ed over Celite, g with CH2Cl2:MeOH. The filtrate was concentrated and the residue was chromatographed on silica gel, eluting with CH2Cl2:MeOH:NH4OH (9:1:0.1) to yield 3-((2S,4R,6R)-2,6- dimethylpiperidinyl)fluoromethoxycinnoline (568 mg, 53%) as yellow solid. This compound is the higher Rf component of the product e. 1H NMR (methanol-d 4) δ: 8.06 (s, 1H), 7.59 (s, 1H), 7.27 (dd, J = 10.5, 1.5 Hz, 1H), 4.06 (s, 3H), 3.43 (tt, J = 12.5, 3.5 Hz, 1H), 3.00 - 3.05 (m, 2H), 2.09 (d, J = 12.5 Hz, 2H), 1.54 (q, J = 12.5 Hz, 2H), 1.25 (d, J = 6.5 Hz, 6H), NH proton not observed.

Step E: A solution of 3-((2S,4R,6R)-2,6-Dimethylpiperidinyl)fluoromethoxycinnoline (565 mg, 1.95 mmol) in MeOH (2 mL) and CH2Cl2 (8 mL) was treated with 37% formaldehyde in water (4 mL, 54 mmol). Sodium triacetoxyborohydride (3.3 g, 16 mmol) was added in three portions over 3 h. The reaction mixture was partitioned between aqueous NaOH and CH2Cl2. The organic layer was dried over MgSO4, filtered, and trated under vacuum to yield 5-fluoro methoxy((2S,4r,6R)-1,2,6-trimethylpiperidinyl)cinnoline (566 mg, 95%) as a yellow solid. 1H NMR (methanol-d 4) δ: 8.06 (s, 1H), 7.59 (s, 1H), 7.27 (dd, J = 10.5, 1.5 Hz, 1H), 4.06 (s, 3H), 3.43 (m, 1H), 2.50 (m, 2H), 2.41 (s, 3H), 2.08 (d, J = 11 Hz, 2H), 1.82 (q, J = 12Hz, 2H), 1.29 (d, J = 6.5 Hz, 6H).

Step F: 5-Fluoromethoxy((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnoline (485 mg, 1.6 mmol) was dissolved in CH2Cl2 (4 mL) at 0 °C. BBr3 (2 mL, 21.2 mmol) was added dropwise.

The mixture became ult to stir after 10 min. The mixture was warmed to room temperature.

The sticky clumps were broken up with a spatula until the mixture could be stirred. The mixture was stirred at room temperature for 16 h. The mixture was added slowly to ice. NaOH s were added until the solution was basic. The volatile material was removed under vacuum. The crude product was re-dissolved in 20 mL H2O. Reverse-phase chromatography was used to desalt the product. Aqueous HCl was added to the purest fractions. The fractions were concentrated under reduced re to afford crude 5-fluoro((2S,4R,6R)-1,2,6-trimethylpiperidin yl)cinnolinol hydrochloride (70% purity, 687 mg, 92%). This material s as a crude 2:1 tautomeric mixture by 1H NMR in CD +. 3OD. MS m/z 290.2 [M+H] Step G: Crude 5-fluoro((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinol hydrochloride (70% purity, 685 mg, 1.47 mmol), N,N-bis(trifluoromethylsulfonyl)aniline (2.7 g, 7.6 mmol), K2CO3 (2.7 g, 20 mmol), and DMF (7 mL) were stirred at room temperature for 15 h. The volatile material was removed under vacuum. The crude product was dissolved in CH2Cl2 and was filtered to remove solid impurities. The filtrate was concentrated under vacuum. The e was chromatographed on silica gel, eluting with 5-20% MeOH in CH2Cl2 to yield 5-fluoro ((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinyl trifluoromethanesulfonate (535 mg, 79% over 2 steps) as a yellow solid. 1H NMR (methanol-d 4) δ: 8.39 (s, 1H), 8.24 (s, 1H), 7.81 (dd, J = 9.5, 2 Hz, 1H), 3.60 (m, 1H), 2.95 (br s, 2H), 2.63 (br s, 3H), 2.23 (d, J = 12.5 Hz, 2H), 2.01 (q, J = 12.5 Hz, 2H), 1.43 (d, J = 6.5 Hz, 6H).

Step H: A mixture of ro((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinyl trifluoromethanesulfonate (36 mg, 0.085 mmol), KOAc (30 mg, 0.30 mmol), bis(pinacolato)diboron (26 mg, 0.1 mmol), Pd(dppf)Cl2 (7 mg, 0.0084 mmol), and 1,4-dioxane (0.35 mL) were heated at 90 °C for 15 h. The reaction mixture was diluted in EtOAc and was filtered over . The filtrate was concentrated under vacuum. The crude boronic acid was dissolved in Et2O and filtered over Celite to remove black insoluble impurities. The filtrate was concentrated by nitrogen stream to afford 51 mg of crude boronic acid as a black oil. 5-Chloro- 2,7-dimethyloxazolo[5,4-b]pyridine (11 mg, 0.06 mmol), Pd(dppf)Cl2 (7 mg, 0.0084 mmol), 1,4- dioxane (0.3 mL), and aqueous K2CO3 (2.0 M, 0.15 mL, 0.3 mmol) were added to the crude boronic acid. The mixture was stirred at 90 °C for 1 h. The mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The e chromatographed on silica gel, eluting with CH2Cl2:MeOH:NH4OH 0.5) to CH2Cl2:MeOH:NH4OH (90:10:1). Recrystallization from 1.5 mL methanol yielded luoro((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinyl)-2,7-dimethyloxazolo[5,4- b]pyridine (17 mg, 47%) as a white solid.

