EA045009B1 - HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR THE TREATMENT OF HUNTINGTON'S DISEASE - Google Patents

Description

An aspect of the present invention relates to compounds, forms and pharmaceutical compositions thereof, and methods of using such compounds, forms or compositions thereof, used to treat or alleviate Huntington's disease. In particular, another aspect of the present invention relates to substituted bicyclic heterocyclic and heteroaryl compounds, forms and pharmaceutical compositions thereof, and methods of using such compounds, forms or compositions thereof, used to treat or alleviate Huntington's disease.

State of the art

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative brain disorder with symptoms characterized by involuntary movements, cognitive impairment, and psychiatric impairment. Death, usually caused by pneumonia or coronary heart disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of Huntington's disease (HD) is three to seven cases per 100,000 population in Western Europe. In North America, an estimated 30,000 people have Huntington's disease, with a further 200,000 people at risk of inheriting the disease from an affected parent. The disease is caused by a continuous increase in the number of trinucleotide CAG repeats in mutant huntingtin, a protein encoded by the Htt gene, which leads to the production of HTT (Htt protein) with an increased number of extensions of polyglutamine (polyQ) residues, also known as CAG repeat sequences. Currently, there are no synthetic drugs that target the underlying cause of the disease, resulting in a high unmet need for drugs that could be used to treat or alleviate Huntington's disease (HD). Therefore, there still remains a need to identify and develop synthetic compounds to treat or alleviate Huntington's disease (HD).

The entire contents of all documents cited in the invention are incorporated herein by reference to those documents.

The essence of the invention

An aspect of the present invention relates to compounds comprising a compound of formula (I)

or forms thereof, wherein R1, R2, W1, W2, W3, W4 and W5 are defined in the invention.

An aspect of the present invention also relates to a method of using a compound of formula (I) or a form or composition thereof for treating or alleviating Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of the compound or form or composition thereof.

Additionally, an aspect of the present invention relates to the use of a compound of formula (I) or a form thereof for treating or alleviating Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of the compound or form or composition thereof.

Additionally, an aspect of the present invention relates to the use of a compound of formula (I) or a form thereof for the preparation of a medicament used to treat or alleviate Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

Additionally, an aspect of the present invention relates to the use of a compound of formula (I) or a form thereof used in combination with other drugs used to treat or alleviate Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of the combination product for the treatment or relief of Huntington's disease (HD).

Detailed Description of the Invention

An aspect of the present invention relates to compounds comprising a compound of formula (I):

or forms thereof, where the dotted lines represent double bonds that are not necessarily present when valence permits this;

W ₁ is independently CR _a , CH-R _a N , NR _b , O or S when valency-appropriate;

W2 is independently C-Ra, CH-Ra, N or N-Rb when acceptable from the point of view

- 1 045009 valency, and

W ₃ is independently C, CH or N when valence permits;

where at least one of W _b W2 or W ₃ represents N or NR _b ;

W ₄ and W ₅ are independently CR _a or N, where when W ₁ is S or O, then W2 is CR _a and W ₃ is C;

R _{a is} , in each case, independently selected from hydrogen, cyano, halogen, hydroxy, C _1-6 αlkyl, deutero-C ₁ . ₆ αlkyl, halogen-C _1-6 alkyl, C _1-6 αlkoxy, halogen-C _1-6 alkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, ^^alkyl-amino, (C _1- 6 alkyl) ₂ -amino, amino-C _1- 6 alkyl and hydroxy-C ₁ . ₆ alkyl;

R _b is selected from hydrogen and C ₁ . ₆ alkyl;

R1 is selected from C ₃ . ₁₀ cycloalkyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N , O or S, and where, in each specific case, C ₃ . ₁₀ cycloalkyl and heterocyclyl are optionally substituted with one, two or three R ₃ substituents and, optionally, with one additional R ₄ substituent, or where, alternatively, in each particular case, C ₃ . ₁₀ cycloalkyl and heterocyclyl are optionally substituted with one, two, three or four R ₃ substituents;

R2 is selected from phenyl, heterocyclyl and heteroaryl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S, and wherein, in each case, phenyl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R ₅ substituents, and optionally with one additional R ₆ substituent;

R ₃ is, in each case, independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C ₁ . ₄ alkyl, halogen- _C1 . ₆ αlkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ αlkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C ₁ . ₆ alkyl and hydroxy-C ₁ . ₆ alkyl;

R4 is selected from _C3 . ₁₀ cycloalkyl, phenyl, heteroaryl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S, and where, in each specific case, C ₃ . ₁₀ cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R7 substituents;

R ₅ is, in each case, independently selected from halogen, hydroxy, cyano, nitro, C ₁ . ₆ αlkyl, deutero-C ₁ . ₄ alkyl, halogen- _C1 . ₆ αlkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, oxime, amino, C ₁ . ₆ alkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino and C ₁ . ₆ αlkyl-thio;

R6 is selected from phenyl and heteroaryl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 ring heteroatoms independently selected from N, O or S, and where In each case, phenyl and heteroaryl are optionally substituted with one, two, three or four R8 substituents;

R ₇ in each particular case is independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C ₁ . ₄ alkyl, halogen- _C1 . ₆ αlkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ αlkyl-αamino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl; And

R8 in each case is independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C ₁ . ₄ alkyl, halogen- _C1 . ₆ αlkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ αlkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl;

wherein the form of the compound is selected from the group consisting of its salt, hydrate, solvate, racemate, enantiomeric, diastereomeric and tautomeric form.

- 2 045009

Aspects of the invention.

One aspect of the present invention includes a compound of formula (I), including a compound of formula (I.1):

Ri

O) or forms thereof, where the dotted lines represent optionally present double bonds when valence permits;

W ₁ is independently CR _a , CH-R _a , N, N-Rb, O or S when valency-appropriate;

W2 is independently CR _a , CH-R _a N, or NR _b when valency-appropriate, and

W3 is independently C, CH or N when valence-appropriate, wherein at least one of W1, W2 or W3 is N or NR _b ;

W ₄ and W5 are independently CR _a or N, where when W ₁ is S or O, then W ₂ is CR _a and W ₃ is C;

Ra in each case is independently selected from hydrogen, cyano, halogen, hydroxy, _C1-6 alkyl, deutero- _C1-4 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _{C1- 6} alkoxy, C _1-6 alkoxy-C _1-6 alkyl, amino, C _1-6 alkyl-amino, (C _1-6 alkyl) _2- amino, amino-C _1-6 alkyl and hydroxy-C _1-6 alkyl;

R _b is selected from hydrogen and C _1-6 alkyl;

R1 is selected from C _3-10 cycloalkyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in ring independently selected from N, O or S, and wherein, in each case, C _3-10 cycloalkyl and heterocyclyl are optionally substituted with one, two or three R 3 substituents and, optionally, with one additional R ₄ substituent, or wherein, alternatively, in each case, C _3-10 cycloalkyl and heterocyclyl are optionally substituted with one, two, three or four R ₃ substituents;

R ₂ is selected from phenyl, heterocyclyl and heteroaryl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring , independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S and wherein, in each case, phenyl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R5 substituents, and optionally with one additional _R6 substituent;

R3 in each case is independently selected from cyano, halogen, hydroxy, _C1-6 alkyl, deutero- _C1-4 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy , C _1-6 alkoxy-C _1-6 alkyl, amino, C _1-6 alkyl-amino, (C _1-6 alkyl) ₂ -amino, amino-C _1-6 alkyl and hydroxy-C _1-6 alkyl;

R ₄ is selected from C _3-10 cycloalkyl, phenyl, heteroaryl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1. 2 or 3 heteroatoms per ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms per ring, independently selected from N, O or S, and wherein, in each case, C _3-10 cycloalkyl, phenyl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R ₇ substituents;

R5 is, in each case, independently selected from halogen, hydroxy, cyano, nitro, _C1-6 alkyl, deutero- _C1-4 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _{C1 -6} alkoxy, oxime, amino, C _1-6 alkyl-amino, (C _1-6 alkyl) ₂ -amino and C _1-6 alkyl-thio;

R ₆ is selected from phenyl and heteroaryl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic

- 3 045009 ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S, and wherein, in each particular case, phenyl and heteroaryl are optionally substituted with one, two, three or four R8 substituents;

R7 is, in each case, independently selected from cyano, halogen, hydroxy, C _1-6 alkyl, deutero-C _1-4 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy , C _1-6 alkoxy-C _1-6 alkyl, amino, C _1-6 αlkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C _1-6 alkyl and C ₃ _ ₁₀ cycloalkyl;

R8, in each case, is independently selected from cyano, halogen, hydroxy, C _1-6 alkyl, deutero-C _1-4 alkyl, halogen-C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, _C1-6alkoxy - _C1-6alkyl , amino, _C1-6αalkyl -amino, ( _C1-6alkyl ) _2- amino, amino- _C1-6alkyl or _{C3-10cycloalkyl} .

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₄ is N.

Another aspect includes a compound of formula (I) wherein W1 is NR _b , W ₂ is CR _a , W ₃ is C, W ₄ is N, and W ₅ is CR _a .

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, W ₂ is CH-R _a , W ₃ is CH, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W ₂ represents NR _b and W 4 represents N.

Another aspect includes a compound of formula (I) wherein W1 is CH-R _a , W ₂ is NR _b , W ₃ is CH, W4 is N, and W ₅ is CR _a .

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

Another aspect includes a compound of formula (I) wherein W1 is CR _a , W ₂ is CR _a , W ₃ is N, W4 is N, and W ₅ is CR _a .

Another aspect includes a compound of formula (I) wherein W1 is CH-R _a , W ₂ is CH-R _a , W ₃ is N, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W1, _W2 and W4 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, _W2 is N, _W3 is CH, W4 is N, and _W5 is _CRa .

One aspect includes a compound of formula (I) wherein W1 and _W2 are N-Rb and W4 is N.

Another aspect includes a compound of formula (I) wherein W1 and _W2 are NR _b , _W3 is CH, W4 is N, and _W5 is C-Ra.

One aspect includes a compound of formula (I) wherein W1, _W3 and W4 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W ₂ is CR _a , W ₃ is N, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₃ and W4 are N.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, W ₂ is CH-R _a , W ₃ is N, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W ₂ , W ₃ and W ₄ are N.

Another aspect includes a compound of formula (I) wherein W1 is CR _a , W ₂ is N, W ₃ is N, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W2 is N-Rb and W3 and W4 are N.

Another aspect includes a compound of formula (I) wherein W1 is CH-R _a , W ₂ is NR _b , W ₃ is N, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W1, _W2 , _W3 and _W4 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, _W2 is N, _W3 is N, W4 is N, and _W5 is CR _a .

One aspect includes a compound of formula (I) wherein W1 is S and W4 is N.

Another aspect includes a compound of formula (I) wherein W1 is S, W ₂ is CR _a , W ₃ is C, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W1 is O and W4 is N.

Another aspect includes a compound of formula (I) wherein W1 is O, W ₂ is CR _a , W ₃ is C, W4 is N, and W ₅ is CR _a .

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₅ is N.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, _W2 is _CRa , _W3 is C, W4 is _CRa , and _W5 is N.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, _W2 is

- 4 045009 is CH-R _a , W ₃ is CH, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W2 is NR _b and W5 is N.

Another aspect includes a compound of formula (I) wherein W1 is CH-R _a , W2 is NR _b , W ₃ is CH, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W ₃ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W ₁ is CR _a , W ₂ is CR _a , W ₃ is N, W ₄ is CR _a , and W ₅ is N.

Another aspect includes a compound of formula (I) wherein W1 is CH-Ra, W2 is CH-R _a , W ₃ is N, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1, W2 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W2 is N, _W3 is CH, _W4 is _CRa , and _W5 is N.

One aspect includes a compound of formula (I) wherein W1 and W2 are N-Rb and _W5 is N.

Another aspect includes a compound of formula (I) wherein W ₁ and W ₂ are NR _b , W ₃ is CH, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1, _W3 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is N, W ₂ is CR _a , W ₃ is N, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₃ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, W2 is CH-R _a , W ₃ is N, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W2, _W3 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is CR _a , W ₂ is N, W ₃ is N, W ₄ is CR _b , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W2 is NR _b and W ₃ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W ₁ is CH-R _a , W ₂ is NR _b , W ₃ is N, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1, W2, _W3 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W2 is N, _W3 is N, _W4 is CR _a , and _W5 is N.

One aspect includes a compound of formula (I) wherein W1 is S and _W5 is N.

Another aspect includes a compound of formula (I) wherein W1 is S, W2 is CR _a , W ₃ is C, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1 is O and _W5 is N.

Another aspect includes a compound of formula (I) wherein W ₁ is O, W ₂ is CR _a , W ₃ is C, W ₄ is CR _a , and W ₅ is N.

One aspect includes a compound of formula (I) wherein W1 is N-Rb.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, W2 is CR _a , W ₃ is C, and W ₄ and W ₅ are C-Ra.

Another aspect includes a compound of formula (I) wherein W1 is N-Rb, W2 is CH-R _a , W ₃ is CH, and W ₄ and W ₅ are C-Ra.

One aspect includes a compound of formula (I) wherein W2 is N-Rb. Another aspect includes a compound of formula (I) wherein W ₁ is CR _a , W ₂ is NR _b , W ₃ is C, and W ₄ and W ₅ are C-Ra.

Another aspect includes a compound of formula (I) wherein W ₁ is CH-R _a , W ₂ is NR _b , W ₃ is CH, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W ₃ is N.

Another aspect includes a compound of formula (I) wherein W ₁ is CR _a , W ₂ is CR _a , W ₃ is N, and W ₄ and W ₅ are C-Ra.

Another aspect includes a compound of formula (I) wherein W1 is CH-Ra, W2 is CH-R _a , W ₃ is N, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 and W2 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W2 is N, _W3 is CH, and _W4 and _W5 are _CRa .

One aspect includes a compound of formula (I) wherein W ₁ and W ₂ are NR _b .

Another aspect includes a compound of formula (I) wherein W ₁ and W ₂ are NR _b , W ₃ pre

- 5 045009 is CH, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 and _W3 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W2 is CR _a , W ₃ is N, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₃ is N.

Another aspect includes a compound of formula (I) wherein W1 is NR _b , W2 is CH-R _a , W ₃ is N, and W ₄ and W ₅ are CR _a .

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

Another aspect includes a compound of formula (I) wherein W1 is C-Ra, W2 is N, _W3 is N, and _W4 and _W5 are CR _a .

One aspect includes a compound of formula (I) wherein W2 is N-Rb and W3 is N.

Another aspect includes a compound of formula (I) wherein W1 is CH-Rb, W2 is NR _b , W ₃ is N, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1, W2 and _W3 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is N, W ₂ is N, W ₃ is N, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 is S.

Another aspect includes a compound of formula (I) wherein W1 is S, W2 is CR _a , W ₃ is C, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 is O.

Another aspect includes a compound of formula (I) wherein W1 is O, W2 is CR _a , W ₃ is C, and W ₄ and W ₅ are CR _a .

One aspect includes a compound of formula (I) wherein W1 is NR _b and W ₄ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W ₁ is NR _b , W ₂ is CR _a , W ₃ is C, and W ₄ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W ₁ is NR _b , W ₂ is CH-R _a , W ₃ is CH, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W2 is NR _b and W ₄ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W1 is CH-Ra, W2 is NR _b , W ₃ is CH, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W ₃ , W ₄ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W1 is C-Ra, W2 is CR _a , _W3 is N, and _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is CH-R _a , W ₂ is CH-R _a , W ₃ is N, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W1, W2, _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is N, W ₂ is N, W ₃ is CH, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W1 and W2 are NR _b and W ₄ and W ₅ are N.

Another aspect includes a compound of formula (I) wherein W1 and W2 are N-Rb, W3 is CH, and _W4 and _W5 are N.

One aspect includes a compound of formula (I) wherein W1, _W3 , _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is N, W2 is CR _a , _W3 is N, and _W4 and _W5 are N.

One aspect includes a compound of formula (I) wherein W1 is N-Rb and _W3 , _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is NR _b , W ₂ is CH-R _a , W ₃ is N, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W2, _W3 , _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is C-Ra, W2 is N, _W3 is N, and _W4 and _W5 are N.

One aspect includes a compound of formula (I) wherein W2 is N-Rb and _W3 , _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is CH-Ra, W2 is _NRb , _W3 is N, and _W4 and _W5 are N.

One aspect includes a compound of formula (I) wherein W1, W2, _W3 , and _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is N, W ₂ is

- 6 045009 is N, W ₃ is N, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein W1 is S and _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W1 is S, W2 is CR _a , _W3 is C, and _W4 and _W5 are N.

One aspect includes a compound of formula (I) wherein W1 is O and _W4 and _W5 are N.

Another aspect includes a compound of formula (I) wherein W ₁ is O, W ₂ is CR _a , W ₃ is C, and W ₄ and W ₅ are N.

One aspect includes a compound of formula (I) wherein R _{a is} , in each instance, independently selected from hydrogen, cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C1- ₄ alkyl, halogen- _C1 . ₆ alkyl, C ₁ . ₆ αlkoxy, halogen-C ₁ . ₆ alkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ αlkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-Cl. ₆ αlkulα and hydroxy-C ₁ . ₆ alkyl.

Another aspect includes a compound of formula (I) wherein Ra is, in each instance, independently selected from hydrogen, hydroxy, C ₁ . ₆ alkyl, C ₁ . ₆ alkoxy and C ₁ . ₆ alkyl amino.

Another aspect includes a compound of formula (I) wherein R _a represents hydrogen.

Another aspect includes a compound of formula (I) wherein R _a is hydroxy.

Another aspect includes a compound of formula (I) wherein R _a is C ₁ . ₆ alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R _a is methyl.

Another aspect includes a compound of formula (I) wherein R _a is C ₁ . ₆ alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy and t-butoxy.

Another aspect includes a compound of formula (I) wherein Ra is methoxy.

Another aspect includes a compound of formula (I) wherein R _a is C ₁ . ₆ alkyl-amino, where C ₁ . ₆ αlkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R _a is C ₁ . ₆ αlkyl-amino selected from methylamino and ethylamino.

One aspect includes a compound of formula (I) wherein R _b is selected from hydrogen and C ₁ . ₆ αlkyl.

Another aspect includes a compound of formula (I) wherein R _b represents hydrogen.

One aspect includes a compound of formula (I) wherein R1 is selected from _C3 . ₁₀ cycloalkyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N , O or S, and where, in each specific case, C ₃ . ₁₀ cycloalkyl and heterocyclyl are optionally substituted with one, two or three R3 substituents and optionally with one additional _R4 substituent, or where, alternatively, in each case, _C3 . ₁₀ cycloalkyl and heterocyclyl are optionally substituted with one, two, three or four R ₃ substituents.

Another aspect includes a compound of formula (I) wherein R1 is _C3 . ₁₀ cycloalkyl, optionally substituted with one, two or three R ₃ substituents and, optionally, with one additional R 4 substituent, or, alternatively, substituted with one, two, three or four R ₃ substituents.

Another aspect includes a compound of formula (I) wherein R1 is _C3 . ₁₀ cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,1]hexanyl and adamantyl, optionally substituted with one, two or three R3 substituents and optionally with one additional R4 substituent , or alternatively substituted with one, two, three or four R ₃ substituents.

Another aspect includes a compound of formula (I) wherein R1 is _C3 . ₁₀ cycloalkyl selected from cyclobutyl and cyclohexyl, optionally substituted with one, two or three R ₃ substituents and optionally with one additional R ₄ substituent, or alternatively substituted with one, two, three or four substituents _R3 .

Another aspect includes a compound of formula (I) wherein R ₁ is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6- tetra-hydropyridinyl, 3-azabicyclo[3,1,0]hexyl, (1R,5S)-3-aza-bicyclo[3,1,0]hexyl, 8-azabicyclo[3,2,1]octyl, (1R ,5S)-8-aza-bicyclo[3,2,1]octyl, 8azabicyclo[3,2,1]oct-2-enyl, (1R,5S)-8-azabicyclo[3,2,1]oct- 2-enyl, 9-azabicyclo[3,3,1]-nonyl, (1R,5S)-9-azabicyclo[3,3,1]nonyl, 3-oxa-9-azabicyclo-[3,3,1] nonyl and 3-oxa-9-azabicyclo[3,3,1]non6-enyl, optionally substituted with one, two or three R3 substituents and optionally with one additional _R4 substituent, or optionally substituted with one, two, three or four R ₃ substituents.

- 7 045009

Another aspect includes a compound of formula (I) wherein R1 is heterocyclyl selected from piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 8-azabicyclo[3,2,1]octyl, (1R,5S)8- azabicyclo[3,2,1]octyl, 8-azabicyclo[3,2,1]-oct-2-enyl, 3-oxa-9-azabicyclo[3,3,1]nonyl and 3-oxa9-azabicyclo[3 ,3,1]non-6-enyl, optionally substituted with one, two or three R ₃ substituents and, optionally, with one additional R ₄ substituent, or, alternatively, optionally substituted with one, two, three or four R ₃ substituents.

Another aspect includes a compound of formula (I) wherein R ₁ is heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin- 1-yl, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4yl, 8-azabicyclo[3,2, 1]oct-3-yl, (1R,5S)-8-aza-bicyclo[3,2,1]-oct-3-yl, 8-azabicyclo[3,2,1]oct-2-en-3yl , (1R,5S)-8-aza-bicyclo[3,2,1]oct-2-en-3-yl, 9-azabicyclo[3,3,1]-non-7-yl, (1R,5S )-9azabicyclo[3,3,1]non-3-yl, 3-oxa-9-azabicyclo[3,3,1]-non-7-yl and 3-oxa-9-azabicyclo[3,3,1 ]non-6-en7-yl, optionally substituted with one, two or three R ₃ substituents and optionally with one additional R 4 substituent, or alternatively optionally substituted with one, two, three or four substituents _R3 .

Another aspect includes a compound of formula (I) wherein R ₁ is heterocyclyl selected from piperidin-4-yl, piperazin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl, 8-azabicyclo-[3 ,2,1]oct-3-yl, (1R,5S)-8-azabicyclo[3,2,1]oct-3-yl, 8-aza-bicyclo[3,2,1]oct-2-ene-3 -yl, 3-oxa-9azabicyclo[3,3,1]non-7-yl and 3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl, optionally substituted with one , two or three R ₃ substituents and, optionally, with one additional R 4 substituent, or, alternatively, optionally substituted with one, two, three or four R 3 substituents.

One aspect includes a compound of formula (I) wherein R ₂ is selected from phenyl, heterocyclyl and heteroaryl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in ring independently selected from N, O or S, and wherein, in each case, phenyl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R5 substituents, and optionally with one additional R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is phenyl, optionally substituted with one, two or three R5 substituents and optionally with one additional R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is a heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetra -hydropyridinyl and 2,3-dihydro-1H-indenyl, optionally substituted with one, two or three R5 substituents and optionally with one additional R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is 2,3-dihydro-shindenyl optionally substituted with one, two or three R5 substituents and optionally with one additional R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is a heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1 -yl, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl and 2,3-dihydro-1H-indene -5-yl, optionally substituted with one, two or three R5 substituents and, optionally, with one additional _R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is 2,3-dihydro-1H-inden5-yl, optionally substituted with one, two or three R5 substituents and optionally with one additional _R6 substituent.

Another aspect includes a compound of formula (I) wherein R ₂ is a heteroaryl selected from furanyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1H-indolyl, 1H-indazolyl, benzofuranyl, 1H-benzimidazolyl, 1H-benzotriazolyl and quinolinyl, optionally substituted with one, two or three R5 substituents and optionally with one additional _R6 substituent.

Another aspect includes a compound of formula (I) wherein R2 is a heteroaryl selected from pyridinyl, 1H-indazolyl, 1H-benzimidazolyl, 1H-benzotriazolyl and quinolinyl, optionally substituted with one, two or three R5 substituents and optionally with one additional substituent R ₆ .

Another aspect includes a compound of formula (I) wherein R ₂ is heteroaryl, selected

- 8 045009 from furan-3-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1Nimidazol-1-yl, 1H -imidazol-2-yl, 1H-imidazol-4-yl, 1,3-oxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4 -yl, pyridazin-5-yl, pyrimidin-4-yl, pyrimidin5-yl, pyrazin-2-yl, pyrazin-3-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indole -5-yl, 1H-indol-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, benzofuran-2-yl, benzofuran-5-yl, 1H-benzimidazol-5-yl, 1Hbenzimidazole -6-yl, 1H-benzo-triazol-4-yl, 1H-benzotriazol-5-yl, 1H-benzotriazol-6-yl, 1H-benzotriazol-7-yl and quinolin-7-yl, optionally substituted with one, two or three _R5 substituents and, optionally, with one additional R6 substituent.

Another aspect includes a compound of formula (I) wherein R ₂ is heteroaryl selected from pyridin-2-yl, 1H-indazol-6-yl, 1H-benzimidazol-6-yl, 1H-benzotriazol-7-yl and quinolin- 7yl, optionally substituted with one, two or three _R5 substituents and, optionally, with one additional R6 substituent.

One aspect includes a compound of formula (I) wherein R ₃ is, in each instance, independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkylα, deutero-C ₁ . ₄ alkyl, halogen- _C1 . ₆ alkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ alkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C ₁ . ₆ alkyl and hydroxy-C ₁ . ₆ alkyl.

Another aspect includes a compound of formula (I) wherein R ₃ is, in each instance, independently selected from halogen, C ₁ . ₆ alkyl and C ₁ . ₆ alkyl-αmino.

Another aspect includes a compound of formula (I) wherein R ₃ is a halogen selected from bromine, chlorine, fluorine and iodine.

Another aspect includes a compound of formula (I) wherein R3 is fluorine.

Another aspect includes a compound of formula (I) wherein R ₃ is C ₁ . ₆ alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R3 is methyl.

Another aspect includes a compound of formula (I) wherein R ₃ is C ₁ . ₆ alkyl-αmino, where C ₁ . _{The 6} alkyls are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R ₃ is tert-butylamino.

One aspect includes a compound of formula (I) wherein R4 is selected from _C3 . ₁₀ cycloalkyl, phenyl, heteroaryl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms in the ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S, and where, in each specific case, C ₃ . ₁₀ cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R ₇ substituents.

One aspect includes a compound of formula (I) wherein R ₅ is, in each case, independently selected from halogen, hydroxy, cyano, nitro, C ₁ . ₆ alkyl, deutero-C ₁ . ₄ αlkyl, halogen-C ₁ . ₆ alkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, oxime, amino, C ₁ . ₆ alkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino and C ₁ . ₆ alkyl thio.

Another aspect includes a compound of formula (I) wherein R ₅ is, in each instance, independently selected from halogen, hydroxy, C ₁ . ₆ αlkyl and oxime.

Another aspect includes a compound of formula (I) wherein R ₅ is a halogen selected from bromine, chlorine, fluorine and iodine.

Another aspect includes a compound of formula (I) wherein R ₅ is a halogen selected from chlorine and fluorine.

Another aspect includes a compound of formula (I) wherein R ₅ is hydroxy.

Another aspect includes a compound of formula (I) wherein R ₅ is C ₁ . ₆ alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R ₅ is methyl.

Another aspect includes a compound of formula (I) wherein R ₅ is an oxime.

One aspect includes a compound of formula (I) wherein R6 is selected from phenyl and heteroaryl, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, regardless selected from N, O or S, and wherein, in each case, phenyl and heteroaryl are optionally substituted with one, two, three or four R8 substituents.

Another aspect includes a compound of formula (I) wherein R6 is phenyl, optionally substituted with one, two, three or four R8 substituents.

Another aspect includes a compound of formula (I) wherein R6 is heteroaryl selected from furanyl, thienyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H

- 9 045009

1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3oxazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazol-yl, pyridinyl, pyridin-2(1H)-on-yl, pyridazinyl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyrazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, benzofuranyl, 1H-benzimidazolyl, 1H-benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 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, imidazo[1,5- a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo [4,5c]pyridinyl, 3H-[1,2,3]triazolo[4,5-c]pyridazinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4] triazolo[4,3-b]pyridazinyl and quinolinyl, optionally substituted with one, two, three or four R8 substituents.

Another aspect includes a compound of formula (I) wherein R6 is heteroaryl selected from furanyl, thienyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H1,2,3-triazolyl , 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3oxazolyl, 1,2,4-thiadiazolyl, 1,3,4 -thiadiazolyl, pyridinyl, pyridin-2(III)-on-yl, pyridazinyl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyrazinyl, 1,3,5-triazinyl, 1H-benzotriazolyl, 1Hpyrrolo-[2, 3-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo-[1,2-a]pyrimidinyl, imidazo[1,2b]pyridazinyl, imidazo-[1,2-a]pyrazinyl, imidazo[1, 5-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3 ]triazolo[4,5-c]pyridinyl, [1,2,4]triazolo[1,5a]pyridinyl and [1,2,4]triazolo[4,3-b]pyridazinyl, optionally substituted with one, two , three or four R8 substituents.

Another aspect includes a compound of formula (I) wherein R6 is heteroaryl selected from furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, 1H-pyrrol-3-yl, 1H -pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1Himidazol-4-yl , 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3triazol -4-yl, 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, 1,3-thiazol-2-yl, 1,3-hyazol-5 -yl, 1,2oxazol-4-yl, 1,3-oxazol-2-yl, 1,3-oxazol-3-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl , 1,2,4thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2(1H)on-4 -yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-4(3H)-on6-yl, pyrazin-1-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, benzofuran-2-yl, benzofuran-5-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-5-yl, 1H-benz-imidazol-6-yl, 1H-benzotriazol-4- yl, 1H-benzotriazol-5-yl, 1H-benzotriazol-6-yl, 1H-benzotriazol-7-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b] pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-5-yl, 2H-pyrazolo[4,3- b]pyridin-5-yl, 2H-pyrazolo[4,3-c]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2- yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2a]pyridin-7-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a] pyrimidin-6-yl, imidazo[1,2c]pyrimidin-2-yl, umidazo[1,2-b]niridazin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1, 2a]pyrazin-2-yl, imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrazin-6-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[ 1,5-a]pyridin-7-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin- 7yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H[ 1,2,3]triazolo[4,5-c]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl, [1,2,4] triazolo[1,5a]pyridin-7-yl, [1,2,4]triazolo[4,3-b]pyridazin-6-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl , optionally substituted with one, two, three or four R ₈ substituents.

Another aspect includes a compound of formula (I) wherein R6 is heteroaryl selected from furan-3-yl, thien-3-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3 -yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-1,2,3-triazole -1yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2 ,4-triazol-1-yl, 4H1,2,4-triazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,2-oxazol-4-yl , 1,3-oxazol-2-yl, 1,3-oxazol5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridine -3-yl, pyridin-4-yl, pyridin-2(1H)-on-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin- 4(3H)-on-6-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1H-benzotriazol-6-yl, 1H-pyrrolo[2,3b]pyridin-4-yl , 1H-pyrrolo[2,3-c]pyridin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2a]pyrimidin-6-yl, imidazo[1,2-b ]pyridazin-6-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2a]pyrazin-6-ylimidazo[1,5-a]pyridin-7-yl, [1,2, 3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5a]pyridin-7-yl, 1H-[1,2,3]triazolo[4,5- b]pyridin-5-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, 3H[1,2,3]triazolo[4,5-c]pyridin-6 -yl and [1,2,4]triazolo[4,3-b]pyridazin-6-yl, optionally substituted with one, two, three or four R8 substituents.

One aspect includes a compound of formula (I) wherein R ₇ is, in each instance, independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C ₁ . ₄ αlkyl, halogen-C ₁ . ₆ αlkyl, C ₁ . ₆ alkoxy, halogen-C ₁ . ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ . ₆ alkyl, amino, C ₁ . ₆ αlkyl-amino, (Cl. ₆ alkul) ₂ -amino, amino-C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl.

- 10 045009

One aspect includes a compound of formula (I), wherein R8 is, in each instance, independently selected from cyano, halogen, hydroxy, C ₁ . ₆ alkyl, deutero-C _1-4 αalkyl, halogen-C ₁ . ₆ αlkyl, C _1- 6 alkoxy, halogen-C ₁ _ ₆ αlkoxy, C ₁ . ₆ alkoxy-C ₁ _ ₆ alkyl, amino, C ₁ . ₆ αlkyl-amino, (C ₁ . ₆ alkyl) ₂ -amino, amino-C ₁ . ₆ alkyl and C ₃ . ₁₀ cycloalkyl.

One aspect includes a compound of formula (I), wherein R8 is, in each instance, independently selected from cyano, halogen, hydroxy, C _1-6 alkyl, deutero-C _1-4 αlkyl, halo-C _1-6 αlkyl, C _{1- 6} alkoxy, halo-C _1-6 αlkoxy, amino, C _1-6 alkyl _- amino, (C _1-6 αlkyl) ₂ -amino and C _{3_10} cycloalkyl.

Another aspect includes a compound of formula (I) wherein R8 is cyano.

Another aspect includes a compound of formula (I) wherein R8 is a halogen selected from bromine, chlorine, fluorine and iodine.

Another aspect includes a compound of formula (I) wherein R8 is a halogen selected from bromine, chlorine and fluorine.

Another aspect includes a compound of formula (I) wherein R8 is hydroxy.

Another aspect includes a compound of formula (I) wherein R8 is _C1-6alkyl selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R8 is C _1-6 alkyl selected from methyl, ethyl and propyl.

Another aspect includes a compound of formula (I) wherein R8 is deutero-C _1-4 alkyl, wherein C _1-4 α alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, partially or completely substituted with one or more deuterium atoms when valency permits.

Another _aspect includes a compound of formula (I) wherein R8 is ( ^2H3 )methyl.

Another aspect includes a compound of formula (I) wherein R8 is a halo-C _1-6 alkyl, wherein C _1-6 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, partially or fully substituted using one or more halogens selected from bromine, chlorine, fluorine and iodine, where valence permits.

Another aspect includes a compound of formula (I) wherein R8 is a halogen-C _1-6 alkyl selected from trifluoromethyl and difluoromethyl.

Another _aspect includes a compound of formula (I) wherein R8 is C _{1_6} alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy and t-butoxy.

Another _aspect includes a compound of formula (I) wherein R8 is C _{1_6} alkoxy selected from methoxy and ethoxy.

Another aspect includes a compound of formula (I) wherein R8 is halogen-C ₁ . ₆ alkoxy, where C ₁ . ₆ alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy and tert-butoxy, partially or completely substituted with one or more halogens selected from bromine, chlorine, fluorine and iodine, when acceptable from a valence point of view.

Another aspect includes a compound of formula (I) wherein R8 is difluoromethoxy.

Another aspect includes a compound of formula (I) wherein R8 is amino.

Another aspect includes a compound of formula (I) wherein R8 is C _{1_6} alkyl-amino, _wherein C ₁ . ₆ αlkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Another aspect includes a compound of formula (I) wherein R8 is methylamino.

Another aspect includes a compound of formula (I) wherein R8 is ( _C1.6alkyl ) ₂ -amino, wherein _C1.6alkyl is independently selected _from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. butyl.

Another aspect includes a compound of formula (I) wherein R8 is dimethylamino.

Another aspect includes a compound of formula (I) wherein R8 is _C3 . ₁₀ cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl.

Another aspect includes a compound of formula (I) wherein R8 is cyclopropyl.

One aspect of a compound of formula (I) includes a compound selected from formula (Ia), formula (Ib), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii ), formulas (Ij), formulas (Ik), formulas (Il), formulas (Im), formulas (In), formulas (Io), formulas (Ip), formulas (Iq), formulas (Is), formulas (It ), formulas (Iu), formulas (Iv), formulas (Iw), formulas (Ix), formulas (Iy), formulas (Iz), formulas (Iaa), formulas (Ibb), formulas (Icc), formulas (Idd ), formulas (Iee), formulas (Iff), formulas (Igg), formulas (Ihh), formulas (Iii), formulas (Ijj), formulas (Ikk), formulas (Ill), formulas (Imm), formulas (Inn ), formulas (Ioo), formulas (Ipp), formulas (Iqq), formulas (Irr), formulas (Iss), formulas (Itt), formulas (Iuu), formulas (Iww), formulas (Ixx), formulas (Iyy ), formula (Izz), formula (Iaaa), formula (Ibbb), formula (Iccc), formula (Iddd), formula (Ieee), formula (Ifff), formula (Iggg) or formula (Ihhh):

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or its shape.

Another aspect of a compound of formula (I) includes a compound selected from formula (Ie), formula (Ii), formula (Ik), formula (Ip), formula (Iq), formula (It), formula (Iu), formula (Ix ), formula (Iz), formula (Ibb), formula (Icc) or formula (Idd):

or its shape.

Another aspect of a compound of formula (I) includes a compound selected from formula (Ia1), formula (Ib1), formula (Id1), formula (Ie1), formula (If1), formula (Ig1), formula (Ih1), formula (Ii1 ), formulas (Ij1), formulas (Ik1), formulas (Il1), formulas (Im1), formulas (In1), formulas (Io1), formulas (Ip1), formulas (Iq1), formulas (Is1), formulas (It1 ), formulas (Iu1), formulas (Iv1), formulas (Iw1), formulas (Ix1), formulas (Iy1), formulas (Iz1), formulas (Iaa1), formulas (Ibb1), formulas (Icc1), formulas (Idd1 ), formulas (Iee1), formulas (Iff1), formulas (Igg1), formulas (Ihh1), formulas (Iii1), formulas (Ijj1), formulas (Ikk1), formulas (Ill1), formulas (Imm1), formulas (Inn1 ), formulas (Ioo1), formulas (Ipp1), formulas (Iqq1), formulas (Irr1), formulas (Iss1), formulas (Itt1), formulas (Iuu1), formulas (Iww1), formulas (Ixx1), formulas (Iyy1 ), formula (Izz1), formula (Iaaa1), formula (Ibbb1), formula (Iccc1), formula (Iddd1), formula (Ieee1), formula (Ifff1), formula (Iggg1) or formula (Ihhh1):

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or its shape.

Another aspect of the compound of formula (I) includes a compound selected from Formula (Ie1), Formula (Ii1), Formula (Ik1), Formula (Ip1), Formula (Iq1), Formula (It1), Formula (Iu1), Formula (Ix1 ), formula (Iz1), formula (Ibb1), formula (Icc1) or formula (Idd1):

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or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ie1):

or its shape.

Another aspect of the compound of formula (I) includes the compound of formula (Ii1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ik1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ip1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Iq1):

or its shape.

Another aspect of the compound of formula (I) includes the compound of formula (It1):

or its shape.

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Another aspect of a compound of formula (I) includes a compound of formula (Iu1):

or its shape.

Another aspect of the compound of formula (I) includes the compound of formula (Ix1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Iz1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ibb1):

or its shape.

Another aspect of the compound of formula (I) includes the compound of formula (Icc1):

or its shape.

Another aspect of the compound of formula (I) includes the compound of formula (Idd1):

or its shape.

An aspect of a compound of formula (I) or a form thereof includes a compound selected from the group consisting of:

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174 175, 176;

and wherein the form of the compound is selected from the group consisting of its salt, hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric and tautomeric forms.