MS m/z 420.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.95 (s, 1H), 8.36 (d, J = 11 Hz, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 3.46 - 3.53 (m, 1H), 2.74 (s, 3H), 2.73 (s, 3H), 2.53 (m, 2H), 2.43 (s, 3H), 2.13 (d, J = 12 Hz, 2H), 1.88 (q, J = 12 Hz, 2H), 1.31 (d, J = 6 Hz, 6H).

Using the procedure described for Example 40, above, additional compounds described herein were prepared by substituting the appropriate heteroaryl halide in Step H, suitable ts and reaction conditions, obtaining compounds such as those selected from: Cpd Data 227 MS m/z 419.3 [M+H]+; 1H NMR (methanol-d 4) δ: 8.89 (s, 1H), 8.53 (s, 1H), 8.39 (dd, J = 11, 1.5 Hz, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 4.33 (s, 3H), 3.45 - 3.51 (m, 1H), 2.76 Cpd Data (s, 3H), 2.50 - 2.55 (m, 2H), 2.43 (s, 3H), 2.13 (d, J = 13.5 Hz, 2H), 1.87 (q, J = 12.5 Hz, 2H), 1.31 (d, J = 6.5 Hz, 6H). 228 MS m/z 420.3 [M+H]+; 1H NMR (methanol-d 4) δ: 9.08 (s, 1H), 8.32 (dd, J = 10, 1 Hz, 1H), 8.20 (s, 1H), 7.55 (s, 1H), 3.48 - 3.55 (m, 1H), 2.84 (s, 3H), 2.68 (s, 3H), 2.50 - 2.55 (m, 2H), 2.43 (s, 3H), 2.14 (d, J = 13.5 Hz, 2H), 1.89 (q, J = 13 Hz, 2H), 1.31 (d, J = 6.5 Hz, 6H).

BIOLOGICAL EXAMPLES The ing in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Huntington’s disease.

To describe in more detail and assist in understanding the present description, the ing non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the t ption that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are ered to fall within the scope of the t description and as after claimed.

Compounds of Formula (I) were tested using the Meso Scale Discovery (MSD) Assay provided in International Application No. , filed on er 11, 2016 and claiming priority to United States Provisional Application U.S. 62/265,652 filed on December 10, 2015, the entire contents of which are incorporated herein by reference.

The Endogenous Huntingtin Protein assay used in Example 1 was developed using the ELISA-based MSD electrochemiluminescence assay platform.

Example 1 Endogenous Huntingtin Protein Assay Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4°C with MW1 (expanded polyglutamine) or MAB2166 monoclonal dy (for capture) at a concentration of 1 µg/mL in PBS (30 µL per well). Plates were then washed three times with 300 µL wash buffer (0.05% Tween-20 in PBS) and blocked (100 µL blocking buffer; 5% BSA in PBS) for 4-5 hours at room temperature with rotational shaking and then washed three times with wash buffer.

Samples (25 µL) were transferred to the antibody-coated MSD plate and incubated overnight at 4°C. After l of the lysates, the plate was washed three times with wash buffer, and 25 µL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 µg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1Hour at room temperature. Following incubation with the secondary antibody, the wells were rinsed with wash buffer after which 25 µL of goat anti-rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) (diluted to 0.25 µg/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 buffer, 150 µL 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 cturers’ instructions provided for 96- or 384-well . The resulting IC50 values (µM) for compounds tested are shown in Table 1.

As shown in Table 1, test nds described herein had the following IC50 values, an IC50 value between > 3 µM and ≤ 9 µM is ted by a single star (*), an IC50 value between > 1 µM and ≤ 3 µM is indicated by two stars (**), an IC50 value n > 0.5 µM and ≤ 1 µM is indicated by three stars (***), an IC50 value between > 0.1 µM and ≤ 0.5 µM is indicated by four stars (****) and an IC50 value of ≤ 0.1 µM is indicated by five stars (*****).

Table 1 Cpd IC50 Cpd IC50 Cpd IC50 1 ** 79 ***** 154 ***** 2 ** 80 ***** 155 ***** 3 **** 81 ***** 156 ***** 4 *** 82 ***** 157 ***** ** 83 ***** 158 ***** 6 *** 84 ***** 159 ***** 7 ** 85 **** 160 ***** 9 ** 86 ***** 161 ***** **** 87 ***** 162 ***** 11 ** 88 ***** 163 ***** 12 *** 89 ***** 164 ***** 13 ** 90 ***** 165 ***** 14 **** 91 ** 166 ***** ***** 92 ***** 167 ***** Cpd IC50 Cpd IC50 Cpd IC50 16 **** 93 ***** 168 **** 17 ***** 94 **** 169 ***** 18 **** 95 ***** 170 **** 19 ***** 96 ***** 171 ***** ***** 97 *** 172 ***** 23 **** 98 **** 173 ***** 24 **** 99 ***** 174 ***** ***** 100 ***** 175 ***** 26 ***** 101 ***** 176 ***** 27 **** 102 ***** 177 ***** 28 ** 103 ***** 178 ***** 29 ** 104 ***** 179 ***** **** 105 ***** 180 ***** 31 **** 106 ***** 181 ***** 32 ***** 107 ***** 182 ***** 33 ***** 108 ***** 183 ***** 34 ***** 109 *** 184 ***** ***** 110 ***** 185 ***** 36 ***** 111 ***** 186 ***** 37 ***** 112 ***** 187 ***** 38 ** 113 ***** 188 ***** 39 ** 114 ***** 189 ***** 40 **** 115 ***** 190 ***** 41 **** 116 **** 191 **** 42 **** 117 ***** 192 ***** 43 ***** 118 **** 193 ***** 44 **** 119 *** 194 **** 45 ***** 120 ** 195 ***** 46 ***** 121 ***** 196 ***** 47 ***** 122 ***** 197 ***** 48 ***** 123 ***** 198 **** 49 ***** 124 ***** 199 ***** 50 ***** 125 ***** 200 ***** 51 ***** 126 ***** 201 ***** 52 ***** 127 ***** 202 ***** Cpd IC50 Cpd IC50 Cpd IC50 53 **** 128 ***** 203 *** 54 **** 129 ***** 204 ***** 55 ***** 130 ***** 205 **** 56 ***** 131 ***** 206 ***** 57 ***** 132 ***** 207 ***** 58 ***** 133 ***** 208 **** 59 ***** 134 ***** 209 **** 60 **** 135 ***** 210 ***** 61 *** 136 ***** 211 ***** 62 ***** 137 ***** 212 **** 63 ***** 138 **** 213 **** 64 ***** 139 ***** 214 **** 65 **** 140 ***** 215 ***** 66 ***** 141 ***** 216 ***** 67 **** 142 **** 217 ***** 68 ***** 143 ***** 218 ***** 69 ***** 144 ***** 219 ***** 70 ***** 145 ***** 220 **** 71 ***** 146 ***** 221 ***** 72 ***** 147 **** 222 **** 73 ***** 148 ***** 223 ***** 74 ***** 149 ***** 224 ***** 75 ***** 150 ***** 225 ***** 76 ***** 151 ***** 226 ***** 77 ***** 152 ***** 227 ***** 78 ***** 153 ***** 228 **** t regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Having now fully described the t 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 ing the scope of the subject matter or particular aspects described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims (15)

What is claimed is:

1. A compound comprising, a compound of Formula (I): or a form thereof, wherein: W1, W2, W3, W4, W5 and W6 are independently C-Ra, C-Rb or N, wherein, when one, two or three of W1, W5 and W6 are N, then W2, W3 and W4 are C-Ra or C-Rb, wherein, when one, two or three of W2, W3 and W4 are N, then W1, W5 and W6 are C-Ra or C-Rb; R1 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, koxy-C1-8alkyl-amino-C1-8alkyl, (C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino, (amino-C1-8alkyl)2-amino, (amino-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl)2-amino, (C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, amino-C1-8alkoxy, C1-8alkyl-amino-C1-8alkoxy, lkyl)2-amino-C1-8alkoxy, C1-8alkoxy-C1-8alkyl-amino-C1-8alkoxy, C1-8alkoxy-C1-8alkyl-amino-C1-8alkoxy, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy, amino-C2-8alkenyl, C1-8alkyl-amino-C2-8alkenyl, (C1-8alkyl)2-amino-C2-8alkenyl, amino-C2-8alkynyl, C1-8alkyl-amino-C2-8alkynyl, (C1-8alkyl)2-amino-C2-8alkynyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, (halo-C1-8alkyl)(C1-8alkyl)amino, hydroxy-C1-8alkyl, hydroxy-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino, (hydroxy-C1-8alkyl)(C1-8alkyl)amino, hydroxy-C1-8alkyl-amino-C1-8alkyl, (hydroxy-C1-8alkyl)2-amino-C1-8alkyl, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, hydroxy-C1-8alkyl-amino-C1-8alkoxy, xy-C1-8alkyl)2-amino-C1-8alkoxy, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkoxy, hydroxy-C1-8alkyl-amino-C1-8alkyl-amino, (hydroxy-C1-8alkyl-amino-C1-8alkyl)2-amino, (hydroxy-C1-8alkyl)2-amino-C1-8alkyl-amino, (hydroxy-C1-8alkyl-amino-C1-8alkyl)(C1-8alkyl)amino, (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl-amino, [(hydroxy-C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, oxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl](C1-8alkyl)amino, C3-14cycloalkyl, aryl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl)2-amino, (aryl-C1-8alkyl)(C1-8alkyl)amino, aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, (aryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C1-8alkyl)amino, heterocyclyl-amino-C1-8alkyl, heterocyclyl-C1-8alkyl-amino, (heterocyclyl-C1-8alkyl)2-amino, (heterocyclyl-C1-8alkyl)(C1-8alkyl)amino, heterocyclyl-C1-8alkyl-amino-C1-8alkyl, (heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, (heterocyclyl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-C1-8alkoxy, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl)2-amino, (heteroaryl-C1-8alkyl)(C1-8alkyl)amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl, (heteroaryl-C1-8alkyl)2-amino-C1-8alkyl or (heteroaryl-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl, wherein, each instance of C3-14cycloalkyl, aryl, cyclyl and heteroaryl is optionally tuted with one, two or three R3 substituents and optionally, with one additional R4 substituent, or, n, alternatively, each instance of C3-14cycloalkyl, aryl, heterocyclyl and aryl is optionally tuted with one, two, three or four R3 substituents; R2 is aryl, heteroaryl, heteroaryl-amino, (heteroaryl)(C1-8alkyl)amino or (heterocyclyl)(C1-8alkyl)amino, wherein, each instance of aryl and heteroaryl is optionally substituted with one, two or three R6 substituents and optionally, with one additional R7 substituent; Ra is, in each instance, independently selected from hydrogen, or C1-8alkyl; Rb is, in each instance, independently selected from en, or halogen; R3 is, in each instance, independently selected from cyano, halogen, hydroxy, C1-8alkyl, halo-C1-8alkyl, C1-8alkyl-carbonyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl]2-amino, lkyl-amino-C1-8alkyl)(C1-8alkyl)amino, [(C1-8alkyl)2-amino-C1-8alkyl](C1-8alkyl)amino, koxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl)2-amino, (C1-8alkoxy-C1-8alkyl)(C1-8alkyl)amino, C1-8alkyl-carbonyl-amino, C1-8alkoxy-carbonyl-amino, hydroxy-C1-8alkyl, y-C1-8alkoxy-C1-8alkyl, hydroxy-C1-8alkyl-amino, (hydroxy-C1-8alkyl)2-amino or (hydroxy-C1-8alkyl)(C1-8alkyl)amino; R4 is C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, C3-14cycloalkyl-amino, aryl-C1-8alkyl, aryl-C1-8alkoxy-carbonyl, aryl-sulfonyloxy-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heteroaryl or heteroaryl-C1-8alkyl; wherein, each instance of C3-14cycloalkyl, aryl, cyclyl and heteroaryl is optionally substituted with one, two or three R5 substituents; R5 is, in each instance, independently ed from halogen, hydroxy, cyano, nitro, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxy-C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, (C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-thio or heteroaryl-C1-8alkyl; R6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C1-8alkyl, C2-8alkenyl, cyano-C1-8alkyl, halo-C1-8alkyl, hydroxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, (C1-8alkyl)2-amino-C1-8alkoxy, C1-8alkoxy-C1-8alkyl, C1-8alkoxy-C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl, C1-8alkyl)amino or C1-8alkyl-thio; and, R7 is C3-14cycloalkyl, C3-14cycloalkyl-oxy, aryl, heterocyclyl, heteroaryl or aryl-C1-8alkoxy, wherein a form of the nd is selected from the group consisting of a g, salt, hydrate, solvate, clathrate, ologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

2. The compound of claim 1, wherein R1 is heterocyclyl selected from inyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, dropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c']dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, dro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, )azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octenyl, (1R,5S)azabicyclo[3.2.1]octenyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 1,4-diazabicyclo[3.1.1]heptyl,3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 1,4-diazabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[4.5]decanyl or 6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

3. The compound of claim 1, wherein R2 is heteroaryl selected from thienyl, azolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, azolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, lo[1,5-a]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, dazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,3]oxazolo[4,5-c]pyridinyl, [1,3]thiazolo[4,5-c]pyridinyl, [1,3]thiazolo[5,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl or quinoxalinyl; wherein, each instance of heteroaryl is optionally substituted with R6 and R7 substituents.

4. The compound of claim 1, wherein the compound of a (I) is selected from a compound of a (Ib1), Formula (Ic1), Formula (Ie1), Formula (If1), Formula (Ig1), Formula (Ii1), Formula (Ij1), Formula (Ik1), Formula (Il1), Formula (Im1) or Formula (In1): (Ib1), (Ic1), (Ie1), (If1), (Ig1) (Ii1), (Ij1), (Ik1), (Il1) (Im1) or (In1), or a form thereof.

5. The compound of claim 1, wherein the form of the nd is a compound salt selected from hydrochloride, hydrobromide, trifluoroacetate, formate, dihydrochloride, dihydrobromide, luoracetate, diformate, trihydrochloride, trihydrobromide, tritrifluororacetate or triformate.