An aspect of a compound of formula (I) or a form thereof (wherein the numeral 1 in the compound number (#1) indicates that a salt form has been isolated) includes a compound selected from the group consisting of the following compounds:

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Connection Name I ¹ 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Nimidazo[4,5-b]pyrazin-5-yl]phenol 2 ¹ 5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-1-(2,2,6,6-tetramethylpiperidin- 4-yl)-1H-imidazo[4,5-b]pyrazine Z ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5-c]pyridazin-3-yl]phenol 4 ¹ 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin- 4-yl)-7H-imidazo[4,5-c]pyridazine 5 ¹ 2-[6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol 6 ¹ 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-methyl-7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-imidazo[4,5 -c]-pyridazine 7 ¹ 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 8 ¹ 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4yl)-5H-pyrrolo[2,3-b ]pyrazin-2-yl]-phenol 9 ¹ 3-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin- 4-yl)-7H-imidazo[4,5-c]pyridazin-6-ol 10 ¹ 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethylpiperidin-4-yl)-5Hpyrrolo[2,3-b]pyrazin-2-yl]phenol II ¹ 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2c]pyridazin-3-yl]phenol 12 ¹ 2-[7-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4yl)phenol 13 ¹ 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazine

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14 ¹ 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazine 15 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2c]pyridazin-3-yl]phenol 16 ¹ 2-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-(2,2,6,6-tetramethylpiperidin- 4-yl)-5H-pyrrolo[2,3-b]pyrazine 17 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4yl)thieno[3,2-c]pyridazin- 3-yl]phenol 18 ¹ 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)thieno[3,2-c]pyridazin-3-yl]-5-(1Hpyrazol-4-yl )phenol 19 ¹ 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]-5-(1H-pyrazol-4yl)phenol 20 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4yl)-5H-pyrrolo[3,2-c ]pyridazin-3-yl]phenol 21 ¹ 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(1H-pyrazol-4yl)phenol 22 ¹ 23 ¹ 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5-yl]phenol 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro- 5H-pyrrolo[2,3-c]pyridazin-3-yl]phenol 24 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)thieno[3,2c]pyridazin-3-yl]phenol 25 ¹ 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)thieno-[3,2-c]pyridazin-3yl]-5-(1H-pyrazole -4-yl)phenol 26 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Hpyrrolo[2,3 -с] pyridazin-3 -yl] phenol 27 ¹ 2-[7-(8-azabicyclo[3,2,1]oct-2-ep-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]- 5-(1H-pyrazol-4-yl)phenol 28 ¹ 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)-5H-pyrrolo[3,2c]pyridazin-3-yl]-5-(1H -pyrazol-4-yl)phenol 29 ¹ 30 ¹ 2-[7-(8-azabicyclo[3,2,1]oct-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5(1H-pyrazol-4-yl )phenol 2-[7-(3-oxa-9-azabicyclo[3,3,1]pop-7-yl)-5H-pyrrolo-[3,2-c]pyridazin-3yl]-5-(1H-pyrazol- 4-yl)phenol

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31 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-5Hpyrrolo[3,2-c]pyridazin-3-yl]phenol 32 ¹ 3-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin- 4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine 33 ¹ 4-fluoro-2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 34 5-(1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 35 ¹ 4-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 36 ¹ 7-[(3-exo)-8-azabicyclo[3,2,1]oct-3-yl]-3-[2,3-difluoro-4-(1H-pyrazol-4yl)phenyl]-6,7 -dihydro-5H-pyrrolo[2,3-c]pyridazine 37 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-1-methyl-pyridin-2(1H)-one 38 ¹ 4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridaz in-6-yl]biphenyl-3,4 '-diol 39 ¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 40 ¹ 2-[6-methoxy-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol 42 ¹ 2-[6-(methylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4 -yl)-phenol 43 2-[7-(piperazin-1-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4yl)phenol 46 5-(1-ethyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 47 5-(1-propyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 48 5-(1H-pyrazol-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 49 ¹ 2-[6-(ethylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4 -yl)-phenol 50 5-(1-methyl-1H-pyrazol-5-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol

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51 5-(1-methyl-1H-pyrazol-3-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 52 ¹ 2-[3-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H -pyrazol-4-yl)phenol 53 ¹ 6-fluoro-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl] [1,1 '-biphenyl]-3,4'-diol 54 ¹ 2-fluoro-3-(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 55 ¹ 4-{2-fluoro-5-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-1-methylpyridin-2(1H)-one 56 ¹ 2-[3-(2,2-dimethylpiperidin-4-yl)-3H-[1,2,3]triazolo-[4,5-c]pyridazin-6yl]-5-(1H-pyrazol-4-yl) )phenol 57 ¹ 2-{3-[(1K,58)-1,5-dimethyl-8-azabicyclo[3,2,1]octan-3-yl]-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol 58 ¹ 2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine -6-yl]benzene-1,4-diol 59 ¹ 3-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 60 ¹ 5-(pyrazin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 61 ¹ 5-(pyridin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 62 ¹ 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl]phenol 63 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-( 1H-1 ,2,4-triazol-1-yl)phenol 64 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(4H-1 ,2,4-triazol-4-yl)phenol 65 ¹ 5-(pyridin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 66 ¹ 5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 67 ¹ 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}pyridin-3-o1

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68 ¹ 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-pyrimidin-5-ol 69 ¹ 5-[1-( ² H3)methyl-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)3H-[1,2,3 ]triazolo[4,5-c]-pyridazin-6-yl]phenol 70 ¹ 5-(1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine -6-yl]phenol 71 ¹ 5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4, 5-c]-pyridazin-6-yl]phenol 72 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-( 1H-1 ,2,3-triazol-1-yl)phenol 73 ¹ 5-(2-methylpyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 74 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5- c]pyridazin-6-yl]-5-[2-(trifluoromethyl)-pyridin-4-yl]phenol 75 ¹ 5-(pyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6 -yl]phenol 76 ¹ 5-(pyridazin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 77 ¹ 5-(2-methoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 78 5-(pyrimidin-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 79 ¹ 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-pyridazin-3-ol 80 5-(1H-pyrrol-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 81 ¹ 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]quinolin-7-ol 82 (3E)-3-(hydroxyimino)-6-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine -6-yl]-2,3-dihydro-1H-inden-5-ol 83 ¹ 4-chloro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 84 5-[6-(dimethylamino)pyridin-3-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c ]-pyridazin-6-yl]phenol

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85 5-(imidazo[1,2-a]pyrazin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]-pyr-idazin-6-yl]phenol 86 1-cyclopropyl-4-{3-hydroxy-4-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}pyridin-2(1H)-one 87 ¹ 4-fluoro-5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5 -c]pyridazin-6-yl]phenol 88 5-(imidazo[1,5-a]pyridin-7-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol 89 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(thiophene-3 -yl)phenol 90 5-(imidazo[1,2-a]pyridin-7-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol 91 5-(1H-imidazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 92 1-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl]-1H-benzimidazole -6-ol 93 ¹ 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}pyridin-2(1H)-one 94 5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-1H-indazol-6- ol 95 ¹ 5-(furan-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 96 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,3 -thiazol-2-yl)phenol 97 2-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl]-1H-benzimidazole -6-ol 98 ¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethyl-piperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5 -yl]phenol 99 5-(2-aminopyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 100 5-[2-(dimethylamino)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c ]-pyridazin-6-yl]phenol 101 5-(3-fluoropyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol

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102 ¹ 5-[1-( ^2H3 )methyl-1H-pyrazol-4-yl]-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)1H-pyrazolo[3,4- c]pyridazin-5-yl]-phenol SW ¹ 5-[5-(difluoromethoxy)pyridin-2-yl]-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5 -c]-pyridazin-6-yl]phenol 104 5-[2-(methylamino)pyridin-4-yl]-2-[3-(2,2,6,6-tetra-methylpiperidin-4-yl)3H-[1,2,3]triazolo[4, 5-c]-pyridazin-6-yl]phenol 105 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4yl)furo[3,2-c]pyridazin- 3-yl]phenol 106 ¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 107 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,3 -thiazol-5-yl)phenol 108 ¹ 5-(3-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 109 ¹ 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-1H-pyrazole-3-carbonitrile BY ¹ 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}-1,3-thiazole-5-carbonitrile 111 ¹ 5-(1,3-oxazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 112 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-1 ,2,3-triazol-4-yl)phenol 113 5-(6-methoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 114 ¹ 5-[2-(difluoromethoxy)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c ]-pyridazin-6-yl]phenol 115 5-(1H-imidazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 116 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-( 1,3 ,4-thiadiazol-2-yl)phenol 117 ¹ 6-[4-(1H-pyrazol-4-yl)-1H-benzotriazol-7-yl]-3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo-[4,5-c]pyridazine 118 ¹ 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl]phenol

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119 ¹ 5-(2-methoxypyrimidin-4-yl)-2-[3-(2,2D6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6 -yl]phenol 120 ¹ 5-(1,2-oxazol-4-yl)-2-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 121 ¹ 5-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl]phenol 122 ¹ 5-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl]phenol 123 ¹ 5-(2-ethoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 124 ¹ 5-(6-ethoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 125 ¹ 2-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1,2,3] triazolo[1,5-a]pyridin-5-yl)phenol 126 ¹ 2-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1,2,4] triazolo[1,5-a]pyridin-7-yl)phenol 127 ¹ 5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2D6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5- c]-pyridazin-6-yl]phenol 128 ¹ 6-{3-hydroxy-4-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-pyrimidin-4(3H)-one 129 ¹ 5-(3-chloro-1H-pyrazol-4-yl)-2-[3-(2,2D6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl]phenol 130 ¹ 5-(3-fluoro-1-methyl-1 H-pyrazol-4-yl)-2-[3-(2,2 Db-tetramethylpiper idin-4yl)-3H-[1,2,3]triazolo[4 ,5-c]-pyridazin-6-yl]phenol 131 ¹ 5-(3-methoxy-1H-pyrazol-4-yl)-2-[3-(2,2D6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 132 ¹ 4-{3-hydroxy-4-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-1-methyl-1H-pyrazole-3carbonitrile 133 ¹ 5-(5-methyl-1,3-thiazol-2-yl)-2-[3-(2,2D6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4,5 -c]pyridazin-6-yl]phenol 134 ¹ 2-[3-(2,2D6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,2,4-thiadiazole -5-yl)phenol

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135 ¹ 5-(4-fluoro-1H-benzotriazol-6-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]-pyr-idazin-6-yl]phenol 136 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Hpyrrolo[2,3 -с]pyridazin-3-yl]pyridin- 3 -о1 137 ¹ 5-(3-bromo-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 138 ¹ 5-(1-methyl-1H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)3H-[1,2,3 ]triazolo[4,5-c]-pyridazin-6-yl]phenol 139 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-[3-( trifluoromethyl)-1H-pyrazol-4-yl]phenol 140 ¹ 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]pyridin-3-ol 141 ¹ 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5-c]pyridazin-3-yl]pyridin-3 -ol 142 ¹ 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]-pyr-idazin-6-yl]phenol 143 ¹ 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 144 ¹ 5-(4-methyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol 145 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-[ 1,2,3]triazolo-[4,5-b]pyridin-6-yl)phenol 146 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(3H-[ 1,2,3]triazolo-[4,5-c]pyridin-6-yl)phenol 147 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-[ 1,2,3]triazolo-[4,5-b]pyridin-5-yl)phenol 148 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetra-methylpiperidin-4yl)-1H-pyrazolo[3,4-c ]pyridazin-5-yl]-phenol 149 ¹ 5-(2,4-dimethyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl]phenol 150 ¹ 5-(2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol 151 ¹ 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2, 3]triazolo[4,5-c]-pyridazin-6-yl]phenol

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152 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1, 2,4]triazolo[4,3-b]pyridazin-6-yl)phenol 153 ¹ 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol 154 5-(4-fluoro-2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2, 3]triazolo[4,5-c]-pyridazin-6-yl]phenol 155 ¹ 5-(5-methyl-1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol 156 5-(4-methyl-1H-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl)phenol 157 ¹ 5-(3-methyl-1H-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl)phenol 158 5-(2-methyl-1,3-oxazol-5-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol 159 ¹ 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)3H-[1,2,3 ]triazolo[4,5-c]-pyridazin-6-yl)phenol 160 ¹ 5-(imidazo[1,2-a]pyrimidin-6-yl)-2-(3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl)phenol 161 ¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-(1 -(2,2,6,6-tetramethyl-piperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5 -yl)phenol 162 ¹ 5-(imidazo[1,2-b]pyridazin-6-yl)-2-(3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]-pyridazin-6-yl)phenol 163 ¹ 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(2H-1 ,2,3-triazol-2-yl)phenol 164 ¹ 2-{3-[(38.48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol 165 ¹ 5-(pyridin-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4c]pyridazin-5-yl]phenol 166 ¹ 5-(pyridin-3-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4c]pyridazin-5-yl]phenol 167 ¹ 5-(pyrimidin-5-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridaz in-5-yl]phenol 168 ¹ 2-{3-[(38.4K)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol

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169 ¹ 5-(1-methyl-1H-pyrazol-3-yl)-2-[1-(2,2,6,6-tetramethyl-piperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazine -5-yl]phenol 170 ¹ 2-{3-[3-(tert-butylamino)cyclobutyl]-3H-[1,2,3]triazolo-[4,5-c]pyridazin6-yl}-5-(1H-pyrazol-4-yl)phenol 171 ¹ 4-(4-{3-[(38.48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl}-3-hydroxyphenyl)-1-methylpyridin- 2(1H)-on 172 ¹ 6-(4-{3-[(38,48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H[1,2,3]triazolo[4,5-c] pyridazin-6-yl}-3-hydroxyphenyl)-3- methylpyrimidin-4(3H)-one 173 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(38.48)-3-fluoro-2,2,6,6- tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo-[4,5-c]pyridazin-6yl}phenol 174 ¹ 2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo-[3,4-c]pyridazin-5yl]-5-(2H-1,2,3-triazol- 2-yl)phenol 175 ¹ 2-{3-[3-(tertbutylamino)cyclopentyl]-3H-[1,2,3]-triazolo[4,5 c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)- phenol, and 176 2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3yl]-5-(2H-1,2,3-triazol-2 -yl)phenol;

wherein the form of the compound is selected from the group consisting of its salt, hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric and tautomeric forms.

Another aspect of the compound of formula (I) or form thereof is a salt of the compound selected from the group consisting of the following salts:______________________________

Compound Name 1 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Nimidazo[4,5-b]pyrazin-5-yl]phenol hydrochloride 2 5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-1-(2,2,6,6- tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazine hydrochloride 3 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5 -c]pyridazin-3-yl]phenol hydrochloride 4 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6- tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazine hydrochloride 5 2-[6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol hydrochloride

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6 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-methyl-7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-imidazo[4,5 -c]-pyride azine hydrochloride 7 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 8 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenol hydrochloride 9 3-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-6 -ol hydrochloride 10 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethylpiperidin-4-yl)-5Hpyrrolo[2,3-b]pyrazin-2-yl]phenol hydrochloride eleven 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)-5H- pyrrolo[3,2-c]pyridazin-3-yl]phenol hydrochloride 12 2-[7-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1Hpyrazol-4-yl)phenol hydrochloride 13 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazine hydrochloride 14 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazine hydrochloride 15 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2c]pyridazin-3-yl]phenol hydrochloride 16 2-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-(2,2,6,6- tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazine hydrochloride 17 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6tetrahydropyridin-4-yl)thieno[3,2-c]pyride azin-3-yl]-phenol hydrochloride 18 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)thieno[3,2-c]pyridazin-3-yl]-5(1H-pyrazol-4 -yl)phenol hydrochloride 19 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]-5-(1H-pyrazol- 4-yl)phenol hydrochloride

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20 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol hydrochloride 21 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(1Hpyrazol-4-yl)phenol hydrochloride 22 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5-yl]phenol hydrochloride 23 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7dihydro-5H-pyrrolo[2,3-c]pyridazin-3 -yl]-phenol hydrochloride 24 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)thieno[3,2c]pyridazin-3-yl]phenol hydrochloride 25 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)thieno-[3,2-c]pyridazin- 3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 26 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H- pyrrolo[2,3-c]pyridazin-3-yl]phenol hydrochloride 27 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3yl]-5-(1H-pyrazol-4 -yl)phenol hydrochloride 28 2-[7-(3-oxa-9-azabicyclo[3,3,1]pop-6-ep-7-yl)-5H-pyrrolo[3,2c]pyridazin-3-yl]-5-(1H -pyrazol-4-yl)phenol hydrochloride 29 2-[7-(8-azabicyclo[3,2,1]oct-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]- 5-(1H-pyrazol-4-yl)phenol hydrochloride thirty 2-[7-(3-oxa-9-azabicyclo[3,3,1]pop-7-yl)-5H-pyrrolo-[3,2c]pyridazin-3-yl]-5-(1H-pyrazol- 4-yl)phenol hydrochloride 31 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-5H- pyrrolo[3,2-c]pyridazin-3-yl]phenol hydrochloride 32 3-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6- tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine hydrochloride 33 4-fluoro-2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 35 4-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrobromide 36 7-[(3-exo)-8-azabicyclo[3,2,1]oct-3-yl]-3-[2,3-difluoro-4-(1H-pyrazol-4yl)phenyl]-6,7 -dihydro-5H-pyrrolo[2,3-c]pyridazine hydrochloride

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38 4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5- c]pyridazin-6-yl]biphenyl-3,4'-diol hydrobromide 39 5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrobromide 40 2-[6-methoxy-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol hydrochloride 42 2-[6-(methylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5-c]pyridazin-3-yl]-5-(1H-pyrazol-4 -yl)-phenol hydrochloride 49 2-[6-(ethylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5-c]pyridazin-3-yl]-5-(1H-pyrazol-4 -yl)-phenol hydrochloride 52 2-[3-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H -pyrazol-4-yl)-phenol dihydrochloride 53 6-fluoro-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl][1,1 '-biphenyl]-3,4'-diol hydrobromide 54 2-fluoro-3-(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 55 4-{2-fluoro-5-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin- 6-yl]phenyl}-1-methylpyridin-2(1H)one hydrochloride 56 2-[3-(2,2-dimethylpiperidin-4-yl)-3H-[1,2,3]triazolo-[4,5-c]pyridazin6-yl]-5-(1H-pyrazol-4- yl)phenol hydrochloride 57 2-{3-[(1K.58)-1,5-dimethyl-8-azabicyclo[3,2,1]octan-3-yl]-3H[1,2,3]triazolo[4,5-c ]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride 58 2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]benzene-1,4-diol dihydrochloride 59 3-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 60 5-(pyrazin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6 -yl]phenol dihydrochloride 61 5-(pyridin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride

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62 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6yl]phenol hydrochloride 63 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-1 ,2,4-triazol-1-yl)phenol hydrochloride 64 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(4H-1 ,2,4-triazol-4-yl)phenol hydrochloride 65 5-(pyridin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 66 5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 67 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}pyridin-3-ol dihydrochloride 68 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}-pyrimidin-5-ol dihydrochloride 69 5-[1-( ² H3)methyl-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2, 3]triazolo[4,5-c]-pyridazin-6-yl]phenol dihydrochloride 70 5-(1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 71 5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6yl]phenol dihydrochloride 72 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-( 1 H- 1,2,3-triazol-1-yl)phenol hydrochloride 73 5-(2-methylpyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 74 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-[2-( trifluoromethyl)-pyridin-4-yl]phenol dihydrochloride 75 5-(pyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride

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76 5-(pyridazin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 77 5-(2-methoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 79 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}-pyridazin-3-ol hydrochloride 81 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]quinolin-7-ol hydrobromide 83 4-chloro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrobromide 87 4-fluoro-5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrobromide 89 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(thiophene-3 -yl)phenol hydrochloride 93 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}pyridin-2(1H)-one hydrochloride 95 5-(furan-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 96 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,3 -thiazol-2-yl)-phenol hydrochloride 98 5-(1-methyl-1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethyl-piperidin-4-yl)- 1H-pyrazolo[3,4-c]pyridazin-5-yl]phenol dihydrochloride 102 5-[1-( ^2H3 )methyl-1H-pyrazol-4-yl]-2-[1-(2,2,6,6-tetra-methylpiperidin-4-yl)-1H-pyrazolo[3,4 -c]pyridazin-5-yl]-phenol dihydrochloride 103 5 - [5 - (d fluoromethoxy)pyridin-2-yl] -2- [3 -(2,2,6,6-tetramethylpiperidin- 4-yl)-3N-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol formate 105 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)furo[3,2-c]pyridazin-3-yl]phenol hydrochloride 106 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride

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107 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,3 -thiazol-5-yl)-phenol hydrochloride 108 5-(3-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 109 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}-1H-pyrazole-3carbonitrile hydrochloride BY 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl] phenyl}-1,3-thiazole-5carbonitrile hydrochloride 111 5-(1,3-oxazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol formate 114 5-[2-(difluoromethoxy)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5 -c]-pyridazin-6yl]phenol hydrochloride 116 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,3 ,4-thiadiazol-2-yl)phenol hydrochloride 117 6-[4-(1H-pyrazol-4-yl)-1H-benzotriazol-7-yl]-3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo-[4,5-c]pyridazine trifluoroacetate 118 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-[3-(2,2,6,6-tetra- Methylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6yl]phenol hydrochloride 119 5-(2-methoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin-6-yl]phenol hydrochloride 120 5-(1,2-oxazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 121 5-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5-c]-pyridazin-6yl]phenol hydrochloride 122 5-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol hydrochloride 123 5-(2-ethoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride

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124 5-(6-ethoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 125 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1, 2,3]triazolo[1,5-a]pyridin-5-yl)phenol hydrochloride 126 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1, 2,4]triazolo[1,5-a]pyridin-7-yl)phenol hydrochloride 127 5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6yl]phenol hydrochloride 128 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-pyrimidin-4(3H)-one hydrochloride 129 5-(3-chloro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 130 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5-c]-pyridazin-6yl]phenol hydrochloride 131 5-(3-methoxy-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4yl)-3H-[1,2,3]triazolo[4, 5-c]pyridazin-6-yl]phenol hydrochloride 132 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenyl}-1-methyl-1H-pyrazole-3carbonitrile hydrochloride 133 5-(5-methyl-1,3-thiazol-2-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride 134 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1,2 ,4-thiadiazol-5-yl)phenol hydrochloride 135 5-(4-fluoro-1H-benzotriazol-6-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3]triazolo[4, 5-c]-pyridazin-6-yl]phenol hydrochloride 136 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Hpyrrolo[2,3-c]pyridazin-3-yl]pyridin-3 -ol dihydrochloride 137 5-(3-bromo-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol hydrochloride

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138 5-(1-methyl-1H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol hydrochloride 139 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-[3 -( trifluoromethyl)-1 H-pyrazol-4-yl]phenol hydrochloride 140 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine -6-yl]pyridin-3-ol hydrochloride 141 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5-c]pyridazin-3-yl]pyridin-3 -ol dihydrochloride 142 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[ 4,5-c]pyridazin-6-yl]phenol hydrochloride 143 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 144 5-(4-methyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4yl)-3H-[1,2,3]triazolo[4, 5-c]pyridazin-6-yl]phenol dihydrochloride 145 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-[ 1,2,3]triazolo-[4,5-b]pyridin-6-yl)phenol dihydrochloride 146 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(3H-[ 1,2,3]triazolo-[4,5-c]pyridin-6-yl)phenol dihydrochloride 147 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(1H-[ 1,2,3]triazolo-[4,5-b]pyridin-5-yl)phenol dihydrochloride 149 5-(2,4-dimethyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol dihydrochloride 150 5-(2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 151 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl]phenol hydrochloride 152 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-([1, 2,4]triazolo[4,3-b]pyridazin-6-yl)phenol hydrochloride

- 46 045009

153 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-[3-(2,2,6,6-tetra-methylpiperidin-4yl)-3H-[1,2,3] triazolo[4,5-c]-pyridazin-6-yl]phenol hydrochloride 155 5-(5-methyl-1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]phenol dihydrochloride 157 5-(3-methyl-1H-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethyl-piperidin-4-yl)- 3N-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenol dihydrochloride 159 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3] triazolo[4,5-c]-pyridazin-6-yl)phenol dihydrochloride 160 5-(imidazo[1,2-a]pyrimidin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3N-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl)phenol hydrochloride 161 5-(3-fluoro-1H-pyrazol-4-yl)-2-(1-(2,2,6,6-tetramethyl-piperidin-4-yl)- 1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol hydrochloride 162 5-(imidazo[1,2-b]pyridazin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H-[1,2,3]triazolo[4,5-c]-pyridazin-6-yl)phenol hydrochloride 163 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]-triazolo[4,5c]pyridazin-6-yl]-5-(2H-1 ,2,3-triazol-2-yl)phenol hydrochloride 164 2-{3-[(38.48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 165 5-(pyridin-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5-yl]phenol hydrochloride 166 5-(pyridin-3-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5-yl]phenol hydrochloride 167 5-(pyrimidin-5-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Hpyrazolo[3,4-c]pyridazin-5-yl]phenol hydrochloride 168 2-{3-[(38.4K)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H[1,2,3]triazolo[4,5-c]pyridazin-6 -yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 169 5-(1-methyl-1H-pyrazol-3-yl)-2-[1-(2,2,6,6-tetramethyl-piperidin-4-yl)- 1 H-pyrazolo[3,4-c]pyridazin-5-yl]phenol hydrochloride 170 2-{3-[3-(tertbutylamino)cyclobutyl]-3H-[1,2,3]triazolo-[4,5c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 171 4-(4-{3-[(38,48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H[1,2,3]triazolo[4,5-c] pyridazin-6-yl}-3-hydroxyphenyl)-1methylpyridin-2(1H)-one hydrochloride 172 6-(4-{3-[(38,48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H[1,2,3]triazolo[4,5-c] pyridazin-6-yl}-3-hydroxyphenyl)-3- Methylpyrimidin-4(3H)-one dihydrochloride 174 2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo-[3,4- c]pyridazin-5-yl]-5-(2H-1,2,3-triazol-2-yl)phenol hydrochloride, and 175 2-{3-[3-(tertbutylamino)cyclopentyl]-3H-[1,2,3]-triazolo[4,5 c]pyridazin-6-yl}-5-(1H-pyrazol-4-yl)- phenol dihydrochloride;

wherein the form of the compound is selected from the group consisting of its salt, hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric and tautomeric forms.

An aspect of the present invention includes a method of using a compound of formula (I) or a form thereof to treat or alleviate Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

Another aspect of the present invention includes a method of using a salt of a compound of formula (I) or a form thereof to treat or alleviate Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

An aspect of the present invention includes the use of a compound of formula (I) or a form thereof for the treatment or amelioration of Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

Another aspect of the present invention includes the use of a salt of a compound of formula (I) or

- 47 045009 forms for treating or alleviating Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

Definitions of chemical terms.

Unless specifically stated otherwise, chemical terms used throughout the present invention are those commonly understood by one of ordinary skill in the art and have the following meanings.

The term C ₁ as used in the present invention. ₆ alkyl generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl ( also called butyl or butanyl), isobutyl, sec-butyl, t-butyl, n-pentyl (also called pentyl or pentanyl), n-hexyl (also called hexyl or hexanyl), and other similar alkyls. In specific aspects, C ₁ . ₆ αlkyl includes, but is not limited to, C ₁ . ₄ alkyl and other similar alkyls. C ₁ . _{The 6} alkyl radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valence.

The term C ₂ as used in the present invention. ₈ alkenyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain and one or more carbon-carbon double bonds, including, but not limited to, ethenyl (also called vinyl), allyl, propenyl and other similar alkenyls. In specific aspects, C ₂ . ₈ αlkenyl includes, but is not limited to, C ₂ . ₆ alkenyl, C ₂ . ₄ alkenyl and other similar alkenyls. _C2 . ₈ the alkenyl radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valence.

The term C ₂ as used in the present invention. ₈ alkynyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain and one or more carbon-carbon triple bonds, including, but not limited to, ethynyl, propynyl, butynyl and other similar alkynyls. In specific aspects, C ₂ . ₈ alkynyl includes, but is not limited to, C ₂ . ₆ alkynyl, C ₂ . ₄ alkynyl and other similar alkynyls. _C2 . ₈ The alkynyl radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valence.

The term C ₁ as used in the present invention. ₆ alkoxy generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain, formula: -O-C ₁ . ₆ alkyl, including, but not limited to, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy and other similar alkoxy. In specific aspects, Cl. ₆ alkoxy includes, but is not limited to, C ₁ . ₄ alkoxy and other similar alkoxy. C ₁ . _{The 6} alkoxy radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valency.

The term C ₃ as used in the present invention. ₁₀ cycloalkyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydronaphthalenyl and other similar cycloalkyls. In specific aspects, C ₃ . ₁₀ cycloalkyl includes, but is not limited to, C ₃ . ₈ cycloalkyl, C ₅ _ ₈ cycloalkyl, C ₃ . ₁₀ cycloalkyl and other similar cycloalkyl. The C ₃ - ₁₀ cycloalkyl radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valence.

As used herein, the term aryl generally refers to a radical with a monocyclic, bicyclic or polycyclic aromatic ring structure of carbon atoms, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and other similar aryls. The aryl radical is optionally substituted with the substituents described in the invention, when this is permissible from the point of view of valency.

As used herein, the term heteroaryl generally refers to a radical with a monocyclic, bicyclic or polycyclic aromatic ring structure of carbon atoms, in which one or more carbon atoms in the ring have been replaced, when this does not interfere with the stability of the structure, by one or more heteroatoms, 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, oxadiazolyl, thiadiazolyl, tetraazolyl, 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, acridinyl, Furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[ 2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3c]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- 48 045009

b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1- b][1,3]-thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,

[1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and other similar heteroaryls. The heteroaryl radical is optionally substituted on the ring carbon or nitrogen atom with substituents described in the present invention, when this is acceptable from a valence point of view.

In particular aspects, the nomenclature for the heteroaryl radical may vary, such as, for example, in non-limiting examples, in which furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl, and 1,3- benzoxazolyl may also be called 1,3benzooxazolyl.

In other specific aspects, the term for a heteroaryl radical may also include other regioisomers, such as in non-limiting examples in which the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and other similar pyrrolyls, the term pyrazolyl may also include 1H-pyrazolyl and other similar pyrazolyls, the term imidazolyl may also include 1H-imidazolyl and other similar imidazolyls, the term triazolyl may also include 1H1,2,3-triazolyl and other similar triazolyls, the term oxadiazolyl may also include 1,2,4oxadiazolyl, 1,3, 4-oxadiazolyl and other similar oxadiazolyls, the term tetraazolyl may also include 1H-tetraazolyl, 2H-tetraazolyl and other similar tetraazolyls, the term indolyl may also include 1H-indolyl and other similar indolyls, the term indazolyl may also include 1H-indazolyl, 2H-indazolyl and others like indazolyls, the term benzoimidazolyl may also include 1H-benzoimidazolyl and the term purinyl may also include 9H-purinyl and other similar purinyls.

As used herein, the term heterocyclyl generally refers to a radical with a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring structure of carbon atoms in which one or more carbon atoms in the ring have been replaced, when this does not impair the stability of the structure, by one or more heteroatoms , such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinil . 3.6 -tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrole -(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol(1H)-yl, (3aS,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,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, octahydro6H-pyrrolo-[3,4-b] pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazinyl (1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo-[1,2-a]pyrazin-(1H)-yl, ( 8aR)hexahydropyrrolo[1,2-a]pyrrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrrazin-(1H)-yl, (8aR)octahydropyrrolo[1,2-a ]pyrazin-(1H)-yl, hexahydropyrrolo-[1,2-a]pyrazin-(2H)-one, octahydro-2Hpyrido[1,2-a]pyrazinyl, 3-aza-bicyclo[3,1,0] hexyl, (1R,5S)-3-azabicyclo[3,1,0]hexyl, 8-azabicyclo[3,2,1]octyl, (1R,5S)-8-azabicyclo[3,2,1]octyl, 8-aza-bicyclo[3,2,1]oct-2-enyl, (1R,5S)-8azabicyclo[3,2,1]-oct-2-enyl, 9-azabicyclo[3,3,1]nonyl , (1R,5S)-9-azabicyclo-[3,3,1]nonyl, 2,5diazabicyclo[2,2,1]heptyl, (1S,4S)-2,5-diaza-bicyclo[2,2, 1]heptyl, 2,5-diazabicyclo[2,2.2]octyl, 3,8diaza-bicyclo[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-diaza-spiro[3,3]heptyl, 2,7-diazaspiro[3,5]nonyl, 5, 8-diazaspiro-[3,5]nonyl, 2,7diazaspiro[4,4]nonyl, 6,9-diazaspiro[4,5]decyl and other similar heterocyclyls. The heterocyclyl is optionally substituted on the ring carbon or nitrogen atom with substituents described in the present invention, when this is acceptable from a valence point of view.

In specific aspects, the nomenclature for the heterocyclyl radical may vary, such as in non-limiting examples in which 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxolyl, and 2,3-dihydro-1,4 -benzodioxynyl may also be called 2,3dihydrobenzo[b][1,4]dioxynil.

As used herein, the term deutero-C ₁ .4 alkyl refers to a radical of the formula -C ₁ .4 alkyl-deutero, wherein the C ₁ .4 alkyl group is partially or fully substituted by one or more deuterium atoms when valence permits.

The term C ₁ as used in the present invention. ₆ alkoxy-C ₁ . ₆ alkyl refers to a radical of the formula -C ₁ . ₆ αlkyl-O-C ₁ . ₆ alkyl.

The term C ₁ as used in the present invention. ₆ alkyl-amino refers to the radical of the formula

- 49 045009

-KH-C _1-6 alkyl.

As used herein, the term (C1.balkyl)2-amino refers to a radical of the formula -K( _C1.6alkyl ) ₂ .

The term C ₁ as used in the present invention. ₆ alkyl-thio refers to the radical of the formula -SC ₁ . ₆ alk.

As used herein, the term amino-C1-balkyl refers to a radical of the formula -C _1-6 alkyl-NH ₂ .

As used in the present invention, the term halogen generally refers to a radical of a halogen atom including fluorine, chlorine, bromine and iodine.

As used herein, the term halogen-C1-balkoxy refers to a radical of the formula -O-C _1-6alkyl -halogen, wherein the _C1-6alkyl is partially or fully substituted by one or more halogen atoms when valence permits.

As used herein, the term halogen-C1-balkyl refers to a radical of the formula -C _1- 6 alkyl-halogen, wherein the C _1- 6 alkyl is partially or fully substituted by one or more halogen atoms when valence-appropriate.

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

The term hydroxy-C ₁ as used in the present invention. ₆ alkyl refers to a radical of the formula -C ₁ . ₆ alkyl-OH, where the C^alkyl is partially or completely substituted by one or more hydroxyl radicals, when this is permissible from the point of view of valency.

As used herein, the term substituent means positional variables on the atoms of the core of a molecule that are subject to substitution at the designated atomic position by replacing one or more hydrogens on the designated atom, provided that the normal valency of the designated atom is not exceeded and that the substitution results in the formation of a stable compound . Combinations of substituents and/or variables are permissible only if such combinations lead to the formation of stable compounds. It should be obvious to one of ordinary skill in the art that any carbon, as well as heteroatom, with valences described or shown in the invention that are unsaturated has a sufficient number of hydrogen atoms to saturate the valencies described or shown. In specific cases, one or more substituents having a double bond (e.g., oxo or =O) as the point of attachment may be described, shown, or listed in the invention within a group of substituents where only a single bond may be shown in the structure as points of attachment to the core of the structure of formula (I). It will be apparent to one of ordinary skill in the art that although only a single bond is shown, the presence of a double bond is nevertheless expected for these substituents.

As used in the present invention, the term and the like, when applied to the definitions of chemical terms provided herein, mean that variations in chemical structures that would be expected by one skilled in the art include, but are not limited to, isomers (including chain-branching isomers). isomers or positional structural isomers), the degree of hydrogenation of the ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations, when permissible in terms of valence, that lead to the formation of a stable compound.

In connection with this invention, in the case where one or more variable substituents for a compound of formula (I) or a form thereof include the functionality introduced into the compound of formula (I), each functionality appearing at any position within the compound described in the invention may be independently selected, and, where appropriate, independently and/or optionally substituted.

As used herein, the terms are independently selected and each selection refers to functional variables in a list of substituents that may appear more than once in the structure of formula (I), and the nature of the substitution on each occurrence is independent of the nature of the substitution on any other occurrence. In addition, it should be borne in mind that the use of a variable substituent belonging to the general class in any formula or structure for a compound described in the invention involves replacing the substituent belonging to the general class with species of substituents that are included in the specific class, for example, aryl may be replaced by phenyl or naphthalenyl and other similar groups, and that the resulting compound must be within the scope of the compounds described in the invention.

It is intended that the terms used in the present invention in each specific case or in each specific case of presence when used before such a phrase as ... C3-cycloalkyl, C3-cycloalkyl-Smalkyl, aryl, aryl-C^alkyl, heteroaryl, heteroaryl -C^alkyl, heterocyclyl and heterocyclyl-C^alkyl refer to C3-^cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each is present either alone or as a substituent.

- 50 045009

As used herein, the term optionally substituted means optional substitution with specified variable substituents, groups, radicals or moieties.

Forms of connection.

As used herein, the term form means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomer form.

In the specific aspects described herein, the form of a compound of formula (I) is its free acid, free base or salt.

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

In the specific aspects described herein, the form of a compound of formula (I) is an isotopologue thereof.

In the specific aspects described herein, the form of a compound of formula (I) is a stereoisomer, racemate, enantiomer, or diastereomer thereof.

In the specific aspects described herein, the form of the compound of formula (I) is a tautomer thereof.

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

In the specific aspects described herein, a compound of formula (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 isolation and/or purification from a synthesis process (e.g., from a reaction mixture) or a natural source, or a combination thereof, by use of an isolation or purification process, or processes described in the invention, or processes that are well known to those skilled in the art (eg, chromatography, recrystallization, and other similar processes) with sufficient purity to characterize the compound by standard analytical methods described in the invention or well known to those skilled in the art.

As used herein, the term protected means that the functional group in a compound of formula (I) or form thereof is in a form modified to prevent unwanted side reactions from occurring at the protected site when the compound is subjected to any reaction. Suitable protecting groups are well known to one of ordinary skill in the art and are also detailed in well-established texts such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxyl group, phenolic group, amino group and carboxylic acid group. Suitable protecting groups for the hydroxyl or phenolic group include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and other similar protecting groups. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, and other similar protecting groups. Suitable carboxylic acid protecting groups include alkyl, aryl or arylalkyl esters. In particular cases, the protecting group may also be a polymer resin such as Wang's resin or 2-chlorotrityl chloride resin. Protecting groups can be introduced or removed by standard methods that are well known to those skilled in the art and described in the invention. It will also be apparent to one skilled in the art that although such protected derivatives of the compounds described herein may not have pharmacological activity as such, they may nevertheless be administered to a subject and thereafter metabolized in the body to form the compounds described herein. compounds that are pharmacologically active. Because of this, such derivatives can be called prodrugs. All prodrugs of the compounds described in the invention are included in the scope of the use described in the invention.

As used herein, the term prodrug refers to a form of a compound described herein (eg, a precursor drug) that is converted in vivo to the active compound of formula (I) or a form thereof. The transformation can occur through various mechanisms (for example, as a result of metabolic and/or non-metabolic chemical processes), such as, for example, hydrolysis and/or metabolism in the blood of the liver and/or other organs and tissues. For a discussion of the use of prodrugs, see T. Higuchi and W. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In one example, when the compound of formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug may include an ester formed by replacing the hydrogen atom of the acidic group with a functional group such as alkyl and other similar groups. In another example, when the compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form can be prepared by replacing the hydroxyl hydrogen atom with another

- 51 045009 functional group such as alkyl, alkylcarbonyl or phosphonate ester and other similar groups. In another example, when the compound of formula (I) or a form thereof contains an amine functional group, the prodrug form can be prepared by replacing one or more hydrogen atoms in the amine with a functional group such as an alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of the compounds of formula (I) or forms thereof include compounds substituted, as appropriate, with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents. As described in the invention, it will be apparent to one of ordinary skill in the art that one or more of such substituents may be used to prepare a compound of formula (I) or a prodrug form thereof.

One or more of the compounds described herein may exist in either unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and other similar solvents, and the invention is intended to cover both solvated and unsolvated forms.

As used herein, the term solvate means the physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In particular cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of the crystalline solid. As used herein, the term solvate covers both solution phase solvates and liberated solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and other similar solvates.

As used herein, the term hydrate means a solvate in which the solvent molecule is water.

The compounds of formula (I) can form salts, which are intended to be within the scope of this invention. It should be understood that reference to a compound of formula (I) or a form thereof in the invention includes reference to its salt form unless otherwise indicated. As used herein, the term salt(s) refers to both acid addition salts formed with inorganic and/or organic acids and base addition salts formed with inorganic and/or organic bases. In addition, when a compound of formula (I) or a form thereof contains both a moiety with basic properties, such as, but not limited to, an amine moiety, and a moiety with acidic properties, such as, but not limited to, a carboxylic acid, zwitter may be formed -ions (internal salts), and these are included in the term salt(s) used in the invention.

As used herein, the term pharmaceutically acceptable salt(s) refers to salts of the compounds described herein that are safe and effective (ie, non-toxic, physiologically acceptable) for use in mammals and that have biological activity, although other salts may also be used. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with a specified amount of acid or base, such as an equivalent amount, in a medium such as the medium in which the salt is precipitated, or in aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in the compounds described herein. Specific aspects of acid salts include, but without limiting this, acetate, ascorbate, benzoate, benzulosulfate, bisulfate, bartral, borage, bromide, butyrate, chloride, citrate, campfind, campfront, ethan sophomic, formal, fumaratic, gentisinate, gluconate, glucaronate, glucaronate, glucaronate. glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalene sulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also called tosylate ), trifluoroacetate salts and other similar salt. Some specific aspects of acid addition salts include chloride, bromide or dichloride.

In addition, acids generally considered suitable for the formation of pharmaceutically acceptable salts from pharmaceutical compounds with basic properties are described in detail, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and on the US Food and Drug Administration website in The Orange Book (Food & Drug Administration, Washington, D.C.). The entire contents of these publications are incorporated herein by reference.

Suitable base addition salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts.

It is assumed that all these acid addition salts and base addition salts are included in

- 52 045009 volume of pharmaceutically acceptable salts described in the invention. Moreover, for purposes of this invention, all of these acid addition salts and base addition salts are considered to be equivalent to the free forms of the corresponding compounds.

In addition, the compounds of formula (I) and their forms may exist in tautomeric form. All of these tautomeric forms are intended to be within the scope of the compounds of formula (I) or forms thereof described herein.

The compounds of formula (I) or forms thereof may contain asymmetric centers or chiral centers and, as a result, exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds of formula (I), as well as mixtures thereof, including racemic mixtures.

The compounds described herein may include one or more chiral centers, and as such may exist in the form of racemic mixtures (R/S) or in the form of substantially pure enantiomers and diastereomers. Compounds can also exist in the form of substantially pure (R) or (S) enantiomers (when a single chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist in the form of enantiomerically pure compositions substantially comprising only the (S) isomer. In one particular aspect, the compounds described herein are (R) isomers and may exist in the form of enantiomerically pure compositions substantially comprising only the (R) isomer. It will be apparent to anyone skilled in the art that, when more than one chiral center is present, the compounds described herein may also exist in the form (R,R), (R,S), (c,R) or (c,S ) isomer, as defined according to IUPAC nomenclature.

As used herein, the term substantially pure refers to compounds containing substantially 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 individual isomer.

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

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

As used herein, the term racemate means any mixture of isomeric forms that are not enantiomerically pure, including mixtures of, for example, but not limited to, about 50/50, about 60/40, about 70/30, or about 80/20.

Moreover, the present invention covers all geometric and positional isomers. For example, if a compound of formula (I) or a form thereof includes a double bond or a fused ring, then both the cis and trans forms, as well as mixtures thereof, are within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated on a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting an enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. In addition, some of the compounds of formula (I) may be atropisomers (eg, substituted biaryls) and are contemplated as part of this invention.

All stereoisomers (e.g., geometric isomers, optical isomers, and other similar isomers) of the compounds of the present invention (including isomers of salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs) are intended to be all, such as isomers which can exist due to asymmetric carbon atoms on various substituents, including enantiomeric forms (which can exist even in the absence of asymmetric carbon atoms), rotameric forms, atropoisomers and diastereomeric forms are within the scope of this invention, as are positional isomers (such as , for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds described in the invention may, for example, contain substantially no other isomers, or they may be present in a racemic mixture as described above.

- 53 045009

The use of the terms salt, solvate, ester, prodrug and other similar terms is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the compounds of the present invention.

The term isotopologue refers to isotopically enriched compounds described in the invention that are identical to the compounds listed in the invention, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁵ Cl and ³⁶ Cl, respectively, each of which is also included within the scope of this invention.

Specific isotopically enriched compounds described herein (eg, compounds labeled with ³ H and ¹⁴ C) are used in compound and/or substrate tissue distribution studies. The isotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or decreased required dose level) and, therefore, may be preferable in some circumstances.

It is further contemplated that polymorphic crystalline and amorphous forms of the compounds of formula (I) and salts, solvates, hydrates, esters and prodrugs of the compounds of formula (I) are included in the present invention.

Application of connections.

An aspect of the present invention relates to a method of using a compound of formula (I) or a form thereof to treat or alleviate Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound or form thereof.

Another aspect of the present invention relates to the use of a compound of formula (I) or a form thereof for the treatment or alleviation of Huntington's disease in a subject in need thereof.

Another aspect of the present invention relates to the use of a compound of formula (I) or a form thereof having activity against Huntington's disease (HD).

An aspect of the present invention relates to the use of a compound of formula (I) or a form thereof for the use of a compound of formula (I) or a form thereof in a combination therapy to achieve additive or synergistic activity to provide a combination product for the treatment or amelioration of Huntington's disease (HD).

In addition to use in monotherapy, the compounds of the present invention are used in combination therapy with existing standard drugs, having additive or synergistic activity with one or more known drugs.

Combination therapy comprising the compounds described herein in combination with one or more known drugs can be used for the treatment of Huntington's disease (HD), regardless of whether a positive response is achieved in the treatment of Huntington's disease (HD) with the known drug or not.

Specific aspects of the present invention include the use of a compound of formula (I) or a form thereof in combination therapy for the treatment or amelioration of Huntington's disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more drugs .

Specific aspects of the present invention include the use of a salt of a compound of formula (I) or a form thereof in combination therapy for the treatment or amelioration of Huntington's disease in a subject in need thereof, comprising administering an effective amount of a salt of a compound of formula (I) or a form thereof and an effective amount of one or more medicines.

In an aspect of the inventive use or method, the compounds of formula (I) or forms thereof, used in combination with one or more additional drugs, can be administered to the subject or brought into contact with the cell(s) of the subject or patient before, simultaneously or after administering to the subject or patient the additional agent(s) or bringing the additional agent(s) into contact with the cells. The compound(s) of formula (I) or form(s) thereof and the additional agent(s) may be administered to a subject or brought into contact with a cell in the same composition or in different compositions. In a particular aspect, the compound(s) of formula (I) or form(s) thereof is used in combination with gene therapy to inhibit HTT expression (using, for example, viral vectors for delivery) or in combination with the administration of another synthetic HTT inhibitor . In another specific aspect, the compound(s) of formula (I) or form(s) thereof is used in combination with cell replacement therapy using dif.

- 54 045009 fermented non-mutant stem cells HTT. In another specific aspect, the compound(s) of formula (I) or form(s) thereof are used in combination with cell replacement therapy using differentiated HTT stem cells.

In one aspect, the invention provides the use of compounds of formula (I) or forms thereof in combination with standard supportive care therapies, including palliative care.

An aspect of the present invention includes the use of a compound of formula (I) or a form thereof in the preparation of a kit comprising a compound of formula (I) or a form thereof and instructions for administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more drugs in combination therapy to treat or alleviate Huntington's disease in a subject in need thereof.

Accordingly, the present invention relates to the use of a compound of formula (I) or a form thereof for the treatment or alleviation of Huntington's disease (HD). In accordance with the use of the present invention, compounds have been identified that are useful in the selective treatment or alleviation of Huntington's disease (HD), and the use of these compounds for the treatment or alleviation of Huntington's disease (HD) has been proposed.

Another aspect of use of the present invention relates to the use of a compound of formula (I) or a form thereof for the treatment or amelioration of Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

Another aspect of use of the present invention relates to a method of using a compound of formula (I) or a form thereof to treat or alleviate Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound.

Another aspect of use of the present invention relates to a method of using a compound of formula (I) or a form thereof to treat or alleviate Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound.

Another aspect of use of the present invention relates to the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or alleviating Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

Another aspect of use of the present invention relates to the use of a compound of formula (I) or a form thereof in the preparation of a kit comprising a compound of formula (I) or a form thereof and instructions for administering the compound for the treatment or amelioration of Huntington's disease in a subject in need thereof.

On the one hand, in the case of each of these aspects, the subject has not been previously treated. On the other hand, in the case of each of these aspects, the subject has already undergone treatment before.

As used herein, the term treatment refers to (i) preventing the occurrence of a disease, disorder, or condition in a subject who may be susceptible to the occurrence of the disease, disorder, or condition, but who has not yet been diagnosed as having the disease, disorder, and/or condition; (ii) to inhibit a disease, disorder or condition, that is, stop its development; and/or (iii) to alleviating the disease, disorder or condition, that is, achieving remission of the disease, disorder and/or condition.

As used in the present invention, the term subject refers to an animal or any living organism that has sensory perception and the ability to carry out conscious movements, and which requires the presence of oxygen and natural food. Non-limiting examples include members of the human, primate, equine, pig, ruminant, mouse, rat, dog and cat species. In particular aspects, the subject is a mammal or warm-blooded vertebrate animal. In other aspects, the subject is a person. As used herein, the term patient may be used interchangeably with the terms subject and person.

As used herein, the terms effective amount or therapeutically effective amount mean the amount of a compound of formula (I) or a form, composition or drug thereof that achieves a target plasma concentration that is effective in treating or alleviating Huntington's disease (HD) as described herein. , and as a result of which the desired therapeutic, improving, inhibitory or prophylactic effect is produced in the subject in need thereof. In one aspect, the effective amount may be the amount required to treat Huntington's disease (HD) in a subject or patient, more particularly in a human.

In another aspect, the biological effect versus concentration relationships observed for a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from about 0.001 μg/mL to about 50 μg/mL, from about 0.01 μg/mL to about 20 μg/ml, about 0.05 μg/ml to about 10 μg/ml, or about 0.1 μg/ml to about 5 μg/ml. To achieve such plasma concentrations described in ISO

- 55 045009 bretening compounds can be administered in doses that vary in a range such as, for example, without limitation, from 0.1 ng to 10,000 mg.

In one aspect, the dose administered to achieve an effective target plasma concentration may be administered based on subject or patient specific factors, where doses administered based on the body weight of the subject or patient may range 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/day kg/day to about 2000 mg/kg/day, or from about 0.001 mg/kg/day to about 1500 mg/kg/day, or from about 0.001 mg/kg/day to about 1000 mg/kg/day, or from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 200 mg/kg/day day, or from about 0.001 mg/kg/day to about 150 mg/kg/day, or from about 0.001 mg/kg/day to about 100 mg/kg/day, or from 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 day to about 10 mg/kg/day, or from about 0.001 mg/kg/day to about 5 mg/kg/day, or from about 0.001 mg/kg/day to about 1 mg/kg/day, or from about 0.001 mg/kg/day to about 0.5 mg/kg/day, or about 0.001 mg/kg/day to about 0.1 mg/kg/day, or about 0.01 mg/kg/day to about 3500 mg/kg/day, or from about 0.01 mg/kg/day to about 3000 mg/kg/day, or from about 0.01 mg/kg/day to about 2500 mg/kg/day, or from 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 mg/kg/day to about 150 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day, or about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 50 mg/kg/day, or about 0 .01 mg/kg/day to about 25 mg/kg/day, or about 0.01 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 5 mg/kg/day, or from about 0.01 mg/kg/day to about 1 mg/kg/day, or from about 0.01 mg/kg/day to about 0.5 mg/kg/day, or from about 0.01 mg/kg/day to about 0.1 mg/kg/day, or about 0.1 mg/kg/day to about 3500 mg/kg/day, or about 0.1 mg/kg/day day to about 3000 mg/kg/day, or from about 0.1 mg/kg/day to about 2500 mg/kg/day, or from about 0.1 mg/kg/day to about 2000 mg/kg/day, or from about 0.1 mg/kg/day to about 1500 mg/kg/day, or from about 0.1 mg/kg/day to about 1000 mg/kg/day, or from about 0.1 mg/kg/day day to about 500 mg/kg/day, or from about 0.1 mg/kg/day to about 250 mg/kg/day, or from about 0.1 mg/kg/day to about 200 mg/kg/day, or from about 0.1 mg/kg/day to about 150 mg/kg/day, or from about 0.1 mg/kg/day to about 100 mg/kg/day, or from about 0.1 mg/kg/day day to about 75 mg/kg/day, or from about 0.1 mg/kg/day to about 50 mg/kg/day, or from about 0.1 mg/kg/day to about 25 mg/kg/day, or from about 0.1 mg/kg/day to about 10 mg/kg/day, or from about 0.1 mg/kg/day to about 5 mg/kg/day, or from about 0.1 mg/kg/day day to about 1 mg/kg/day, or from about 0.1 mg/kg/day to about 0.5 mg/kg/day.

Effective amounts for a given subject can be determined by performing a routine experiment that is well known to the clinician or attending physician, taking into account factors relevant 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 that may be taken into account include genetic screening, severity of disease condition, disease progression status, general health of the subject, ethnicity, age, body weight, sex, diet, time of day and frequency of administration, drug combination(s) agents, response to the drug, experience with other treatments, and tolerability/response to therapy.

The dose administered to achieve the effective target plasma concentration may be administered orally once daily (once over approximately 24 hours; i.e., q.d.), twice daily (once over approximately 12 hours, i.e., b.i.d., or q.12h), three times daily (once for approximately 8 hours, i.e. t.i.d. or q.8h), or four times daily (once for approximately 6 hours, i.e. q.d.s., q.i.d. or q.6h ).

In specific aspects, the dose administered to achieve an effective target concentration in

- 56 045009 plasma, can be administered in the form of a single dose, a divided dose and in the form of a continuous dosage in the case of a patient or subject having a body weight in the range of from about 40 to about 200 kg (this dose can be adjusted for patients or subjects with body weight above or below this range, in particular for children with body weight below 40 kg). A typical adult subject is expected to have an average body weight in the range of approximately 70 kg. Extended-release pharmaceutical compositions may be administered once every 2, 3, or 4 days, once a week, or once every two weeks, depending on the half-life and elimination rate of the particular dosage form.

The compounds and compositions described herein can be administered to a subject by any known method. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral and inhalation routes of administration.

In another aspect, the dose administered may be adjusted based on the dosage form prepared for administration described herein to about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09 , 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1 ,25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500 , 2000, 2500, 3000 or 4000 mg/day.

For any compound, the effective amount can be initially assessed either by performing cell culture studies or appropriate experimental animal models, such as mice, guinea pigs, chimpanzees, marmosets or tamarins. Appropriate animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine appropriate doses and routes of administration for humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical methods in cell cultures or experimental animals, for example, the value of ED ₅₀ (therapeutically effective dose for 50% of the population) and LD ₅₀ (lethal dose for 50% of the population). The ratio of doses characterizing therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio LD ₅₀ /ED ₅₀ . In particular aspects, the effective amount is that amount that achieves a high therapeutic index value. In further specific aspects, the dose amount is within a range of circulating blood concentrations that includes the ED ₅₀ value with little or no toxicity. The dosage amount may vary within this range depending on the dosage form used, patient sensitivity and route of administration.

In one aspect, the invention provides methods for modulating the amount of HTT (huntingtin protein) comprising contacting human cells with a compound of formula (I) or a form thereof. In a particular aspect, the invention provides methods for modulating the amount of HTT, comprising contacting human cells with a compound of formula (I) or a form thereof that modulates the expression of HTT. Human cells may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human body. In a specific aspect, human cells are taken from or located in a human body. In another specific aspect, human cells are taken from or located in the body of a person suffering from Huntington's disease (HD). In another specific aspect, the human cells are from or in the body of a person suffering from Huntington's disease (HD), caused by a CAG repeat in the Htt gene resulting in loss of HTT expression and/or function. In another aspect, human cells are taken from a person suffering from Huntington's disease (HD). In another aspect, human cells are present in the body of a person suffering from Huntington's disease (HD). In one aspect, the compound is a form of the compound of formula (I).

In a specific aspect, the invention provides a method of enhancing inhibition of a mutant HTT transcribed from the Htt gene, comprising contacting human cells with a compound of formula (I) or a form thereof. Human cells may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human body. In a specific aspect, human cells are taken from or located in a human body. In another specific aspect, the human cells are taken from or located in the body of a person suffering from Huntington's disease (HD). In another specific aspect, the human cells are from or in the body of a person suffering from Huntington's disease (HD), caused by a CAG repeat in the Htt gene resulting in loss of expression and/or function of the non-mutant normal HTT. In another aspect, human cells are taken from a person suffering from Huntington's disease (HD). In another aspect, human cells are present in the body of a person suffering from Huntington's disease (HD). In one aspect, the compound is a form of the compound of formula (I).

In another aspect, the invention provides a method of modulating inhibition of mutant HTTT transcribed from the Htt gene, comprising administering to a non-human animal in an experimental animal model of Huntington's disease (HD) a compound for

- 57 045009 mules (I) or its forms. In a specific aspect, the invention provides a method of modulating inhibition of mutant HTTT transcribed from the Htt gene, comprising administering to a non-human animal animal model of Huntington's disease (HD) a compound of formula (I) or a form thereof. In a specific aspect, the compound is a form of the compound of formula (I).

In another aspect, the invention provides a method for reducing the amount of mutant HTT, comprising contacting human cells with a compound of formula (I) or a form thereof. In a specific aspect, the invention provides a method for reducing the amount of mutant HTT, comprising contacting human cells with a compound of formula (I) that inhibits transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific aspect, the invention provides a method for reducing the amount of HTT, comprising contacting human cells with a compound of formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. Human cells may be contacted with a compound of formula (I) or a form thereof in vitro or in vivo, for example in a non-human animal or in a human body. In a specific aspect, human cells are taken from or located in a human body. In another specific aspect, human cells are taken from or located in the body of a person suffering from Huntington's disease (HD). In another specific aspect, the human cells are from or in the body of a person suffering from Huntington's disease (HD), caused by a CAG repeat in the Htt gene resulting in loss of HTT expression and/or function. In another aspect, human cells are taken from a person suffering from Huntington's disease (HD). In another aspect, human cells are present in the body of a person suffering from Huntington's disease (HD). In one aspect, the compound is a form of the compound of formula (I).

In particular aspects, treating or alleviating Huntington's disease (HD) with a compound of formula (I) or a form thereof (alone or in combination with an additional drug) achieves a therapeutic effect and/or a beneficial effect. In a specific aspect, treatment of Huntington's disease (HD) with a compound of formula (I) or a form thereof (alone or in combination with an additional drug) achieves one, two or more of the following effects: (i) reduces or alleviates the severity of the disease Huntington (HD); (ii) delays the onset of Huntington's disease (HD); (iii) inhibits the progression of Huntington's disease (HD); (iv) reduces the subject's frequency of hospitalizations; (v) reduces the length of a subject's hospital stay; (vi) increases the subject's lifespan; (vii) improves the subject's quality of life; (viii) reduces the number of symptoms associated with Huntington's disease (HD); (ix) reduces or alleviates the severity of the symptom(s) associated with Huntington's disease (HD); (x) reduces the duration of symptoms associated with Huntington's disease (HD); (xi) prevents recurrence of symptoms associated with Huntington's disease (HD); (xii) inhibits the development or onset of symptoms of Huntington's disease; and/or (xiii) inhibits the progression of a symptom associated with Huntington's disease (HD).

Metabolites.

The present invention also includes the use of in vivo metabolism products of the compounds described herein. Such products can be formed, for example, as a result of oxidation, reduction, hydrolysis, amidation, esterification and other similar reactions of the administered compound, mainly as a result of enzymatic processes. Accordingly, the invention includes the use of compounds prepared by a process comprising contacting a compound of the invention with tissue of a mammal or with a mammal for a period of time sufficient to form its metabolic product.

Such products are typically identified by preparing a radiolabeled (eg, ¹⁴ C or ³ H) isotopologue of the inventive compound by administering the radiolabeled compound at a detectable dose (eg, greater than about 0.5 mg/kg) to a mammal such such as a rat, mouse, guinea pig, dog, monkey, or human, by allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours) and by identifying metabolic products from urine, bile, blood, or other biological samples. The conversion products can be easily isolated because they are radiolabeled as a result of isotope enrichment (other conversion products can be isolated using antibodies that can bind the surviving epitopes in the metabolite). The structures of metabolites are determined by conventional methods, for example, mass spectrometry or nuclear magnetic resonance (NMR). Typically, metabolite analysis can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The transformation products, provided they are not otherwise detectable in vivo, are used in diagnostic studies to determine therapeutic doses of the compounds described in the invention, even if they do not have intrinsic biological activity.

- 58 045009

Pharmaceutical compositions.

Aspects of the present invention include the use of a compound of formula (I) or a form thereof in a pharmaceutical composition for treating or alleviating Huntington's disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients substances.

An aspect of the present invention includes the use of a pharmaceutical composition of a compound of formula (I) or a form thereof in the preparation of a kit comprising a pharmaceutical composition of a compound of formula (I) or a form thereof and instructions for administering the compound for treating or alleviating Huntington's disease in a subject in need thereof.

As used herein, the term composition refers to a product comprising the specified ingredients in the specified amounts, as well as any product that is obtained, directly or indirectly, by the combination of the specified ingredients in the specified amounts.

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

The term pharmaceutically acceptable excipient refers to an excipient for the administration of a drug, such as the compounds described in the invention. The term refers to any pharmaceutical excipient that can be administered without causing excessive toxicity. Pharmaceutically acceptable excipients may be selected, in part, based on the particular composition being administered, as well as the particular route of administration and/or the particular dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, diluents, stabilizers, adjuvants, diluent, and the like. Accordingly, there are a wide variety of suitable pharmaceutical composition formulations for the compounds described herein (see, for example, Remington's Pharmaceutical Sciences manual).

Suitable excipients may be carrier molecules that include large, slowly metabolizing macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, copolymers of amino acids and inactivated antibodies.

Other examples of 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 solution, glycerin and ethanol, wetting agents or emulsifiers, pH buffering agents and other similar substances. Liposomes also fall within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described in the invention can be prepared in any form suitable for the intended use described in the invention. Suitable forms for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalation forms for inhalation administration include liquids and powders. Alternative forms include syrups, creams, ointments, tablets and lyophilized solids, which can be resuspended in a physiologically compatible vehicle prior to administration.

For oral administration, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, non-aqueous solutions, dispersible powders and granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral administration may be prepared by any known method of preparing pharmaceutical compositions, and such compositions may contain one or more substances including sweeteners, flavoring agents, coloring agents and preservatives in order to obtain a preparation with a pleasant taste and odor.

Pharmaceutically acceptable excipients suitable for use in tablets include, for example, inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate, disintegrants such as croscarmellose sodium, cross-linked povidone, corn starch or alginic acid , binders such as povidone, starch, gelatin or gum acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known methods, including microencapsulation, to slow disintegration and absorption in the gastrointestinal tract, resulting in prolonged action over a long period. For example, a time-delayed release material such as glyceryl monostearate or glyceryl distearate may be used on its own.

- 59 045009 or together with wax.

Oral forms may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as cellulose, lactose, calcium phosphate or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with a non-aqueous or an oily medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

In other aspects, the pharmaceutical compositions described herein can be prepared in the form of suspensions comprising a compound of formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipients suitable for the preparation of the suspension. In yet other aspects, the pharmaceutical compositions described herein can be formulated in the form of dispersible powders and granules suitable for suspension by the addition of one or more excipients.

Excipients suitable for the preparation of suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as natural phosphatide (e.g. lecithin), product a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester formed by a fatty acid and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate), and thickeners such as carbomer, beeswax, paraffin wax or cetyl alcohol. Suspensions may also contain one or more preservatives, such as acetic acid, methyl and/or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

The pharmaceutical compositions described in the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture of these oils. Suitable emulsifiers include natural gums such as gum acacia and gum tragacanth, natural phosphatides such as soy lecithin, fatty acid esters or partial esters, hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs can be prepared using sweeteners such as glycerin, sorbitol or sucrose. Such forms may also contain a demulcent, preservative, flavoring or coloring agent.

In addition, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oily suspension. Such an emulsion or suspension can be prepared by known methods using suitable dispersing or wetting agents and suspending agents, which have already been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared in the form of a lyophilized powder. Suitable media and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be used as a solvent or suspending medium. Any non-irritating, non-volatile oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectable dosage forms.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but are generally soluble in medium chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters with medium chain fatty acids. Therefore, the invention includes compounds that have been modified by substitution or introduction of chemical or biochemical moieties that make them more suitable for delivery into the body (for example, increasing their solubility, biological activity, improving palatability, reducing adverse reactions, etc.) , for example, by esterification, glycosylation, PEGylation and so on.

In specific aspects, a compound described herein is formulated for oral administration in the form of a lipid-based composition useful for compounds of low solubility. Lipid-based compositions may generally increase the oral bioavailability of such compounds. Accordingly, the pharmaceutical compositions described herein may comprise an 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

- 60 045009 their esters with propylene glycol (for example, propylene glycol esters with edible fatty acids such as caprylic and capric fatty acids) and with pharmaceutically acceptable surfactants such as polysorbate 20 or 80 (also called Tween® 20 or Tween® 80 , respectively) or hydrogenated castor oil polyoxyl 40.

In other aspects, the bioavailability of poorly soluble compounds can be increased by optimizing particle size, including by preparing nanoparticles or nanosuspensions using methods well known to those skilled in the art. The forms of the compound present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

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

Receiving connections

General synthesis methods.

The general methods described in the invention for preparing the compounds of formula (I) described in the invention or their forms are standard well known methods of synthesis. Many of the starting materials are commercially available or, if not commercially available, they can be prepared by the methods described below using techniques known to those skilled in the art. The synthesis schemes presented in the invention include several reaction steps, each of which is carried out independently and can be carried out with or without any preceding or subsequent step. In other words, each of the individual reaction steps of the synthesis schemes presented in the invention is considered separately.

Scheme A.

Compounds of formula (I) wherein R ₁ represents a C ₃ - ₁₀ cycloalkyl or heterocyclyl ring system and R 2 represents a phenyl, heterocyclyl or heteroaryl ring system can be prepared as shown in Scheme A below.

Compound A1 (wherein X1 and X2 are independently bromine, chlorine, and the like; W2 and _W3 are independently CH or N) is converted to compound A2 by performing a nucleophilic substitution reaction with a primary amine in the presence of a suitable base (such as _Et3 N and other similar base) in a suitable solvent (such as decanol or other similar solvent). Alternatively, compound A1 is converted to compound A2 by performing a cross-coupling reaction with a primary amine in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and a base (such as sodium t-butoxide and the like) in a suitable solvent such as 1,4-dioxane and the like). Compound A2 is converted to compound A3 by sequential diazotization/cyclization reactions while being treated with a suitable reagent (such as sodium nitrite and the like) in a suitable solvent (such as acetic acid and the like). Compound A3 is converted to compound A4 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound A3 is converted to compound A4 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), a ligand (such as XPhos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Any protecting groups on R ₁ and R 2 are removed by treatment with an appropriate reagent (such as HCl in dioxane, dioxane for the Boc protecting group, and the like) in a suitable solvent (such as dioxane and the like).

Scheme B.

Compounds of formula (I) wherein R1 is a C _{3_10} cycloalkyl or heterocyclyl ring system and R2 is a phenyl, heterocyclyl or heteroaryl ring _system can be prepared as shown in Scheme B below. O

Compound B1 (where X1 and X2 are independently bromine, chlorine and other similar substituents; W2 and W3 are independently CH or N) is converted to compound B2 by sequential nucleophilic substitution/cyclization reactions with treatment with hydrazine (R1NH2NH2) and a suitable base (such as Et3N and the like) in a suitable solvent (such as methanol and the like). Compound B2 is converted to compound B3 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as K2CO3 and the like base) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound B2 is converted to compound B3 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound B3 is converted to compound B4 by treatment with an activated triflate (such as Tf ₂ O or Tf2NPh and other similar triflate) in the presence of a suitable base (such as Et ₃ N and other similar base) in a suitable solvent (such as dichloromethane and other similar solvent) . Compound B4 is converted to compound B5 by carrying out a hydrogenation reaction using a suitable hydrogen source (such as ammonium formate and other such hydrogen source) in the presence of a suitable catalyst (such as Pd(dppf)Cl ₂ and other such catalyst) in a suitable solvent (such as tetrahydrofuran and other similar solvent). Any protecting groups on R1 and R2 are removed by treatment with an appropriate reagent (such as HCl in dioxane for the Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

Scheme C.

Compounds of formula (I) wherein R1 is a C _3-10 cycloalkyl or heterocyclyl ring system and _R2 is a phenyl, heterocyclyl or heteroaryl ring system can be prepared as shown in Scheme C below.

Compound C1 (wherein X1 and X2 are, independently, bromine, chlorine, and the like; W2 and W3, are independently CH or N) is converted to compound C2 by coupling Sonogashira with TMS-protected acetylene in the presence of a suitable catalyst (such as Pd(PPh ₃ ) ₂ Cl ₂ and the like catalyst and CuI and the like catalyst) and a suitable base (such as Et ₃ N and another suitable base) in a suitable solvent (such as acetonitrile and the like). Compound C2 is converted to compound C3 by heating in a suitable solvent (such as DMF and the like) in the presence of a suitable base (such as K ₂ CO ₃ and the like). Compound C3 is converted to compound C4 by performing a Suzuki coupling reaction with an aryl or heteroa

- 62 045009 ril boronic acid (or pinacol ester of boronic acid) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K2CO3 and other similar base) in a suitable solvent (such as 1. 4-dioxane and other similar solvent). Alternatively, compound C3 is converted to compound C4 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd2(dba) ₃ and other like catalyst), a ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound C4 is converted to compound C5 (where X3 is iodine, bromine, and the like) by halogenation with a suitable reagent (such as NIS and the like) in a suitable solvent (such as DMF and the like). Compound C5 is converted to compound C6 by performing a Suzuki coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkyl/cycloalkenyl pinacol boronic acid ester in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as an aqueous solution K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound C5 is converted to compound C6 by performing a Negishi coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkylzinc halide in the presence of a catalyst (such as Pd(dppf)Cl2 and other similar catalyst) in a suitable solvent (such as 1,4 -dioxane and other similar solvent). After treatment with a deprotection reagent that matches the protecting group used (such as HCl in dioxane for the Boc protecting group and the like), the C6 compound is converted to the C7 compound. In cases where unsaturation exists in the ring containing the amino group with basic properties, the compound can be converted to its fully saturated counterpart under an _H2 atmosphere in a suitable solvent (such as methanol and other similar solvent) and in the presence of a catalyst (such as 10% Pd /C and other similar catalyst).

Scheme D.

Compounds of formula (I) wherein R1 is a C _3-10 cycloalkyl or heterocyclyl ring system and _R2 is a phenyl, heterocyclyl or heteroaryl ring system can be prepared as shown in Scheme D below.

Compound D1 (wherein X1, X2 and X3 are independently bromine, chlorine and other like substituents; W2 and W3 are independently CH or N) is converted to compound D2 by performing a Suzuki coupling reaction with boronic acid vinyl pinacol ester in the presence of a catalyst (such such as Pd(dppf)Cl2 and the like) and a base (such as an aqueous solution of K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound D2 is converted to compound D3 by heating with a primary amine (R1NH2) in a suitable solvent (such as acetonitrile and the like). Compound D3 is converted to compound D4 by performing a Suzuki coupling reaction with arylyl heteroarylboronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl2 and other similar catalyst) and a base (such as an aqueous solution of K ₂ CO ₃ and another like base) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound D3 is converted to compound D4 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4dioxane and the like). Compound D4 is converted to compound D5 by treatment with a suitable oxidizing agent (such as manganese dioxide and the like) in a suitable solvent (such as toluene and the like). Any protecting groups on R1 and R2 are removed by treatment with an appropriate reagent (such as HCl in dioxane for the Boc protecting group and other similar reagent) in a suitable solvent (such as dioxane and

- 63 045009 other similar solvent).

Scheme E.

Compounds of formula (I) wherein R1 is a C _3-10 cycloalkyl or heterocyclyl ring system and R2 is a phenyl, heterocyclyl or heteroaryl ring system can be prepared as shown in Scheme E below.

Compound E1 (where X1 and X2 are, independently, bromine, chlorine, and other similar substituents; W2 and W ₃ are, independently, CH or N) is converted to compound E2 by sequential condensation/cyclization reactions in the presence of a suitable base (such as Et ₃ N and the like) in a suitable solvent (such as acetonitrile and the like). Compound E2 is converted to compound E3 by TIPS protection of the hydroxyl group by using a suitable reagent (such as TIPSCl or TIPSOTf and other similar reagent) in the presence of a suitable base (such as imidazole and other similar base) in a suitable solvent (such as DMF and other similar solvent ). Compound E3 is converted to compound E4 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound E3 is converted to compound E4 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound E4 is converted to compound E5 by hydrolyzing the methyl ester in the presence of a suitable base (such as aqueous NaOH and the like) in a suitable solvent (such as methanol and the like), then decarboxylating the resulting carboxylic acid by heating in a suitable solvent ( such as DMSO and other similar solvent). Compound E5 is converted to compound E6 by treatment with an activated triflate (such as Tf ₂ O or Tf2NPh and other similar triflate) in the presence of a suitable base (such as Et ₃ N and other similar base) in a suitable solvent (such as dichloromethane and the like solvent). Compound E6 is converted to compound E7 by performing a Suzuki coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkyl/cycloalkenyl pinacol boronic ester in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as an aqueous solution K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound E6 is converted to compound E7 by performing a Negishi coupling reaction with an optionally substituted and suitably protected amino-cycloalkylzinc halide in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) in a suitable solvent (such as 1,4-dioxane and other similar solvent). In cases where unsaturation exists in the ring containing the amino group with basic properties, the compound can be converted to its fully saturated counterpart under an _H2 atmosphere in a suitable solvent (such as methanol and other similar solvent) and in the presence of a catalyst (such as 10% Pd /C and other similar catalyst). Any protecting groups on R1 and R2 are removed by treatment with an appropriate reagent (such as HCl in dioxane for the Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

- 64 045009

Scheme F.

Compounds of formula (I) wherein R1 represents ^-cycloalkyl or heterocyclyl ring systems and R2 represents phenyl, heterocyclyl or heteroaryl ring systems can be prepared as shown in Scheme F below.

Compound F1 (where X1 and X2 are independently bromine, chlorine and other similar substituents; W2 and _W3 are independently CH or N) is converted to compound F2 by performing a nucleophilic substitution reaction with methyl 2-hydroxyacetate in the presence of a suitable base (such such as NaH and the like) in a suitable solvent (such as THF and the like). Compound F2 is converted to compound F3 by carrying out a cyclization reaction upon treatment with a suitable base (such as NaOMe and the like) in a suitable solvent (such as THF and the like). Compound F3 is converted to compound F4 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound F3 is converted to compound F4 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound F4 is converted to compound F5 by sequential hydrolysis/decarboxylation reactions in the presence of a suitable base (such as aqueous NaOH and the like) in a suitable solvent (such as DMSO and the like). Compound F5 is converted to compound F6 by treatment with an activated triflate (such as Tf2O or Tf2NPh and other like triflate) in the presence of a suitable base (such as Et ₃ N and other like base) in a suitable solvent (such as dichloromethane and other like solvent) . Compound F6 is converted to compound F7 by performing a Suzuki coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkyl/cycloalkenyl pinacol boronic ester in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as an aqueous solution K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound F6 is converted to compound F7 by performing a Negishi coupling reaction with an optionally substituted and suitably protected amino-cycloalkylzinc halide in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) in a suitable solvent (such as 1,4-dioxane and other similar solvent). In cases where unsaturation exists in the ring containing the amino group with basic properties, the compound can be converted to its fully saturated counterpart under an _H2 atmosphere in a suitable solvent (such as methanol and other similar solvent) and in the presence of a catalyst (such as 10% Pd /C and other similar catalyst). Any protecting groups on R1 and R2 are removed by treatment with an appropriate reagent (such as HCl in dioxane for the Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

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Scheme G.

Compounds of formula (I) wherein R1 is a C _3-10 cycloalkyl or heterocyclyl ring system and R2 is a phenyl, heterocyclyl or heteroaryl ring system can be prepared as shown in Scheme F below.

(RO) ₂ BR ₂

14^^2,^2 4ΐ,£

Ri

G4

Compound G1 (wherein X1 and X2 are independently bromine, chlorine, and the like; W2 and _W3 are independently CH or N) is converted to compound G2 by undergoing nucleophilic substitution reaction with a primary amine in the presence of a suitable base (such as Et ₃ N and the like) in a suitable solvent (such as decanol and the like). Alternatively, compound G1 is converted to compound G2 by performing a cross-coupling reaction with a primary amine in the presence of a suitable catalyst (such as RuPhos Pd G2 and other similar catalyst) and a base (such as sodium t-butoxide and other similar base) in a suitable a solvent (such as 1,4-dioxane and the like). Compound G2 is converted to compound G3 (where R ₃ is H, Me, Et and the like) by performing a cyclization reaction using an appropriate reagent (such as triethyl orthoformate and the like) in the presence of an appropriate catalyst (such as HCl and the like catalyst). Compound G3 is converted to compound G4 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound G3 is converted to compound G4 by performing a Still coupling reaction with an aryl heteroarylstanne in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), a ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Any protecting groups on R1 and R2 are removed by treatment with an appropriate reagent (such as HCl in dioxane for the Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

Scheme N.

Compounds of formula (I) wherein R ₁ is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, R ₂ is hydrogen, fluorine, chlorine, hydroxy, methoxy, aryl or heteroaryl, and R ₃ is monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be obtained as shown in diagram H below.

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Compound H1 (wherein X1, X2 and X3 are independently bromine, chlorine and other similar substituents; W2 and _W3 are independently CH or N) is converted to compound H2 by performing a nucleophilic substitution reaction with sodium benzenesulfinate in a suitable solvent (such as THF, DMSO and other similar solvent). Compounds H2 are converted to compound H3 by performing a nucleophilic substitution reaction with a primary amine in the presence of a suitable base (such as K ₂ CO ₃ and the like) in a suitable solvent (such as dioxane and the like). Alternatively, compound H2 is converted to compound H3 by performing a cross-coupling reaction with a primary amine in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and a base (such as sodium tert-butoxide and the like) in a suitable solvent, such as 1,4-dioxane and other similar solvent). Compound H3 is converted to compound H4 by treatment with sodium azide in an appropriate solvent (such as DMSO and the like). Compound H4 is converted to compound H5 by carrying out a reduction reaction by treating with a suitable reagent (such as zinc metal and the like) in the presence of a suitable acid (such as acetic acid and the like) in a suitable solvent (such as CH ₂ Cl ₂ and other similar solvent). Compound H5 is converted to compound H6 by sequential diazotization/cyclization reactions upon treatment with a suitable reagent (such as sodium nitrite and the like) in a suitable solvent (such as acetic acid and the like). Compound H6 is converted to Compound H8 by a Suzuki coupling reaction with aryl boronic acid (or pinacol boronic acid ester) H7 (where X4 is bromine, chlorine and other similar substituent; R2 is hydrogen, fluorine, chlorine, hydroxy, methoxy, aryl or heteroaryl; and P represents a protecting group such as MOM and other similar protecting group) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other like catalyst) and a base (such as aqueous K2CO3 and other like base) in a suitable solvent (such as 1,4-dioxane and the like). Compound H8 is converted to compound H9 by performing a Suzuki coupling reaction with an aryl or heteroaryl boronic acid (or pinacol boronic acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other similar catalyst) and a base (such as aqueous K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound H8 is converted to compound H9 by performing a Still coupling reaction with an aryl or heteroaryl stannane in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other like catalyst), ligand (such as X-Phos and other like ligand) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound H8 is converted to compound H9 by treatment with pinacolatodiboron and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) in an appropriate solvent (such as 1. 4-dioxane and other like solvent), then adding an aryl or heteroaryl halide in the presence of a catalyst (such as Pd(dppf)Cl ₂ and other like catalyst) and a base (such as aqueous K ₂ CO ₃ and other like base) in a suitable a solvent (such as 1,4-dioxane and the like). Alternatively, compound H8 is converted to compound H9 by performing a Buchwald-Hartwig coupling reaction with a heteroaryl or amine in the presence of a catalyst (such as Pd ₂ (dba) ₃ and other similar catalyst), a ligand (such as tBuX-Phos and other similar ligand ) and a base (such as K ₃ PO ₄ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound H9 is converted to compound H10 by treatment under conditions suitable to remove the protecting groups (such as HCl in dioxane for the MOM protecting group) in a suitable solvent (such as dioxane and the like).

Specific examples of syntheses.

To further describe and facilitate the understanding of the present invention, non-limiting examples are provided below to more fully illustrate the scope of the compounds described herein, and these examples should not be construed as specifically limiting the scope of the invention. It is believed that variants of the compounds described in the invention which are now known or which may be synthesized later and which are obvious to those skilled in the art are included within the scope of the compounds described in the invention and claimed further in the claims. These examples illustrate the preparation of specific compounds. It will be apparent to those skilled in the art that the methods described in these examples represent methods described by those skilled in the art that are well established for use in organic synthesis, and as such, represent preferred methods for their application in practice. However, it should be appreciated that, in light of the present invention, it will be apparent to those skilled in the art that many changes can be made to the specific methods disclosed and still achieve the same or similar result without departing from the spirit and scope of the present invention.

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Unless otherwise indicated, with the exception of the following examples of synthesized compounds, all numbers used in the specification and claims in which quantities of ingredients, reaction conditions, experimental data, etc., are represented are to be understood as modified by the term approximately. Accordingly, all such numbers are approximate values that may vary depending on the desired properties sought to be achieved by the reaction or by changes in experimental conditions. Therefore, within the expected range of experimental reproducibility, the term approximately, when applied to data obtained, refers to the range of data presented, which may vary with the standard deviation of the mean value. In addition, for experimental data provided, the resulting values may be rounded up or down to ensure consistency in the presentation of data without losing significant figures. At the very least, but not in an attempt to limit the application of the theory of equivalents to determine the scope of the claims, each numerical parameter should be interpreted in light of the number of significant figures and rounding techniques used by those skilled in the art.

Although the numerical ranges and parameters defining the scope of the present invention are approximate values, the numerical values presented in the following examples are stated to the greatest possible accuracy. However, any numerical value inherently contains certain errors, which are necessarily the result of the standard deviation detected during the corresponding test measurements.

Connection examples

Unless otherwise indicated, throughout the specification and claims, the following abbreviations have the following meanings.

U verbal abbreviations Meaning Δ heating (in chemistry) or deletion (in biology) AcOH or HO Ac acetic acid Ac ₂ O acetic anhydride Ag argon ACN or CH ₃ CN or MeCN acetonitrile atm atmosphere(s) VVg ₃ boron tribromide VpON benzyl alcohol Vos tert-butoxycarbonyl Vos ₂ O ditertbutyl dicarbonate B ₂ pin ₂ bis(pinacolato)dibor

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BuOH i-butanol (RVi)zR HBF4 tritertbutylphosphonium tetrafluoroborate °C degrees Celsius Celite® or Celite diatomaceous earth (celite) (COC1) ₂ oxalyl chloride CsCl cesium chloride _{Cs2CO3 _} cesium carbonate CsF cesium fluoride Cui Copper iodide(1) d/h/hour/hours /min/s day(d)/hour(h, hour or hours)/minute(min)/second(s) DAST (diethylamino)sulfur trifluoride DCM or CH ₂ C1 ₂ dichloromethane DIEA or DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide Etl iodoethane Et ₃ N triethylamine EtOAc ethyl acetate EtOH ethanol Et ₂ O diethyl ether H ₂ hydrogen HCl hydrochloric acid H2SO4 sulfuric acid HCOOH formic acid K2CO3 potassium carbonate KOAc potassium acetate KOtBu potassium tertbutoxide KOH potassium hydroxide KSCN potassium thiocyanate LAH lithium aluminum hydride

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LC/MS, LCMS or LC-MS liquid chromatography with mass spectrometry LDA lithium diisopropylamine LiOH lithium hydroxide MeOH methanol Mel iodomethane _MgSO4 magnesium sulfate M.O.M. methoxymethyl MOMC1 chloromethyl methyl ether MS mass spectroscopy N.B.S. N-bromosuccinimide NCS N-chlorosuccinimide NH ₄ C1 ammonium chloride _NH4OAc ammonium acetate NH4OH ammonium hydroxide or aqueous ammonia solution NH2OHHCI hydroxylamine hydrochloride NaBH ₄ sodium borohydride Na ₂ CO ₃ sodium carbonate NaH sodium hydride _NaHCO3 bicarbonate of soda NaH sodium hydride NaOAc sodium acetate NaOH sodium hydroxide NaOMe sodium methoxide _Na2SO4 sodium sulfate n ₂ nitrogen NH4CI ammonium chloride NMP N-methylpyrrolidone NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Pd palladium Pd/C palladium on coal Pd ₂ (dba) ₃ or Pd ₂ dba ₃ tris(dibenzyl indenacetone)dipalladium(0)

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Pd(dppf)C12 or Pd(dppf)Cl ₂ CH ₂ C1 ₂ [1,1 '-bis(diphenylphosphino)ferrocene] dichloro-palladium(P), complex with dichloromethane Pd(PPh3)4 or Pd(Ph ₃ P) ₄ tetrakis(triphenylphosphate)palladium(0) Pd(PPh ₃ ) ₂ Cl ₂ , PdCl ₂ (PPh ₃ ) ₂ or PdCl ₂ (Ph ₃ P) ₂ bis(triphenylphosphine)palladium(P) dichloride PhMe toluene Psi pressure in pounds per square inch _Pt2O platinum oxide(1U) PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBroP® Bromotripyrrolidinophosphonium hexafluorophosphate RT retention time RuPhos Pd G2 chloro(2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, Gbiphenyl)[2-(2'-amino-1,1'-biphenyl)]-palladium(P) SOC1 ₂ thionyl chloride SO ₂ C1 ₂ sulfuryl chloride TEA, Et ₃ N or NEt ₃ triethylamine T.F.A. trifluoroacetic acid Tf ₂ NPh M-phenyl-bis(trifluoromethanesulfonimide) or Ι,Ι,Ι-τρπφτορ-Νphenyl-K-[(trifluoromethyl)sulfonyl]-methanesulfonamide or Ν, Νbis(trifluoromethanesulfonyl)aniline or N-phenyltrifluoromethanesulfonimide _Tf2O trifluoromethanesulfonic anhydride THF tetrahydrofuran THP tetrahydropyranyl TIPS triisopropylsilane TIPSC1 triisopropylsilyl chloride TIPSOTf triisopropylsilyl trifluoromethanesulfonate or trifluoromethanesulfonic acid triisopropylsilyl ether or triisopropylsilyl triflate TLC thin layer chromatography TMEDA tetramethylethylenediamine TMS trimethylsilane TMSC1 trimethylchlorosilane or trimethylsilyl chloride t-Bu tert-butyl UPLC ultra-performance liquid chromatography

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Example 1.

Getting connection 11.

Vos

Step 1: To a suspension of 3,6-dichloropyridazin-4-amine (1.48 g, 9.02 mmol) in CH ₂ Cl ₂ (25 ml) was added one portion di-tert-butyl dicarbonate (2.2 g, 10 mmol ), then some DMAP crystals were added. The reaction mixture was stirred at room temperature for 4 hours. Almost complete conversion was observed, accompanied by the formation of di-Boc material. The solvent was removed under reduced pressure and the product was isolated by silica gel column chromatography eluting with a gradient of EtOAc/hexanes (0-20% EtOAc) to give tert-butyl N-(3,6-dichloropyridazin-4-yl)carbamate (1.71 g , 72%) as a white solid.

Step 2. To a mixture of tert-butyl N-(3,6-dichloropyridazin-4-yl)carbamate (1.71 g, 6.47 mmol), CuI (75 mg, 0.39 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (140 mg, 0.20 mmol) in CH ₃ CN (25 ml) under argon was added Et ₃ N (4.50 ml, 32.3 mmol), then ethynyl(trimethyl)silane (1.10 ml , 7.78 mmol). The mixture was heated under argon for 1 hour, after which the presence of starting material was not detected by UPLC. The solvent was concentrated and the residue was treated with EtOAc. The solid was filtered, washed thoroughly with EtOAc and discarded. The mother liquor was concentrated and the residue was purified by silica gel column chromatography, eluting with an EtOAc/hexanes (020% EtOAc) gradient to give tert-butyl N-[6-chloro-3-(2-trimethylsilylethynyl)pyridazin-4-yl]carbamate (1.12 g, 53%) as an oil that solidified on standing.

Step 3: To a solution of tert-butyl N-[6-chloro-3-(2-trimethylsilylethynyl)pyridazin-4-yl]carbamate (1.1 g, 3.4 mmol) in DMF (10 ml) was added K2CO3 powder ( 1.00 g, 7.24 mmol). The mixture was heated at 60°C for 30 minutes. The reaction mixture was then diluted with water and extracted with EtOAc.

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After drying the organic phase over Na ₂ SO ₄ and concentrating the solvent, the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc), to give tert-butyl 3-chloropyrrolo[3,2-c]pyridazine -5-carboxylate (0.600 g, 70%) as a white solid. MS m/z 254.3 [M+H]+.

Step 4: 1-Bromo-4-iodo-2-methoxybenzene (50 g, 160 mmol) was suspended in dichloromethane (75 ml) at -10°C. 1 N BBr ₃ in CH ₂ Cl ₂ (250 ml, 250 mmol) was added through a glass tube over 30 minutes, keeping the internal temperature below 0°C throughout the addition. After addition, the mixture was stirred at 0°C for 1 hour, and then at room temperature for an additional 16 hours. The mixture was cooled in an ice bath. A 10% aqueous solution of Na ₂ CO ₃ (250 ml) was added in portions. The mixture was then partitioned between H2O and dichloromethane. The dichloromethane layer was dried over MgSO ₄ and then filtered. 2-Bromo-5-iodophenol (46 g, 96%) was obtained from the filtrate as a pinkish-white solid.

1H NMR (acetone-d ₆ ) δ: 9.24 (br.s, 1H), 7.38 (d, J=2 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H) , 7.17 (dd, J=8.5 Hz, 2 Hz, 1H).

Step 5: 2-Bromo-5-iodophenol (54.9 g, 184 mmol) was dissolved in DMF (240 ml) at 0°C. 2.5 M sodium tertpentoxide in THF (90 mL, 230 mmol) was then added dropwise. The reaction mixture was stirred at 0°C for 15 minutes after completion of the addition operation. Chloromethyl methyl ether (18 mL, 225 mmol) was added dropwise over 30 min. The mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was diluted with H ₂ O (1500 ml) and extracted into EtOAc (2x400 ml). The combined organic layers were washed with H2O (300 ml), and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was passed through a pad of silica gel using CH ₂ Cl ₂ in hexanes (0-10%) to give 1-bromo-4-iodo-2-(methoxymethoxy)benzene (61 g, 97%) as a clear liquid.

1H NMR (acetone-d ₆ ) δ: 7.56 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.33 (dd, J=8 Hz, 2 Hz, 1H), 5.35 (s, 2H), 3.50 (s, 3H).

Step 6. 1-Bromo-4-iodo-2-(methoxymethoxy)benzene (49 g, 143 mmol), 1-(tetrahydro-2H-pyran-2-yl)4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole (48.4 g, 174 mmol), PdCl ₂ adduct (dppf)dichloromethane (3.1 g, 3.6 mmol), dioxane (500 ml ) and an aqueous solution of 1N K2CO3 (350 ml, 350 mmol) was heated at 90°C for 2 hours. The reaction mixture was then partitioned between H2O and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (EtOAc in hexanes, 20-50%), then trituration with hexanes to give 4-(4-bromo-3(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H -pyrazole (40.4 g, 77%) as a yellowish-white solid.