6. A compound selected from the group consisting of: ethyl-2H-indazolyl)(piperidinyl)quinoline 6-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline 6-(2-methyl-2H-indazolyl)(piperidinyl)quinolone 3-(2-methyl-2H-indazolyl)(1,2,3,6-tetrahydropyridinyl)cinnoline 4-methyl(2-methyl-2H-indazolyl)(piperidinyl)quinoline 6-(2-methyl-2H-indazolyl)(1-methylpiperidinyl)quinoline ethyl-2H -indazolyl)(piperazinyl)quinoline 2-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline 2-(2-methyl-2H-indazolyl)(piperidinyl)quinazoline 6-(2,7-dimethyl-2H-indazolyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)quinolinamine N-methyl(2-methyl-2H-indazolyl)-N-(2,2,6,6-tetramethylpiperidinyl)quinolin- 2-amine 6-(2,7-dimethyl-2H-indazolyl)(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin- 4-yl)quinoline 6-(2,7-dimethyl-2H-indazolyl)(2,2,6,6-tetramethylpiperidinyl)quinoline 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoline 7-(2,7-dimethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 3-(2,7-dimethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 6-(2,8-dimethylimidazo[1,2-a]pyrazinyl)(piperidinyl)quinoline 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)quinoline -dimethyl-2H-indazolyl)fluoro(piperidinyl)quinoline 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinazoline 6-[2-methyl(trifluoromethyl)-2H-indazolyl](piperidinyl)quinoxaline 3-(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 2-methyl[7-(piperidinyl)-1,2,4-benzotriazinyl]-2H-indazolecarbonitrile 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)(piperidinyl)-1,2,4-benzotriazine 3-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)(piperidinyl)-1,2,4-benzotriazine 3-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoline 7-(2,7-dimethyl-2H-indazolyl)(piperidinyl)isoquinoline 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoxaline ro(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline 5-[8-fluoro(piperidinyl)quinazolinyl]methyl-2H-indazolecarbonitrile 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinazoline 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinazoline 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine ro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine 7-(2,7-dimethyl-2H-indazolyl)fluoro-N-methyl-N-(piperidinyl)- 1,2,4-benzotriazinamine 3-(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)-1,2,4-benzotriazine 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)-1,2,4-benzotriazine 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)quinoline 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 8-fluoroquinoline 8-fluoro(7-methoxymethyl-2H-indazolyl)(piperidinyl)quinoline 8-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)quinoline 8-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- uinoline 3-(7-methoxymethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine 8-fluoro[8-(2-methoxyethoxy)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)quinoline luoro(piperidinyl)quinolinyl]-N-(2-methoxyethyl)- 2-methylimidazo[1,2-b]pyridazinamine -dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline 7-(8-azabicyclo[3.2.1]octyl)(8-fluoromethylimidazo[1,2-a]pyridinyl)- benzotriazine 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine 7-(8-ethoxymethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 5-fluoro[2-methyl(trifluoromethyl)imidazo[1,2-a]pyridinyl](piperidin- 4-yl)-1,2,4-benzotriazine 7-(2,4-dimethyl-1,3-benzoxazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine 7-(2,4-dimethyl-1H-benzimidazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 7-(2,7-dimethylpyrazolo[1,5-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine 5-fluoro(4-fluoromethyl-1,3-benzoxazolyl)(piperidinyl)- 1,2,4-benzotriazine 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidinyl)- 1,2,4-benzotriazine 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)fluoro- 1,2,4-benzotriazine 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)isoquinoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)isoquinoline 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}ethanol 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-propylpiperidin- 4-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(propanyl)piperidin- 4-yl]cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperazinyl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(3R,5S)-3,5-dimethylpiperazinyl]- 5-fluorocinnoline 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoxaline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)piperidin- 4-yl]cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)cinnoline 2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]-N,N- dimethylpyrrolidinamine 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2S,6S)-2,6-dimethylpiperidinyl]- 5-fluorocinnoline 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N-dimethylpiperidinamine (3R)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- methylpyrrolidinamine 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,4r,6S)-2,6-dimethylpiperidin- 4-yl]fluorocinnoline 5-fluoro(2-methylimidazo[1,2-a]pyrimidinyl)(piperidinyl)cinnoline 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-a]pyridine- 8-carbonitrile 5-fluoro(2-methyl[1,2,4]triazolo[1,5-a]pyridinyl)(piperidinyl)cinnoline 5-fluoro(2-methyl-2H-indazolyl)(piperidinyl)cinnoline 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 5-fluoro(6-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 3-[1-(2,2-difluoroethyl)piperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- rocinnoline 5-fluoro(2-methylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline 3-(1-ethylpiperidinyl)fluoro(2-methylimidazo[1,2-b]pyridazinyl)cinnoline -dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline 3-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- 6-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)cinnoline 5-[5-fluoro(piperidinyl)cinnolinyl]methyl-2H-indazolecarbonitrile 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 5-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- innoline {6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}methanol 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazine- 8-carbonitrile ro(4-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 8-fluoroquinoxaline 3-(1-ethylpiperidinyl)fluoro(8-methoxymethylimidazo[1,2-b]pyridazin- 6-yl)cinnoline 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)fluoro(piperidin- 4-yl)cinnoline {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}methanol 6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazine- 8-carbonitrile 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 7-(2,4-dimethyl-1,3-benzothiazolyl)fluoro(piperidinyl)cinnoline 7-(6,8-dimethylimidazo[1,2-a]pyrazinyl)(1-ethylpiperidinyl)fluorocinnoline 7-(2,4-dimethyl-1,3-benzothiazolyl)(1-ethylpiperidinyl)fluorocinnoline 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline 2-{4-[7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluorocinnolin- 3-yl]piperidinyl}ethanol 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[(2S,6S)- 1,2,6-trimethylpiperidinyl]cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,6R)ethyl- methylpiperidinyl]fluorocinnoline 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridinyl)fluoro(piperidinyl)cinnoline 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylethanamine 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 3-(azepanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 3-[(2S,6S)-2,6-diethylpiperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-[(2S,6S)-2,6-diethylmethylpiperidinyl]- 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline 5-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluoro(piperidinyl)cinnoline 2-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylethanamine 3-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylpropanamine ro{2-methyl[2-(1H-pyrazolyl)ethoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 5-fluoro{2-methyl[3-(1H-pyrazolyl)propoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 5-fluoro{8-[3-(1H-imidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(pyrrolidinyl)cinnoline 7-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- 6-yl)cinnoline 3-{1-[3-(1H-benzimidazolyl)propyl]piperidinyl}- 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 7-(5,7-dimethylfuro[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridinyl)fluoro(piperidinyl)cinnoline 7-{8-[3-(1H-benzimidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- ro(piperidinyl)cinnoline ro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 7-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- 5-yl)cinnoline 7-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)cinnoline 2-{(2S,6S)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- methylpiperidinyl}ethanol 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 3-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline 3-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylpropanamine 3-{1-[2-(1H-benzimidazolyl)ethyl]piperidinyl}(2,8- dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro{1-[3-(1H-pyrazol- 1-yl)propyl]piperidinyl}cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro- 3-[(2R,6S)-1,2,6-trimethylpiperidinyl]cinnoline 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)cinnoline 5-fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridinyl)(piperidin- 4-yl)cinnoline -dimethyl-2H-pyrazolo[4,3-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinazoline 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinoline 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2R,6S)ethyl- 2,6-dimethylpiperidinyl]fluorocinnoline 3-[(1R,3r,5S)azabicyclo[3.2.1]octanyl](2,8-dimethylimidazo[1,2-b]pyridazin- 6-yl)fluorocinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[(2R,6S)(2-fluoroethyl)- 2,6-dimethylpiperidinyl]cinnoline 5-fluoro(7-fluoromethyl-2H-benzotriazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 7-(7-ethylmethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidin- 4-yl)cinnoline 3-(1-ethylpiperidinyl)fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridin- 5-yl)cinnoline thylmethyl-2H-pyrazolo[4,3-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 5-[5-fluoro(1,2,3,6-tetrahydropyridinyl)cinnolinyl]methyl-2H-indazole- 7-carbonitrile 6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]- 2-methylimidazo[1,2-b]pyridazinecarbonitrile 3-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline 6-{5-fluoro[1-(2-hydroxyethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile 6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile {6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]- 2-methylimidazo[1,2-b]pyridazinyl}methanol 2-(4-{5-fluoro[8-(hydroxymethyl)methylimidazo[1,2-b]pyridazinyl]cinnolin- 3-yl}piperidinyl)ethanol (6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinyl)methanol -dimethyl-2H-indazolyl)(1-ethylpiperidinyl)fluorocinnoline 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- 5-yl)quinoline 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline {6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- cetonitrile 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylazepan- innoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylazepanyl)fluorocinnoline 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]azepan- 1-yl}ethanol 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinoline 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinoline 5-fluoro[8-(1H-imidazolyl)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline ro(2-methylphenoxyimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridinyl)fluoro(piperidinyl)cinnoline 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline 3-(2,7-dimethyl-2H-indazolyl)fluoro(2,3,6,7-tetrahydro-1H-azepin- 4-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)azepan- 4-yl]cinnoline 3-(1-ethylpiperidinyl)fluoro(2-methylphenoxyimidazo[1,2-b]pyridazin- 6-yl)cinnoline 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- uinazoline 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinazoline )[3-(2,7-dimethyl-2H-indazolyl)fluorocinnolinyl]piperidine-3,4-diol 5-fluoro(2-methylpropylimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}acetonitrile 2-{6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]- 2-methylimidazo[1,2-b]pyridazinyl}ethanol 2-{6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}ethanol 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridinyl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(5-methyl- 2,5-diazabicyclo[2.2.1]heptanyl)cinnoline 5-fluoro(2-methylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline 5-fluoro[2-methyl(propanyl)imidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline 3-(1-ethylpiperidinyl)fluoro(2-methylpropylimidazo[1,2-b]pyridazin- 6-yl)cinnoline 2-{4-[7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluorocinnolinyl]piperidin- 1-yl}ethanol 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[(1S,4S)methyl- 2,5-diazabicyclo[2.2.1]heptanyl]cinnoline 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-(2,6-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline 3-(1-ethylpiperidinyl)fluoro[2-methyl(propan- 2-yl)imidazo[1,2-b]pyridazinyl]cinnoline (1R,5S,6s)[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N-dimethylazabicyclo[3.1.0]hexanamine 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]- N,N,4-trimethylpiperidinamine 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline 5-(5-fluoro((2S,4R,6R)-1,2,6-trimethylpiperidinyl)cinnolinyl)- 2,7-dimethyloxazolo[5,4-b]pyridine 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro((2S,4R,6R)- 1,2,6-trimethylpiperidinyl)cinnoline and 7-(4,6-dimethyloxazolo[4,5-c]pyridinyl)fluoro((2S,4R,6R)- trimethylpiperidinyl)cinnoline; wherein a form of the nd is selected from the group ting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