1H NMR (acetone-d6) δ: 8.22 (s, 1H), 7.88 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.47 (d, J =2 Hz, 1H), 7.23 (dd, J=8.5 Hz, 2 Hz, 1H), 5.44 (dd, J=9.5 Hz, 2.5 Hz, 1H), 5.38 (s, 2H), 4.01 (m, 1H), 3.72 (m, 1H), 3.51 (s, 3H), 2.12.23 (m, 1H), 2.0-2, 1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.7 (m, 2H).

Step 7 Potassium acetate (22 g, 224 mmol) was charged dry at 180°C for 2 hours and the flask was then filled with argon. 4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazole (20 g, 54.5 mmol), PdCl ₂ (dppf)-dichloromethane adduct ( 1.22 g, 1.47 mmol), bis(pinacolato)diboron (20.8 g, 81.9 mmol), and dried toluene (200 ml). This mixture was heated at 110°C for 2 days. The mixture was filtered through celite, eluting with ether. The filtrate was concentrated in vacuo, redissolved in ether and again filtered through celite to remove solid impurities. Purification by chromatography on silica gel (EtOAc in hexanes, 20-50%) gave the crude product (12 g) which contained virtually no protodeboronated by-product. The crude product was dissolved in ether (100 ml) and washed with aqueous NaHCO ₃ (2x1.5 L) and brine, then dried over MgSO ₄ and then filtered. The filtrate was concentrated to give pure product (7.05 g, 32%) as a glassy solid.

1H NMR (500 MHz, acetone-d6): δ 8.24 (s, 1H), 7.90 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.33 (d, J=1.5 Hz, 1H), 7.29 (dd, J=8 Hz, 1.5 Hz, 1H), 5.45 (dd, J=10 Hz, 2.5 Hz, 1H), 5, 25 (s, 2H), 4.01 (m, 1H), 3.69-3.74 (m, 1H), 3.52 (s, 3H), 2.15-2.2 (m, 1H) , 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.68 (m, 2H), 1.35 (s, 12H).

Step 8. Mixture of tert-butyl 3-chloropyrrolo[3,2-c]pyridazine-5-carboxylate (150 mg, 0.59 mmol), 4[3-(methoxymethoxy)-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetra-hydropyran-2ylpyrazole (0.300 g, 0.724 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) ( 25 mg, 0.033 mmol) and K2CO3 (250 mg, 1.81 mmol) in the flask was evacuated and filled with argon. 1,4-Dioxane (2 ml) and water (0.5 ml) were added to the mixture and heated at 90°C for 5 hours. The mixture was cooled to room temperature, diluted with water, and the product was extracted with CH2Cl2 (3 times) . The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (70-100% EtOAc) to give tert-butyl 3-[2(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl ]pyrrolo[3,2-c]pyridazine-5carboxylate (0.15 g, 0.297 mmol, 100 wt.%, 50.2%) as a white solid.

MS m/z 506.6 [M+H]+; 1H NMR (acetone^) δ: 8.67 (s, 1H), 8.30 (d, J=0.9 Hz, 1H), 8.10 (d, J=4.1 Hz,

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1H), 8.02 (d, J=8.2 Hz, 1H), 7.97 (d, J=0.9 Hz, 1H), 7.58 (d, J=l.6 Hz, 1H) , 7.48 (dd, J=7.9, 1.6 Hz, 1H), 7.08 (dd, J=3.8, 0.9 Hz, 1H), 5.49 (dd, J=9 ,8, 2.5 Hz, 1H), 5.40 (s, 2H), 3.98-4.06 (m, 1H), 3.70-3.79 (m, 1H), 3.45 ( s, 3H), 2.17-2.26 (m, 1H), 2.03-2.09 (m, 2H), 1.81 (s, 1H), 1.74 (s, 9H), 1 .57-1.68 (m, 2H).

Step 9. Mixture of tert-butyl 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4yl)phenyl]pyrrolo[3,2-c]pyridazine-5-carboxylate (140 mg, 0. 28 mmol) in diphenyl ether (1.6 ml) was heated at 200°C for 15 min and the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to room temperature and a precipitate formed. The mixture was then diluted with pentane. The solid was filtered and washed with additional pentane. After drying, 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol4-yl)phenyl]-5H-pyrrolo[3,2-c]pyridazine (110 mg, 0.27 mmol) was dissolved in DMF (1.5 ml) and Niodosuccinimide (68 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, and the product precipitated from solution. The reaction mixture was diluted with water, and the solid was filtered and washed with water and dried. 7-Iodo-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2ylpyrazol-4-yl)phenyl]-5H-pyrrolo[3,2-c]pyridazine (140 mg, 97%) was obtained as yellowish brown solid. MS m/z 532.4 [M+H]+.

Step 10. 7-Iodo-3-[2-(methoxymethoxy)-4-(1-tetrahydro-pyran-2-ylpyrazol-4-yl)phenyl]-5Hpyrrolo[3,2-c]pyridazine (140 mg, 0 .26 mmol) was suspended in CH ₂ Cl ₂ (2 ml) and di-tert-butyl dicarbonate (80 mg, 0.37 mmol) was added, followed by a few DMAP crystals. The reaction mixture was stirred at room temperature and the reaction was monitored by UPLC until complete consumption of the starting material was detected (20 min). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (60-100% EtOAc in hexanes) to give tert-butyl 7-iodo-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazole -4yl)phenyl]pyrrolo[3,2-c]pyridazine-5-carboxylate (122 mg, 71%) as a pale yellow foam.

MS m/z 632.5 [M+H]+; ^1H NMR (acetone- _d6 ) δ: 8.66 (s, 1H), 8.31 (d, J=0.6 Hz, 1H), 8.27 (s, 1H), 8.03 (d , J=7.9 Hz, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.49 (dd, J =7.9, 1.6 Hz, 1H), 5.49 (dd, J=9.8, 2.5 Hz, 1H), 5.41 (s, 2H), 3.98-4.06 ( m, 1H), 3.69-3.80 (m, 1H), 3.45 (s, 3H), 2.14-2.28 (m, 1H), 2.02-2.08 (m, 2H), 1.77-1.84 (m, 1H), 1.75 (s, 9H), 1.60-1.69 (m, 2H).

Step 11. The oven-dried flask was equipped with a magnetic stirrer and tert-butyl 7-iodo-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyrrolo[ 3,2c]pyridazine-5-carboxylate (122 mg, 0.19 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (75 mg, 0.24 mmol), Pd(PPh ₃ ) ₄ (25 mg, 0.022 mmol) and K2CO3 (80 mg, 0.58 mmol). The flask was sealed with a rubber stopper and diaphragm, and then evacuated and filled with argon (3X). 1,4-dioxane (1.2 ml) water (0.3 ml) was added and the reaction mixture was heated to 90°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml), and then extracted using CH ₂ Cl ₂ (3 X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (60-100% EtOAc) to give tert-butyl 7-(1-tertbutoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3- [2-(methoxy-methoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyrrolo-[3,2-c]pyridazine-5-carboxylate (38 mg, 29%) and tert- butyl 4-[3-[2(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-5H-pyrrolo[3,2-c]pyridazin-7-yl]3,6- Dihydro-2H-pyridine-1-carboxylate (25 mg, 22%).

Step 12. K tert-butyl 7-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-[2(methoxymethoxy)-4-(1-tetrahydro-pyran-2- ilpyrazol-4-yl)phenyl]pyrrolo[3,2-c]pyridazine-5carboxylate (38 mg, 0.055 mmol) was added with 4N HCl in dioxane (1 mL, 4.0 mmol), followed by MeOH (1 mL). The reaction mixture was heated at 55°C for 8 hours. Solvents were removed under reduced pressure and the residue was triturated in Et2O. The resulting solid was filtered, washed thoroughly with excess Et ₂ O and dried under a stream of nitrogen to give 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-1- ii-4yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol hydrochloride (15 mg, 71%) as a bright yellow solid.

MS m/z 359.3 [M+H]+; 1H NMR (DMSO-d ₆ ) δ: 13.26 (br.s, 1H), 9.49 (s, 2H), 8.60 (s, 1H), 8.50 (br.s, 1H), 8.20 (s, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.41 (td, J=4.3, 1.9 Hz, 2H), 6.97-7 .16 (m, 1H), 3.81-4.00 (m, 2H), 3.35-3.55 (m, 2H), 2.77-2.97 (m, 2H); 1H was not detected (NH or OH).

Using the procedure described for Example 1 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

- 74 045009

Compound Data 20 MS m/z 415.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 8.61 (s, 1H), 8.45 (s, 1H), 8.26 (s, 2H), 7.77 (d, J=7.9 Hz, 1H ), 7.45 (dd, J=7.9, 1.6 Hz, 1H), 7.36 (d, J=l.6 Hz, 1H), 7.06 (s, 1H), 3.73 -3.79 (m, J=6.6 Hz, 1H), 3.57-3.63 (m, J=5.0 Hz, 1H), 1.71 (s, 6H), 1.64 ( s, 6H); 4 H were not detected (3 NH and OH). 27 MS m/z 385.4 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 8.60 (s, 1H), 8.42-8.49 (m, J=2.5 Hz, 2H), 8.39 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.48 (dd, J=8.0, 1.7 Hz, 1H), 7.40 (d, J=l.6 Hz, 1H), 7 .35 (d, J=5.7 Hz, 1H), 4.54 (dd, J=6.3, 5.4 Hz, 1H), 4.43 (dd, J=7.3, 4.1 Hz, 1H), 3.35-3.41 (m, 1H), 2.87 (d, J=18.0 Hz, 1H), 2.42-2.52 (m, 1H), 2.37 -2.42 (m, 1H), 2.25-2.36 (m, 1H), 2.03-2.16 (m, 1H); 4 H were not detected (3 NH and OH). 28 MS m/z 401.4 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 8.62 (s, 1H), 8.50 (s, 2H), 8.47 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.49 (dd, J=8.2, 1.6 Hz, 1H), 7.41 (d, J=l.6 Hz, 1H), 7.25 (d, J=5.7 Hz, 1H), 4.33 (d, J=6.0 Hz, 1H), 4.11-4.15 (m, 2H), 4.06 (dd, J=12.6, 1.9 Hz , 1H), 3.97 (d, J=7.3 Hz, 1H), 3.93 (d, J=12.6 Hz, 1H), 3.39 (dd, J=18.6, 8, 2 Hz, 1H), 3.10 (dd, J=18.3, 1.6 Hz, 1H); 4 H were not detected (3 NH and OH).

Example 2.

Getting connection 30.

Step 1. Solution of tert-butyl 7-[5-tert-butoxycarbonyl-3-[2-(methoxymethoxy)-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyrrolo[3,2-c]pyridazin- 7-yl]-3-oxa-9-azabicyclo[3,3,1]non-6-ene-9-carboxylate (prepared according to the method described in Example 1, Step 11) (100 mg, 0.14 mmol) in MeOH (2 ml) and EtOAc (0.2 ml) were hydrogenated over a catalyst of 10% Pd/C (20 mg, 0.02 mmol, 10 wt.%) in 10% Pd(OH) ₂ /C (20 mg, 0.014 mmol, 10 wt.%) in a shaker hydrogenation apparatus from Parr at a pressure of 0.345 MPa H ₂ for 72 hours. The catalysts were filtered and washed with MeOH. The mother liquor was concentrated and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-10% MeOH), to give tert-butyl 7-[5-tert-butoxycarbonyl-3-[2-(methoxy -methoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4yl)phenyl]pyrrolo-[3,2-c]pyridazin-7-yl]-3-oxa-9-azabicyclo[3,3,1]nonane -9-carboxylate (46 mg, 46%) as a pale yellow foam. MS m/z 631.4 [M+H]+.

Step 2. K tert-butyl 7-[5-tert-butoxycarbonyl-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2ylpyrazol-4-yl)phenyl]pyrrolo[3,2-c]pyridazin- 7-yl]-3-oxa-9-azabicyclo[3,3,1]nonane-9-carboxylate (46 mg, 0.063 mmol) was added with 4N HCl in dioxane (0.5 ml, 2 mmol), then MeOH (1 ml). The reaction mixture was stirred at 50°C for 16 hours. The volatile components were then removed under reduced pressure, the residue was then triturated with Et ₂ O, and the solid was filtered and dried under a stream of nitrogen to give 2-[7-(3-oxa-9 -azoniabicyclo[3,3,1]nonan-7-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(III-pyrazol4-yl)phenol hydrochloride (16 mg, 58% ) as a yellow solid. Stereochemistry was determined based on data obtained by the NOESY method.

MS m/z 403.4 [M+H]+; ^1H NMR (methanol^) δ: 8.53 (s, 1H), 8.46 (s, 2H), 8.26 (d, J=0.6 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.47 (dd, J=8.2, 1.9 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 3.96 (dd , J=12.6, 1.9 Hz, 2H), 3.90 (d, J=12.6 Hz, 2H), 3.85 (dd, J=9.4, 3.2 Hz, 2H) , 3.66-3.78 (m, 1H), 2.82 (ddd, J=14.5, 9.4, 6.0 Hz, 2H), 2.51 (ddd, J=14.5, 11.4, 3.2 Hz, 2H); 4H were not detected (3 NH and OH).

Using the procedure described for Example 2 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

- 75 045009

Compound Data 12 MS m/z 361.3 [M+H] ⁺ 29 MS m/z 387.4 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 8.53 (s, 1H), 8.49 (s, 2H), 8.20 (d, J=0.9 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.48 (dd, J=8.2, 1.6 Hz, 1H), 7.40 (d, J=l.6 Hz, 1H), 4.20- 4.27 (m, 2H), 3.74-3.84 (m, 1H), 3.66-3.71 (m, 2H), 2.33-2.41 (m, J=2.5 Hz, ZN), 2.25-2.32 (m, ZN); 4 H were not detected (3 NH and OH). 31 MS m/z 417.5 [M+H] ⁺ ; 'H NMR (D ₂ O) δ: 8.15 (s, 1H), 7.89 (s, 2H), 7.72 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.81-6.92 (m, 1H), 3.603.70 (m, 1H), 2.01 (dd, J=14 ,2, 2.8 Hz, 2H), 1.70 (t, J=14.2 2H), 1.54 (s, 6H), 1.40 (s, 6H); 4 H were not detected (3 NH and OH).

Example 3.

Getting connection 43.

Stage 1. The oven-dried flask was equipped with a magnetic stirrer and tert-butyl 7-iodo-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyrrolo[ 3,2c]pyridazine-5-carboxylate (43 mg, 0.07 mmol), tert-butyl piperazine-1-carboxylate (15 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.3 mg , 0.007 mmol), S-Phos (5.7 mg, 0.014 mmol) and Cs ₂ CO ₃ (45 mg, 0.14 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). DME (3 ml) was added and the reaction mixture was heated to 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (40-80% EtOAc) to give tert-butyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(2-(methoxymethoxy )-4-(1-(tetrahydro-2H-pyran-2-yl)1H-pyrazol-4-yl)phenyl)-5H-pyrrolo[3,2-c]pyridazine-5-carboxylate (18 mg, 38% ) as a brownish solid. MS m/z 690.4 [M+H]+.

Step 2. To a solution of tert-butyl 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-3-[2(methoxymethoxy)-4-(1-tetrahydropyran-2-yl-pyrazol-4-yl)phenyl ]pyrrolo[3,2-c]pyridazine-5carboxylate (18 mg, 0.026 mmol) in CH ₂ Cl ₂ (0.5 ml) plus 1 drop of MeOH was added 4 M HCl in 1,4dioxane (0.03 ml, 0.12 mmol), and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 2-(7piperazin-1-yl-5H-pyrrolo[3,2-c]pyridazin-3-yl)- 5-(1H-pyrazol-4-yl)phenol (5 mg, 53%) as an orange solid.

MS m/z 362.0 [M+H]+; ^1H NMR (methanol^) δ: 8.45 (s, 1H), 8.15 (br.s, 2H), 7.80 (s, 1H), 7.70 (d, J=8.0 Hz , 1H), 7.42 (dd, J=8.0, 1.9 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 3.69-3.76 (m, 4H), 3.50-3.56 (m, 4H); 4 N not ob-

were detected (3 NH and OH). Example 4. Preparation of compound 8. 4-%/=w-n' ^thp D-o' D-2 t _ , N.. Br ° O T —-—- fl N NT stage 1 ⁿ n THP fl yx | stage 2 tg 3// H step ³ ,NH CXTAH N-4 H ^x

- 76 045009

Step 1. Mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (50 mg, 0.25 mmol), 4-[3-methoxy-4-(4,4,5,5tetramethyl-1,3 ,2-dioxa-borolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole (107 mg, 0.28 mmol), [1,G-bis(diphenylphosphino)ferrocene]dichloro-palladium(P) (19 mg, 0.025 mmol) was purged with argon. 1,4-dioxane (2 ml) and aqueous 2 M K ₂ CO ₃ (0.35 ml, 0.7 mmol) were added and the reaction mixture was heated at 90°C for 16 hours. The reaction mixture was then cooled to room temperature temperature and diluted with water. The aqueous layer was extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (50-100% EtOAc), to give 2-[2-methoxy-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-5H-pyrrolo[2 ,3-b]pyrazine (76 mg, 80%) as a yellow foam.

MS m/z 376.3 [M+H]+; 1H NMR (DMSO- _d6 ) δ: 8.67 (s, 1H), 8.51 (s, 1H), 8.06 (s, 1H), 7.82-7.88 (m, 1H), 7.71-7.76 (m, 1H), 7.39-7.44 (m, 1H), 7.32-7.38 (m, 1H), 6.63-6.69 (m, 1H ), 5.41-5.46 (m, 1H), 3.94-4.00 (m, 1H), 3.93 (s, 3H), 3.63-3.71 (m, 1H), 2.10-2.20 (m, 2H), 1.94-1.98 (m, 2H), 1.52-1.60 (m, 2H).

Step 2. Mixture of 2-[2-methoxy-4-(1-tetrahydropyran-2-yl-pyrazol-4-yl)phenyl]-5H-pyrrolo[2,3b]pyrazine (76 mg, 0.20 mmol), (2,2,6,6-tetramethyl-1,3-dihydropyridin-4-yl) trifluoromethanesulfonate (120 mg, 0.42 mmol), aqueous solution of 1 M K ₃ PO ₄ (0.1 ml, 0. 1 mmol), XPhos (18 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.02 mmol) and 1,4-dioxane (2 ml) were heated under argon at 90°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with CH ₂ Cl ₂ (3X). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of MeOH/EtOAc (0-10% MeOH) to give 5-[2-methoxy-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1-(2,2 ,6,6-tetramethyl-1,3-Dihydropyridin-4-yl)pyrrolo[3,2b]pyridine (40 mg, 39%) as an orange foam.

MS m/z 513.3 [M+H] ⁺ ; 1H NMR (CDCl ₃ ) δ: 8.73 (s, 1H), 7.87 (s, 1H), 7.81 (d, J=0.8 Hz, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.18 (dd, J=7.9, 1.6 Hz, 1H), 7.06 (d, J=1.5 Hz, 1H), 6.69 (d, J=3.7 Hz, 1H), 6.06 (t, J=1.5 Hz, 1H), 5.37 (dd, J= 9.1, 3.3 Hz, 1H), 4.02-4.05 (m, 2H), 3.85 (s, 3H), 3.63-3.73 (m, 1H), 2.56 (d, J=1.4 Hz, 2H), 2.00-2.16 (m, 3H), 1.54-1.71 (m, 3H), 1.29 (s, 6H), 1, 26 (s, 6H).

Step 3. Solution of 2-[2-methoxy-4-(1-tetrahydropyran-2-yl-pyrazol-4-yl)phenyl]-5-(2,2,6,6tetramethyl-1,3-dihydropyridin-4- yl)pyrrolo[2,3-b]pyrazine (40 mg, 0.08 mmol) and NaSEt (85 mg, 0.8 mmol) in NMP (2 ml) were heated to 180°C using microwave radiation for 30 min . The reaction mixture was then cooled to room temperature and diluted with CH ₂ Cl ₂ (10 ml). The precipitate was filtered using vacuum filtration. The filtrate was concentrated and used without further purification.

A mixture of crude 5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,3dihydropyridin-4-yl)pyrrolo[2,3-b] pyrazin-2-yl]phenol (0.039 g, 0.08 mmol) and 4 M HCl in dioxane (0.5 ml, 2 mmol) were stirred at room temperature for 1 hour. The resulting precipitate was collected by vacuum filtration and rinsed with CH2Cl2 (10 ml) to give 5-(1Hpyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,3-dihydropyridin-4-yl)pyrrolo[2,3-b ]pyrazin-2-yl]phenol hydrochloride (7 mg, 43%) as a yellow solid.

MS m/z 415.4 [M+H] ⁺ ; 1H NMR (DMSO-d6) δ: 9.15-9.25 (m, 2H), 8.16-8.20 (m, 1H), 8.13-8.16 (m, 2H), 8. 08-8.12 (m, 1H), 7.22-7.27 (m, 2H), 6.92-6.97 (m, 1H), 6.40-6.46 (m, 1H), 3.02-3.06 (m, 2H), 1.63 (s, 6H), 1.56 (s, 6H).

Example 5.

Receiving connection 10.

Step 1: To a mixture of 2,2,6,6-tetramethylpiperidin-4-amine (4.2 g, 27 mmol) in acetonitrile (10 ml) was added 2,5-dichloropyrazine (4.0 g, 27 mmol). The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was then cooled to room temperature, and the precipitate was collected by vacuum

- 77 045009 smart filtration to obtain 5-chloro-A2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2-amine in the form of a light yellow solid (3.1 g, 43%).

MS m/z 269.3 [M+H]+; 1H NMR (DMSO-d6) δ: 8.02 (d, J=1.3 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.09 (d, J=7 .7 Hz, 1H), 4.09 (dd, J=7.7, 3.7 Hz, 1H), 1.77 (dd, J=12.4, 3.7 Hz, 2H), 1.16 (s, 6H), 1.03 (s, 6H), 0.95-0.99 (m, 2H).

Step 2: To a suspension of 5-chloro-N-(2,2,6,6-tetramethyl-4-piperidyl)pyrazin-2-amine (0.7 g, 3 mmol) in acetic acid (5 ml) at room temperature NBS (0.5 g, 3 mmol) was added. After stirring for 30 minutes, a yellow precipitate formed. The precipitate was collected by vacuum filtration to give 3-bromo-5-chloro-N-(2,2,6,6-tetramethyl-4-piperidyl)pyrazin-2-amine (0.7 g, 80%) as a yellow solid substances.

MS m/z 347.2, 349.2 [M+H] ⁺ ; ^1H NMR (DMSO- _d6 ) δ: 8.19 (s, 1H), 6.91-6.95 (m, 1H), 4.31-4.36 (m, 1H), 1.90- 1.96 (m, 2H), 1.72-1.76 (m, 2H), 1.39-1.45 (m, 12H).

Step 3. Mixture of 3-bromo-5-chloro-N-(2,2,6,6-tetramethyl-4-piperidyl)pyrazin-2-αmine (1.4 g, 4.0 mmol), CuI (0. 05 g, 0.3 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.17 g, 0.24 mmol) were purged with argon. THF (20 ml), Et ₃ N (2.2 ml, 16 mmol) and ethynyl(trimethyl)silane (0.8 ml, 6 mmol) were added successively. The resulting mixture was stirred under argon at 60°C for 1 hour. The reaction mixture was then cooled to room temperature and concentrated. The crude residue was purified by chromatography on silica gel, eluting with a MeOH/CH ₂ Cl ₂ (0-10% MeOH) gradient to give 5-chloro-N-(2,2,6,6-tetramethyl-4piperidyl)-3-(2 -tri-methylsilylethynyl)pyrazin-2-amine (1.42 g, 97%) as a dark yellow solid.

MS m/z 365.3 [M+H] ⁺ ; 1H NMR (DMSO4) δ: 8.19 (s, 1H), 4.32-4.37 (m, 1H), 1.98-2.03 (m, 2H), 1.631.67 (m, 2H) , 1.43 (s, 6H), 1.40 (s, 6H), 0.26 (s, 9H).

Step 4: To a solution of 5-chloro-N-(2,2,6,6-tetramethyl-4-piperidyl)-3-(2-trimethylsilylethynyl)pyrazin-2-amine (1.42 g, 3.89 mmol) in THF (20 ml) a solution of 1 M TBAF in THF (12 ml) was added. The reaction mixture was stirred under argon at 60°C for 2 hours, then cooled to room temperature and concentrated. The crude residue was purified by silica gel chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-10% MeOH) to give 2-chloro-5-(2,2,6,6-tetramethyl-4piperidyl)pyrrolo[2,3- b]pyrazine (450 mg, 56%) as a dark red oil.

MS m/z 293.3 [M+H] ⁺ ; 1H NMR (DMSO4) δ: 8.36 (s, 1H), 8.16-8.19 (m, 1H), 6.64-6.68 (m, 1H), 5.075.12 (m, 1H) , 1.72-1.81 (m, 4H), 1.26 (s, 6H), 1.11 (s, 6H).

Step 5. Mixture of 2-chloro-5-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolo[2,3-b]pyrazine (50 mg, 0.1708 mmol), 4-[3-( methoxy-methoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1tetrahydropyran-2-ylpyrazole (85 mg, 0.2052 mmol), PdCl ₂ (dppf) (13 mg, 0.01741 mmol) was purged with argon. An aqueous solution of 2 N K2CO3 (0.5 ml, 1 mmol) and 1,4-dioxane (2 ml) were added and the reaction mixture was heated under argon at 100°C for 16 hours. The reaction mixture was then cooled to room temperature and diluted with CH2Cl2, and then filtered through a phase separation column, and then concentrated. The crude residue was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-10% MeOH) to give 2-[2-(methoxymethoxy)-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl]- 5-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolo[2,3-b]pyrazine (55 mg, 59%) as a dark brown oil contaminated with ~20% 2-chloro-5- (2,2,6,6-tetramethyl-4piperidyl)pyrrolo[2,3-b]pyrazine. MS m/z 545.5 [M+H] ⁺ .

Step 6. To a solution of 2-[2-(methoxymethoxy)-4-(1-tetra-hydropyran-2-ylpyrazol-4-yl)phenyl]-5(2,2,6,6-tetraαmethyl-4-piperidyl) pyrrolo[2,3-b]pyrazine (55 mg, 0.10 mmol) in CH ₂ Cl ₂ (1 ml), 4N HCl in dioxane (0.5 ml, 2 mmol) was added and the reaction mixture was stirred at room temperature in for 1 hour. The yellow solid that precipitated was collected by vacuum filtration, rinsed with CH ₂ Cl ₂ and dried to give 5-(1H-pyrazol-4-yl)-2-(5-(2,2,6 ,6tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol hydrochloride (18 mg, 23%).

MS m/z 417.4 [M+H] ⁺ ; 1H NMR (DMSO4) δ: 9.10 (s, 1H), 8.06-8.19 (m, 4H), 7.20-7.27 (m, 2H), 6.816.85 (m, 1H) , 5.20-5.24 (m, 1H), 2.33-2.45 (m, 2H), 2.12-2.17 (m, 2H), 1.59 (s, 6H), 1 .50 (s, 6H).

Using the procedure described for Example 5 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 16 MS m/z 437.2 [M+ASHNMR (methanol-sC) δ: 8.82 (d, J=2.2 Hz, 1H), 8.50 (d, J=l.3 Hz, 2H ), 8.11 (d, J=3.8 Hz, 1H), 7.88 (dd, J=11.3, 6.3 Hz, 1H), 7.78 (dd, J=11.3, 6.6 Hz, 1H), 6.84 (d, J=3.8 Hz, 1H), 5.34-5.46 (m, 1H), 2.49 (t, J=13.9 Hz, 2H), 2.29 (dd, J=13.9, 3.8 Hz, 2H), 1.70 (s, 6H), 1.58 (s, 6H); 2 H was not detected (2 NH).

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Example 6.

Getting connection 23.

Step 1. The oven-dried flask was equipped with a magnetic stirrer and 4-bromo-3,6-dichloropyridazine (0.227 g, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) was charged into it. (75.0 mg, 0.1 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.171 ml, 1.0 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (6 ml) and 2N aqueous K ₂ CO ₃ (1.5 ml, 3.0 mmol) were added and the reaction mixture was heated to 50°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc) to give 3,6-dichloro4-vinyl-pyridazine (0.145 g, 82%) .

Step 2: A mixture of 3,6-dichloro-4-vinylpyridazine (0.34 g, 1.94 mmol) and 2,2,6,6-tetramethylpiperidin4-amine (0.72 ml, 4.6 mmol) was dissolved in acetonitrile (5 ml), and the resulting solution was heated to 90°C for 16 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc), to give 3-chloro- 7-(2,2,6,6tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.29 g, 62%). MS m/z 295.4 [M+H]+.

Stage 3. The oven-dried flask was equipped with a magnetic stirrer and 3-chloro-7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3] was loaded into it -c]pyridazine (0.15 g, 0.5 mmol), 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-1-(tetrahydro-2Hpyran-2-yl)-1H-pyrazole (0.32 mg, 0.76 mmol, obtained in example 1, step 7), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and Na ₂ CO ₃ (160 mg, 1.5 mmol). The flask was closed with a rubber stopper with a membrane and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (10 ml) and water (1.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3 X). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-20% MeOH) to give 3-(2-(methoxymethoxy)-4-( 1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo [2,3-c]pyridazine (0.145 mg, 52%) as an orange solid. MS m/z 547.3 [M+H] ⁺ .

Step 4. 3-(2-(Methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-7(2,2,6,6- tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (20 mg, 0.037 mmol) was dissolved in 1 ml methanol, then 4 N HCl in 1,4-dioxane (0 .5 ml, 2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then triturated with 20% MeOH/ether. The precipitate was filtered and dried to give 5-(1H-pyrazol-4yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo-[2, 3-c]pyridazin-3-yl)phenol hydrochloride (10 mg, 66%) as a yellow solid.

MS m/z 419.5 [M+H] ⁺ ; ^1H NMR (methanol^) δ: 8.17 (s, 2H), 8.07 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.36 (dd, J =8.2, 1.6 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 4.49-4.58 (m, 1H), 3.94 (t, J= 7.9 Hz, 2H), 3.42 (dd, J=8.5, 7.3 Hz, 2H), 2.12 (dd, J=13.9, 3.5 Hz, 2H), 2, 00 (t, J=13.9 Hz, 2H), 1.61 (s, 6H), 1.55 (s, 6H); 3H were not detected (1 OH and 2 NH).

Using the procedure described for Example 6 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

- 79 045009

Compound Data 32 MS m/z 439.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 8.23 (s, 2H), 7.93 (s, 1H), 7.69-7.76 (m, 1H), 7.55-7.64 (m, 1H), 4.55-4.67 (m, 1H), 4.01-4.07 (m, 2H), 3.44 (br.s., 2H), 2.12-2.19 (m, 2H), 2.02-2.08 (m, 2H), 1.64 (s, 6H), 1.57 (s, 6H); 2 N were not detected (2 ΝΗ). 36 MS m/z 409.3 [M+H] ⁺ ; Ή NMR (methanol-c1 ₄ ) δ: 8.17 (s, 2H), 7.89 (d, J=l.9 Hz, 1H), 7.66-7.74 (m, 1H), 7.55-7.61 (m, 1H), 4.48-4.58 (m, 1H), 4.21-4, 26 (m, 2H), 3.99 (t, J=7.6 Hz, 2H), 3.39-3.43 (m, 2H), 2.22-2.31 (m, 6H), 2.082 .16 (m, 2H); 2 H was not detected (2 NH).

Example 7.

Getting connection 26.

Step 1. Mixture of 3-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)7-(2,2,6,6 -tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.28 g, 0.49 mmol, obtained in example 6, step 3) and manganese dioxide (0. 28 g, 3.21 mmol) in toluene (10 ml) was heated at 125°C in a sealed tube for 24 hours. The reaction mixture was cooled to room temperature, filtered through a short pad of celite and concentrated. The crude compound was purified by column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-20% MeOH) gradient to give 3-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl)phenyl)-7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazine (0.2 g, 71%) as yellowish-brown solid. MS m/z 545.4 [M+H]+.

Step 2. To a solution of 3-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-7-(2,2,6,6 -tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazine (0.2 g, 0.36 mmol) in 1,4dioxane (4 ml) was added 4N HCl in 1,4-dioxane (0. 5 ml, 2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, triturated with 20% MeOH/ether, and the precipitate was filtered and dried to give 5-(1H-pyrazol-4-yl) -2-(7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol hydrochloride (120 mg, 78%) as an orange solid .

MS m/z 417.4 [M+H] ⁺ ; 1H NMR (methanol-d ₄ ) δ: 8.84 (s, 1H), 8.68 (d, J=3.5 Hz, 1H), 8.39 (br.s, 2H), 7.74 ( d, J=7.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.33-7.39 (m, 1H), 7.14 (d, J=3 .5 Hz, 1H), 5.42-5.58 (m, 1H), 2.53 (t, J=13.6 Hz, 2H), 2.42 (dd, J=13.6, 3, 2 Hz, 2H), 1.72 (s, 6H), 1.63 (s, 6H); 3H were not detected (1 OH and 2 NH).

Using the procedure described for Example 7 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 176 MS m/z 418.5 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 8.64 (s, 1H), 8.09-8.19 (m, 1H), 8.02-8.06 (m, 1H), 7.97 ( s, 2H), 7.70-7.76 (m, 2H), 6.79 (d, J=l.8 Hz, 1H), 5.47-5.60 (m, 1H), 2.51 -2.59 (m, 2H), 2.37 (br.d, J=13.7 Hz, 2H), 1.74 (s, 6H), 1.60 (s, 6H); 2 H were not detected (NH and OH).

- 80 045009

Example 8.

Getting connection 17.

Step 1: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (2.05 g, 9.9 mmol) in CH ₃ CN (26 ml) was added dropwise a solution of methyl 2-sulfanylacetate (0.90 ml, 10. 0 mmol) in CH3CN (8.5 ml) at 0°C. After completion of the addition operation, Et ₃ N (1.40 ml, 10.0 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. After 15 minutes, additional Et ₃ N (1.40 mL, 10.0 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and concentrated. The mixture was acidified with 4N HCl to pH ® 3, and the bright yellow solution became colorless and a white precipitate formed. The solid was collected by filtration and washed with water to give methyl 3-chloro-7-hydroxythieno[3,2c]pyridazine-6-carboxylate (2.26 g, 93.1% yield) as a white solid. MS m/z 245.1 [M+H]+.

Step 2: To a solution of methyl 3-chloro-7-hydroxythieno[3,2-c]pyridazine-6-carboxylate (2.26 g, 9.24 mmol) in DMF (30 ml) was added imidazole (1.0 g, 15 mmol) and TIPSCl (2.25 ml, 10 mmol). The mixture was stirred at room temperature for 15 minutes and then heated to 50°C for 24 hours. After heating was complete, the reaction mixture was cooled to room temperature and then diluted with water, and the product was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ , concentrated, and the residue was purified by silica gel column chromatography, eluting with an EtOAc/CH ₂ Cl ₂ (0-5% EtOAc) gradient to give methyl 3-chloro-7triisopropylsilyloxythieno[3,2- c]pyridazine-6-carboxylate (2.04 g, 55.1% yield) as a yellowish-white solid.

Step 3. Mixture of methyl 3-chloro-7-triisopropylsilyloxy-thieno[3,2-c]pyridazine-6-carboxylate (800 mg, 1.9 mmol), 4-[3-(methoxymethoxy)-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1tetrahydropyran-2-yl-pyrazole (prepared in Example 1, Step 7, 1.00 g, 2.4 mmol), complex of [1,1'bis(diphenylphosphino)ferrocene] dichloropalladium(II) with dichloromethane (85 mg, 0.10 mmol) and K ₂ CO ₃ (830 mg, 6.0 mmol) in the flask was evacuated and filled with N2 ( this operation was repeated 3 times), 1,4dioxane (7 ml) and water (1.8 ml) were added and the mixture was heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and acidified with 4N HCl. The product was extracted with CH ₂ Cl ₂ (3X). The organic phases were combined, dried over Na ₂ SO ₄ and concentrated. Crude methyl 7-hydroxy-3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]thieno[3,2-c]pyridazine-6-carboxylate was directly used in the next step without cleaning.

Step 4: The above crude methyl 7-hydroxy-3-[2-(methoxymethoxy)-4-(1tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-thieno[3,2-c]pyridazine-6-carboxylate was mixed with 5 N NaOH (3 ml, 15 mmol) and MeOH (15 ml) and heated at 95°C until hydrolysis was completely completed (6 h). After completion of hydrolysis, the reaction mixture was cooled to room temperature and carefully acidified with 4N HCl to pH 3-4. The intermediate carboxylic acid was extracted with CH ₂ Cl ₂ /MeOH. The organic phase was dried over Na ₂ SO ₄ . The volatile components were removed under reduced pressure and the residue was dissolved in DMSO (10 ml). The mixture was heated at 80°C for 60 min, after which the completion of the decarboxylation reaction of the intermediate aketoacid was detected. After cooling to room temperature, the mixture was diluted with water and the product was extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed. The residue was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-5% MeOH) gradient to give 3-[2-(methoxy-methoxy)-4-(1-tetrahydropyran-2-yl-pyrazol- 4-yl)phenyl]thieno[3,2c]pyridazin-7-ol (0.64 g, 76% yield) as a yellow solid. MS m/z 439.4 [M+H]+.

- 81 045009

Step 5. To a solution of 3-[2-(methoxymethoxy)-4-(1-tetra-hydropyran-2-ylpyrazol-4yl)phenyl]thieno[3,2-c]pyridazin-7-ol (204 mg, 0. 47 mmol) in CH ₂ Cl ₂ (2.5 ml) was added DIPEA (0.16 ml, 0.92 mmol). The reaction mixture was cooled to 0°C and trifluoromethanesulfonic anhydride (0.09 mL, 0.53 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, then diluted with water, and the products were extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ , volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAc (0-5% MeOH) to give [3-[2(methoxymethoxy)-4- (1-tetrahydropyran-2-yl-pyrazol-4-yl)phenyl]thieno[3,2-c]pyridazin-7yl]trifluoromethane sulfonate (0.13 g, 48% yield) as a white foam. MS m/z 571.3 [M+H]+.

Step 6. The oven-dried flask was equipped with a magnetic stirrer and [3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]thieno[3,2-c] was charged into it. pyridazin-7yl]trifluoromethanesulfonate (127 mg, 0.22 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 ,3-dihydropyridine (64 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (18 mg, 0.02 mmol) and K ₂ CO ₃ (100 mg, 0. 72 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (1.2 ml) and water (0.8 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and then extracted with EtOAc ( 3 X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of MeOH (with 2.5% NH ₄ OH)/CH ₂ Cl ₂ (0-10% MeOH/NH ₄ OH) to give 3-(2(methoxymethoxy)-4-( 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethyl1,2,3,6-tetrahydropyridin-4- yl)thieno[3,2-c]pyridazine (55.6 mg, 45% yield) as a brownish foam. MS m/z 560.5 [M+H] ⁺ .

Step 7. To 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-7-(2,2,6,6tetramethyl-1,3-dihydropyridin-4- yl)thieno[3,2-c]pyridazine (13.8 mg, 0.025 mmol) was added with 4N HCl in dioxane (0.5 mL, 2 mmol) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 30 min and then for ~2 h at 50°C. The volatile components were then removed under reduced pressure, the residue was triturated with Et ₂ O, and the solid was filtered and dried to give 5(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl- 1,3-dihydropyridin-4-yl)thieno[3,2-c]pyridazin-3-yl]phenol hydrochloride (7 mg, 60% yield) as a yellow solid.

MS m/z 432.4 [M+H] ⁺ ; ^1H NMR (methanol^) δ: 9.37 (s, 1H), 8.49 (s, 1H), 8.22 (s, 2H), 7.93 (d, J=8.2 Hz, 1H ), 7.42 (dd, J=8.2, 1.6 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.20 (s, 1H), 3.56 -3.77 (m, 2H), 1.72 (s, 6H), 1.65 (s, 6H); 3 H were not detected (2 NH and OH).

Using the procedure described for Example 8 above, additional compounds described in the invention can be prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 15 MS m/z 376.3 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.41 (br.s, 2H), 9.38 (s, 1H), 8.40 (s, 1H), 8.26 (s, 2H), 8. 11 (d, J=9.1 Hz, 1H), 7.58-7.68 (m, 1H), 7.40 (d, J=l.9 Hz, 1H), 7.37-7.39 (m, 1H), 3.84-4.03 (m, 2H), 3.41-3.51 ( m, 2H), 2.87-3.02 (m, 2H); 1H was not detected (NH or OH). 18 MS m/z 402.3 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.47 (s, 1H), 8.55 (s, 1H), 8.36 (s, 2H), 7.91 (d, J=8.2 Hz, 1H), 7.59 (dt, J=6.3, 1.6 Hz, 1H), 7.48 (dd, J=8.2, 1.6 Hz, 1H), 7.40 (d, J =l.6 Hz, 1H), 4.57 (dd, J=6.6, 6.0 Hz, 1H), 4.45 (dd, J=6.6, 5.0 Hz, 1H), 3 .38-3.46 (m, 1H), 2.84-3.01 (m, 1H), 2.40-2.53 (m, 2H), 2.24-2.37 (m, 1H) , 2.06-2.19 (m, 1H); 3 H were not detected (2 NH and OH). 25 MS m/z 418.4 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.51 (s, 1H), 8.66 (s, 1H), 8.43 (s, 2H), 7.91 (d, J=8.2 Hz , 1H), 7.49 (dd, J=8.2, 1.6 Hz, 1H), 7.44-7.47 (m, 1H), 7.41 (d, J=l.6 Hz, 1H), 4.37 (d, J=5.7 Hz, 1H), 4.16 (d, J=12.6 Hz, 1H), 4.12 (dd, J=12.6, 1.9 Hz, 1H), 4.07 (dd, J=12.6, 1.9 Hz, 1H), 3.98 (s, 2H), 3.39-3.48 (m, 1H), 3.18 (dd, J=18.3, 1.9 Hz, 1H); 3 H were not detected (2 NH and OH).

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Example 9.

Receiving connection 24.

Step 1. Solution of 3-[2-(methoxymethoxy)-4-(1-tetrahydro-pyran-2-ylpyrazol-4-yl)phenyl]-7(2,2,6,6-tetramethyl-1,3-Dihydro -pyridin-4-yl)thieno[3,2-c]pyridazine (50 mg, 0.089 mmol, from Example 8, Step 6) in MeOH (3 ml) was hydrogenated in a Parr hydrogenation shaker over Pt ₂ O (100 mg, 0.44 mmol) for 72 hours at a pressure of 0.345 MPa H ₂ . The catalyst was then filtered and washed with MeOH. The mother liquor was concentrated and the residue, crude 3-[2(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethyl-4piperidyl) )thieno[3,2-c]pyridazine was directly used in the next step.

Step 2. Solution of crude 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4yl)phenyl]-7-(2,2,6,6-tetramethyl-4-piperidyl)thieno[3 The ,2-c]pyridazine obtained in step 1 above in MeOH (1 ml) was treated with 4N HCl in dioxane (0.5 ml, 2 mmol). The reaction mixture was stirred at room temperature for 30 min and then for ~2 h at 50°C. The volatile components were then removed under reduced pressure, the residue was triturated with Et ₂ O, and the solid was filtered and washed with Et ₂ O. The crude product was purified by preparative HPLC using a polar solvent (20-65% CH3CN/H2O). Concentration of the desired fractions and treatment of the residue with 4N HCl in dioxane (0.5 ml, 2 mmol) gave 5-(1H-pyrazol-4-yl)-2-(7(2,2,6,6-tetramethylpiperidine -4-yl)thieno[3,2-c]pyridazin-3-yl)phenol dihydrochloride (2.4 mg, 6% yield) as a yellow solid.

MS m/z 434.3 [M+H]+; 1H NMR (DMSO-d ₆ ) δ: 9.32 (br.s) 1H), 9.30 (s, 1H), 8.19 (s, 2H), 8.15 (br.s, 1H), 8.12 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.27-7.36 (m, 2H), 3.91-4.00 (m, 1H) , 2.18 (dd, J=12.3, 2.5 Hz, 2H), 1.89-2.07 (m, 2H), 1.60 (s, 6H), 1.50 (s, 6H ); 1H was not detected (NH or OH).

Example 10.

Receiving connection 98.

Step 1. Methyl 3,6-dichloropyridazine-4-carboxylate (500 mg, 2.42 mmol), (2,2,6,6tetramethyl-4-piperidyl)-hydrazine dihydrochloride (590 mg, 2.84 mmol) and DIPEA (1.3 ml, 7.26 mmol) was mixed in MeOH (2 ml) and heated to 70°C overnight. UPLC analysis showed 2 peaks with the required mass in an approximate ratio of 2:3. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel, eluting with a MeOH/CH ₂ Cl ₂ (0-30%) gradient to give 5chloro-2-(2,2,6,6-tetramethyl-4-piperidyl) pyrazolo[3,4-c]pyridazin-3-ol (230 mg, 31%) as a dark purple solid and 5-chloro-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3 ,4-c]pyridazin-3ol (200 mg, 13.4%) as a brownish-orange solid.

MS m/z 310.8 [M+H]+; Ή NMR (methanol^) δ: 7.84 (s, 1H), 5.24 (tt, J=12.3, 3.8 Hz, 1H), 2.30 (dd, J=14.2, 12 .3 Hz, 2H), 2.05 (dd, J=14.2, 3.8 Hz, 2H), 1.66 (s, 6H), 1.54 (s, 6H); 2 H were not detected (NH and OH).

Stage 2. The oven-dried flask was equipped with a magnetic stirrer and 5-chloro-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-3-ol ( 500 mg, 1.61 mmol), tri

- 83 045009 zopropyl-[3-(methoxymethoxy)-4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)phenoxy]silane (775 mg, 1.78 mmol ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (121 mg, 0.16 mmol) and K2CO3 (451 mg, 3.23 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 5-[2(methoxymethoxy)-4 -triisopropylsilyloxyphenyl]-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4c]pyridazin-3-ol (200 mg, 21%) as a brownish solid. MS m/z 584.4 [M+H]+.

Step 3. To a suspension of 5-[2-(methoxymethoxy)-4-triisopropyl-silyloxyphenyl]-1-(2,2,6,6tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-3-ol ( 200 mg, 0.34 mmol) in CH ₂ Cl ₂ (4 ml) was added N,N-bis(trifluoromethylsulfonyl)aniline (247 mg, 0.69 mmol) and Et ₃ N (0.15 ml, 1.03 mmol ), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH), to obtain [5 -[2-(methoxymethoxy)-4triisopropylsilyloxyphenyl]-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-3yl]trifluoromethanesulfonate (236 mg, 96%) as a yellowish-brown solid. MS m/z 716.6 [M+H] ⁺ .

Step 4. To a mixture of [5-[2-(methoxymethoxy)-4-triisopropyl-silyloxy-phenyl]-1-(2,2,6,6-tetramethyl4-piperidyl)pyrazolo[3,4-c]pyridazin-3 -yl]trifluoromethanesulfonate (236 mg, 0.33 mmol), dppf (38 mg, 0.066 mmol), [1,G-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (49 mg, 0.066 mmol) and ammonium formate (104 mg, 1.65 mmol) in dried THF (4 ml) was added Et ₃ N (0.23 ml, 1.65 mmol). The mixture was purged with argon and then heated at 60°C for 6 hours in a sealed tube. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (015% MeOH) to give triisopropyl-[3-(methoxymethoxy)-4-[1-(2,2,6,6-tetramethyl-4piperidyl) pyrazolo[3,4-c]pyridazin-5-yl]phenoxy]silane (170 mg, 91%) as a gray solid.

MS m/z 568.5 [M+H]+; 1H NMR (methanol- _d4 ) δ: 8.45 (s, 1H), 8.32 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 5.74 (tt, J=12.6, 3.8 Hz, 1H), 5.22 (s, 2H), 3.42 (s, 3H), 2.062.33 (m, 4H), 1.56 (s, 6H), 1.39 (s, 6H), 1.35 (spt , J=7.6 Hz, 3H), 1.19 (d, J=7.6 Hz, 18H); 1 H was not detected (NH).

Step 5. To a solution of triisopropyl-[3-(methoxymethoxy)-4-[1-(2,2,6,6-tetramethyl-4piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]phenoxy]silane (273 mg, 0.48 mmol) in THF (4 mL), 1.0 M TBAF in THF (0.53 mmol, 0.53 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 3(methoxymethoxy)-4-[1-(2,2,6,6 -tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]phenol (101 mg, 51%) as a clear solid. MS m/z 412.4 [M+H] ⁺ .

Step 6. To a suspension of 3-(methoxymethoxy)-4-[1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4c]pyridazin-5-yl]phenol (101 mg, 0. 25 mmol) in CH ₂ Cl ₂ (2 ml) was added N,N-bis(trifluoromethylsulfonyl)aniline (133 mg, 0.37 mmol) and Et ₃ N (0.104 ml, 0.74 mmol). The reaction mixture was stirred at room temperature for 16 hours. UPLC analysis showed complete conversion. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (20-100% EtOAc) to give [3-(methoxymethoxy)-4-[1(2,2,6,6-tetramethyl -4-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]phenyl]trifluoromethanesulfonate (121 mg, 91%) as a clear solid.

MS m/z 544.4 [M+H]+; 1H NMR (methanol-d ₄ ) δ: 8.53 (s, 1H), 8.38 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.24 (dd, J=8.5, 2.5 Hz, 1H), 5.79 (tt, J=12.6, 3.8 Hz, 1H), 5.31 (s, 2H), 3.44 (s, 3H), 2.39 (t, J=13.6 Hz, 2H), 2.28 (dd, J=13.6, 3.8 Hz , 2H), 1.66 (s, 6H), 1.50 (s, 6H); 1 H was not detected (NH).

Step 7. The oven-dried flask was equipped with a magnetic stirrer and [3-(methoxymethoxy)-4-[1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4-c] was loaded into it. pyridazin-5-yl]phenyl]trifluoromethanesulfonate (51 mg, 0.094 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrazole (23 mg, 0 .11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(P) (7 mg, 0.009 mmol) and K ₂ CO ₃ (26 mg, 0.19 mmol). The flask was closed with a rubber stopper with a membrane and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (1 ml) and water (0.25 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X) . The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified

- 84 045009 column chromatography on silica gel, eluting with a gradient of MeOH/CH2C12 (0-30% MeOH) to give 5-[2-(methoxymethoxy)-4-(1-methylpyrazol-4-yl)phenyl]-1-(2 ,2,6,6-tetramethyl-4piperidyl)pyrazolo[3,4-c]pyridazine (40 mg, 89%) as an orange solid. MS m/z 476.5 [M+H]+.

Step 8. To a solution of 5-[2-(methoxymethoxy)-4-(1-methyl-pyrazol-4-yl)phenyl]-1-(2,2,6,6-tetramethyl4-piperidyl)pyrazolo[3,4 -c]pyridazine (40 mg, 0.084 mmol) in 1 ml CH ₂ Cl ₂ with 2 drops MeOH, 4N HCl in 1,4-dioxane (42 μl, 0.17 mmol) was added and the reaction mixture was stirred for 5 hours until until UPLC analysis showed complete consumption of the starting material. The solvent was removed under reduced pressure and the residue was triturated in Et ₂ O and the precipitate was collected by filtration, the solid was further washed with diethyl ether and dried to give 5-(1-methylpyrazol-4yl)-2-[1-(2,2,6 ,6-tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]phenol dihydrochloride (32 mg, 75%) as a yellow solid.

MS m/z 432.5 [M+H]+; ^1H NMR (methanol^) δ: 9.11 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.86 (d , J=7.9 Hz, 1H), 7.35 (dd, J=8.2, 1.5 Hz, 1H), 7.29 (d, J=1.5 Hz, 1H), 5.74 (tt, J=12.6, 4.0 Hz, 1H), 4.00 (s, 3H), 2.52 (t, J=13.8 Hz, 2H), 2.44 (dd, J= 13.8, 4.0 Hz, 2H), 1.76 (s, 6H), 1.62 (s, 6H); 2H were not detected (NH and OH).

Using the procedure described for Example 10 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 21 MS m/z 362.4 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.12 (s, 1H), 8.68 (s, 1H), 8.42 (s, 2H), 7.89 (d, J=8.2 Hz, 1H ), 7.44 (dd, J=8.2, 1.9 Hz, 1H), 7.38 (d, J=l.6 Hz, 1H), 5.52 (tg, J=10.4, 4.4 Hz, 1H), 3.67-3.72 (m, 2H), 3.43 (td, J=12.3, 3.2 Hz, 2H), 2.58-2.70 (m , 2H), 2.46-2.55 (m, 2H); 3 H were not detected (2 NH and OH). 102 MS m/z 435.5 [M+H] ⁺ ; Ή NMR (methanol-cU) δ: 8.84 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.97 (d, J=8.2 Hz, 1H ), 7.89 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.23 (s, 1H), 5.78 (tg, J=12.4, 3, 4 Hz, 1H), 2.51 (t, J=13.7 Hz, 2H), 2.40 (dd, J=13.7, 3.4 Hz, 2H), 1.76 (s, 6H) , 1.60 (s, 6H); 2 H were not detected (NH and OH). 148 MS m/z 450.4 [M+H] ⁺ ; Ή NMR (methanol-sc) δ: 8.81 (s, 1H), 8.40 (s, 1H), 7.77-7.86 (m, 2H), 7.25-7.32 (m, 1H), 6.91-7.00 (m, 1H), 5.56-5.72 (m, 1H), 3.26 (s, ZN), 2.42 (t, J=13.4 Hz , 2H), 2.28 (dd, J=13.4, 2.8 Hz, 2H), 1.65 (s, 6H), 1.50 (s, 6H); 2H were not detected (OH and NH). 161 MS m/z 436.5 [M+H] ⁺ ; 'H NMR (methanol-cU) δ: 8.81 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 7.86-8.07 (m, 2H), 7, 23-7.31 (m, 1H), 7.04 (d, J=8.6 Hz, 1H), 5.61-5.74 (m, 1H), 1.98-2.18 (m, 4H), 1.48 (s, 6H), 1.30 (s, 6H), 3 H was not detected (2 NH and OH).

Example 11.

Getting connection 22.

Stage 1. The oven-dried flask was equipped with a magnetic stirrer and 5-chloro-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrazolo[3,4-c]pyridazin-3-ol ( 186 mg, 0.60 mmol), 4-[3(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2ylpyrazole (obtained in example 1, step 7, 298.5 mg, 0.72 mmol), [1.1'

- 85 045009 bis(diphenylphosphino)ferrocene]dichloropalladium(P) (45 mg, 0.06 mmol) and K2CO3 (252 mg, 1.80 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X) . The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 5-(2-(methoxymethoxy)-4-(1 -(tetrahydro-2Hpyran-2-yl)-1 H-pyrazol-4-yl)phenyl)-1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1 H-pyrazolo [3,4с] pyridazin-3-ol (229 mg, 68%) as a dark yellow solid. MS m/z 562.5 [M+H]+.

Step 2. To a solution of 5-[2-(methoxymethoxy)-4-(1-tetra-hydropyran-2-ylpyrazol-4-yl)phenyl]-1(2,2,6,6-tetramethyl-4-piperidyl) pyrazolo[3,4-c]pyridazin-3-ol (229 mg, 0.41 mmol) in CH2Cl2 (4 ml) was added N,N-bis(trifluoromethylsulfonyl)aniline (294 mg, 0.82 mmol) and Et ₃ N (0.17 mL, 1.22 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with CH2Cl2 (3X). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-25% MeOH) gradient to give 5-(2(methoxymethoxy)-4-(1-(tetrahydro -2H-pyran-2-yl)-III-pyrazol-4-yl)phenyl)-1-(2,2,6,6tetramethylniperidin-4-yl)-1H-pyrazolo[3,4-c]niridazin-3 -yl trifluoromethanesulfonate (166 mg, 59%) as a clear solid.

MS m/z 694.3 [M+H] ⁺ ; ^1H NMR (acetone-dg) δ: 8.50 (s, 1H), 8.17 (d, J=0.6 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H) , 7.83 (d, J=0.6 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.37 (dd, J=8.2, 1.6 Hz, 1H), 5.73 (tt, J=12.3, 4.0 Hz, 1H), 5.34 (dd, J=9.8, 2.5 Hz, 1H), 5.27 (s, 2H ), 3.85-3.92 (m, 1H), 3.54-3.64 (m, 1H), 3.30 (s, 3H), 2.15-2.27 (m, 4H), 1.60-1.68 (m, 2H), 1.54 (s, 6H), 1.45-1.52 (m, 4H), 1.37 (s, 6H), 1 H not detected (NH ).

Step 3. To a solution of 5-(2-(methoxymethoxy)-4-(1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-1-(2,2,6 ,6-tetramethylpineridin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-3-yl trifluoromethanesulfonate (166 mg, 0.24 mmol), Pd(OAc)2 (11 mg, 0.048 mmol), dppf (27 mg, 0.048 mmol) and Et ₃ N (0.17 ml, 1.2 mmol) in dried THF (0.5 ml) ammonium formate (77 mg, 1.2 mmol) was added. The mixture was purged with argon and heated at 60°C for 2.5 hours in a sealed tube. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (020% MeOH), to give 5-(2-(methoxymethoxy)-4-(1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c] pyridazine (115 mg, 88%) in the form of a clear foam. MS m/z 546.5 [M+H] ⁺ .

Step 4. To a solution of 5-(2-(methoxymethoxy)-4-(1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-1-(2,2,6 ,6-tetra-methyl-piperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazine (115 mg, 0.21 mmol) in 1 ml CH2Cl2 with 1 drop of MeOH was added 4N HCl in dioxane (0. 11 mL, 0.44 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The precipitating yellow solid was collected by vacuum filtration, rinsed with CH2Cl2, Et2O and dried to give 5(1H-pyrazol-4-yl) -2-(1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol hydrochloride (78 mg, 89%) as yellow solid matter.

MS m/z 418.5 [M+H] ⁺ ; ^1H NMR (methanol- _d4 ) δ: 9.20 (s, 1H), 8.75 (s, 1H), 8.62 (s, 2H), 7.91 (d, J=8.2 Hz , 1H), 7.49 (dd, J=8.2, 1.9 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 5.75 (tg, J=12, 0, 4.1 Hz, 1H), 2.53 (t, J=14.2 Hz, 2H), 2.46 (dd, J=14.2, 4.1 Hz, 2H), 1.76 ( s, 6H), 1.63 (s, 6H); 3 H were not detected (2 NH and OH).

Using the procedure described for Example 11 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds: _________________

Compound Data 165 MS m/z 429.3 [M+H] ⁺ ; Ή NMR (methanol- _c14 ) δ: 8.90 (s, 1H), 8.61 (d, J=4.6 Hz, 2H), 8.41 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.79 (br.d, J=4.9 Hz, 2H), 7.39 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 5.61-5.75 (m, 1H), 1.94-2.16 (m, 4H), 1.45 (s, 6H), 1.26 (s, 6H); 2 H were not detected (NH and OH).

- 86 045009

166 MS m/z 429.3 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.31 (br.s, 1H), 9.01-9.10 (m, 2H), 8.92 (br.d, J=3.l Hz, 1H), 8.57 (s, 1H), 8.17-8.31 (m, 2H), 7.56 (br.s, 2H), 5.71-5.88 (m, 1H), 2 .49-2.60 (m, 2H), 2.35-2.48 (m, 2H), 1.77 (s, 6H), 1.63 (s, 6H); 2 H were not detected (NH and OH). 167 MS m/z 430.3 [M+H] ⁺ ; 'H NMR (methanol-ce) δ: 9.19 (s, 1H), 9.16 (br.s, 2H), 8.93 (s, 1H), 8.46 (s, 1H), 8. 17 (d, J=8.5 Hz, 1H), 7.35-7.50 (m, 2H), 5.76-5.89 (m, 1H), 2.49-2.56 (m, 2H), 2.42 (br.dd, J=13.6, 3.2 Hz, 2H), 1.77 (s, 6H), 1.61 (s, 6H); 2 H were not detected (NH and OH). 169 MS m/z 432.4 [M+H] ⁺ ; 'H NMR (methanol-SH) δ: 8.83 (s, 1H), 8.39 (s, 1H), 7.93-8.05 (m, 1H), 7.65 (s, 1H), 7.35-7.54 (m, 2H), 6.65-6.78 (m, 1H), 5.545.83 (m, 1H), 3.95 (s, ZN), 2.12-2, 46 (m, 4H), 1.61 (br.s, 6H), 1.44 (br.s, 6H); 2 H were not detected (ΝΗ and OH). 174 MS m/z 419.4 [M+H] ⁺ ; 'H NMR (methanol-SH) δ: 8.77-8.95 (m, 1H), 8.38 (br.s, 1H), 8.01-8.14 (m, 1H), 7.97 (s, 2H), 7.55-7.78 (m, 2H), 5.58-5.73 (m, 1H), 1.94-2.22 (m, 4H), 1.46 (s , 6H), 1.26 (s, 6H); 2 H were not detected (ΝΗ and OH).

Example 12.

Receiving connection 19.

Step 1: 3,6-Dibromopyrazine-2-carbaldehyde (340 mg, 1.28 mmol) and benzyl 4-hydrazinopiperidine 1-carboxylate dihydrochloride (412 mg, 1.28 mmol) were mixed in DMF (3 ml) and stirred at room temperature within 5 min. The reaction mixture was partitioned between EtOAc and water. The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-30% EtOAc), to give benzyl 4-[(2E)-2-[ (3,6-dibromopyrazin-2-yl)methylene]hydrazino]piperidine-1carboxylate (550 mg, 87%) as a yellow solid.

MS m/z 496.0, 498.0, 500.0 [M+H]+; 1H NMR (acetone^) δ: 8.27-8.33 (m, 1H), 8.17 (d, J=4.7 Hz, 1H), 7.90 (s, 1H), 7.36- 7.45 (m, 4H), 7.29-7.36 (m, 1H), 5.14 (s, 2H), 4.05-4.15 (m, 2H), 3.64-3, 74 (m, 1H), 2.08-2.10 (m, 2H), 2.01-2.05 (m, 2H), 1.49-1.64 (m, 2H).

Step 2: A solution of benzyl 4-[(2E)-2-[(3,6-dibromopyrazin-2-yl)methylene]hydrazino]piperidine-1carboxylate (550 mg, 1.11 mmol) in CH3CN (2 ml) was heated at exposure to microwave radiation at 200°C for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of EtOAc/CH ₂ Cl ₂ (0-60% EtOAc), to give benzyl 4-(5 -bromo-III-pyrazolo[3,4-b]pyrazin-1-yl)piperidine-1-carboxylate (78 mg, 16%). MS m/z 416.0, 418.0 [M+H] ⁺ .

Step 3. The oven-dried flask was equipped with a magnetic stirrer and benzyl 4-(5-bromopyrazolo[3,4-b]pyrazin-1-yl)piperidine-1-carboxylate (78 mg, 0.19 mmol) was charged into it. 4-[3(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2ylpyrazole (prepared in Example 1, Step 7, 93 mg, 0.23 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) (14 mg, 0.019 mmol) and K2CO3 (78 mg, 0.56 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X) . The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with

- 87 045009 gradient EtOAc/CH2Cl2 (0-60% EtOAc), to obtain benzyl 4-(5-(2-(methoxymethoxy)-4-(1(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole -4-yl)phenyl)-1 H-pyrazolo[3,4-b]pyrazin-1 -yl)piperidin-1 carboxylate (69 mg, 59%) as a brownish solid. MS m/z 624.3 [M+H]+.

Step 4. To a solution of benzyl 4-[5-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4yl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]piperidin-1 -carboxylate (69 mg, 0.11 mmol) in EtOH (3 ml) was added 10% Pd/C (10 mg), and the reaction mixture was hydrogenated at a pressure of 0.1 MPa H2 for 16 hours. The catalyst was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH). 5-[2(Methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1-(4-piperidyl)pyrazolo[3,4b]pyrazine (15 mg, 28%) was obtained as a white solid. MS m/z 490.4 [M+H]+.

Step 5. To a solution of 5-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1-(4piperidyl)pyrazolo[3,4-b]pyrazine (15 mg, 0.031 mmol) in CH ₂ Cl ₂ (1 ml, with one drop of MeOH), 4N HCl in 1,4-dioxane (15 µl, 0.06 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The precipitate was collected filtration, washed with Et ₂ O (3 X) and dried to give 2-[1-(4-piperidyl)pyrazolo[3,4-b]πyrazin-5-yl]-5-(1H-pyrazol-4 -yl)phenol hydrochloride (8 mg, 66%) as a yellow solid.

MS m/z 362.3 [M+H]+; 1H NMR (DMSO-d6) δ: 11.68 (br.s, 1H), 10.09 (br.s, 1H), 9.38 (d, J=1.6 Hz, 1H), 8.95 (br.s, 1H), 8.68 (br.s, 1H), 8.56 (s, 1H), 8.14 (br.s, 1H), 8.05 (dd, J=8.8 , 1.6 Hz, 1H), 7.27 (s, 2H), 5.18-5.28 (m, 1H), 3.58-3.66 (m, 1H), 3.42-3, 53 (m, 1H), 3.17-3.39 (m, 2H), 2.76-2.88 (m, 1H), 2.34-2.45 (m, 1H), 2.14- 2.31 (m, 2H).

Example 13.

Receiving connection 80.

stage 4

Step 1: To a suspension of 3,6-dichloropyridazin-4-amine (2.0 g, 12.2 mmol) in 1-decanol (3.5 ml) was added 2,2,6,6-tetramethylpiperidin-4-amine ( 2.3 ml, 1.1 equiv) and N,N-diisopropylethylamine (3 ml, 1.4 equiv) in a 60 ml screw cap tube. The reaction mixture was stirred at 150°C for 72 hours, after which the partially solidified reaction mixture was transferred to a round bottom flask with methanol. The organic components were concentrated to a viscous oil, which was rinsed with hexanes to remove 1-decanol (this may cause solidification). The crude product was purified by column chromatography, eluting with a gradient of MeOH (with 2.5% NH ₄ OH)/CH ₂ Cl ₂ (530% MeOH/NH ₄ OH). The first compound eluted was the unreacted starting material 3,6-dichloropyridazin-4-amine. Then a mixture of 6-χλορ-N3-(2,2,6,6tetramethylpiperidin-4-yl)pyridazin-3,4-diamine and 6-chloro-N3-(2,2,6,6-tetramethylpiperidin-4yl)pyridazine was eluted -3,5-diamine (they eluted simultaneously), then N3,N6-6uc(2,2,6,6tetramethylpiperidin-4-yl)pyridazin-3,4,6-triamine was eluted. Column chromatography usually provides 50-60% yield of 6-chloro-N3-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3,4-diamine and 6-chloroN3-(2,2,6, 6-tetramethylpiperidin-4-yl)pyridazin-3,5-diamine (at a ratio of 2:1). A mixture of 6-χλορ-Ν3(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3,4-diamine and 6-chloro-N3-(2,2,6,6-tetramethylpiperidin-4yl)pyridazin- 3,5-diamine (2.7 g, 77%) obtained from chromatography was used in the next step without further purification.

Step 2. To a solution of a mixture of 6-chloro-N3-(2,2,6,6-tetramethyl-4-piperidyl)pyridazine-3,4-diamine and 6chloro-N3-(2,2,6,6-tetra- Methyl 4-piperidyl)pyridazine-3,5-diamine (2.7 g, 9.5 mmol) in AcOH (8 ml) was added portionwise with NaNO ₂ (1.3 g, 19 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by slowly adding saturated aqueous sodium bicarbonate until pH ~7 was reached. The aqueous layer was extracted three times with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-20% MeOH) gradient to give 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[ 4,5-c]pyridazine (1.22 g, 43%) as cinnamon

- 88 045009 non-cotton solid:

MS m/z 295.8 [M+H]+; ^1H NMR (500 MHz, methanol- _d4 ) δ: 8.56 (s, 1H), 5.76 (tt, J=12.6, 4.1 Hz, 1H), 2.30 (dd, J =12.6, 4.1 Hz, 2H), 2.23 (t, J=12.6 Hz, 2H), 1.47 (s, 6H), 1.32 (s, 6H).

Stage 3. The oven-dried flask was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (1, 11 g, 3.77 mmol), triisopropyl(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)silane (1.81 g , 4.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (138 mg, 0.19 mmol) and K ₂ CO ₃ (1.56 g, 11.31 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (18 ml) and water (4 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc (3 X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude 6(2-(methoxymethoxy)-4-((triisopropylsilyl)oxy)phenyl)-3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine (1.67 g, 78%) as a brown solid, which was used in the next step without further purification.

Step 4. To a solution of 6-(2-(methoxymethoxy)-4-((triiso-propylsilyl)oxy)phenyl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2, 3]triazolo[4,5-c]pyridazine (1.67 g, 2.94 mmol) in THF (10 ml) was added 1.0 M TBAF in THF (3.1 ml, 3.1 mmol). The reaction mixture was stirred at room temperature for 1 hour until TLC analysis indicated complete consumption of the starting material. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (10-80% EtOAc), to give 3-(methoxymethoxy)-4-(3-(2,2,6,6 -tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl)phenol (985 mg, 81%) as a tan oil. To a solution of 3(methoxymethoxy)-4-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl)phenol (985 mg, 2.39 mmol) in CH ₂ Cl ₂ (8 ml) was added N,N-bis(trifluoromethylsulfonyl)-aniline (1.71 g, 4.78 mmol) in Et ₃ N (1.0 ml, 7.2 mmol). The reaction mixture was stirred for 5 hours until UPLC analysis indicated complete conversion. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-60% EtOAc), to give 3-(methoxymethoxy)-4-(3-(2,2,6,6- tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenyl trifluoromethanesulfonate (20 mg, 71%).

MS m/z 545.6 [M+H]+; ^1H NMR (acetone^) δ: 8.68 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.8, 2.5 Hz, 1H), 5.67 (tt, J=11.2, 5.4 Hz, 1H), 5.31 (s, 2H), 3 .35 (s, 3H), 2.04-2.27 (m, 4H), 1.36 (s, 6H), 1.16 (s, 6H), 1H not detected (NH).

Step 5. The oven-dried flask was equipped with a magnetic stirrer and [3-(methoxymethoxy)-4-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c] was loaded into it. pyridazin-6-yl]-phenyl] trifluoromethanesulfonate (50 mg, 0.092 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrole-1-carboxylate ( 32 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (7 mg, 0.009 mmol) and K2CO3 (26 mg, 0.18 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4Dioxane (18 ml) and water (4 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc (3X) . The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by chromatography on silica gel eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give tert-butyl 3-[3-(methoxymethoxy) -4-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5c]pyridazin-6-yl]phenyl]pyrrole-1-carboxylate (40 mg, 78%) as orange solid matter. MS m/z 562.3 [M+H] ⁺ .

Step 6. To a solution of tert-butyl 3-[3-(methoxymethoxy)-4-[3-(2,2,6,6-tetramethyl-4piperidyl)triazolo[4,5-c]pyridazin-6-yl]- phenyl]pyrrole-1-carboxylate (40 mg, 0.071 mmol) in CH ₂ Cl ₂ (2 ml) with 2 drops of MeOH was added 4N HCl in 1,4-dioxane (36 µl). The reaction mixture was stirred for 5 hours until UPLC analysis indicated complete consumption of the starting material. Solvents were removed under reduced pressure and the product was purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (with 2.5% NH4OH) (5-30% MeOH/NH ₄ OH) to give 5-(1Hpyrrol-3- yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenol (22 mg, 74%) as an orange solid.

MS m/z 418.5 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 9.00 (s, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H ), 7.22-7.24 (m, 1H), 7.18 (d, J=1.6 Hz, 1H), 6.83 (dd, J=2.8, 1.9 Hz, 1H) , 6.52 (dd, J=2.8, 1.6 Hz, 1H), 5.89 (tt, J=10.4, 5.5 Hz, 1H), 2.47-2.68 (m , 4H), 1.72 (s, 6H), 1.57 (s, 6H); 3 H were not detected (2 NH and OH).

Using the procedure described for Example 13 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

- 89 045009

Compound Data 37 MS m/z 460.6 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.15 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.82 (d, J=6.9 Hz, 1H) , 7.41 (dd, J=8.2, 1.9 Hz, 1H), 7.39 (d, J=l.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.84 (dd, J=6.9, 2.2 Hz, 1H), 5.99 (tg, J=10.4, 4.7 Hz, 1H), 3.67 (s, ZN ), 2.64-2.74 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH). 38 MS m/z 445.5 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 9.17 (s, 1H), 8.97-9.06 (m, 1H), 8.15 (br.s, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.49-7.61 (m, 2H), 7.29 (d, J=l.6 Hz, 1H), 7.27 (s, 1H), 6, 80-6.96 (m, 2H), 5.93 (tg, J=12.0, 4.4 Hz, 1H), 2.53-2.67 (m, 4H), 1.66 (s, 6H), 1.53 (s, 6H); 1H was not detected (NH). 39 MS m/z 433.5 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.11 (s, 1H), 8.14 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.00 (s, 1H), 7.31 (dd, J=8.8, 1.9 Hz, 1H), 7.28 (d, J=l,9 Hz, 1H), 5.97 (tg, J=12.3 , 4.0 Hz, 1H), 4.01 (s, ZN), 2.56-2.76 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H), 2 H was not detected (NH and OH). 46 MS m/z 447.6 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.11 (s, 1H), 8.21 (d, J=0.9 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H ), 8.02 (s, 1H), 7.32 (dd, J=8.2, 1.9 Hz, 1H), 7.29 (d, J=l.9 Hz, 1H), 5.97 (tg, J=10.l, 6.3 Hz, 1H), 4.30 (kv, J=7.3 Hz, 2H), 2.55-2.76 (m, 4H), 1.79 ( s, 6H), 1.64 (s, 6H), 1.55 (t, J=7.3 Hz, ZH), 2H were not detected (NH and OH). 47 MS m/z 461.6 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.03 (s, 1H), 8.11 (d, J=0.9 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H ), 7.92 (d, J=0.9 Hz, 1H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 7.26 (d, J=l.9 Hz , 1H), 5.82 (t, J=12.3, 4.6 Hz, 1H), 4.19 (t, J=7.3 Hz, 2H), 2.23-2.45 (m, 4H), 1.95 (sext, J=7.3 Hz, 2H), 1.54 (s, 6H), 1.38 (s, 6H), 0.97 (t, J=7.3 Hz, ZH), 2H were not detected (NH and OH). 48 MS m/z 419.5 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.15 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.04 (s, 1H), 7.45-7, 57 (m, 2H), 7.00 (s, 1H), 5.97 (tg, J=12,l, 4.7 Hz, 1H), 2.59-2.76 (m, 4H), 1 .79 (s, 6H), 1.65 (s, 6H), 3 H was not detected (2 NH and OH). 50 MS m/z 433.5 [M+H] ⁺ ; 'H NMR (methanol-0 ₄ ) δ: 9.19 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.95-8.06 (m, 1H), 7 ,21-7.37 (m, 2H), 6.72-6.81 (m, 1H), 5.99 (tg, J=11.3, 5.5 Hz, 1H), 4.11 (s , ZN), 2.59-2.76 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 51 MS m/z 433.5 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.20 (s, 1H), 8.14 (dd,

- 90 045009

J=7.6, 0.9 Hz, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.54 (d, J=l.9 Hz, 1H), 7.52 ( s, 1H), 6.90 (d, J=2.5 Hz, 1H), 5.98 (tg, J=10.7, 5.7 Hz, 1H), 4.09 (s, ZN), 2.59-2.78 (m, 4H), 1.79 (s, 6H), 1.66 (s, 6H), 2H not detected (NH and OH). 65 MS m/z 430.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.29 (s, 1H), 9.18 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 8.30 ( s, 1H), 8.23 (s, 1H), 7.54 (s, 2H), 5.96 (s, 1H), 2.52-2.68 (m, 4H), 1.78 (s , 6H), 1.64 (s, 6H); 2 H were not detected (ΝΗ and OH). 66 MS m/z 430.4 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.11 (s, 1H), 8.82 (d, J= 6.9 Hz, 2H), 8.38 (d, J= 6.9 Hz, 2H), 8.24 (d, J= 7.9 Hz, 1H), 7.56-7.65 (m, 2H), 5.88-6.02 (m, 1H), 2.53-2.63 ( m, 4H), 1.68 (s, 6H), 1.54 (s, 6H); 2 H were not detected (NH and OH). 69 MS m/z 436.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.11 (s, 1H), 8.17 (d, J=0.6 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 8.03 (d, J=0.6 Hz, 1H), 7.31 (dd, J=8.2, 1.9 Hz, 1H), 7.28 (d, J=l.9 Hz, 1H ), 5.97 (tg, J=11.0, 5.7 Hz, 1H), 2.61-2.74 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H), 2H were not detected (NH and OH). 71 MS m/z 469.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.11 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=8.2 Hz, 1H ), 7.55 (t, J=59.9 Hz, 1H), 7.37 (dd, J=8.2, 1.6 Hz, 1H), 7.34 (d, J=l.6 Hz , 1H), 5.97 (tg, J=10,l, 6.3 Hz, 1H), 2.56-2.73 (m, 4H), 1.78 (s, 6H), 1.64 ( s, 6H), 2H were not detected (NH and OH). 77 MS m/z 460.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.22 (s, 1H), 8.40 (d, J= 6.3 Hz, 1H), 8.32 (d, J= 7.9 Hz, 1H), 7.79 (dd, J= 6.3, 1.6 Hz, 1H), 7.75 (d, J= 0.9 Hz, 1H), 7.60-7.65 (m, 2H), 5 .97-6.02 (m, 1H), 4.31 (s, ZN), 2.62-2.78 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H ); 2 H were not detected (NH and OH). 93 MS m/z 446.4 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.17 (s, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.40-7.50 (m, 2H), 7.14 (d, J=8.8 Hz, 1H), 7.08 (br.s, 1H), 5.89-6.05 (m, 1H), 2.58-2.76 (m, 4H), 1.79 (s, 6H), 1.65 (s, 6H); 3 H were not detected (NH and 2 OH).

Example 14.

Getting connection 67.

Step 1. The oven-dried flask was equipped with a magnetic stirrer and [3-(methoxymethoxy)-4-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c] was loaded into it. pyridazin-6-yl]-phenyl] trifluoromethanesulfonate (obtained in example 13, step 4, 60 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (35 mg, 0.14 mmol), complex of 1,1'bis(diphenylphosphino)ferrocene palladium(I) dichloride with dichloromethane (5 mg , 0.006 mmol) and potassium acetate (33 mg, 0.33 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (1 ml) was added and the reaction mixture was heated at 90°C for 90 min, after which UPLC analysis showed complete

- 91 045009 transformation into a borylated product. The crude product was cooled to room temperature and used directly in the next step.

Step 2. To crude 6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-3-(2,2,6,6 -tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (~0.11 mmol) was added 6-bromopyridin-3-ol (25 mg, 0.14 mmol) , complex of 1,1'bis(diphenylphosphino)ferrocene palladium(H) dichloride with dichloromethane (9 mg, 0.011 mmol) and an aqueous solution of 2 M K2CO3 (141 μl, 0.282 mmol). The mixture was purged with argon for 5 minutes, then heated to 85°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by chromatography on silica gel, eluting with a MeOH/CH ₂ Cl ₂ (0-30% MeOH) gradient to give 6-[3-(methoxymethoxy)-4- [3-(2,2,6,6-tetramethyl-4piperidyl)triazolo[4,5-c]pyridazin-6-yl]phenyl]pyridin-3-ol (37.5 mg, 68%) as a light brown solid substances. MS m/z 490.3 [M+H]+.

Step 3. 6-[3-(methoxymethoxy)-4-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazin-6yl]phenyl]pyridine-3- ol (37.5 mg, 0.077 mmol) was dissolved in 1 ml methanol, then 4N HCl in 1,4-dioxane (0.5 ml, 2 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Reaction mixture concentrated, triturated with 20% MeOH/ether, and the resulting precipitate was filtered to give 6-[3-hydroxy-4-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5c] pyridazin-6-yl]phenyl]pyridin-3-ol dihydrochloride (31 mg, 78%) as a light brown solid.

MS m/z 446.4 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 9.23 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H ), 8.30 (d, J=8.8 Hz, 1H), 8.12 (dd, J=9.1, 2.8 Hz, 1H), 7.54-7.59 (m, 2H) , 5.95-6.04 (m, 1H), 2.62-2.77 (m, 4H), 1.75 (s, 6H), 1.65 (s, 6H); 3 H were not detected (NH and 2 OH).

Using the procedure described for Example 14 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:________________

Compound Data 60 MS m/z 431.3 [M+H] ⁺ ; ^X H NMR (methanol- _c14 ) δ: 9.23 (s, 1H), 9.17 (s, 1H), 8.79 (s, 1H), 8.64 (s, 1H), 8.24 (d, J= 8.2 Hz, 1H), 7.79-8.00 (m, 2H), 5.956.02 (m, 1H), 2.55-2.75 (m, 4H), 1, 79 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 61 MS m/z 430.5 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.25 (s, 1H), 8.91 (d, J= 5.4 Hz, 1H), 8.76 (t, J= 7.6 Hz, 1H ), 8.51 (d, J= 7.9 Hz, 1H), 8.42 (d, J= 7.9 Hz, 1H), 8.13 (t, J= 6.5 Hz, 1H), 7.63-7.71 (m, 2H), 6.00 (m, 1H), 2.59-2.79 (m, 4H), 1.80 (s, 6H), 1.66 (s, 6H); 2 H were not detected (NH and OH). 68 MS m/z 447.4 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.15 (s, 1H), 8.47 (s, 2H), 8.13-8.19 (m, 1H), 7.98-8.02 ( m, 2H), 5.92-6.04 (m, 1H), 2.65-2.74 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 3 H were not detected (ΝΗ and 2 OH). 73 MS m/z 444.6 [M+H] ⁺ ; Ή NMR (methanol- _c14 ) δ: 9.23 (s, 1H), 8.75 (d, J= 6.3 Hz, 1H), 8.32-8.37 (m, 2H), 8. 26 (dd, J= 6.1, 1.7 Hz, 1H), 7.63-7.71 (m, 2H), 5.98-6.02 (m, 1H), 2.90 (s, ZN), 2.64-2.75 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 74 MS m/z 498.3 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.18 (s, 1H), 8.82 (d, J=5.4 Hz, 1H), 8.27 (d, J=8.2 Hz, 1H ), 8.15 (d, J=l.9 Hz, 1H), 8.03 (dd, J=5.0, 1.9 Hz, 1H), 7.55 (dd, J=8.2, 1.9 Hz, 1H), 7.52 (d, J=l.9 Hz, 1H), 5.89-6.05 (m, 1H), 2.57-2.79 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH). 75 MS m/z 431.5 [Μ+Η] ⁺ ;Ή NMR (methanol-c1 ₄ ) δ: 9.42 (d, J= 1.3 Hz, 1H),

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9.21 (s, 1H), 8.97-9.03 (m, 1H), 8.35 (dd, J= 6.0, 1.3 Hz, 1H), 8.31 (d, J= 8.5 Hz, 1H), 8.04 (s, 1H), 7.99 (dd, J= 8.2, 1.9 Hz, 1H), 5.98-6.02 (m, 1H), 2.632.76 (m, 4H), 1.79 (s, 6H), 1.65 (s, 6H); 2 H were not detected (ΝΗ and OH). 76 MS m/z 431.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.96 (dd, J= 2.4, 1.1 Hz, 1H), 9.57 (dd, J= 6.0, 0.9 Hz, 1H), 9 .24 (s, 1H), 8.71 (dd, J= 5.8, 2.4 Hz, 1H), 8.38 (d, J= 7.9 Hz, 1H), 7.71-7, 78 (m, 2H), 5.98-6.02 (m, 1H), 2.57-2.78 (m, 4H), 1.79 (s, 6H), 1.65 (s, 6H) ; 2 H were not detected (NH and OH). 78 MS m/z 431.4 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 9.24 (s, 1H), 9.20 (s, ZH), 8.23 (d, J=8.2 Hz, 1H), 7.48 (d , J=8.2 Hz, 1H), 7.46 (s, 1H), 5.68 (tg, J=12.5, 3.4 Hz, 1H), 2.21 (dd, J=12, 5, 3.4 Hz, 2H), 2.11 (t, J=12.5 Hz, 2H), 1.36 (s, 6H), 1.19 (s, 6H); 2 H were not detected (NH and OH). 79 MS m/z 447.5 [M+H] ⁺ , Ή NMR (methanol-b ₄ ) δ: 9.12 (s, 1H), 8.64 (d, J=l.3 Hz, 1H), 8 .28 (d, J=8.8 Hz, 1H), 7.94 (d, J=l.3 Hz, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.57 (dd, J=8.5, 2.2 Hz, 1H), 5.74-5.90 (m, 1H), 2.27-2.44 (m, 4H), 1.52 (s, 6H ), 1.36 (s, 6H); 3 H were not detected (2 OH and NH). 84 MS m/z 473.3 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.19 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H) , 7.88 (dd, J=8.9, 2.6 Hz, 1H), 7.18-7.36 (m, 2H), 6.75 (d, J=8.9 Hz, 1H), 5.67 (tg, J=12.5, 3.9 Hz, 1H), 3.09 (s, 6H), 2.20 (dd, J=12.5, 3.9 Hz, 2H), 2 .11 (t, J=12.5 Hz, 2H), 1.28-1.42 (m, 6H), 1.18 (s, 6H); 2 H were not detected (NH and OH). 85 MS m/z 470.3 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.19 (d, J=l.6 Hz, 1H), 9.17 (s, 1H), 8.72 (dd, J=4.9, 1.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 8.01 (d, J=4.9 Hz, 1H), 7.41- 7.45 (m, 2H), 5.69 (tg, J=12.2, 3.7 Hz, 1H), 2.22 (dd, J=12.2, 3.7 Hz, 2H), 2 .13 (t, J=12.2 Hz, 2H), 1.37 (s, 6H), 1.20 (s, 6H); 2 H were not detected (NH and OH). 86 MS m/z 486.4 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H) , 7.24-7.42 (m, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.54 (dd, J=7.3, 2.0 Hz, 1H), 5.64-5.82 (m, 1H), 3.10-3.21 (m, 1H), 2.08-2.33 (m, 4H), 1.42 (s, 6H), 1. 26 (s, 6H), 0.98-1.07 (m, 2H), 0.83-0.95 (m, 2H); 2 H were not detected (NH and OH). 88 MS m/z 469.4 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 11.69 (br.s, 2H), 9.18 (s, 1H), 8.45 (d, J=7.3 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.48 (s, 1H), 7.44 (dd, J=8, 2, 1.8 Hz, 1H), 7.41 (d, J=l.7 Hz, 1H), 7.09