7. The compound of claim 6, wherein the form of the compound is a compound salt or a form f selected from the group consisting of: ethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 6-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline hydrochloride 6-(2-methyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 3-(2-methyl-2H-indazolyl)(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 4-methyl(2-methyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 6-(2-methyl-2H-indazolyl)(1-methylpiperidinyl)quinoline hydrochloride 2-(1-ethylpiperidinyl)(2-methyl-2H-indazolyl)quinoline hydrochloride 2-(2-methyl-2H-indazolyl)(piperidinyl)quinazoline hydrochloride ethyl(trifluoromethyl)-2H-indazolyl](piperidinyl)quinoxaline hydrochloride 3-(7-fluoromethyl-2H-indazolyl)(piperidinyl)-1,2,4-benzotriazine dihydrochloride 6-(2,7-dimethyl-2H-indazolyl)(piperidinyl)quinoxaline hydrochloride 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 5-[8-fluoro(piperidinyl)quinazolinyl]methyl-2H-indazolecarbonitrile ochloride 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinazoline dihydrochloride 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinazoline dihydrochloride 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 6-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)quinazoline dihydrochloride 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)quinoline hloride 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)quinoline hydrochloride 6-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- roquinoline hydrochloride 8-fluoro(7-methoxymethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 8-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)quinoline hydrochloride 8-fluoro(8-methoxymethylimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)quinoline hydrochloride 8-fluoro[8-(2-methoxyethoxy)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)quinoline hydrochloride 6-[8-fluoro(piperidinyl)quinolinyl]-N-(2-methoxyethyl)- 2-methylimidazo[1,2-b]pyridazinamine hydrochloride 7-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 7-(8-azabicyclo[3.2.1]octyl)(8-fluoromethylimidazo[1,2-a]pyridinyl)- 1,2,4-benzotriazine hydrochloride 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)- 1,2,4-benzotriazine hydrochloride 7-(8-ethoxymethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 5-fluoro[2-methyl(trifluoromethyl)imidazo[1,2-a]pyridinyl](piperidin- 4-yl)-1,2,4-benzotriazine hydrochloride 7-(2,4-dimethyl-1,3-benzoxazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine hydrochloride 7-(2,4-dimethyl-1H-benzimidazolyl)fluoro(piperidinyl)-1,2,4-benzotriazine hydrochloride 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hloride 7-(2,7-dimethylpyrazolo[1,5-a]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine hydrochloride 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine ochloride 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl)fluoro(piperidinyl)- 1,2,4-benzotriazine dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidinyl)- 1,2,4-benzotriazine dihydrochloride 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)isoquinoline hydrochloride -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)isoquinoline hydrochloride 7-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline hloride -dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperazinyl)cinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(3R,5S)-3,5-dimethylpiperazinyl]- 5-fluorocinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro[1-(2-fluoroethyl)piperidin- 4-yl]cinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)[(2S,6S)-2,6-dimethylpiperidinyl]- 5-fluorocinnoline hydrochloride 5-fluoro(2-methylimidazo[1,2-a]pyrimidinyl)(piperidinyl)cinnoline dihydrochloride 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline ochloride 6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-a]pyridine- 8-carbonitrile dihydrochloride 5-fluoro(2-methyl[1,2,4]triazolo[1,5-a]pyridinyl)(piperidinyl)cinnoline ochloride 5-fluoro(2-methyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 5-fluoro(6-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 3-[1-(2,2-difluoroethyl)piperidinyl](2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline dihydrochloride 5-fluoro(2-methylimidazo[1,2-b]pyridazinyl)(piperidinyl)cinnoline dihydrochloride 3-(1-ethylpiperidinyl)fluoro(2-methylimidazo[1,2-b]pyridazinyl)cinnoline dihydrochloride 7-(1,3-dimethylpyrrolo[1,2-a]pyrazinyl)fluoro(piperidinyl)cinnoline ochloride 3-(1-ethylpiperidinyl)fluoro(8-fluoromethylimidazo[1,2-a]pyridin- 6-yl)cinnoline dihydrochloride 7-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(piperidinyl)cinnoline dihydrochloride 5-[5-fluoro(piperidinyl)cinnolinyl]methyl-2H-indazolecarbonitrile hydrochloride ro(4-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride 7-(8-cyclopropylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline formate 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 7-(2,4-dimethyl-1,3-benzothiazolyl)(1-ethylpiperidinyl)fluorocinnoline formate 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline dihydrochloride 7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluoro(1-methylpiperidin- 4-yl)cinnoline dihydrochloride 2-{4-[7-(8-ethylmethylimidazo[1,2-b]pyridazinyl)fluorocinnolin- iperidinyl}ethanol dihydrochloride 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluorocinnolinyl]piperidin- 1-yl}-N,N-dimethylethanamine trihydrochloride 5-fluoro(8-fluoromethylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline dihydrochloride 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)fluoro(piperidinyl)cinnoline formate 5-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridinyl)(1-ethylpiperidinyl)- 5-fluorocinnoline formate 2-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylethanamine trihydrochloride 3-({6-[5-fluoro(piperidinyl)cinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}oxy)-N,N-dimethylpropanamine trihydrochloride ro{2-methyl[2-(1H-pyrazolyl)ethoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline dihydrochloride 5-fluoro{2-methyl[3-(1H-pyrazolyl)propoxy]imidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline trihydrochloride 5-fluoro{8-[3-(1H-imidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- 3-(piperidinyl)cinnoline trihydrochloride 3-(1H-benzimidazolyl)propyl]piperidinyl}- -dimethylimidazo[1,2-b]pyridazinyl)fluorocinnoline trihydrochloride 7-(5,7-dimethylfuro[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline hydrochloride 7-{8-[3-(1H-benzimidazolyl)propoxy]methylimidazo[1,2-b]pyridazinyl}- 5-fluoro(piperidinyl)cinnoline trihydrochloride 5-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)cinnoline hydrochloride thyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- 5-yl)cinnoline hydrochloride 3-(2,8-dimethylimidazo[1,2-a]pyridinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 3-(2,7-dimethyl-2H-indazolyl)fluoro(1,2,3,6-tetrahydropyridinyl)cinnoline hydrochloride 5-fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridinyl)(piperidin- 4-yl)cinnoline formate 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinazoline hydrochloride 8-fluoro(7-fluoromethyl-2H-indazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)quinoline hydrochloride 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 5-fluoro(7-fluoromethyl-2H-benzotriazolyl)(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline hydrochloride 3-(1-ethylpiperidinyl)fluoro(7-methoxymethyl-2H-pyrazolo[4,3-b]pyridin- 5-yl)cinnoline formate 5-[5-fluoro(1,2,3,6-tetrahydropyridinyl)cinnolinyl]methyl-2H-indazole- 7-carbonitrile hloride 6-[5-fluoro(1-methylpiperidinyl)cinnolinyl]- ylimidazo[1,2-b]pyridazinecarbonitrile rochloride 3-(2,7-dimethyl-2H-indazolyl)fluoro(piperidinyl)cinnoline hydrochloride 6-{5-fluoro[1-(2-hydroxyethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinecarbonitrile trihydrochloride 6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- ylimidazo[1,2-b]pyridazinecarbonitrile trihydrochloride 2-(4-{5-fluoro[8-(hydroxymethyl)methylimidazo[1,2-b]pyridazinyl]cinnolin- 3-yl}piperidinyl)ethanol trihydrochloride (6-{5-fluoro[1-(2-fluoroethyl)piperidinyl]cinnolinyl}- 2-methylimidazo[1,2-b]pyridazinyl)methanol trihydrochloride 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- uinoline hydrochloride 3-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline hydrochloride 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridinyl)fluoro(piperidinyl)cinnoline dihydrochloride 8-fluoro(7-fluoromethyl-2H-indazolyl)(piperidinyl)quinoline hydrochloride 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinoline hydrochloride 5-fluoro[8-(1H-imidazolyl)methylimidazo[1,2-b]pyridazinyl](piperidin- 4-yl)cinnoline formate 5-fluoro(2-methylphenoxyimidazo[1,2-b]pyridazinyl)(piperidin- 4-yl)cinnoline formate 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridinyl)fluoro(piperidinyl)cinnoline formate 6-(1-ethyl-1,2,3,6-tetrahydropyridinyl)fluoro(7-fluoromethyl-2H-indazol- 5-yl)quinazoline hydrochloride 6-(1-ethylpiperidinyl)fluoro(7-fluoromethyl-2H-indazolyl)quinazoline hydrochloride {6-[3-(1-ethylpiperidinyl)fluorocinnolinyl]methylimidazo[1,2-b]pyridazin- 8-yl}acetonitrile e 5-fluoro(2-methylimidazo[1,2-a]pyridinyl)(piperidinyl)cinnoline ochloride 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(piperidinyl)cinnoline dihydrochloride 3-(2,6-diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline trihydrochloride 3-(2,6-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline trihydrochloride 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline ditrifluoroacetate -diazaspiro[3.4]octanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline luoroacetate 3-(2,7-diazaspiro[3.5]nonanyl)(2,8-dimethylimidazo[1,2-b]pyridazinyl)- 5-fluorocinnoline ditrifluoroacetate and 7-(2,8-dimethylimidazo[1,2-b]pyridazinyl)fluoro(1,2,3,6-tetrahydropyridin- 4-yl)cinnoline dihydrochloride; 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 f.

8. A method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an ive amount of the compound of any of claims 1, 6 or

9. The method of claim 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. A use for the compound of any of claims 1, 6 or 7 for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound.

11. The use of claim 10, wherein the ive amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

12. A use for the compound of any of claims 1, 6 or 7 in the manufacture of a medicament for treating or rating HD in a subject in need thereof comprising, administering to the subject an effective amount of the ment.

13. The use of claim 12, wherein the effective amount of the compound in the medicament is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.

14. A use for the compound of any of claims 1, 6 or 7 in the preparation of a pharmaceutical composition for treating or ameliorating HD in a t in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a form f in admixture with one or more of the pharmaceutically acceptable excipients.

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