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(dd, J=7.5, 1.8 Hz, 1H), 5.68 (tg, J=13.0, 3.9 Hz, 1H), 2.21 (dd, J=12.5, 3 .7 Hz, 2H), 2.11 (t, 1=12.5 Hz, 2H), 1.36 (s, 6H), 1.19 (s, 6H). 89 MS m/z 435.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 8.94-9.13 (m, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.75 (t, J=2.2 Hz , 1H), 7.51 (d, J=l,9 Hz, 2H), 7.38 (dd, J=8.2, 1.6 Hz, 1H), 7.34 (d, J=l, 9 Hz, 1H), 5.76-5.96 (m, 1H), 2.42-2.58 (m, 4H), 1.63 (s, 6H), 1.48 (s, 6H); 2H were not detected (OH and NH). 90 MS m/z 469.4 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) d: 11.64 (br.s, 1H), 9.18 (s, 1H), 8.67 (d, J=7.5 Hz, 1H), 8.12- 8.24 (m, 2H), 8.01 (s, 1H), 7.93 (s, 1H), 7.66 (s, 1H), 7.51 (dd, J=8.3, 1, 9 Hz, 1H), 7.47 (d, J=l.9 Hz, 1H), 7.33 (dd, J=7.l, 1.9 Hz, 1H), 5.75 (tg, J= 12.5, 4.0 Hz, 1H), 2.17-2.36 (m, 4H), 1.44 (s, 6H), 1.28 (s, 6H). 91 MS m/z 419.3 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 12.64 (br.s, 1H), 9.16 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.67 (d, J=l.9 Hz, 1H), 7.59 (dd, J=8.3, 1.9 Hz, 1H), 7.30 (br.s, 1H), 7.08 (br.s. s, 1H), 5.67 (tg, J=12.2, 3.7 Hz, 1H), 2.20 (dd, J=12.2, 3.7 Hz, 2H), 2.10 (t , 1=12.2 Hz, 2H), 1.35 (s, 6H), 1.18 (s, 6H); 2 H were not detected (NH and OH). 95 MS m/z 419.5 [M+H] ⁺ , 'H NMR (methanol-b ₄ ) δ: 9.10 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.01-8.03 (m, 1H), 7.61-7.63 (m, 1H), 7.30 (dd, J=7.9, 1.9 Hz, 1H), 7.26 ( d, J=l.9 Hz, 1H), 6.86-6.89 (m, 1H), 5.92-6.03 (m, 1H), 2.65-2.70 (m, 4H) , 1.78 (s, 6H), 1.63 (s, 6H); 2H were not detected (OH and NH). 96 MS m/z 436.4 [M+H] ⁺ ; 'H NMR (methanol- _b4 ) δ: 9.16 (s, 1H), 8.16-8.29 (m, 1H), 7.96-8.07, (m, 1H), 7.80 (s, 1H), 7.68 (s, 2H), 5.84-6.06 (m, 1H), 2.67 (d, J=4.4 Hz, 4H), 1.77 (s, 6H), 1.62 (s, 6H); 2 H were not detected (OH hNH). 99 MS m/z 445.1 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 11.50 (br.s, 2H), 9.12 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.00 (d, J=4.6 Hz, 1H), 7.19-7.40 (m, 2H), 6.81 (d, J=4.6 Hz, 1H), 6.75 (s, 1H) , 6.05 (s, 2H), 5.60-5.77 (m, 1H), 2.20 (d, J=12.2 Hz, 2H), 2.11 (t, J=12.5 Hz, 2H), 1.36 (s, 6H), 1.19 (s, 6H). 100 MS m/z 473.1 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 9.17 (s, 1H), 8.08-8.22 (m, 2H), 7.39 (s, 1H), 7.37 (d, J= l.6 Hz, 1H), 6.87 (dd, J=5.l, 1.6 Hz, 1H), 6.85 (s, 1H), 5.67 (tg, J=12.2, 3 .7 Hz, 1H), 3.10 (s, 6H), 2.20 (dd, J=12.2, 3.7 Hz, 2H), 2.11 (t, J=12.2 Hz, 2H ), 1.35 (s, 6H), 1.18 (s, 6H); 2 H were not detected (NH and OH). 101 MS m/z 448.1 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.71 (d, J=2.4

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Hz, 1H), 8.55 (d, J=5.l Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.71 (dd, J=7.l, 5 ,1 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 5.69 (tg, J=12.2, 4.2 Hz, 1H ), 2.21 (dd, J=12.2, 4.2 Hz, 2H), 2.12 (t, J=12.2 Hz, 2H), 1.36 (s, 6H), 1.19 (s, 6H); 2 H were not detected (NH and OH). 103 MS m/z 496.7[M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 9.14 (s, 1H), 8.62 (d, J= 2.4 Hz, 1H), 8.35 (s, 1H), 8.17 (d , J= 8.0 Hz, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.797.84 (m, 2H), 7.71 (d, J= 6.4 Hz, 1H ), 7.21-7.58 (m, 1H), 5.69-5.72 (m, 1H), 2.13-2.27 (m, 4H), 1.40 (s, 6H), 1.23 (s, 6H); 1 H was not detected (NH or OH)). 104 MS m/z 459.8[M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 8.08 (d, J= 5.2 Hz, 1H) , 7.30-7.34 (m, 2H), 6.81 (dd, J= 5.2, 1.2 Hz, 1H), 6.72 (s, 1H), 6.58-6.62 (m, 1H), 5.63-5.72 (m, 1H), 2.83 (d, J= 4.8 Hz, ZN), 2.17-2.22 (m, 2H), 2, 06-2.14 (m, 2H), 1.35 (s, 6H), 1.18 (s, 6H). 106 MS m/z 437.5 [M+H] ⁺ ; Ή NMR (methanol-d4) δ: 9.10 (s, 1H), 8.09 (d, J=9.2 Hz, 1H), 8.03 (d, J=l.7 Hz, 1H), 7.32 (d, J=7.2 Hz, 2H), 5.93-6.01 (m, 1H), 2.65-2.70 (m, 4H), 1.78 (s, 6H) , 1.64 (s, 6H); 3 H was not detected (1 OH or 2 NH). 107 MS m/z 436.5 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.58 (s, 1H), 9.17 (s, 1H), 8.57 (s, 1H), 8.21 (d, J=9.9 Hz , 1H), 7.44 (dd, J=10.2, 3.2 Hz, 2H), 5.90-6.04 (m, 1H), 2.61-2.75 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 2 H were not detected (1 OH or 1 NH). 108 MS m/z 433.6 [M+H] ⁺ ; 'H NMR (DMSO- _d6 ) δ: 9.41-9.58 (m, 1H), 9.14 (s, 1H), 8.23-8.37 (m, 1H), 8.8 ( d, J=6.6 Hz, 1H), 7.86-7.91 (m, 1H), 7.14-7.19 (m, 2H), 5.83-5.95 (m, 1H) , 2.56-2.65 (m, 2H), 2.46-2.56 (m, 2H), 2.44 (s, ZN), 1.66 (s, 6H), 1.54 (s , 6H); 1H was not detected (NH or OH). 109 MS m/z 444.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.17 (s, 1H), 8.55 (s, 1H), 8.18 (d, J=10.5 Hz, 1H), 7.42 (d, J=l.8 Hz, 1H), 7.34-7.38 (m, 1H), 5.65-5.83 (m, IH), 2.11-2.34 (m, 4H), 1 .41 (s, 6H), 1.24 (s, 6H); 3 Η were not detected (2 NH and OH). BY MS m/z 461.5 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.16 (s, 1H), 8.57 (s, 1H), 8.23 (d, J=9.2 Hz, 1H), 7.68-7 .74 (m, 2H), 5.95-6.02 (m, 1H), 2.65-2.71 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H ); 2H were not detected (OH and NH). 111 MS m/z 420.2 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 9.10 (s, 1H), 8.30-8.39 (m, 2H), 8.28 (s, 1H), 8.17 (d, J= 8.0 Hz, 1H), 7.71(d, J= 1.2 Hz, 1H), 7.63 (dd,

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J= 8.4, 1.6 Hz, 1H), 7.44 (d, J= 0.8 Hz, 1H), 5.68-5.71 (m, 1H), 2.11-2.25 (m, 4H), 1.38 (s, 6H), 1.21 (s, 6H). 112 MS m/z 420.1 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.42 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 1.6 Hz, 1H), 7.53 (dd, J= 8.4, 1.6 Hz, 1H), 5.66-5.69 (m, IH), 2.06-2.23 (m, 4H), 1.36 (s, 6H), 1.19 (s, 6H); 3 H were not detected (2 ΝΗ and OH). 113 MS m/z 461.2 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.14 (s, IH), 8.89 (d, J= 1.2 Hz, IH), 8.17 (d, J= 8.4 Hz, IH) , 7.91 (d, J= 1.6 Hz, IH), 7.80 (dd, J= 8.0, 1.6 Hz, IH), 7.51 (d, J= 0.8 Hz, IH), 5.64-5.71 (m, IH), 3.99 (s, ZH), 2.072.22 (m, 4H), 1.35 (s, 6H), 1.18 (s, 6H ); 2 H were not detected (NH and OH). 114 MS m/z 496.4 [M+H] ⁺ ; 'H NMR (methanol-0 ₄ ) δ: 9.15 (s, 1H), 8.32 (d, J= 5.5 Hz, 1H), 8.22 (d, J= 8.2 Hz, 1H ), 7.63-7.78 (m, 1H), 7.57 (dd, J= 5.5, 1.5 Hz, 1H), 7.43-7.50 (m, 2H), 7, 32 (d, J= 0.9 Hz, 1H), 5.99 (tg, J= 10.9, 5.4 Hz, 1H), 2.63-2.75 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH). 115 MS m/z 419.1 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 12.27 (s, IH), 11.59 (m, IH), 9.13 (d, J= 8.0 Hz, IH), 8.07 (d, J= 8.0 Hz, IH), 7.10-7.76 (m, 2H), 7.40-7.53 (m, 2H), 5.61-5.70 (m, 1H), 2 .06-2.22 (m, 4H), 1.35 (s, 6H), 1.18 (s, 6H); 1 H was not detected (NH or OH). 116 MS m/z 437.4 [M+H] ⁺ ; Ή NMR (methanol-0 ₄ ) δ: 9.53 (s, 1H), 9.15 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.74 (d, J=l.8 Hz, 1H), 7.70 (dd, J=7.9, 1.8 Hz, 1H), 5.87-6.00 (m, 1H), 2.57 (d, J =7.6 Hz, 4H), 1.70 (s, 6H), 1.55 (s, 6H); 2H were not detected (OH and NH). 118 MS m/z 469.5 [M+H] ⁺ ; Ή NMR (methanol-0 ₄ ) δ: 9.22 (s, 1H), 8.52 (d, J= 6.1 Hz, 1H), 8.33-8.38 (m, 1H), 7, 83 (d, J= 3.4 Hz, 1H), 7.79 (d, J= 6.1 Hz, 1H), 7.58-7.64 (m, 2H), 7.13 (d, J = 3.4 Hz, 1H), 5.96 -6.05 (m, 1H), 2.642.76 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 3 H were not detected (2 NH and OH). 119 MS m/z 461.5 [M+H] ⁺ ; Ή NMR (methanol-0 ₄ ) δ: 9.24 (s, 1H), 8.70 (d, J= 6.4 Hz, 1H), 8.34 (d, J= 8.2 Hz, 1H) , 8.10 (d, J= 1.5 Hz, 1H), 8.04 (dd, J= 8.2, 1.5 Hz, 1H), 7.20 (d, J= 6.7 Hz, 1H), 6.00 (tg, J= 11.0, 5.5 Hz, 1H), 4.33 (s, ZN), 2.61-2.77 (m, 4H), 1.79 (s , 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH).

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120 MS m/z 420.5 [M+H] ⁺ ; 'Η NMR (methanol-SH) δ: 9.19-9.22 (m, 1H), 9.129.15 (m, IH), 8.91-8.95 (m, 1H), 8.14 (d , J=9.2 Hz, 1H), 7.35 (dd, J=14.2, 8.4 Hz, 2H), 5.94-6.02 (m, 1H), 2.64-2, 71 (m, 4H), 1.78 (s, 6H), 1.63 (s, 6H); 2 H were not detected (NH and OH). 121 MS m/z 451.5 [M+H] ⁺ ; 'H NMR (methanol-SH) δ: 9.09 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.77-7.89 (m, 1H), 7, 27 (s, 2H), 5.91-6.02 (m, 1H), 3.84 (s, ZN), 2.59-2.70 (m, 4H), 1.78 (s, 6H) , 1.63 (s, 6H); 2 H were not detected (NH and OH). 122 MS m/z 465.6 [M+H] ⁺ ; 'H NMR (methanol-SH) δ: 9.04 (s, 1H), 8.10-8.08 (d, J=9.6 Hz, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.24-7.31 (m, 2H), 5.74-5.88 (m, 1H), 4.20 (kv, J=7.2 Hz, 2H), 2.24 -2.41 (m, 4H), 1.51 (s, 6H), 1.50 (t, J=7.5 Hz, ZN), 1.40 (s, 6H); 2 H were not detected (NH and OH). 123 MS m/z 474.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.21 (s, 1H), 8.38 (d, J= 6.1 Hz, 1H), 8.31 (d, J= 8.2 Hz, 1H), 7.77 (d, J= 6.4 Hz, 1H), 7.72 (s, 1H), 7.58-7.64 (m, 2H), 5.99 (tg, J= 10.7, 5.6 Hz, 1H), 4.65 (kv, J= 6.9 Hz, 2H), 2.63-2.75 (m, 4H), 1.79 (s, 6H), 1.64 ( s, 6H), 1.59 (t, J= 7.0 Hz, ZN); 2 H were not detected (NH and OH). 124 MS m/z 475.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.23 (s, 1H), 9.16 (s, 1H), 8.36 (d, J= 8.2 Hz, 1H), 7.63-7.74 (m, ZN), 5.98-6.02 (m, 1H), 4.71-4.79 (kV, J= 7.2 Hz, 2H), 2.59-2.79 (m, 4H ), 1.79 (s, 6H), 1.65 (s, 6H), 1.54 (t, J= 7.2 Hz, ZH); 2 H were not detected (NH and OH). 125 MS m/z 470.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.17 (s, 1H), 9.01 (d, J= 7.3 Hz, 1H), 8.27 (d, J= 4.9 Hz, 2H), 8.23 (d, J= 8.2 Hz, 1H), 7.61 (dd, J= 7.3, 1.8 Hz, 1H), 7.52 (dd, J= 8.2, 1, 8 Hz, 1H), 7.50 (d, J= 1.8 Hz, 1H), 5.98 (ddd, J= 16.3, 10.2, 6.4 Hz, 1H), 2.60- 2.76 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 126 MS m/z 470.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.21 (s, 1H), 9.14 (d, J= 7.0 Hz, 1H), 9.04 (s, 1H), 8.27-8.35 (m, 2H), 7.97 (dd, J= 7.0, 1.5 Hz, 1H), 7.59-7.64 (m, 2H), 6.00 (tg, J= 10.9 , 5.5 Hz, 1H), 2.64 -2.75 (m, 4H), 1.79 (s, 6H), 1.65 (s, 6H), 2H not detected (NH and OH). 127 MS m/z 467.5 [M+H] ⁺ ; Ή NMR (methanol-SH) δ: 9.12 (s, 1H), 8.08-8.10 (m, 1H), 8.07-8.11 (m, 1H), 8.01 (s, 1H), 7.28-7.44 (m, 2H), 5.89-6.05 (m, 1H), 3.90-3.96 (m, ZN), 2.63-2.71 ( m, 4H), 1.76-1.80 (s, 6H), 1.59-1.66 (s, 6H); 1H was not detected (ΝΗ or OH).

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128 MS m/z 447.5 [M+H] ⁺ ; 'H NMR (methanol-0 ₄ ) δ: 9.17 (s, 1H), 8.54 (s, 1H), 8.22 (d, J= 8.2 Hz, 1H), 7.71 (d , J= 1.8 Hz, 1H), 7.67 (dd, J= 8.2, 1.8 Hz, 1H), 7.01 (s, 1H), 5.99 (tt, J= 10, 9, 5.5 Hz, 1H), 2.61-2.77 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H), 3 H not detected (2 NH and OH ). 129 MS m/z 453.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.08 (s, 1H), 8.01-8.11 (m, 2H), 7.30-7.41 (m, 2H), 5.86-5 .99 (m, 1H), 2.56-2.63 (m, 4H), 1.71 (s, 6H), 1.56 (s, 6H); 3 H were not detected (2 ΝΗ and OH). 130 MS m/z 451.5 [M+H] ⁺ ; 'H NMR (methanol- ₀₄ ) δ: 9.00-9.11 (m, 1H), 8.078.07 (m, 1H), 8.07-8.08 (m, 1H), 8.04- 8.10 s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.93-7.99 (s, 1H), 7.22-7.29 (m, 2H), 5.67-5.94 (m, 1H), 3.85 (s, ZN), 2.282.42 (m, 4H), 1.53 (s, 6H), 1.37 (s, 6H); 1 H was not detected (NH or OH). 131 MS m/z 449.5 [M+H] ⁺ ; Ή NMR (methanol-c1 ₄ ) δ: 9.06 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.44-7, 46 (m, 1H), 7.39 (d, J=9.8 Hz, 1H), 5.90-6.01 (m, 1H), 4.05 (s, ZN), 2.62-2 .74 (m, 4H), 1.78 (s, 6H), 1.63 (s, 6H); 3 H were not detected (2 NH and OH). 132 MS m/z 458.5 [M+H] ⁺ ; Ή NMR (methanol- _c14 ) δ: 9.06-9.15 (m, 1H), 8.118.23 (m, 1H), 7.98-8.07 (m, 1H), 7.41-7 .49 (m, 2H), 5.78-5.93 (m, 1H), 4.094.18 (m, ZN), 2.39-2.53 (m, 4H), 1.56 (s, 6H ), 1.44 (s, 6H); 2 H were not detected (ΝΗ and OH). 133 MS m/z 450.5 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.20 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.68 (m, 2H), 7.55 (s , 1H), 5.94-6.05 (m, 1H), 2.61-2.73 (m, 4H), 2.61 (s, ZN), 1.79 (s, 6H), 1, 63 (s, 6H); 2 H were not detected (NH and OH). 134 MS m/z 437.5 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.16 (s, 1H), 8.83 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.77 (s , 2H), 5.87-5.97 (m, 1H), 2.49-2.58 (m, 4H), 1.66 (s, 6H), 1.51 (s, 6H); 2 H were not detected (NH and OH). 135 MS m/z 488.5 [M+H] ⁺ ; Ή NMR (methanol- _c14 ) δ: 9.15 (s, 1H), 8.21 (d, J= 8.2 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J= 12.2 Hz, 1H), 7.46 (d, J= 8.2 Hz, 1H), 7.43 (s, 1H), 5.95-6.02 (m, 1H), 2, 63-2.76 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H), 3 H was not detected (2 NH and OH). 137 MS m/z 497.4, 499.4 [M+H] ⁺ ; Ή NMR (methanol-с1 ₄ ) δ: 9.11 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J=l,4 Hz, 1H), 7.35 (dd, J=8.3, 1.6 Hz, 1H), 5.92-6.01 (m, 1H), 2.64-2.70 (m, 4H), 1.78 (s, 6H), 1.63 (s, 6H); 3

- 98 045009

H was not detected (2 NH and OH). 138 MS m/z 434.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.17 (s, 1H), 8.48 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.52-7, 57 (m, 2H), 5.92-6.03 (m, 1H), 4.22-4.26 (m, ZN), 2.66-2.71 (m, 4H), 1.79 ( s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH). 139 MS m/z 487.4 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.09 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.05 (s, 1H), 7.19 (s, 2H), 5.93 (s, 1H), 2.40-2.53 (m, 4H), 1.571.66 (m, 6H), 1.42-1.50 (m, 6H); 3 H were not detected (2 NH and OH). 142 MS m/z 470.3 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.12-9.15 (m, 3H), 8.21 (d, J=8.l Hz, 1H), 8.14 (s, 1H), 7, 87 (d, J=0.9 Hz, 1H), 7.79 (d, J=l.7 Hz, 1H), 7.74 (dd, J=8.2, 1.8 Hz, 1H), 5.83-5.95 (m, 1H), 2.23-2.69 (m, 4H), 1.63 (s, 6H), 1.49 (s, 6H); 2 H were not detected (NH and OH). 145 MS m/z 471.3 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 11.65 (br.s, 1H), 9.23 (br.s, 1H), 9.09 (br.s, 1H), 8.71 (br.s , 1H), 8.23 (d, J= 7.9 Hz, 1H), 7.457.64 (m, 2H), 7.37 (br.s, 1H), 5.92 (br.s, 1H) , 2.56-2.72 (m, 4H), 1.67 (s, 6H), 1.55 (s, 6H); 1H was not detected (NH or OH). 146 MS m/z 471.3 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.89 (s, 1H), 9.23 (s, 1H), 8.59 (d, J= 0.9 Hz, 1H), 8.36 (d, J = 7.9 Hz, 1H), 7.72 (d, J= 1.8 Hz, 1H), 7.69 (dd, J= 8.2, 2.1 Hz, 1H), 6.00 (tg , J= 10.8, 5.6 Hz, 1H), 2.62-2.76 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 3 H were not detected (2 NH and OH). 147 MS m/z 471.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.18 (s, 1H), 8.48 (d, J= 8.9 Hz, 1H), 8.23 (d, J= 8.2 Hz, 1H), 8.14 (d, J= 8.5 Hz, 1H), 7.92 (d, J= 1.8 Hz, 1H), 7.88 (dd, J= 8.2, 1.8 Hz, 1H ), 5.99 (tg, J= 10.8, 5.5 Hz, 1H), 2.612.76 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 3 H were not detected (2 NH and OH). 150 MS m/z 450.4 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 11.51 (br.s, 2H), 9.27 (d, J= 12.8 Hz, 1H), 9.15 (s, 1H), 8.23 ( d, J= 13.4 Hz, 1H), 8.12 (s, 1H), 8.12 (d, J= 8.2 Hz, 1H), 7.35 (dd, J= 7.9, 1 ,8 Hz, 1H), 7.28 (d, J= 1.5 Hz, 1H), 5.92 (tg, J= 12.3, 3.9 Hz, 1H), 2.72 (s, ZN ), 2.52-2.66 (m, 4H), 1.66 (s, 6H), 1.54 (s, 6H). 151 MS m/z 434.3 [M+H] ⁺ ; 'H NMR (methanol-d4) δ: 9.09-9.13 (m, 1H), 8.14 (d, J=8.7 Hz, 1H), 8.08 (s, 1H), 7, 49-7.60 (m, 2H), 5.91-6.05 (m, 1H), 4.26 (s, ZN), 2.65-2.70 (m, 4H), 1.78 ( s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH).

- 99 045009

152 MS m/z 471.3 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.56 (s, 1H), 9.17 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 8.29 (d, J =8.5 Hz, 1H), 8.03 (d, J=9.7 Hz, 1H), 7.777.86 (m, 2H), 5.83-5.91 (m, 1H), 2.42 (d, J=2.9 Hz, 4H), 1.57 (s, 6H), 1.42 (s, 6H); 2 H were not detected (NH and OH). 153 MS m/z 451.3 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.14 (s, 1H), 8.24 (d, J=7.3 Hz, 1H), 7.71 (d, J=l.5 Hz, 2H), 5.82-5.90 (m, 1H), 2.73 (s, ZN), 2.35-2.44 (m, 4H), 1.55 (s, 6H), 1.39 (s, 6H); 2 H were not detected (NH and OH). 154 MS m/z 468.4 [M+H] ⁺ ; 'H NMR (1:1 CDC1 ₃ : methanol-sc) δ: 8.88 (s, 1H), 7.95 (d, J= 7.9 Hz, 1H), 7.19 (d, J= 1 ,8 Hz, 1H), 7.16 (dd, J= 8.2, 1.8 Hz, 1H), 5.66-5.77 (m, 1H), 2.60 (s, ZN), 2 .26-2.34 (m, 4H), 1.47 (s, 6H), 1.32 (s, 6H); 2 H were not detected (NH and OH). 158 MS m/z 434.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 8.89 (s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.26-7.34 (m, ZH), 5, 76 (tg, J=12.5, 4.0 Hz, 1H), 2.56 (s, ZN), 2.47 (t, J=12.5 Hz, 2H), 2.39 (dd, J = 13.1, 4.0 Hz, 2H), 1.60 (s, 6H), 1.47 (s, 6H); 2 H were not detected (NH and OH). 159 MS m/z 462.6 [M+HlYH NMR (methanol-sc) d: 9.16 (s, 1H), 9.00 (s, 1H), 7.92-8.46 (m, ZH), 5.89-6.08 (m, 1H), 4.20 (s, ZN), 2.54-2.79 (m, 4H), 1.79 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 160 MS m/z 470.2 [M+H] ⁺ ; 'H NMR (methanol-d ₄ ) δ: 9.18 (s, 1H), 8.23-8.28 (m, 2H), 8.14 (d, J=9.5 Hz, 1H), 7 .86 (d, J=9.8 Hz, 1H), 7.79 (d, J=8.2 Hz, ZN), 5.94-6.03 (m, 1H), 2.63-2, 71 (m, 4H), 1.79 (s, 6H); 1.63 (s, 6H), 2H was not detected (NH and OH). 162 MS m/z 470.4 [M+N^H NMR (methanol-0 ₄ ) δ: 9.25-9.29 (m, 1H), 9.12 (s, 1H), 8.98 (s, 1H), 8.24 (d, J=8.9 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.427.47 (m, 2H), 5.80- 5.85 (m, 1H), 2.34-2.42 (m, 4H), 1.55 (s, 6H), 1.39 (s, 6H); 2 H were not detected (NH and OH).

Example 15.

Obtaining connection 70.

Step 1. Mixture of imidazole (0.1 g, 1.47 mmol), 1-bromo-4-iodo-2-methoxybenzene (0.5 g, 1.6 mmol), 2(2-pyridyl)-benzimidazole (58 .0 mg, 0.3 mmol), cesium carbonate (1.2 g, 3.66 mmol), copper(I) iodide (56 mg 0.29 mmol) in DMF (2 ml) was heated at 100°C for 48 hours. The reaction mixture was cooled to room temperature, filtered through Celite, washed with EtOAc and concentrated. The crude material was purified by silica gel chromatography, eluting with an EtOAc/hexane (080% EtOAc) gradient to give 1-(4-bromo-3-methoxyphenyl)-1H-imidazole (0.25 g, 62%).

MS m/z 253.3, 255.3 [M+H]+; 1H NMR (methanol^) δ: 8.19 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.62 (t, J=1.4 Hz, 1H), 7 .25 (d, J=2.2 Hz, 1H), 7.14-7.17 (m, 1H), 7.08 (dd, J=8.5, 2.2 Hz, 1H), 3, 97 (s, 3H).

Step 2. The oven-dried flask was equipped with a magnetic stirrer and 1-(4-bromo-3-methoxyphenyl)-1H-imidazole (127.0 mg, 0.5 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxa-borolane (254.0 mg, 1.0 mmol), complex 1, 1'

- 100 045009 bis(diphenylphosphino)ferrocene palladium(P) dichloride with dichloromethane (38.0 mg, 0.05 mmol) and potassium acetate (200.0 mg, 2.0 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (1 ml) was added and the reaction mixture was heated at 90°C for 90 minutes, after which UPLC analysis showed complete conversion to the borylated product. The crude mixture was cooled to room temperature and used directly in the next step.

Step 3. To the crude mixture from the reaction described above was added a complex of 1,1'bis(diphenylphosphino)ferrocenepalladium(P)-dichloride with dichloromethane (38.0 mg, 0.05 mmol) and 6-chloro3-(2,2,6 ,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (obtained in Example 13, Step 2, 100.0 mg, 0.34 mmol). The test tube was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). An aqueous solution of 2.0 M K2CO3 (0.75 mL, 1.5 mmol) was added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3 X ). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 6-(4-(1Himidazol-1-yl) -2-methoxyphenyl)-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]Ίriazolo[4,5c]pyridazine (85 mg, 39%). MS m/z 433.3 [M+H]+.

Step 4. To a solution of 6-(4-(1H-imidazol-1-yl)-2-methoxy-phenyl)-3-(2,2,6,6-tetramethylpiperidin-4yl)-3H-[1,2, 3]triazolo[4,5-c]pyridazine (50 mg, 0.115 mmol) in dichloromethane (3 ml) was added 1 M BBr ₃ in CH ₂ Cl ₂ (0.6 ml, 0.6 mmol). The mixture was stirred at room temperature for 3 hours. Methanol (3 ml) was added and the reaction mixture was stirred for another 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of MeOH/CH ₂ C1 ₂ (with 2.5% NH4OH) (0-30% MeOH/NH ₄ OH) to give 5-(1H-imidazol-1-yl)-2-( 3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenol (33 mg, 70%) as yellow solid matter.

MS m/z 419.4 [M+H]+; Ή NMR (methanol^) δ: 9.08 (s, 1H), 8.25 (t, J=1.3 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 7 .67 (t, J=1.3 Hz, 1H), 7.27 (d, J=1.6 Hz, 2H), 7.19 (t, J=0.9 Hz, 1H), 5.72 -5.87 (m, 1H), 2.24-2.40 (m, 4H), 1.51 (s, 6H), 1.35 (s, 6H); 2H were not detected (OH and NH).

Using the procedure described for Example 15 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds: ______________

Compound Data 63 MS m/z 420.4 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.20 (s, 1H), 9.10 (s, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.54 (dd, J=8.5, 2.2 Hz, 1H), 5.75-5.91 (m, 1H ), 2.30-2.47 (m, 4H), 1.55 (s, 6H), 1.40 (s, 6H); 2H were not detected (OH and NH). 64 MS m/z 420.5 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.17 (s, 1H), 9.12 (s, 2H), 8.30 (d, .1=9.1 Hz, 1H), 7.35-7 .41 (m, 2H), 5.93-6.03 (m, 1H), 2.67 (s, 4H), 1.78 (s, 6H), 1.64 (s, 6H); 2 H were not detected (OH and ΝΗ). 72 MS m/z 420.4 [M+H] ⁺ ; ^X NMR (methanol-sC) δ: 9.11 (s, 1H), 8.63 (d, J=l.3 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.94 (d, J=l,3 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.57 (dd, J=8.5, 2.2 Hz, 1H ), 5.77-5.87 (m, 1H), 2.28-2.39 (m, 4H), 1.51 (s, 6H), 1.36 (s, 6H); 2H were not detected (OH and NH). 143 MS m/z 437.3 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 12.05 (s, 1H), 9.24 (s, 1H),

- 101 045009

9.14 (d, J= 11.0 Hz, 1H), 8.22 (d, J= 8.5 Hz, 1H), 8.18 (d, J= 12.8 Hz, 1H), 8, 13 (t, J= 1.5 Hz, 1H), 7.63 (dd, J= 8.1, 1.7 Hz, 1H), 7.36 (dd, J= 8.4, 2.3 Hz , 1H), 7.32 (d, J= 2.4 Hz, 1H), 5.92 (tg, J= 12.2, 4.0 Hz, 1H), 4.02-4.16 (m, 1H), 2.52-2.66 (m, 4H), 1.66 (s, 6H), 1.53 (s, 6H). 144 MS m/z 433.4 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.50 (s, 1H), 9.21 (s, 1H), 8.33 (d, J= 9.5 Hz, 1H), 7.93 (s, 1H ), 7.44 (br.s, 2H), 5.93-6.05 (m, 1H), 2.62-2.78 (m, 4H), 2.45-2.54 (m, ZN ), 1.80 (s, 6H), 1.67 (s, 6H); 2 H were not detected (NH and OH). 149 MS m/z 447.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.19 (s, 1H), 8.34 (d, J= 8.2 Hz, 1H), 7.48 (d, J= 1.2 Hz, 1H), 7.21-7.29 (m, 2H), 5.95-6.05 (m, 1H), 2.67-2.75 (m, 4H), 2.66 (s, ZN), 2, 43 (d, J= 1.2 Hz, ZH), 1.79 (s, 6H), 1.64 (s, 6H); 2 H were not detected (NH and OH). 155 MS m/z 433.5 [M+H] ⁺ ; Ή NMR (methanol-sC) δ: 9.18 (s, 1H), 8.28 (d, J= 9.2 Hz, 1H), 7.92 (d, J= 2.1 Hz, 1H), 7.27 (sext, J= 2.1 Hz, 2H), 6.52-6.55 (m, 1H), 5.99 (spt, J= 5.5 Hz, 1H), 2.64-2 .75 (m, 4H), 2.50 (s, ZN), 1.79 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH). 156 MS m/z 433.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 11.70 (s, 1H), 9.16 (s, 1H), 8.92-9.04 (m, IH), 8.33 (s, 1H), 8.16 (d, J= 8.5 Hz, 1H), 7.61-7.64 (m, 1H), 7.54 (d, J= 2.1 Hz, IH), 7.46 (dd , J= 8.5, 2.1 Hz, IH), 5.89-5.97 (m, IH), 2.53-2.67 (m, 4Η), 2.40 (s, ZN), 1.65 (s, 6H), 1.52 (s, 6H). 157 MS m/z 433.6 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.14 (s, 1H), 8.23 (d, J= 2.4 Hz, 1H), 8.18 (d, J= 8.8 Hz, 1H ), 7.45 (s, 1H), 7.44 (dd, J= 10.7, 2.1 Hz, 1H), 6.42 (d, J= 2.4 Hz, 1H), 5.97 (tg, J= 10.4, 5.8 Hz, 1H), 2.64-2.75 (m, 4H), 2.41 (s, ZN), 1.79 (s, 6H), 1, 64 (s, 6H); 2 H were not detected (NH and OH).

Example 16.

Receiving connection 52.

Step 1. A mixture of 3,6-dichloropyridazin-4-amine (1.0 g, 6.0 mmol), 1,2,2,6,6-pentamethylpiperidin-4amine (1.0 g, 6.1 mmol) and DIPEA (1.6 ml, 9.1 mmol) in decanol (10 ml) was heated at 150°C for 7 days. The solvent was removed by blowing air and the residue was purified by chromatography on silica gel, eluting with a gradient of MoOH/CH ₂ C1 ₂ (2.5% NH4OH) (0-30% MeOH/NH ₄ OH), to give a mixture of 6chloro-N3-(1 ,2,2,6,6-pentamethyl-4-piperidyl)pyridazine-3,5-diamine and 6-chloro-N3-(1,2,2,6,6-pentamethyl-4piperidyl)pyridazine-3,4- diamine (0.85 g, 47%) as a brown solid, which was used in the next step without purification.

Step 2: To a solution of 6-chloro-N3-(1,2,2,6,6-pentamethyl-4-piperidyl)pyridazine-3,4-diamine prepared above (0.85 g, 2.9 mmol, ~ 59% purity), NaNO2 (0.50 g, 1.21 mmol) was added to AcOH (4 ml) and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by slowly adding saturated aqueous sodium bicarbonate until pH - 7. The aqueous layer was extracted with ethyl acetate three times. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-20% MeOH), to give 6-chloro-3

- 102 045009 (1,2,2,6,6-pentamethyl-4-piperidyl)triazolo[4,5-c]pyridazine (375 g, 43%) as a tan solid. MS m/z 309.1 [M+H]+.

Step 3. The oven-dried flask was equipped with a magnetic stirrer and [6-chloro-3-(1,2,2,6,6-pentamethyl-4-piperidyl)triazolo[4,5-c]pyridazine (72) was loaded into it mg, 0.23 mmol), 4-[3(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2ylpyrazole ( obtained in example 1, step 7, 116 mg, 0.28 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.023 mmol) and K2CO3 (65 mg, 0.47 mmol) . The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X) . The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by chromatography on silica gel eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH) to give 6-(2-(methoxymethoxy)-4- (1-(tetrahydro-2Hpyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3H-[1,2 ,3]triazolo[4,5c]pyridazine (75 mg, 57%). MS m/z 561.4 [M+H] ⁺ .

Step 4. To a solution of 6-[2-(methoxymethoxy)-4-(1-tetrahydro-pyran-2-ylpyrazol-4-yl)phenyl]-3(1,2,2,6,6-pentamethyl-4- piperidyl)triazolo[4,5-c]pyridazine (61 mg, 0.11 mmol) in CH ₂ Cl ₂ (1 ml) was added 4N HCl in 1,4-dioxane (0.14 ml, 0.54 mmol), and the reaction mixture was stirred for 16 hours. The precipitate formed during this time was collected by filtration, washed with CH ₂ Cl ₂ (3X) and dried to obtain 2-[3-(1,2,2,6,6-pentamethyl- 4-piperidyl)triazolo[4,5-c]pyridazin-6-yl]-5-(1Hpyrazol-4-yl)phenol dihydrochloride (41 mg, 75%) as a yellow solid.

MS m/z 433.3 [M+H]+; ¹ H NMR (methanol-b ₄ ) δ: 9.13 (s, 1H), 8.52 (s, 2H), 8.12 (d, J=8.2 Hz, 1H), 7.40 (dd , J=8.2, 1.9 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 5.95 (tt, J=12.9, 3.5 Hz, 1H) , 3.03 (s, 3H), 2.95 (t, J=14.2 Hz, 2H), 2.77 (dd, J=14.2, 3.5 Hz, 2H), 1.76 ( s, 6H), 1.70 (s, 6H); 2H were not detected (NH and OH).

Using the procedure described for Example 16 above, additional compounds described herein were prepared by appropriate substitution of starting materials, reagents, and reaction conditions to provide compounds selected from the following compounds:

Compound Data 56 MS m/z 391.5 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.09 (s, 1H), 8.37 (br.s, 2H), 8.09 (d, J=8.2 Hz, 1H), 7.36 ( d, J=8.5 Hz, 1H), 7.34 (s, 1H), 5.70-5.90 (m, 1H), 3.57-3.64 (m, 2H), 2.70 (us.s, 4H), 1.68 (s, ZN), 1.58 (s, ZN); 3 H was not detected (OH and 2 NH). 57 MS m/z 417.6 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.09 (s, 1H), 8.26 (s, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.34 (dd , J=8.2, 1.9 Hz, 1H), 7.32 (d, J=l.6 Hz, 1H), 5.80-5.92 (m, 1H), 2.76 (dd, J=13.6, 12.6 Hz, 2H), 2.61-2.66 (m, 2H), 2.50 (d, J=9.5 Hz, 2H), 2.17 (d, J =9.1 Hz, 2H), 1.64 (s, 6H); 3 H was not detected (OH and 2 NH).

Example 17.

Getting connection 7.

Stage 1. The oven-dried flask was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5-c]pyridazine (prepared in Example 13, Step 2, 75 mg, 0.25 mmol), 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolane -2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (obtained in example 1, step 7, 150 mg, 0.36 mmol) and complex [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(P) with dichloromethane (25 mg, 0.029 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (4 ml) and aqueous 2.0 M K2CO3 (0.3 ml, 0.60 mmol) were added and the reaction mixture was heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0

- 103 045009

20% MeOH), to give 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-nirazol-4yl)phenyl)-3-(2,2,6 ,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (125 mg, 90%) as a yellow solid. MS m/z 547.4 [M+H]+.

Step 2. To a solution of 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-nirazol-4yl)phenyl)-3-(2,2,6,6 -tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (125 mg, 0.23 mmol) in CH ₂ Cl ₂ (1 ml) was added 4N HCl in dioxane ( 3 mL, 12 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The precipitated yellow solid was collected by vacuum filtration, washed with CH ₂ Cl ₂ and Et ₂ O and dried to give 5-(1Hpyrazol- 4-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenol dihydrochloride (95 mg, 91%).

MS m/z 419.5 [M+H] ⁺ ; ¹ H NMR (methanol-d ₄ ) δ: 9.11 (s, 1H), 8.34 (s, 2H), 8.11 (d, J=8.2 Hz, 1H), 7.37 (dd , J=8.2, 1.9 Hz, 1H), 7.35 (d, J=l.9 Hz, 1H), 5.97 (tt, J=11.0, 5.4 Hz, 1H) , 2.62-2.74 (m, 4H), 1.79 (s, 6H), 1.64 (s, 6H); 3H were not detected (2 NH and OH).

Example 18.

Getting connection 34.

Stage 1. The oven-dried flask was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5-c]pyridazine (prepared in Example 13, Step 2, 50 mg, 0.17 mmol), 1-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2yl)phenyl]pyrazole (61 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (13 mg, 0.17 mmol) and K ₂ CO ₃ (71 mg, 0.51 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (4 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3X) . The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-20% MeOH) to give 6-(2-methoxy-4-pyrazole-1 -yl-phenyl)-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (55 mg, 75%) as a yellow solid. MS m/z 433.5 [M+H] ⁺ .

Step 2. To a solution of 6-(2-methoxy-4-pyrazol-1-yl-phenyl)-3-(2,2,6,6-tetramethyl-4piperidyl)triazolo[4,5-c]pyridazine (55 mg , 0.13 mmol) in CH ₂ Cl ₂ (1 ml), 1 M BBr ₃ in CH ₂ Cl ₂ (0.64 ml, 0.64 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours, after which UPLC analysis showed complete consumption of the starting material. The reaction was quenched with MeOH (10 ml), concentrated under reduced pressure and purified by silica gel chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (2.5% NH4OH) (0-30% MeOH/NH ₄ OH) to give 5-pyrazol-1-yl-2-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazin-6-yl]phenol (38 mg, 71%) as a yellow solid.

MS m/z 419.5 [M+H] ⁺ ; 1H NMR (DMSO-d ₆ ) δ: 9.18 (s, 1H), 8.97-9.07 (m, 1H), 8.58 (d, J=2.2 Hz, 1H), 8, 19 (d, J=8.8 Hz, 1H), 8.11-8.17 (m, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.62 (d, J =2.5 Hz, 1H), 7.54 (dd, J=8.7, 2.4 Hz, 1H), 6.61 (dd, J=2.4, 1.7 Hz, 1H), 5 .93 (tt, J=12.3, 4.1 Hz, 1H), 2.52-2.65 (m, 4H), 1.66 (s, 6H), 1.53 (s, 6H).

Example 19.

Getting connection 14.

- 104 045009

Step 1. The oven-dried flask was equipped with a magnetic stirrer and charged with 1,4-dibromo-2,5-difluorobenzene (3.2 g, 12 mmol), 1-tetrahydropyran-2-yl-4-(4,4 ,5,5-tetramethyl-1,3,2Dioxaborolan-2-yl)pyrazole (2.95 g, 10.6 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (430 mg, 0.50 mmol) . The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (50 ml) and an aqueous solution of 2.0 M K ₂ CO ₃ (15 ml, 30 mmol) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc), to give 4-(4-bromo-2,5difluorophenyl)-1- tetrahydropyran-2-ylpyrazole (1.51 g, 42%) as a brown oil. MS m/z 343.0, 345.0 [M+H]+.

Stage 2. The oven-dried flask was equipped with a magnetic stirrer and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (200 mg, 0.23 mmol), 4-(4-bromo-2,5-difluorophenyl)- was loaded into it. 1-tetrahydropyran-2-ylpyrazole (1.51 g, 4.40 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1,3,2dioxaborolane (2.90 g, 11.4 mmol) and KOAc (1.73 g, 17.6 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (22 ml) was added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc/hexanes (5-50% EtOAc) to give 4-[2,5-difluoro-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2ylpyrazole (1.54 g, 89%) as a brownish solid.

¹ H NMR (CDCl ₃ ) δ: 8.09 (d, J=1.9 Hz, 1H), 7.95 (s, 1H), 7.47 (dd, J=10.7, 4.7 Hz , 1H), 7.23 (dd, J=9.5, 5.7 Hz, 1H), 5.38-5.51 (m, 1H), 4.01-4.16 (m, 1H), 3.73-3.78 (m, 1H), 2.05-2.20 (m, 3H), 1.66-1.79 (m, 3H), 1.39 (s, 12H).

Step 3. The oven-dried test tube was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (obtained in example 13, step 2, 75 mg, 0.25 mmol), 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ]-1tetrahydropyran-2-ylpyrazole (199 mg, 0.51 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (25 mg, 0.029 mmol). The tube was closed with a screw-on rubber stopper and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (1 ml) and aqueous 2.0 M K2CO3 (0.3 ml, 0.6 mmol) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH), to give 6-[2,5difluoro-4-(1-tetrahydropyran-2 -ylpyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (96 mg, 72%) as a brown solid. MS m/z 523.4 [M+H]+.

Step 4. To a solution of 6-[2,5-difluoro-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-3-(2,2,6,6tetramethyl-4-piperidyl)-triazolo[ 4,5-c]pyridazine (96 mg, 0.18 mmol) in CH2Cl2 (1 ml), 4N HCl in dioxane (2 ml, 8 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The yellow solid was collected by vacuum filtration, rinsed with CH ₂ Cl ₂ and Et ₂ O and dried to give 6-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3(2, 2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine dihydrochloride.

MS m/z 439.5 [M+H]+; 1H NMR (DMSO-d ₆ ) δ: 9.56 (d, J=15.8 Hz, 1H), 8.97 (d, J=1.6 Hz, 1H), 8.36 (d, J= 12.9 Hz, 1H), 8.25 (s, 1H), 7.70-7.91 (m, 1H), 5.93 (tt, J=12.9, 4.1 Hz, 1H), 2.59-2.67 (m, 4H), 1.67 (s, 6H), 1.56 (s, 6H), 2 H not detected (2 NH).

Using the procedure described for Example 19 above, additional compounds described herein were prepared by appropriate substitution of starting materials, reagents, and reaction conditions to provide compounds selected from the following compounds:

Compound Data 13 MS m/z 439.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 9.64 (d, J=12.8 Hz, 1H), 8.95 (d, J=l.3 Hz, 1H), 8.39 (d, J= 12.8 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.92-7.99 (m, IH), 5.93 (tg, J=12.3, 3 .8 Hz, 1H), 2.58-2.65 (m, 4H), 1.67 (s, 6H), 1.56 (s, 6H); 2 H was not detected (2 NH). 58 MS m/z 435.5 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.02 (s, 1H), 8.79 (s, 2H), 7.61 (s, 1H), 7.37 (s, 1H), 5.97 (tg, J=11.7, 4.7 Hz, 1H), 2.60-2.77 (m, 4H) , 1.79 (s, 6H), 1.66 (s, 6H); 4 H was not detected (2 NH and 2 OH).

- 105 045009

Example 20.

Getting connection 53.

Step 1. The oven-dried flask was equipped with a magnetic stirrer and 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (100 mg, 0.42 mmol), (4-methoxyphenyl)boronic acid (69, 8 mg, 0.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (17.1 mg, 0.021 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (1.0 mL) and aqueous 1 M K2CO3 (0.5 mL, 0.5 mmol) were added and the reaction mixture was heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-10% EtOAc) to give 1-chloro-5-fluoro-2-methoxy-4-(4-methoxyphenyl)benzene (89.2 mg, 80 %) as a yellowish-white solid.

MS m/z 267.8 [M+H]+; ¹ H NMR (CDCl ₃ ) δ: 7.39 (dd, J=8.8, 1.6 Hz, 2H), 7.13 (d, J=9.5 Hz, 1H), 6.92 (d , J=8.8 Hz, 2H), 6.85 (d, J=6.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H).

Step 2. The oven-dried flask was equipped with a magnetic stirrer and charged with 1-chloro-5-fluoro-2-methoxy-4-(4-methoxyphenyl)benzene (56 mg, 0.21 mmol), bis(pinacolato)diboron (66.6 mg, 0.26 mmol), potassium acetate (61.8 mg, 0.63 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)-[ 2-(2'-amino-1,G-biphenyl)]palladium(P) (8.3 mg, 0.011 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (1.4 ml) was added and the reaction mixture was heated to 120°C for 64 hours. The reaction mixture was cooled to room temperature and an aqueous solution of 1 M K ₂ CO ₃ (0.7 ml, 0. 7 mmol), then 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (obtained in example 13, step 2, 40.9 mg, 0 .14 mmol), and a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium(P)dichloride with dichloromethane (8.6 mg, 0.011 mmol). The mixture was purged with argon and heated at 90°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-30% MeOH) gradient to give 6-[5-fluoro-2methoxy-4-(4-methoxyphenyl)phenyl]-3-(2, 2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (28.5 mg, 29%). MS m/z 491.5 [M+H] ⁺ .

Step 3. 6-[5-Fluoro-2-methoxy-4-(4-methoxyphenyl)phenyl]-3-(2,2,6,6-tetramethyl-4piperidyl)triazolo[4,5-c]pyridazine (28 .5 mg, 0.058 mmol) was mixed with dichloromethane (2 ml) and 1N BBr ₃ in dichloromethane (0.6 ml, 0.6 mmol). The mixture was stirred at room temperature for 3 hours. Methanol (0.5 ml) was added and the reaction mixture was stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue was triturated with MeOH (3x2 ml) and dried under vacuum to give 6 -fluoro-4-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]niridazin-6-yl)-[1 ,1'biphenyl]-3,4'-diol hydrobromide as a yellowish-white solid (11.3 mg, 36%).

MS m/z 463.5 [M+H]+; Ή NMR (DMSO-d6) δ: 11.22 (s, 1H), 9.75 (s, 1H), 9.20 (s, 1H), 8.95 (d, J=12.0 Hz, 1H ), 8.11 (d, J=12.0 Hz, 1H), 7.98 (d, J=11.7 Hz, 1H), 7.45 (dd, J=8.5, 1.6 Hz , 2H), 7.13 (d, J=6.9 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 5.94 (tt, J=12.3, 4, 1 Hz, 1H), 2.59 (d, J=12.0 Hz, 2H), 2.54 (d, J=10.1 Hz, 2H), 1.66 (s, 6H), 1.52 (s, 6H).

Using the procedure described for Example 20 above, additional compounds described herein were prepared by appropriate substitution of starting materials, reagents, and reaction conditions to provide compounds selected from the following compounds:

- 106 045009

Compound Data 33 MS m/z 437.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 10.13-10.31 (m, 1H), 9.559.70 (m, IH), 8.82 (d, J=l.3 Hz, 1H), 8, 32-8.42 (m, 1H), 8.26 (s, 2H), 7.70 (d, J=12.3 Hz, 1H), 7.64 (d, J=6.9 Hz, 1H ), 5.91 (tg, J=12.3, 3.8 Hz, 1H), 2.56-2.70 (m, 4H), 1.67 (s, 6H), 1.56 (s, 6H). 55 MS m/z 478.2 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.18 (s, 1H), 8.03 (d, J= 12.0 Hz, 1H), 7.79 (s, 1H), 7.22 (d, J= 6.6 Hz, 1H), 6.83 (s, 1H), 6.70 (dt, J= 6.9, 1.9 Hz, 1H), 5.99 (tt, J= 11.3 , 5.4 Hz, 1H), 3.66 (s, 3H), 2.63-2.71 (m, 4H), 1.78 (s, 6H), 1.63 (s, 6H); 2 H were not detected (NH and OH). 59 MS m/z 437.5 [M+H] ⁺ ; 'H NMR (methanol-d4) δ: 8.75 (s, 1H), 8.06 (s, 2H), 7.04-7.18 (m, 2H), 5.99 (tg, J= 12 ,0, 4.7 Hz, 1H), 2.62-2.74 (m, 4H), 1.78 (s, 6H), 1.63 (s, 6H); 3 H were not detected (2 NH and OH). 62 MS m/z 451.5 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 11.51 (br.s, 2H), 9.48 (d, J= 12.3 Hz, 1H), 9.23 (s, 1H), 8.31 ( d, J= 12.0 Hz, 1H), 8.21 (d, J= 1.9 Hz, 1H), 8.03 (d, J= 12.3 Hz, 1H), 7.92 (s, 1H), 7.35 (d, J= 6.9 Hz, 1H), 5.91 (tg, J= 12.6, 4.1 Hz, 1H), 3.94 (s, ZN), 2, 59 (d, J= 12.9 Hz, 2H), 2.50-2.54 (m, 2H), 1.67 (s, 6H), 1.55 (s, 6H). 87 MS m/z 448.3 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.26 (s, 1H), 8.96-9.03 (m, 2H), 8.44 (dd, J=6.9, 1.3 Hz, 2H ), 8.21 (d, J=12.6 Hz, 1H), 7.50 (d, J=6.6 Hz, 1H), 6.01 (tg, J=10.7, 5.5 Hz , 1H), 2.63-2.73 (m, 4H), 1.80 (s, 6H), 1.65 (s, 6H); 2 H were not detected (NH and OH).

Example 21.

Obtaining connection 35.

Step 1: The oven-dried flask was equipped with a magnetic stirrer and charged with 4-bromo-5-fluoro-2-methoxyaniline (1.0 g, 4.5 mmol), 1-tetrahydropyran-2-yl-4- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (1.6 g, 5.5 mmol), Pd(dppf)Cl ₂ (340 mg, 0.45 mmol) and K ₂ CO ₃ (1.9 g, 14 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (20 ml) and water (2 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc/hexanes (0-60% EtOAc), to give 5-fluoro-2-methoxy-4-(1-tetrahydropyran- 2ylpyrazol-4-yl)aniline (1.25 g, 94%) as a colorless oil. MS m/z 292.3 [M+H]+

Step 2: To a well stirred suspension of 5-fluoro-2-methoxy-4-(1-tetrahydropyran-2ylpyrazol-4-yl)aniline (1.25 g, 4.29 mmol) in THF (40 ml) under a stream of nitrogen successively added CsI (1.67 g, 6.44 mmol), I ₂ (1.09 g, 4.29 mmol), CuI (0.41 g, 2.15 mmol) and tBuONO (1.33 ml, 10. 7 mmol). The reaction mixture was vigorously stirred at 65-70°C for 6 hours. After cooling in an ice bath, the solid was filtered off. The filtrate was diluted with dichloromethane (500 ml), washed

- 107 045009

30% aqueous ammonium hydroxide (150 ml), sodium thiosulfate (300 ml), brine and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc/hexanes (0-80% EtOAc), to give 4-(2-fluoro4-iodo-5-methoxyphenyl)-1-tetrahydropyran-2-ylpyrazole (0.92 g, 53% ) as a brownish solid. MS m/z 403.1 [M+H]+

Step 3: The oven-dried flask was equipped with a magnetic stirrer and charged with 4-(2-fluoro-4-iodo-5-methoxy-phenyl)-1-tetrahydropyran-2-ylpyrazole (0.92 g, 2.23 mmol ), Pd(dppf)Cl ₂ (171 mg, 0.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,3,2dioxaborolane (1.17 g, 4.57 mmol) and KOAc (0.68 g, 6.85 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-Dioxane (10 ml) was added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a gradient of EtOAc/hexanes (0-50% EtOAc) to give 4-(2-fluoro-5-methoxy-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2Hpyran-2-yl)-1H-pyrazole (0.745 g, 81%) as a clear oil . MS m/z 403.3 [M+H]+.

Step 4. The oven-dried test tube was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (obtained in example 13, step 2, 98 mg, 0.33 mmol), 4-(2-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl )-1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazole (267 mg, 0.66 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (50 mg, 0.066 mmol) and K2CO3 (276 mg, 2.0 mmol). The tube was closed with a screw-on rubber cap, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-25% MeOH) to give 6-(5-fluoro-2-methoxy-4-(1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo [4,5-c]pyridazine (150 mg, 42%) as a brownish solid. MS m/z 535.4 [M+H]+.

Step 5. 6-(5-Fluoro-2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(2,2,6 ,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (80 mg, 0.15 mmol) was dissolved in dichloromethane (2 ml) and treated with 1N BBr ₃ in dichloromethane (0.74 ml, 0.74 mmol). The mixture was stirred at room temperature for 3 hours. Methanol (0.5 ml) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was triturated in MeOH and the resulting solid was filtered, washed with Et ₂ O and dried in vacuo to give 4-fluoro-5-(1H-pyrazol-4-yl)-2-(3-(2,2,6, 6-Tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenol dihydrobromide (33 mg, 41%) as an orange solid.

MS m/z 437.5 [M+H]+; ^1H NMR (DMSO- _d6 ) δ: 11.51 (br.s, 1H), 9.25 (s, 1H), 8.92-9.03 (m, 1H), 8.078.16 (m, 2H), 8.03 (d, J=12.3 Hz, 1H), 7.38 (d, J=6.8 Hz, 1H), 5.93 (tt, J=12.3, 4.8 Hz, 1H), 2.53-2.63 (m, 4H), 1.66 (s, 6H), 1.52 (s, 6H); 1H was not detected (NH or OH).

Using the procedure described for Example 21 above, additional compounds described herein were prepared by appropriate substitution of starting materials, reagents, and reaction conditions to provide compounds selected from the following compounds:

Compound Data 83 MS m/z 453.9 [M+H] ⁺ ; 'H NMR ( _methanolD4 ) δ: 9.18 (s, 1H), 8.63 (s, 2H), 8.28 (s, 1H), 7.34 (s, 1H), 5.98 (tg , J=12.0, 4.5 Hz, 1H), 2.61-2.79 (m, 4H), 1.80 (s, 6H), 1.66 (s, 6H); 3 H were not detected (2 NH and OH).

- 108 045009

Example 22.

Receiving connection 54.

Step 1: (4-Chloro-2-fluoro-3-methoxyphenyl)boronic acid (200 mg, 0.98 mmol) was mixed with 4-bromo-1-tetrahydropyran-2-yl-pyrazole (271 mg, 1.17 mmol) and complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (80.0 mg, 0.098 mmol), then 1,4dioxane (2.0 ml) and an aqueous solution of 1 M K ₂ CO ₃ ( 1.0 ml, 1.0 mmol). The mixture was stirred at 110°C for 2 hours. The mixture was then partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in hexanes to give 4-(4-chloro-2-fluoro-3-methoxy-phenyl)-1-tetrahydropyran-2-ylpyrazole (165.7 mg, 54%) as a yellowish-white solid.

MS m/z 311.0 [M+H]+; ¹ H NMR (CDCl ₃ ) δ: 7.93 (d, J=1.9 Hz, 1H), 7.82 (s, 1H), 7.13 (dd, J=8.5, 7.3 Hz , 1H), 7.07 (dd, J=8.5, 1.3 Hz, 1H), 5.37 (dd, J=9.0, 3.0 Hz, 1H), 4.02 (d, J=9.8 Hz, 1H), 3.91 (s, 3H), 3.67 (td, J=11.2, 2.8 Hz, 1H), 2.08-2.18 (m, 2H ), 1.88-2.01 (m, 1H), 1.60-1.72 (m, 2H), 1.57 (d, J=2.5 Hz, 1H).

Step 2: 4-(4-Chloro-2-fluoro-3-methoxy-phenyl)-1-tetrahydro-pyran-2-ylpyrazole (48.0 mg, 0.15 mmol) was mixed with bis(pinacolato)diboron (49 .0 mg, 0.19 mmol), potassium acetate (45.5 mg, 0.46 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2 '-amino-1,1'biphenyl)]palladium(P) (5.6 mg, 0.008 mmol) and 1,4-dioxane (1.0 ml). The mixture was stirred at 120°C for 24 hours. The mixture was cooled to room temperature. An aqueous solution of 1 M K2CO3 (0.5 ml, 0.5 mmol), 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)-triazolo[4,5-c] was added to the mixture. pyridazine (obtained in example 13, step 2, 30.0 mg, 0.102 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) complex with dichloromethane (4.2 mg, 0.008 mmol). The mixture was stirred at 90°C for 6 hours. The mixture was then partitioned between EtOAc and H ₂ O. 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 0-30% MeOH in CH ₂ Cl ₂ to give 6-[3-fluoro-2-methoxy-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl] -3-(2,2,6,6tetramethyl-4-piperidyl)-triazolo[4,5-c]pyridazine (10.6 mg, 20%). MS m/z 535.5 [M+H] ⁺ .

Step 3. 6-[3-Fluoro-2-methoxy-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-3-(2,2,6,6tetramethyl-4-piperidyl)-triazolo[ 4,5-c]pyridazine (11 mg, 0.02 mmol) was mixed with dichloromethane (0.5 ml) and 1 N BBr ₃ in dichloromethane (0.10 ml, 0.10 mmol). The mixture was stirred at room temperature for 5 hours. Methanol (0.5 ml) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The material was chromatographed on silica gel, eluting with 0-30% MeOH in CH ₂ Cl ₂ , and then further purified by reverse phase chromatography on C18 silica gel, eluting with 10-100% MeCN in H2O, to give 2-fluoro-3 -(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazin-6yl]phenol dihydrochloride (1.1 mg , eleven%).

MS m/z 437.3 [M+H] ⁺ ; 1H NMR (methanol-d ₄ ) δ: 9.11 (s, 1H), 8.19 (br.s, 1H), 8.10 (br.s, 1H), 7.90 (dd, J=8 ,5, 1.3 Hz, 1H), 7.38 (dd, J=8.2, 6.9 Hz, 1H), 5.88-5.95 (m, 1H), 2.52-2, 63 (m, 4H), 1.71 (s, 6H), 1.56 (s, 6H); 2 H were not detected (NH and OH).

- 109 045009

Example 23.

Getting connection 81.

Step 1. The oven-dried flask was equipped with a magnetic stirrer and 6-chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (prepared in example 13, step 2, 85 mg, 0.29 mmol), (7-methoxy-6-quinolyl)boronic acid (70 mg, 0.35 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II ) (22 mg, 0.029 mmol), and K2CO3 (811 mg, 0.58 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). Dioxane (2 ml) and water (0.5 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH), to give 7-methoxy-6-(3 -(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)quinolone (110 mg, 91%) as a yellowish brown solid. MS m/z 418.4 [M+H]+.

Step 2. 7-Methoxy-6-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin6-yl)quinolone (110 mg, 0.26 mmol) was dissolved in CH ₂ Cl ₂ (2 ml), and 1N BBr ₃ in dichloromethane (1.3 ml, 1.3 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. Methanol (5 ml) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was triturated in Et ₂ O, and the resulting precipitate was collected by vacuum filtration, washed with with CH2Cl2, Et2O and dried to give 6-(3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl) quinolin-7-ol hydrobromide (97 mg, 76%) as an orange solid.

MS m/z 404.5 [M+H] ⁺ ; ¹ H NMR (methanol-d ₄ ) δ: 9.21-9.25 (m, 2H), 9.11 (dd, J=5.7, 1.3 Hz, 1H), 9.03 (s, 1H), 7.94 (dd, J=8.2, 5.7 Hz, 1H), 7.73 (s, 1H), 6.00-6.08 (m, 1H), 2.60-2 .80 (m, 4H), 1.81 (s, 6H), 1.66 (s, 6H); 2 H were not detected (NH and OH).

Example 24.

Receiving connection 97.

stage 3

Step 1: To a solution of 5-bromo-6-methoxy-2-methyl-1H-benzo-[b]imidazole (360 mg, 1.5 mmol) in DMF (5 ml) was added 60% NaH in mineral oil (90 mg , 2.25 mmol) at 0°C in an atmosphere of N ₂ . The mixture was stirred at 0°C for 15 min and then SEMCl (400 μl, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the mixture was quenched with ice water (10 ml). The mixture was extracted with EtOAc (50 ml x 2). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a residue, which was purified by silica gel column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (2-5% MeOH) to give a mixture of 5-bromo -6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo-[b]imidazole and (5methoxy-2-methyl-1 -((2-(trimethylsilyl)ethoxy) -methyl)-1 H-benzo[d]imidazol-6-yl)bromonium as a brown oil (416 mg, 75%). MS m/z 371 [M+H] ⁺ .

Step 2. Mixture of 5-bromo-6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hbenzo[d]imidazole and (5-methoxy-2-methyl-1-( (2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)bromonium (370 mg, 1 mmol), B ₂ (pin) ₂ (280 mg, 1.1 mmol), Pd( dppf)Cl ₂ (73 mg, 0.1 mmol) and KOAc (196 mg, 2 mmol) in 1,4-dioxane (5 ml) were stirred at 90°C under N ₂ for 3 hours. The solution was concentrated to give crude mixture of 6-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidαzole and 2-(5-methoxy-2-methyl

- 110 045009

-((2-(trimethylsilyl)ethoxy)methyl)-1 H-6eH3o[d]-imidazol-6-yl)-4,4,5,5-tetramethyl-1,3,2dioxaborolan-1-ium, which was used at the next stage without cleaning.

Step 3. The above-described crude mixture of 6-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 -((2-(trimethylsilyl)ethoxy) methyl)-1 H-benzo[d]imidazole and 2-(5-methoxy-2-methyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]-imidazol-6-yl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-1-ium (150 mg, 0.51 mmol), 6-chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)- 3H[1,2,3]triazolo[4,5-c]pyridazine (obtained in example 13, step 2, 147 mg, 0.5 mmol), Pd(dppf)Cl ₂ (73 mg, 0.1 mmol) and K ₂ CO ₃ (178 mg, 1.3 mmol) in 1,4-dioxane-H ₂ O (4 ml, 3/1, v/v) were stirred at 90°C under N2 for 3 hours. The solution was concentrated , and the residue was purified by silica gel column chromatography, eluting with a gradient of CH ₂ Cl ₂ /MeOH (0-5% MeOH) to give a mixture of 6-(6methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-benzo[d]-imidazol-5-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazinα and 6-(5-methoxy-2-methyl-1-((2(trimethylsilyl)ethoxy)-methyl)-1H-benzo[d]imidazol-6-yl)-3-(2,2,6, 6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine as a brown oil (220 mg, 79%). MS m/z 551 [M+H]+.

Step 4. To a solution of a mixture of 6-(6-methoxy-2-methyl-1-((2-(tri-methylsilyl)ethoxy)methyl)-1Hbenzo[d]imidazol-5-yl)-3-(2,2 ,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine and 6(5-methoxy-2-methyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c ]pyridazineα (220 mg, 0.4 mmol) in CH ₂ Cl ₂ (1 ml) was added TFA (912 mg, 8 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give crude 6-(6-methoxy-2-methyl-1H-benzo[d]imidazol-5-yl)-3(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine, which was used in the next step without further purification (151 mg, 90%). MS m/z 421 [M+H]+.

Step 5. To a solution of 6-(6-methoxy-2-methyl-1H-benzo[d]-imidazol-5-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1 ,2,3]triazolo[4,5-c]pyridazine (150 mg, 0.36 mmol) in CH ₂ Cl ₂ (3 ml) was added 1.0 M BBr ₃ in CH ₂ Cl ₂ (3 ml, 3 mmol) . The reaction mixture was stirred at room temperature for 16 hours, then quenched with MeOH (5 ml) and concentrated. The residue was dissolved in MeOH (with 2.5% NH4OH), filtered, concentrated and purified by preparative HPLC to give 2-methyl-5-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[ 1,2,3]triazolo[4,5-c]pyridazin-6-yl)-1Hbenzo[d]imidazol-6-ol as a yellow solid (30 mg, 21%).

MS m/z 407.3 [M+H]+; ^1H NMR (methanol- _d4 ) δ 9.00 (s, 1H), 8.11 (s, 1H), 7.09 (s, 1H), 5.83-5.79 (m, 1H), 2.58 (s, 3H), 2.39 -2.24 (m, 4H), 2.18 (s, 1H), 1.50 (s, 6H), 1.35 (s, 6H); 2H were not detected (NH and OH).

Example 25.

Receiving connection 92.

Step 1: 5-Methoxy-2-nitroaniline (7.2 g, 43 mmol) and NBS (7.5 g, 43 mmol) were dissolved in acetonitrile (70 ml) and cooled to 0°C. TFA (3.2 mL, 43 mmol) was then added dropwise to the mixture. The ice bath was removed and the reaction mixture was stirred for 4 hours at room temperature. Water (100 ml) was added and the pH was adjusted to 8 by adding 2.5 M NaOH. The resulting precipitate was recrystallized from methanol to give 4-bromo-5-methoxy-2-nitroaniline as a yellow solid (9.65 g, 82%). MS m/z 247, 249 [M+H]+.

Step 2: To a solution of 4-bromo-5-methoxy-2-nitroaniline (4.92 g, 20 mmol) t TEA (5.6 ml, 40 mmol) in CH ₂ Cl ₂ (50 ml) was added TFAA (5, 6 ml, 40 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated to give the crude intermediate, which was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (4-10% EtOAc), to give N-(4-bromo-5 -methoxy-2-nitrophenyl)-2,2,2-trifluoroacetamide as a yellow solid (4.5 g, 66%). MS m/z 343.345 [M+H] ⁺ .

Step 3. To a solution of N-(4-bromo-5-methoxy-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.42 g, 10 mmol) and Cs ₂ CO ₃ (9.78 g, 3 mmol ) in DMF (50 ml) was added MeI (3.8 ml, 25 mmol). The mixture was stirred at room temperature for 3 hours. 1 M NaOH (10 ml) was added and the reaction mixture was stirred

- 111 045009 was sewn for another 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and concentrated to give 4-bromo-5-methoxy-N-methyl-2-nitroaniline as a yellow oil without further purification (2.34 g, 90%). MS m/z 261.263 [M+H]+.

Step 4: A mixture of 4-bromo-5-methoxy-N-methyl-2-nitroaniline (2.0 g, 7.7 mmol) and Fe (4.3 g, 77 mmol) in formic acid (20 ml) was stirred at 100°C overnight. The mixture was diluted with MeOH (100 ml). The filtrate was concentrated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 5bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole, which was used in the next step without further purification (1.63 g, 88 %).

^1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.76 (s, 1H), 6.83 (s, 1H), 3.96 (s, 3H), 3.81 ( s, 3H).

Step 5. Mixture of 5-bromo-6-methoxy-1-methyl-1H-benzo[d]-imidazole (240 mg, 1 mmol), B ₂ (pin) ₂ (280 mg, 1.1 mmol), Pd( dppf)Cl ₂ (73 mg, 0.1 mmol) and KOAc (196 mg, 2 mmol) in 1,4-dioxane (4 ml) were stirred at 90°C under N2 for 3 hours. The solution was filtered through celite and concentrated to give crude 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hbenzo[d]imidazole without purification for the next step. MS m/z 289 [M+H]+.

Step 6. A mixture of the above-described crude 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-benzo-[d]imidazole, 6- chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine (prepared in example 13, step 2, 200 mg, 0 .68 mmol), Pd(dppf)Cl ₂ (50 mg, 0.068 mmol) and K ₂ CO ₃ (188 mg, 1.36 mmol) in 1,4-dioxane (4 ml) and water (1 ml) were stirred at 90°C in an atmosphere of N ₂ for 3 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-5% MeOH), to obtain 6-(6-methoxy1-methyl -1H-benzo[d]imidazol-5-yl)-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazine in the form brown oil (228 mg, 80%). MS m/z 421 [M+H] ⁺ .

Step 7. To a solution of 6-(6-methoxy-1-methyl-1H-benzo[d]-imidazol-5-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1 ,2,3]triazolo[4,5-c]pyridazine (100 mg, 0.24 mmol) in CH ₂ Cl ₂ (3 ml) was added 1 M BBr ₃ in CH ₂ Cl ₂ (3 ml, 3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (5 ml) and concentrated. The residue was dissolved in MeOH (with 2.5% NH4OH), filtered and concentrated, and purified by preparative TLC eluting with CH ₂ Cl/30% MeOH (with 2.5% NH4OH) to give 1-methyl-5-( 3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-1H-benzo[d]-imidazol-6 -ol as a yellow solid (48 mg, 50%).

MS m/z 407.1 [M+H]+; 1H NMR (methanol- _d4 ) δ: 8.95 (s, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.41 (s, 2H), 7.11 ( s, 1H), 5.74 (tt, J=11.0, 5.5 Hz, 1H), 3.87 (s, 3H), 2.10-2.39 (m, 4H), 1.48 (s, 6H), 1.33 (s, 6H).

Example 26.

Receiving connection 94.

stage 3

Step 1: To a solution of 5-bromo-6-methoxy-1H-indazole (250 mg, 1.1 mmol) in DMF (5 ml) was added 60% NaH in mineral oil (66 mg, 1.65 mmol) at 0° C in an atmosphere of N ₂ . The mixture was stirred at 0°C for 15 min and then SEMCl (300 μl, 1.65 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then quenched with ice water (10 ml). The mixture was extracted with EtOAc (50 ml x 2). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude residue, which was purified by silica gel column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-3% MeOH) to give a mixture of 5- bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 5-bromo-6-methoxy-2-((2(tri-methylsilyl)ethoxy)methyl)-2H -indazole as a brown oil (315 mg, 80%). MS m/z 357, 359 [M+H] ⁺ .

Step 2. Mixture of 5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 5-bromo-6methoxy-2-((2-(trimethylsilyl)ethoxy) methyl)-2H-indazole (300 mg, 0.84 mmol), B ₂ (pin) ₂ (235 mg, 0.924 mmol), Pd(dppf)Cl ₂ (61 mg, 0.084 mmol) and KOAc (165 mg, 1 .68 mmol) in 1,4-dioxane (5 ml) was stirred at 90°C under N ₂ for 3 hours. The solution was concentrated to give a crude mixture of 6methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxa-borolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 112 045009 indazole and 6-methoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxa-borolan-2-yl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-indazole, which was used in the next step without further purification. MS m/z 405 [M+H]+.

Step 3. Mixture of 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-indazole and 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole, 6-chloro -3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine (obtained in example 13, step 2, 170 mg, 0. 58 mmol), Pd(dppf)Cl ₂ (42 mg, 0.058 mmol) and K2CO3 (199 mg, 1.45 mmol) in 1,4-dioxane-H ₂ O (4 ml) were stirred at 90°C in an N2 atmosphere for 3 hours. The solution was concentrated and the residue was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-3% MeOH) gradient to give a mixture of 6-(6-methoxy-1((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-5-yl)-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine and 6-(6-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazine as a brown oil (217 mg, 70%). MS m/z 537 [M+H] ⁺ .

Step 4. Into a solution of 6-(6-methoxy-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazol-5-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl ) -3H-[1,2,3]triazolo[4,5-c]pyridazine and 6-(6-methoxy-2-((2(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)- 3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazine (217 mg, 0.4 mmol) in CH ₂ Cl ₂ ( 1 ml) TFA (912 mg, 8 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give the crude trifluoroacetic acid salt 6-(6-methoxy-1H-indazol-5-yl)-3-(2,2,6,6tetramethylpiperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazine, which was used in the next step without further purification (150 mg, 90%). MS m/z 407 [M+H] ⁺ .

Step 5. To a solution of 6-(6-methoxy-1H-indazol-5-yl)-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazine (150 mg, 0.37 mmol) in CH ₂ Cl ₂ (3 ml) was added 1 M BBr ₃ in CH ₂ Cl ₂ (3 ml, 3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with MeOH (5 ml) and concentrated. The residue was dissolved in MeOH (with 2.5% NH4OH), filtered and concentrated to give the crude product, which was purified by preparative TLC eluting with CH ₂ Cl/30% MeOH (with 2.5% NH4OH) to give 5-( 3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-1H-indazol-6-ol as yellow solids (70 mg, 48%).

MS m/z 393.8 [M+H] ⁺ ; ^1H NMR (DMSO-d6) δ: 12.79 (br.s, 1H), 11.00 (br.s, 1H), 8.98 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.06 (s, 1H), 5.58-5.87 (m, 1H), 2.17-2.35 (m, 4H), 1.43 (s, 6H), 1.26 (s, 6H); 1H was not detected (NH).

Example 27.

Receiving connection 82.

Step 1: Mixture of 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden1-one (1.04 g , 3.6 mmol), 6-chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazine (obtained in example 13 , stage 2, 882 mg, 3 mmol), Pd (dppf)Cl ₂ (220 mg, 0.3 mmol) and K2CO3 (828 mg, 6 mmol) in 1,4-dioxane (12 ml) and water (3 ml ) was stirred at 90°C under N2 for 3 hours. The solution was concentrated and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-5% MeOH), to give 6-methoxy-5- (3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-2,3-dihydro-1H-indene -1-one as an orange-yellow solid (1 g, 79%).

MS m/z 421 [M+H] ⁺ ; 1H NMR (CDCl ₃ ) δ 8.75 (s, 1H), 8.18 (s, 1H), 7.40 (d, J=5.0 Hz, 1H), 5.85-5.67 (m , 1H), 3.95 (s, 3H), 3.26-3.13 (m, 2H), 2.88-2.72 (m, 2H), 2.28 (d, J=7.3 Hz, 4H), 1.27 (d, J=21.2 Hz, 12H).

Step 2. Mixture of 6-methoxy-5-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6-yl) -2,3-dihydro-1H-inden-1-one (210 mg, 0.5 mmol), NH ₂ OH-HCl (69 mg, 1 mmol) and Et ₃ N (0.17 ml, 1.25 mmol ) in EtOH (4 ml) was stirred at 90°C for 4 hours. The reaction mixture was cooled

- 113 045009 to room temperature. The precipitate was collected by filtration, washed with Et2O and dried to give the oxime 6-methoxy-5-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4 ,5c]pyridazin-6-yl)-2,3-dihydro-1H-inden-1-one as a white solid (174 mg, 80%). MS m/z 436 [M+H]+.

Step 3. To a solution of 6-methoxy-5-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6 oxime -yl)-2,3-dihydro-1H-inden-1-one (66 mg, 0.15 mmol) in CH ₂ Cl ₂ (3 ml) was added 1 M BBr ₃ in CH ₂ Cl ₂ (2 ml, 2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then quenched with MeOH (5 ml) and concentrated. The residue was dissolved in MeOH (with 2.5% NH4OH), filtered, concentrated and then purified by preparative HPLC to give the oxime 6-hydroxy-5-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H -[1,2,3]triazolo[4,5-c]pyridazin6-yl)-2,3-dihydro-1H-inden-1-one as a yellow solid (33 mg, 52%).

MS m/z 421.9 [M+H] ⁺ ; ^1H NMR (DMSO- _db ) δ: 10.93-11.19 (m, 2H), 9.02 (s, 1H), 7.96 (s, 1H), 7.22 (s, 1H) , 5.67 (tm, J=12.3, 3.4 Hz, 1H), 2.91-3.08 (m, 2H), 2.74-2.91 (m, 2H), 2.20 (dd, J=12.1, 3.3 Hz, 2H), 2.11 (t, J=12.3 Hz, 2H), 1.35 (s, 6H), 1.18 (s, 6H) ; 1H was not detected (NH or OH).

Example 28.

Getting connection 42.

Step 1. Mixture of 6-chloro-1H-(2,2,6,6-tetramethyl-4-niperidyl)pyridazine-3,4-diamine (prepared in Example 13, Step 1, 200 mg, 0.35 mmol) in triethylorthoformate (8 ml) and aqueous 4N HCl (1 drop) were stirred at 100°C for 24 hours. The crude reaction mixture was diluted with MeOH to obtain a clear solution and concentrated. The residue was purified by silica gel column chromatography, eluting with a MeOH (2.5% NH ₄ OH)/CH ₂ Cl ₂ (0-20% MeOH/NH4OH) gradient to give 3-chloro-7-(2,2,6, 6-Tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazine (144 mg, 70%) as a clear oil that solidified under high vacuum. MS m/z 294.5 [M+H] ⁺ .

Step 2. To a suspension of 3-chloro-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazine (95 mg, 0.32 mmol) in CHCl ₃ (0. 5 ml) and MeOH (0.5 ml), N-bromosuccinimide (178 mg, 0.98 mmol) was added. The reaction mixture was heated at 70°C for 48 hours. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with MeOH (with 2.5% NH ₄ OH)/CH ₂ Cl ₂ (0-10% MeOH/NH ₄ OH), to obtain 6-bromo-3-chloro-7-(2,2,6,6-tetramethyl-4piperidyl)imidazo[4,5-c]pyridazine (80 mg, 66%) as white solid.

Step 3. To a solution of 6-bromo-3-chloro-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazine (25 mg, 0.07 mmol) in MeOH (1 ml) 8 M methylamine in MeOH (63 µl, 0.5 mmol) was added. The reaction mixture was stirred at 50°C until complete conversion of the starting material was achieved. The reaction mixture was concentrated and purified by silica gel column chromatography, eluting with a gradient of MeOH (with 2.5% NH ₄ OH)/CH ₂ Cl ₂ (0-30% MeOH/NH ₄ OH) to give 3-chloro-N-methyl -7(2,2,6,6-tetra-methyl-4-piperidyl)imidazo[4,5-c]pyridazin-6-amine (20 mg, 65%) as a clear solid. MS m/z 323.2 [M+H] ⁺ .

Step 4. Mixture of 3-chloro-N-methyl-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazin-6amine (20 mg, 0.062 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (3.3 mg, 0.004 mmol) and 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl]-1tetrahydropyran-2-ylpyrazole (prepared in Example 1, step 7, 32 mg, 0.077 mmol) in 1,4-dioxane (1 ml) was purged with argon for 10 minutes. A solution of potassium carbonate (15 mg, 0.11 mmol) in water (0.2 ml) was then added and the reaction mixture was heated to 90°C for 3 hours. The reaction mixture was diluted with EtOAc and filtered through a short pad of celite (rinsing using 20% MeOH/CH ₂ C1 ₂ ). The organic solution was concentrated and purified by silica gel column chromatography, eluting with MeOH/CH ₂ Cl ₂ (0-20% MeOH) to give 3-[2-(methoxymethoxy)-4-(1tetrahydro-pyran-2-ylpyrazol-4 -yl)phenyl]-N-methyl-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5c]pyridazin-6-amine (17 mg, 68%) as light brown solid matter. MS m/z 575.4 [M+H] ⁺ .

Step 5. To 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-methyl-7

- 114 045009 (2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazin-6-amine (17 mg, 0.03 mmol) was added 4N HCl in dioxane (1 ml, 4 mmol). The reaction mixture was stirred for 4 hours and then filtered to collect precipitated solids. The solid was further washed with diethyl ether and dried to obtain 2-[6-(methylamino)-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazin-3yl]-5 -(1H-pyrazol-4-yl)phenol dihydrochloride as a yellow solid (12.6 mg, 60%).

MS m/z 447.9 [M+H]+; 1H NMR (methanol- _d4 ) δ: 8.79 (s, 1H), 8.50-8.62 (m, 2H), 7.44-7.55 (m, 2H), 7.40 (s , 1H), 5.26-5.41 (m, 1H), 3.85 (s, 3H), 2.50-2.64 (m, 2H), 2.32-2.49 (m, 2H ), 1.71 (s, 6H), 1.63 (s, 6H); 4H were not detected (3 NH and OH).

Using the procedure described for Example 28 above, additional compounds described herein were prepared by appropriate substitution of starting materials, reagents, and reaction conditions to provide compounds selected from the following compounds:

Compound Data 9 MS m/z 434.4 [M+H] ⁺ , 'H NMR (methanol- _c14 ) δ: 8.15 (br.s, 2H), 7.99 (s, 1H), 7.69 (d , J=8.2 Hz, 1H), 7.40 (dd, J=7.6, 1.3 Hz, 1H), 7.31 (d, J=l.9 Hz, 1H), 4.96 -5.07 (m, 1H), 2.71 (t, 1=13.6 Hz, 2H), 2.18 (dd, 1=13.6, 3.5 Hz, 2H), 1.66 ( s, 6H), 1.58 (s, 6H); 4 H were not detected (2 OH and 2 NH). 40 MS m/z 448.2 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 9.13 (s, 1H), 8.26 (s, 2H), 7.55 (d, J= 8.2 Hz, 1H), 7.38 (d , J= 1.3 Hz, 1H), 7.31 (d, J= 1.3 Hz, 1H), 5.40-5.51 (m, 1H), 4.79 (s, ZN), 2 .54-2.70 (m, 4H), 1.73 (s, 6H), 1.65 (s, 6H); 3 H were not detected (2 NH and OH). 49 MS m/z 461.9 [M+H] ⁺ ; 'H NMR (methanol- _c14 ) δ: 8.78 (s, 1H), 8.28-8.36 (m, 2H), 7.34-7.50 (m, 2H), 7.30 ( s, 1H), 5.25-5.41 (m, 1H), 4.11-4.15 (kv, J= 6.0 Hz, 2H), 2.51-2.65 (m, 2H) , 2.33-2.49 (m, 2H), 1.71 (s, 6H), 1.63 (s, 6H), 1.38-1.41 (t, J= 6.0 Hz, ZN ); 4 H were not detected (3 NH and OH).

Example 29.

Getting connection 3.

Step 1. The oven-dried flask was equipped with a magnetic stirrer and 3-chloro-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazine (obtained in example 29, step 1, 60 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.015 mmol) and 4-[3(methoxymethoxy)-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2ylpyrazole (obtained in example 1, step 7, 75 mg, 0.15 mmol) and Na ₂ CO ₃ (46 mg, 0 .45 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (3 ml) and water (0.4 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3 X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-20% MeOH) to give 3-(2-(methoxymethoxy)-4-( 1-(tetrahydro-2Hpyran-2-yl)-III-pyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazine (60 mg, 75%) as a yellow solid. MS m/z 546.2 [M+H] ⁺ .

Step 2. 3-(2-(Methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-7(2,2,6,6- Tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazine (35 mg, 0.05 mmol) was dissolved in 1 ml of methanol. 4N HCl in 1,4-dioxane (500 µl, 2 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, triturated with 20% MeOH/ether, and the precipitate was filtered and dried to give 5 -(1H-pyrazol-4-yl)-2-(7-(2,2,6,6tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)phenol (25 mg , 86%).

MS m/z 418.1 [M+H]+, ^1H NMR (methanol-64) δ: 9.19 (s, 1H), 8.86 (s, 1H), 8.15 (s, 2H) , 7.86 (d, J=8.2 Hz, 1H), 7.39 (dd, J=8.2, 1.9 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 5.39-5.58 (m, 1H), 2.68 (t, J=13.9 Hz, 2H), 2.48 (dd, J=13.9, 3.5 Hz, 2H ), 1.72 (s, 6H), 1.63 (s, 6H); 3 H was not detected (OH and 2 NH).

Using the procedure described for Example 29 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 4 MS m/z 438.3 [M+H] ⁺ ; Ή NMR (methanol- _c14 ) δ: 9.29 (s, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.41 (d, J=l.3 Hz, 2H) , 7.84-7.95 (m, 2H), 5.44-5.65 (m, 1H), 2.73 (t, J=13.9 Hz, 2H), 2.51 (dd, J =13.9, 3.2 Hz, 2H), 1.74 (s, 6H), 1.65 (s, 6H); 2 H was not detected (2 NH).

Example 30.

Getting connection 5.

Step 1: Mixture of 6-chloro-1H-(2,2,6,6-tetramethyl-4-piperidyl)pyridazine-3,4-diamine (prepared in Example 13, Step 1, 180 mg, 0.63 mmol) in triethylorthoacetate (4 ml) and HCOOH (0.2 ml) were stirred at 100°C for 24 hours. The reaction mixture was then cooled to room temperature and the precipitate was collected by filtration and dried under vacuum to give 3-chloro-7-(2. 2,6,6-tetramethyl-4piperidyl)imidazo[4,5-c]pyridazine (112 mg, 56%). MS m/z 308.2 [M+H]+.

Stage 2. The oven-dried flask was equipped with a magnetic stirrer and 3-chloro-6-methyl-7-(2,2,6,6-tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazine ( 50 mg, 0.14 mmol), tetrakis(triphenylphosphine) palladium(0) (25 mg, 0.015 mmol), 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl1,3,2 -dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-ylpyrazole (obtained in example 1, step 7, 75 mg, 0.15 mmol) and Na ₂ CO ₃ (46 mg, 0.45 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4dioxane (1 ml) and water (0.25 ml) were added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography, eluting with a MeOH/CH ₂ Cl ₂ 0-20% MeOH gradient to give 3-(2-(methoxymethoxy)-4-(1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-6-methyl-7(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4 ,5-c]pyridazine (60 mg, 66%) as a yellow solid. MS m/z 560.5 [M+H] ⁺ .

Step 3. To a solution of 3-(2-(methoxymethoxy)-4-(1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-6-methyl-7-(2 ,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazine (45 mg, 0.05 mmol) in 1 ml of methanol was added 4N HCl in 1,4-dioxane (500 μl , 2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the residue was triturated in 20% MeOH/ether, and the precipitate was filtered and dried to give 2-(6-methyl-7-(2,2,6,6tetramethylpineridine- 4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol hydrochloride (30 mg, 88%) as a yellow solid.

MS m/z 432.5 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 8.74 (s, 1H), 8.31-8.44 (m, 2H), 7.79 (d, J=8.2 Hz, 1H), 7 .45 (dd, J=8.2, 1.6 Hz, 1H), 7.37 (s, 1H), 5.05-5.20 (m, 1H), 3.02 (s, 3H), 2.96 (t, J=13.6 Hz, 2H), 2.30-2.40 (m, 2H), 1.71 (s, 6H), 1.63 (s, 6H); 3 H was not detected (OH and 2 NH).

Using the procedure described for Example 30 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds:

Compound Data 6 MS m/z 452.4 [M+H] ⁺ ; Ή NMR (methanol-c1 ₄ ) δ: 8.65 (s, 1H), 8.38 (d, J=1.6 Hz, 2H), 7.90 (dd, J=11.3, 6.0 Hz, 1H), 7.85 (dd, 1=10.7, 6.0 Hz, 1H), 5.095.22 (m, 1H), 3.05 (s, ZN), 3.02 (t, 1 =13.6 Hz, 2H), 2.37 (dd, J=13.6, 3.8 Hz, 2H), 1.72 (s, 6H), 1.63 (s, 6H); 2 H was not detected (2 NH).

- 116 045009

Example 31.

Getting connection 1.

Step 1: To a solution of 3,6-dibromopyrazin-2-amine (504 mg, 2 mmol) and 2,2,6,6-tetramethylpiperidin4-amine (0.35 ml, 2 mmol) in EtOH (2 ml) was added (0.38 ml, 2 mmol). The reaction mixture was exposed to microwave radiation at 180°C for 3.5 hours. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography, eluting with a MeOH (2.5% NH ₄ OH)/CH ₂ Cl ₂ (0-30% MeOH/NH ₄ OH) gradient to give 5-bromo-N-(2,2, 6,6tetramethylpiperidin-4-yl)pyrazin-2,3-diamine (0.35 g, 54%). MS m/z 328.0, 330.0 [M+H]+.

Step 2: 5-Bromo-N2-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazin-2,3-diamine (0.18 mg, 0.54 mmol) was dissolved in formic acid (0.36 ml), and the resulting solution was heated to 100°C for 3 hours. The solution was concentrated to obtain crude 5-bromo-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1Himidazo[4,5-b ]pyrazine (0.18 g, 97%). MS m/z 338.1, 340.1 [M+H] ⁺ .

Stage 3. The oven-dried flask was equipped with a magnetic stirrer and 5-bromo-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazine (50 mg, 0.15 mmol), 4-(3(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H -pyran-2-yl)1H-pyrazole (obtained in example 1, step 7, 62 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.015 mmol) and Na ₂ CO ₃ (46 mg, 0.45 mmol). The flask was closed with a rubber stopper with a membrane, and then evacuated and filled with argon (this operation was repeated a total of 3 times). 1,4-dioxane (3 ml), water (0.4 ml) was added and the reaction mixture was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (2 ml) and extracted with EtOAc (3 X). The combined organic phases were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography eluting with a MeOH/CH ₂ Cl ₂ 0-20% MeOH gradient to give 5-(2-(methoxymethoxy)-4-(1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl)phenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-III-imidazo[4,5-b] pyrazine (60 mg, 75%) as a yellow solid. MS m/z 546.4 [M+H] ⁺ .

Step 4. 5-(2-(Methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-1 (2,2,6,6- tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazine (30 mg, 0.05 mmol) was dissolved in methanol (1 ml), then 4N HCl in 1,4-dioxane (500 µl, 2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, triturated with 20% MeOH/ether, and the precipitate was filtered and dried to give 5-(1H-pyrazol-4-yl)-2-( 1-(2,2,6,6tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)phenol hydrochloride (22 mg, 86%) as a yellow solid.

MS m/z 418.5 [M+H] ⁺ ; ^1H NMR (methanol- _d4 ) δ: 9.29 (s, 1H), 8.96-9.07 (m, 1H), 8.32 (s, 2H), 8.08-8.15 ( m, 1H), 7.21-7.39 (m, 2H), 5.29-5.44 (m, 1H), 2.59-2.72 (m, 2H), 2.39-2. 49 (m, 2H), 1.70 (s, 6H), 1.59 (s, 6H); 3H were not detected (OH and 2 NH).

Using the procedure described for Example 31 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds: ____________

Compound Data 2 MS m/z 438.4 [M+H] ⁺ ; 'H NMR (methanol-sC) δ: 9.33 (s, 1H), 9.09 (d, J=l.6 Hz, 1H), 8.36 (d, J=l.3 Hz, 2H) , 7.97 (dd, 1=11.7, 6.3 Hz, 1H), 7.77 (dd, J=12.0, 6.3 Hz, 1H), 5.39-5.49 (m , 1H), 2.67 (t, J=13.9 Hz, 2H), 2.46 (dd, J=13.9, 3.5 Hz, 2H), 1.71 (s, 6H), 1 .61 (s, 6H). 2 H was not detected (2 NH).

- 117 045009

Example 32.

Getting connection 140.

Step 1: To a solution of 5-bromo-2-chloro-pyridin-3-ol (5 g, 23.9 mmol) in DMF (50 ml) was added sodium hydride (1.2 g, 30 mmol, 60 wt.% in mineral oil), and the reaction mixture was stirred for 30 minutes at room temperature. MOMCl (2.2 mL, 29.1 mmol) was added and the reaction mixture was stirred for another hour. The reaction mixture was quenched with water and partitioned between EtOAc and water. The combined organic layers were dried over MgSO ₄ and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc/hexanes (0-25% EtOAc), to give 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (4.8 g) as a white solid.

^1H NMR (CDCl3) δ: 8.14 (d, J=2.1 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 5.30 (s, 2H), 3 .55 (s, 3H).

Step 2. Mixture of 5-bromo-2-chloro-3-(methoxymethoxy)pyridine (1 g, 3.96 mmol), 1-(tetrahydro-2Hpyran-2-yl)-4-(4,4,5,5 -tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 5.40 mmol), complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium(P) with dichloromethane ( 0.33 g, 0.40 mmol) and potassium acetate (1.3 g, 13 mmol) were purged with argon. 1,4-dioxane (12 ml) and water (3 ml) were added and the reaction mixture was heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite and washed with MeOH. The organic layers were concentrated and the residue was chromatographed on silica gel, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc) to give 2-chloro-3-(methoxymethoxy)-5-(1-tetrahydropyran-2-yl-pyrazol- 4-yl)pyridine (1.2 g, 93%).

MS m/z 324.2 [M+H]+, ¹ H NMR (CDCl ₃ ) δ: 8.20 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.56 (d, J=2.0 Hz, 1H), 5.42 (d, J=6.6 Hz, 1H), 5.32 (s, 2H), 4.08-4.16 (m , 1H), 3.74 (td, J=11.2, 2.8 Hz, 1H), 3.55 (s, 3H), 2.032.18 (m, 3H), 1.61-1.78 ( m, 3H).

Step 3: 2-chloro-3-(methoxymethoxy)-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyridine (110 mg, 0.34 mmol), tributyl was added to the reaction vial under microwave irradiation (tributylstannyl)stannane (410 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol) and lithium chloride (90 mg, 2.0 mmol). The mixture was purged with argon. 1,4-dioxane (2 ml) was added and the reaction mixture was heated using microwave radiation for 1.5 hours at 150°C. The reaction mixture was cooled to room temperature, filtered through celite and washed with MeOH. The organic layers were concentrated and the residue was purified by silica gel column chromatography, eluting with a gradient of EtOAc/hexanes (0-50% EtOAc) to give 3-(methoxymethoxy)-5(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-2-(tributylstannyl)pyridine (106 mg, 55%).

MS m/z 580.6 [M+H] ⁺ , 1H NMR (CDCl3) δ: 8.58 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7. 40 (s, 1H), 5.38-5.45 (m, 1H), 4.03 (br.d, J=11.6 Hz, 1H), 3.93-4.07 (m, 1H) , 3.66-3.77 (m, 1H), 3.63 (s, 1H), 2.16 (s, 3H), 1.26-1.40 (m, 18H), 1.11-1 .18 (m, 6H), 0.90 (t, J=7.3 Hz, 9H).

Step 4: 3-(methoxymethoxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(tributylstannyl) was added to the reaction vial under microwave irradiation. pyridine (0.11 g, 0.19 mmol), 6-chloro-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с] pyridazine (300 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) and 1,4dioxane (2 ml). Argon was bubbled through the mixture and heated using microwave radiation for 1.5 hours at 150°C. The solvent was removed and the crude mixture was purified by silica gel chromatography using MeOH/CH ₂ Cl ₂ (0-15% MeOH) to give 6-(2-(methoxymethoxy)-4-(4-methyl1H-imidazol-1-yl) phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (0.04 g, 72%) with minor impurities. MS m/z 548.6 [M+H] ⁺ . The compound was used in the next step without further purification.

Step 5. To a solution of 6-(2-(methoxymethoxy)-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N-methyl-N(2,2,6,6-tetramethylpiperidin-4- yl)-1,2,4-triazin-3-amine (0.02 g, 0.04 mmol) in MeOH (0.5 ml) was added 4.0 M HCl in dioxane (1 ml). The mixture was stirred for 1 hour at room temperature. Rastvo

- 118 045009 Rite was removed and the crude mixture was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH2C12 (0-15% MeOH), to give 5-(1H-pyrazol-4-yl)-2-(3-(2, 2,6,6-tetramethylpiperidin-4yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)pyridin-3-ol (7 mg) as a yellow solid.

MS m/z 420.5 [M+H]+, ^1H NMR (methanol- _d4 ) δ: 9.13-9.20 (m, 1H), 8.48 (s, 1H), 8.17 (d, J=8.9 Hz, 1H), 7.56 (m, 2H), 5.97 (dt, J=11.1, 5.5 Hz, 1H), 2.65-2.75 ( m, 4H), 1.77-1.80 (m, 6H), 1.64 (s, 6H); 3H were not detected (1 OH and 2 NH).

Example 33.

Receiving connection 136.

stage 3

Step 1. 1-Tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.57 g, 20.0 mmol), 5 -bromo-2-chloro-3-fluoropyridine (4.01 g, 19.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (493.4 mg, 0.60 mmol), 1,4-dioxane (20.0 ml) and aqueous potassium carbonate (2.0 M, 12.0 ml) were mixed, purged with argon and stirred at 80°C for 3 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel, eluting with a gradient of EtOAc/hexanes 0-60% EtOAc) to give 2-chloro-3-fluoro-5-(1-tetrahydropyran-2-ylpyrazol4-yl)pyridine (3.89 g, 73%). MS m/z 282.3 [M+H]+.

Step 2: Nickel(N) chloride (484.4 mg, 2.04 mmol), triphenylphosphine (2.14 g, 8.14 mmol) and N,Ndimethylformamide (11.0 ml) were mixed, degassed with argon, then stirred at 50°C for 45 minutes. 2-chloro-3-fluoro-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyridine (286.7 mg, 1.02 mmol) and 3-chloro-7-(2,2,6, 6,-Tetramethyl-4-piperidyl)-5,6-dihydropyrrolo-[2,3-c]pyridazine (300.0 mg, 1.02 mmol), the reaction mixture was degassed with argon and then stirred at 50°C in for 16 hours. The reaction mixture was partitioned between CH ₂ Cl ₂ , MeOH, brine and aqueous ammonium hydroxide (30%) (approximately 9:1:5:5). The aqueous layer was extracted twice with CH ₂ Cl ₂ /MeOH (9:1) and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and then filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH with 2.5% by volume with the addition of 30% aqueous ammonium hydroxide) to give 3-[3-fluoro-5-( 1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-7(2,2,6,6-tetramethyl-4-piperidyl)-5,6-dihydropyrrolo[2,3-c]pyridazine (735.0 mg, 19%). MS m/z 506.4 [M+H]+.

Step 3. 3-[3-Fluoro-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-7-(2,2,6,6-tetramethyl-4piperidyl)-5,6 -Dihydro-pyrrolo[2,3-c]pyridazine (413.7 mg, 0.82 mmol) was dissolved in a methanol solution of sodium methoxide (25 wt.%, 15.0 ml) and stirred at 50°C for 3 hours The reaction mixture was partitioned between CH ₂ Cl ₂ and H ₂ O, the aqueous layer was extracted with CH ₂ Cl ₂ , and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was mixed with manganese dioxide (activated, 3.56 g, 41.11 mmol) in CH ₂ Cl ₂ (6.0 ml) and stirred at 50°C in a sealed tube for 16 hours. The reaction mixture was filtered through celite and rinsed minimum amount of CH ₂ Cl ₂ . The filtrate was mixed with manganese dioxide (activated, 3.7 g, 42.5 mmol) and stirred at 60°C in a sealed tube for 24 hours. The reaction mixture was filtered through celite, rinsed with CH ₂ Cl ₂ /MeOH, and the filtrate concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-100% MeOH with 2.5% by volume with the addition of 30% aqueous ammonium hydroxide) to give 3-[3-methoxy-5-( 1tetrahydro-pyran-2-ylpyrazol-4-yl)-2-pyridyl]-7-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolo[2,3c]pyridazine (47.3 mg, 11% ). MS m/z 516.3 [M+H]+.

Step 4. 3-[3-Methoxy-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-7-(2,2,6,6-tetramethyl4-piperidyl)pyrrolo[2, 3-c]pyridazine (47.3 mg, 0.09 mmol) and boron tribromide (1.0 M in CH2Cl2, 2.0 mL, 2.0 mmol) were combined and stirred at room temperature under argon for 20 h .

- 119 045009

The reaction mixture was quenched with MeOH and concentrated. The residue was chromatographed on a C18 reverse phase column, eluting with a gradient of 0-100% CH ₃ CN in H2O (added 0.1% v/v TFA) to give 5-(1H-pyrazol-4-yl)-2-[ 7-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolo[2,3-c]pyridazine

3-yl]pyridin-3-ol dihydrochloride (33.6 mg, 75%).

MS m/z 418.4 [M+H]+, 1H NMR (methanol^) δ: 9.53 (s, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.71 (d, J=3.1 Hz, 1H), 8.67 (br.s, 2H), 7.86 (s, 1H), 7.20 (d, J=3.4 Hz, 1H), 5 .57 (tt, J=13.1, 2.8 Hz, 1H), 2.61 (t, J=13.1 Hz, 2H), 2.42 (dd, J=13.4, 2.7 Hz, 2H), 1.74 (s, 6H), 5.55 (s, 6H), 3H not detected (2 NH and OH).

Example 34.

Getting connection 141.

Stage 1. Nickel(II) chloride hexahydrate (515.8 mg,

10.6 mmol), triphenylphosphine (11.1 g, 42.3 mmol) and N,N-dimethylformamide (52.5 ml) were mixed, degassed with argon and then stirred at 50°C for 45 minutes. 2-chloro-3-fluoro-5-(1-tetrahydropyran-2-ylpyrazol-4yl)pyridine (1.49 g, 5.3 mmol) and 6-chloro-N3-(2,2,6,6- tetramethyl-4-piperidyl)pyridazine-3,4-diamine (1.5 g, 5.3 mmol), the reaction mixture was degassed with argon and stirred at 50°C for 16 hours. The reaction mixture was partitioned between CH ₂ Cl ₂ , MeOH, saline and aqueous ammonium hydroxide (30%) (approximately 9:1:5:5). The aqueous layer was extracted twice with CH ₂ Cl ₂ /MeOH (9:1) and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was subjected to reverse phase C18 column chromatography, eluting with 0-100% CH ₃ CN in H ₂ O to give 6-[3-fluoro-5-(1tetrahydropuran-2-ulnirazol-4-yl)-2- pyrudyl]-N3-(2,2,6,6-tetramethyl-4-piperidyl)pyridazine-3,4diamine (540.0 mg, 21%). MS m/z 495.5 [M+H] ⁺ .

Step 2. 6-[3-Fluoro-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-N3-(2,2,6,6-tetramethyl-4piperidyl)pyridazin-3, 4-diamine (102.0 mg, 0.21 mmol) was dissolved in methanolic sodium methoxide solution (25 wt.%, 4.0 ml) and stirred at 50°C for 2 hours. The reaction mixture was partitioned between CH ₂ Cl ₂ and H ₂ O, the aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-100% MeOH with 2.5% by volume with the addition of 30% aqueous ammonium hydroxide) to give 6-[3-methoxy-5-( 1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]N3-(2,2,6,6-tetramethyl-4-niperudyl)pyridazin-3,4-diamine (48.1 mg, 46%) . MS m/z 507.4 [M+H] ⁺ .

Step 3. 6-[3-Methoxy-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-N3-(2,2,6,6tetramethyl-4-piperidyl)pyridazin-3, 4-Diamine (48.1 mg, 0.095 mmol), N,N-dimethylformamide (3.0 mL) and Brederek's reagent (0.2 mL, 0.99 mmol) were mixed and stirred at 100°C for 20 min. The reaction mixture was concentrated to dryness. The residue was partitioned between brine and CH ₂ Cl ₂ , and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 3-[3-methoxy-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2pyridyl]-7-(2,2,6, 6-Tetramethyl-4-piperidyl)imidazo[4,5-c]pyridazine (50.9 mg, 104%). MS m/z 517.3 [M+H] ⁺ .

Step 4. 3-[3-Methoxy-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)-2-pyridyl]-7-(2,2,6,6-tetramethyl4-piperidyl)imidazo[4, 5-c]pyridazine (50.9 mg, 0.099 mmol) and boron tribromide (1.0 M in CH2Cl2, 2.0 mL, 2.0 mmol) were mixed and stirred at room temperature under argon for 16 h. Reaction the mixture was quenched in MeOH and concentrated. The residue was purified on a reverse phase C18 column, eluting with 0-100% CH3CN in H2O (added 0.1% v/v TFA), and then subjected to silica gel chromatography, eluting with 0-100% MeOH (2.5% by volume of addition of a 30% aqueous solution of ammonium hydroxide) in CH ₂ Cl ₂ to obtain 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-4

- 120 045009 piperidyl)imidazo[4,5-c]pyridazin-3-yl]pyridin-3-ol (12.3 mg, 25%).

MS m/z 419.4 [M+H]+; 1H NMR (methanol- _d4 ) δ: 9.28 (s, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.52 (s, 2H), 8.01 ( s, 1H), 5.50 (br t, J=12.7 Hz, 1H), 2.67 (br t, J=13.0 Hz, 2H), 2.41 (br.d, J=11 .6 Hz, 2H), 1.64 (s, 6H), 1.56 (s, 6H), 3H were not detected (2 NH and OH).

Example 35.

Receiving connection 117.

stage 3

Step 1. 1-Tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (105.0 mg, 0.38 mmol), 4 ,7-dibromo-1H-benzotriazole (195.7 mg, 0.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (16.1 mg, 0.020 mmol), 1,4- dioxane (2.0 ml) and aqueous potassium carbonate (1.0 M, 1.0 ml) were mixed and stirred at 80°C for 16 hours. The reaction mixture was partitioned between EtOAc, H ₂ O and AcOH, and the aqueous layer extracted once with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc/hexanes (0-100% EtOAc), to give 7-bromo-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1H-benzotriazole (67.6 mg, 51%). MS m/z 348.2 [M+H]+.

Step 2. 7-Bromo-4-(1-tetrahydropyrαn-2-ylpyrazol-4-yl)-1H-benzotriazole (67.6 mg, 0.19 mmol), cesium carbonate (238.5 mg, 0.73 mmol ), acetonitrile (2.0 ml) and 1-(chloromethyl)-4-methoxybenzene (70.0 µl, 0.516 mmol) were mixed and stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was partitioned between EtOAc and H2O . The aqueous layer was extracted once with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of ESA/hexanes (0100% EtOAc) to give 7-bromo-1-[(4-methoxyphenyl)methyl]-4-(1-tetrahydropyran-2-yl-pyrazol-4yl) -benzotriazole (26.4 mg, 29%). MS m/z 490.3 [M+Na]+.

Step 3. 7-Bromo-1-[(4-methoxyphenyl)methyl]-4-(1-tetrahydro-pyran-2-ylpyrazol-4yl)benzotriazole (26.4 mg, 0.056 mmol), chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)[2(2'-amino-1,G-biphenyl)]palladium(P) (4.8 mg, 0.0065 mmol), bis(pinacolato) diboron (18.5 mg, 0.072 mmol) and potassium acetate (dried at 250°C under vacuum immediately before use, 21.7 mg, 0.22 mmol) and 1,4-dioxane (1.0 ml) were mixed, degassed with argon and stirred at 110°C for 1 hour. 6-Chloro-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (from Example 13, step 2, 16.6 mg, 0.0563 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl) palladium(II) (4.1 mg, 0.006 mmol) and aqueous potassium carbonate (1.0 M, 0.5 ml), the solution was degassed with argon and then stirred at 80°C for 64 hours. The reaction mixture was partitioned between EtOAc and H ₂ O, and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with a MeOH/CH ₂ Cl ₂ (0-30% MeOH) gradient to give 6-[3-[(4-methoxyphenyl)methyl]-7-(1-tetrahydropyran-2-ylpyrazol- 4-yl)-benzotriazol-4-yl]3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (9.2 mg, 25%). MS m/z 648.7 [M+H]+.

Step 4. 6-[3-[(4-Methoxyphenyl)methyl]-7-(1-tetrahydropyran-2-ylpyrazol-4-yl)benzotriazol-4yl]-3-(2,2,6,6- tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazine (9.2 mg, 0.014 mmol) was dissolved in trifluoroacetic acid (2.0 ml) and stirred at 60°C for 2 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to reverse phase C18 column chromatography, eluting with 0-100% CH3CN in H2O (add 0.1% v/v TFA) to give 6-[7-(1H-pyrazol-4-yl)-3Hbenzotriazole -4-yl]-3-(2,2,6,6-tetramethyl-4-piperidyl)triazolo[4,5-c]pyridazin-2,2,2-trifluoroacetic acid (1.7 mg, 21%) .

MS m/z 444.5 [M+H]+; 1H NMR (methanol- _d4 ) δ: 9.24 (br.s, 1H), 8.64 (s, 2H), 8.37-8.41 (m, 1H), 7.91 (d, J =7.6 Hz, 1H), 6.03 (ddd, J=16.1, 10.8, 5.5 Hz, 1H), 2.66-2.74 (m, 4H), 1.76- 1.85 (m, 6H), 1.61-1.70 (m, 6H), 3 H not detected (NH).

- 121 045009

Example 36.

Getting connection 105.

Step 1: To a solution of methyl 2-hydroxyacetate (218 mg, 2.37 mmol) in THF (3 ml) was added NaH (93 mg, 2.33 mmol, 60 wt%) at 0°C. The reaction mixture was stirred for 30 min at 0°C and the resulting suspension was slowly added to a solution of methyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.37 mmol) in THF (3 ml) at 0°C. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc and H2O. The organic phase was dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (20-50% EtOAc) to give methyl 6-chloro-4-(2methoxy-2-oxo-ethoxy)pyridazine-3-carboxylate (284 mg, 46%) as a white solid. MS m/z 261.4 [M+H]+.

Step 2: To a solution of methyl 6-chloro-4-(2-methoxy-2-oxo-ethoxy)pyridazine-3-carboxylate (284 mg, 1.09 mmol) in THF (11.0 ml) add sodium methoxide dropwise (0.22 ml, 1.2 mmol, 5.4 mol/L in MeOH) at room temperature. The reaction mixture was stirred at room temperature for 15 min, then quenched with 1 M HCl. The mixture was partitioned between H2O and EtOAc and the organic phases were collected and washed with brine and concentrated to give methyl 3-chloro-7hydroxyfuro[3,2-c]pyridazine-6-carboxylate (230 mg, 92%) as an off-white solid substances. MS m/z 229.2 [M+H] ⁺ .

Step 3. Mixture of 1,G-bis(diphenylphosphino)ferrocene-palladium(P)dichloride complex with dichloromethane (18 mg, 0.022 mmol), 4-(3-(methoxymethoxy)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (118 mg, 0.29 mmol), methyl 3-chloro-7hydroxyfuro[3 ,2-c]pyridazine-6-carboxylate (50 mg, 0.22 mmol) and an aqueous solution of 2 M K ₂ CO ₃ (0.22 ml, 0.44 mmol) in dioxane (1 ml) were bubbled with argon for 10 minutes, then heated to 90°C for 3 hours. The reaction mixture was cooled to room temperature and filtered through celite, washing with MeOH. The organic layers were concentrated and the residue was purified by chromatography on silica gel, eluting with a gradient of MeOH/CH ₂ Cl ₂ (5-20% MeOH) to give methyl 7hydroxy-3 -(2-(methoxy-methoxy)-4-( 1 -( tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-4-yl)phenyl)-furo[3,2c]pyridazine-6-carboxylate (75 mg, 71%) as a light brown solid. MS m/z 481.4 [M+H] ⁺ .

Step 4. To a solution of methyl 7-hydroxy-3-(2-(methoxy-methoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)1H-pyrazol-4-yl)phenyl)-furo[ 3,2-c]pyridazine-6-carboxylate (280 mg, 0.58 mmol) in DMSO (7 ml) was added to an aqueous solution of 1 M NaOH (1.5 ml, 1.5 mmol). The reaction mixture was heated to 50°C for 1 hour, then cooled to room temperature. DMF (7 ml), Cs ₂ CO ₃ (360 mg, 1.1 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (300 mg, 0.84) were added mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted once with CH2Cl2. The organic phase was dried over Na ₂ SO ₄ , concentrated, and the residue was purified by chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (20-60% EtOAc), to give 3-(2-(methoxymethoxy)-4-(1-(tetra -hydro-2H-pyran-2-yl)1H-pyrazol-4-yl)phenyl)furo[3,2-c]pyridazin-7-yl trifluoromethanesulfonate (43 mg, 13%) as a white solid. MS m/z 555.2 [M+H] ⁺ .

Step 5. Mixture of 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6tetrahydropyridine (27 mg , 0.10 mmol), complex of 1'-bis(diphenylphosphino)ferrocenepalladium(I) dichloride with dichloromethane (7 mg, 0.0085 mmol), 3-(2-(methoxymethoxy)-4-(1-(tetrahydro2H-pyran -2-yl)-1H-pyrazol-4-yl)phenyl)furo[3,2-c]pyridazin-7-yl trifluoromethanesulfonate (43 mg, 0.078 mmol) and an aqueous solution of 2 M K2CO3 (0.12 ml, 0 .24 mmol) in dioxane (0.5 ml) was bubbled with argon for 10 minutes, then heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite, washing with MeOH. The organic layers were collected and the residue was purified by silica gel chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-50% MeOH) to give 3-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran -2-yl)-1H-pyrazol-4yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c ]pyridazine (7 mg, 16%) in the form of a yellow film. MS m/z 544.5 [M+H] ⁺ .

- 122 045009

Step 6. 3-(2-(Methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-7(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridazine (7 mg, 0.013 mmol) was dissolved in MeOH (0.5 ml). HCl (0.3 ml, 1.2 mmol, 4M in dioxane) was added and the reaction mixture was stirred at 40°C for 30 minutes. The reaction mixture was concentrated and the residue was purified by reverse phase column chromatography, eluting with 0-100% MeCN/H2O (0.1% TFA). The product was dissolved in HCl (2 ml, 1.25 M in MeOH) and concentrated to give 5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6tetramethyl-1,2,3 ,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridazin-3-yl)phenol hydrochloride as a yellow film (2.0 mg, 34%).

MS m/z 416.5 [M+H]+; ¹ H NMR (methanol-d ₄ ) δ: 8.96 (s, 1H), 8.81 (s, 1H), 8.39 (br.s, 2H), 7.92 (d, J=8, 2 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 2.85 (s, 2H), 1 .72 (s, 6H), 1.60-1.66 (m, 6H), 3 H was not detected (2 NH and OH).

Example 37.

Receiving connection 163.

Step 1. Mixture of Pd ₂ (dba) ₃ (4.3 mg, 0.0047 mmol), (Me) ₄ tert-butyl XPhos (5.8 mg, 0.012 mmol), toluene (0.6 ml) and 1, 4-dioxane (0.15 ml) was bubbled with argon, then heated to 120°C for 5 min and cooled to room temperature. Anhydrous K ₃ PO ₄ (41.0 mg, 0.19 mmol), triazole (9.5 mg, 0.11 mmol), and 3-(methoxymethoxy)-4-(3-(2,2,6, 6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl)phenyl trifluoromethanesulfonate (Example 13, Step 4, 50.0 mg, 0.091 mmol), and the reaction mixture was bubbled with argon and stirred at 120°C for 2 hours. After completion of stirring, the mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography, eluting with a gradient of MeOH//CH2Cl2 (030% MeOH), with producing 6-(2-(methoxymethoxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-3-(2,2,6,6tetramethylpiperidin-4-yl)-3H-[1 ,2,3]triazolo[4,5-c]pyridazine (30.0 mg, 71% yield) as a light yellow solid. MS m/z 464.4 [M+H]+.

Step 2. 6-(2-(Methoxymethoxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-3-(2,2,6,6-tetramethylpiperidin4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazine (30.0 mg, 0.065 mmol) was dissolved in methanol (0.5 ml) and HCl in dioxane (1.0 ml, 4.0 mmol, 4.0 mol/l). The reaction mixture was stirred at 45°C for 1 hour and then concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/N^OH/C^Ch (0-30% MeOH/2.5% NH4OH) to give 2-(3-(2,2,6,6tetramethylpiperidine-4 -yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (19.0 mg, 70% yield) as a yellow solid.

MS m/z 420.5 [M+H]+; ^1H NMR (methanol^) δ: 9.09 (s, 1H), 8.19-8.25 (m, 1H), 7.98 (s, 2H), 7.71-7.83 (m, 2H), 5.74-5.94 (m, 1H), 2.31-2.41 (m, 4H), 1.53 (s, 6H), 1.37 (s, 6H); 2H were not detected (NH and OH).

Example 38.

Getting connection 171.

Step 1. To a solution of 3,4,6-trichloropyridazine (20.04 g, 106 mmol) in a mixture of THF and DMSO (5:1, 200

- 123045009 ml) sodium benzenesulfinate (18.6 g, 111.1 mmol) was added and the mixture was stirred vigorously at room temperature. Complete conversion was observed after 40 min. After completion of the reaction, the reaction mixture was diluted with EtOAc (100 ml) and washed with water and brine. The combined organic phases were dried over MgSO ₄ . The volume of solvent was reduced by evaporation. Recrystallization from EtOAc/hexanes gave 3,6-dichloro-4-(phenylsulfonyl)pyridazine (28.5 g, 93% yield) as a white solid.

MS m/z 289.0 [M+H]+; ^1H NMR ( _CDCl3 ) δ: 8.34 (s, 1H), 8.07-7.98 (m, 2H), 7.80-7.74 (m, 1H), 7.68-7, 61 (m, 2H).

Step 2: Add 3,6-dichloro-4-(phenylsulfonyl)pyridazine (1.0 g, 3.46 mmol), (3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidine to the round bottom flask -4-amine (1.3 g, 5.2 mmol), K ₂ CO3 (2.18 g, 15.6 mmol) and dioxane (14.0 ml). The mixture was stirred at 100°C for 16 hours, then cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, and the solvent was removed in vacuo to give crude 6-chloro-N-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)- 4-(phenylsulfonyl)pyridazin-3-amine, which was used in the next step without further purification.

MS m/z 427.2, 429.2 [M+H]+; 1H NMR (CDCl ₃ ) δ: 8.00-7.93 (m, 2H), 7.77 (s, 1H), 7.76-7.73 (m, 1H), 7.64-7.61 (m, 2H), 6.73 (d, J=7.9 Hz, 1H), 5.04-4.88 (m, 1H), 4.34 (d, J=50.0 Hz, 1H) , 1.81-1.72 (m, 1H), 1.611.49 (m, 1H), 1.29 (s, 6H), 1.22 (s, 6H); 1H (NH) was not detected.

Step 3: The crude mixture from Step 2 was dissolved in dioxane (8 ml) and DMSO (2 ml). NaN ₃ (400.0 mg, 6.15 mmol) was added and the mixture was stirred at 50°C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with brine (4 times) to remove DMSO. The combined organic phases were dried over MgSO ₄ and concentrated to give crude 4-azido-6-chloro-N-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4yl)pyridazin-3-amine as a dark brown oil, which was used in the next step without further purification.

MS m/z 328.2, 330.2 [M+H]+; 1H NMR (CDCl ₃ ) δ: 6.88 (s, 1H), 4.90-4.69 (m, 2H), 4.33 (d, J=50.0 Hz, 1H), 1.73- 1.63 (m, 1H), 1.46-1.35 (m, 1H), 1.23 (s, 6H), 1.11 (s, 6H); 1H (NH) was not detected.

Step 4 The crude product from step 3 was dissolved in CH ₂ Cl ₂ (10 ml) and AcOH (2 ml) and the mixture was cooled at 0°C. Pieces of zinc mesh (640.0 mg, 9.8 mmol) were added in portions and the mixture was stirred for 3 hours at 0°C. After completion of the reaction, the reaction mixture was quenched with an aqueous saturated solution of NaHCO ₃ . The organic phase was washed with brine, dried over MgSO ₄ and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography, eluting with a gradient of MeOH/CH ₂ Cl ₂ (0-30% MeOH), to give 6-chloro-N3-((3S,4S)-3fluoro-2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3,4-diamine (860.0 mg, 82% yield in 3 steps).

MS m/z 302.2, 304.2 [M+H]+; 1H NMR (DMSO-d6) δ: 6.46 (s, 2H), 6.41 (s, 1H), 6.02 (d, J=7.5 Hz, 1H), 4.76-4.62 (m, 1H), 4.45 (d, J=55.0 Hz, 1H), 1.61-1.54 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H); 1H (NH) was not detected.

Step 5. Solution of 6-chloro-N3-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3,4diamine (860 mg, 2.8 mmol) in AcOH (6 ml) was cooled to 0°C. NaNO ₂ (280 mg, 4.0 mmol) was dissolved in water (1 ml), and the solution was slowly added dropwise to the reaction mixture. The mixture was then gradually warmed to room temperature and stirred for 1 hour at room temperature. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-10% MeOH) gradient to give 6-chloro-3-((3S,4S)-3fluoro- 2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine bishydrochloride (450 mg, 50% yield).

MS m/z 313.1, 315.1 [M+H]+; 1H NMR (DMSO-d6) δ: 9.87 (br.s, 1H), 8.96 (s, 1H), 8.59 (br.s, 1H), 6.31-6.16 (m, 1H), 5.30 (d, J=45.0 Hz, 1H), 3.08 (t, J=13.6 Hz, 1H), 2.61-2.54 (m, 1H), 1, 73 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H), 1.52 (s, 3H); the additional 2H is due to the bis HCl salt.

Step 6. 6-chloro-3-((3S,4S)-3-fluoro-2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5-c]pyridazine (200.0 mg, 0.64 mmol), Pd(PPh ₃ ) ₄ (70.0 mg, 10 mol.%) and 2-(4-chloro-2-(methoxymethoxy)phenyl )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (270.0 mg, 0.90 mmol). The vial was evacuated under vacuum and purged with argon, then dioxane (2.2 ml) and aqueous K2CO3 (2.0 M, 0.8 ml, 1.92 mmol) were added. The mixture was heated at 70°C for 16 hours. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-15% MeOH) gradient to give 6-( 4-chloro-2(methoxy-methoxy)phenyl)-3-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5c]pyridazine (279.0 mg, 97%) as a brownish solid. MS m/z 449.4, 451.4 [M+H] ⁺ .

Step 7. 6-(4-chloro-2(methoxymethoxy)phenyl)-3-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl was loaded into a dry screw cap bottle )-3H-[1,2,3]triazolo[4,5c]pyridazine (40.0 mg, 0.9 mmol), bis(pinacolato)diboron (30.0 mg, 0.12 mmol), Pd X- Phos G3 (4.0 mg, 0.05 mmol) and KOAc (18.0 mg, 0.18 mmol). The bottle was evacuated and filled with argon. The Ar-124 045009 gon/vacuum cycle was carried out at least three times, and then dioxane (0.5 ml) was added to the vial under Ar overpressure. The reaction mixture was then heated at 100°C for 2 hours. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3H-[1,2,3]triazolo[4,5-c]pyridazine was used in the next step without highlighting. MS m/z 541.4 [M+H]+.

Step 8: To the mixture from Step 7 was added 2 M aqueous solution of K ₂ CO ₃ (0.1 ml), Pd X-Phos G3 (4.0 mg, 0.05 mmol) and 4-bromo-1-methylpyridin-2 (1H)-one (20.0 mg, 0.11 mmol). The reaction mixture was then heated at 100°C for 12 hours. The crude product was purified by silica gel column chromatography, eluting with a MeOH/CH ₂ Cl ₂ (0-30% MeOH) gradient to give 4-(4-(3-(( 3S,4S)-3-fluoro-2,2,6,6tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-3-(methokCimethoxy )phenyl)-1methylpyridin-2(1H)-one (35 mg, 75% yield). MS m/z 522.4 [M+H] ⁺ .

Step 9. To a solution of 4-(4-(3-((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl)-3-(methoxymethoxy)phenyl)-1-methylpyridin-2(III)-one (35.0 mg, 0.067 mmol) in dichloromethane (1.0 ml) and MeOH ( 100 µl) 2.0 M HCl in Et ₂ O (1.5 ml, 0.75 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The volume of solvent was reduced by evaporation. The residue was purified by silica gel column chromatography, eluting with a gradient of MeOH/N^OH/C^C^ (0-30% MeOH/2.5%NH4OH) to give 4-(4-(3-((3S,4S) -3-fluoro2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-3-hydroxyphenyl)-1methylpyridin-2 (1H)-one (16.0 mg, 50% yield) as a tan solid.

MS m/z 478.4 [M+H] ⁺ ; 1H NMR (methanol-d4) δ: 9.19 (s, 1H), 8.23 (d, J=7.9 Hz, 1H), 8.00 (br.d, J=6.9 Hz, 1H ), 7.49-7.36 (m, 2H), 7.15-7.04 (m, 2H), 6.30-6.21 (m, 1H), 5.42 (d, J=50 Hz, 1H), 3.79 (s, 3H), 3.55-3.45 (m, 1H), 2.80-2.69 (m, 1H), 1.88 (s, 3H), 1 .81 (s, 3H), 1.74 (s, 3H), 1.67 (s, 3H); 2H were not detected (NH and OH).

Using the procedure described for Example 38 above, additional compounds described in the invention were prepared by appropriate substitution of starting materials, reagents and reaction conditions, obtaining compounds selected from the following compounds: ____________

Compound Data 164 MS m/z 437.3 [M+H] ⁺ ; 'H NMR (DMSO-d ₆ ) δ: 10.74-10.49 (m, 1H), 9.22 (s, 1H), 8.47 (br.d, J=12.2 Hz, 1H) , 8.15 (s, 2H), 8.13-8.05 (m, 1H), 7.32 (br.s, 2H), 6.32-6.16 (m, 1H), 5.37 (d, J=45 Hz, 1H), 3.09 (t, J=13.6 Hz, 1H), 2.67-2.57 (m, 1H), 1.79 (s, ZN), 1 .71 (s, ZN), 1.68-1.61 (m, ZN), 1.611.49 (m, ZN); 1H was not detected (OH). 168 MS m/z 437.3 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.19 (s, 1H), 8.70 (s, 2H), 8.16 (d, J=8.l Hz, 1H), 7.47-7 .39 (m, 2H), 6.22-6.10 (m, 1H), 5.52 (dd, J=50.0, 10.0 Hz, 1H), 3.17-3.05 (m , 1H), 2.73-2.62 (m, 1H), 1.89-1.79 (m, 6H), 1.75 (s, ZN), 1.68 (s, ZN); 3 H was not detected (OH and 2 NH). 170 MS m/z 405.5 [M+H] ⁺ ; 'H NMR (methanol-b ₄ ) δ: 9.00 (s, 1H), 8.03 (br.d, J=8.2 Hz, ZN), 7.16-7.37 (m, 2H) , 5.44-5.61 (m, 1H), 3.52-3.65 (m, 1H), 3.13-3.19 (m, 2H), 2.93 (br.dd, J= 9.2, 2.5 Hz, 2H), 1.21 (s, 9H); 3 H were not detected (2 NH and OH). 172 MS m/z 479.5 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.22 (s, 1H), 9.08 (s, 1H), 8.25 (d, J=8.l Hz, 1H), 7.68-7, 55 (m, 2H), 7.04 (s, 1H), 6.36-6.15 (m, 1H), 5.42 (d, J=55.0 Hz, 1H), 3.72-3 .65 (m, 1H), 3.68 (s, 4H), 2.75 (br.d, J=12.2 Hz, 1H), 1.88 (s, ZN), 1.81 (s, ZN), 1.74 (s, ZN), 1.67 (s, ZN); 2 H were not detected (NH and OH). 173 MS m/z 455.4 [M+H] ⁺ ; Ή NMR (DMSO-d ₆ ) δ: 12.69 (s, 1H), 11.55 (s, 1H), 9.15 (s, 1H), 8.26 (s, 1H), 8.11 ( d, J=10 Hz, 1H), 7.29-7.26 (m, 2H), 6.105.90 (m, 1H), 5.95 (d, J=55 Hz, 1H), 2.67- 2.57 (m, 1H), 2.19-2.25 (m, 1H), 1.41 (s, ZN), 1.34 (s, ZN), 1.26 (m, ZN), 1 ,14 (m, ZN); 1H was not detected. 175 MS m/z 419.5 [M+H] ⁺ ; Ή NMR (methanol-b ₄ ) δ: 9.00 (s, 1H), 8.02 (br.d, J=8.l Hz, ZN), 7.24-7.30 (m, 2H), 5.92-6.00 (m, 1H), 4.30 (br t, J=8.0 Hz, 1H), 2.98-3.06 (m, IH), 2.75 (br.dd , J=8.6, 4.0 Hz, 1H), 2.55-2.67 (m, ZN), 1.99-2.11 (m, 1H), 1.45 (s, 9H); 3 H were not detected (2 NH and OH).

- 125 045009

Examples of biological activity studies.

The following examples of in vitro biological activity studies demonstrate the utility of the compounds of the present invention for the treatment of Huntington's disease.

To further describe and facilitate the understanding of the present invention, the following are non-limiting examples of biological activity assays to more fully illustrate the scope of the invention, and these examples should not be construed as specifically limiting the scope of the invention. It is intended that variations of the present invention which may now be known or may be proposed later by any person skilled in the art within the scope of his or her skill are intended to be included within the scope of the present invention and the following claims.

Compounds of formula (I) were tested using the Meso Scale Discovery (MSD) assay described in International Application No. PCT/US2016/066042, filed December 11, 2016, which claims priority to US Provisional Patent Application US 62/265652, filed 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 an MSD enzyme-linked immunosorbent assay (ELISA) electrochemiluminescence assay platform.

Example 1.

Analysis of endogenous huntingtin protein.

Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4°C with monoclonal antibody MW1 (for expanded polyglutamine recognition) or monoclonal antibody MAB2166 (for capture) at a concentration of 1 μg/ml in PBS (30 µl per well). The plates were then washed three times with 300 μl wash buffer (0.05% Tween-20 in PBS) and blocked (with 100 μl blocking buffer, 5% BSA in PBS) for 4-5 h at room temperature with rotary shaking and then washed three times with wash buffer.

Samples (25 μl) were transferred to an MSD plate coated with an antibody layer and incubated overnight at 4°C. After removing the lysates, the plate was washed three times with wash buffer, and 25 μl of secondary antibody #5656S (Cell signaling, rabbit monoclonal 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 1 hour at room temperature. After incubation with the secondary antibody, the wells were washed with wash buffer, and then 25 μl of goat anti-rabbit SULFO TAG secondary detection antibody (a required aspect of the MSD system) (diluted to 0.25 μg/ml in 0.05% Tween) was added to each well. 20 in blocking buffer) and incubated with shaking for 1 h at room temperature.

After washing three times with wash buffer, 150 μl of T reading buffer with surfactant (MSD) was added to each empty well and the plate was imaged on an SI 6000 imager (MSD) according to the manufacturer's instructions included with 96 -well or 384-well plates. The obtained IC ₅₀ values (μM) for the tested compounds are presented in table. 1.

As shown in table. 1, the tested compounds described in the invention had the following IC ₅₀ values, the IC ₅₀ value in the range between > 3 μM and < 9 μM is indicated by one asterisk (*), the IC ₅₀ value in the range between > 1 μM and < 3 μM is indicated by two asterisks ( **), IC ₅₀ value in the range between > 0.5 µM and < 1 µM is indicated by three asterisks (***), IC ₅₀ value in the range between > 0.1 µM and < 0.5 µM is indicated by four asterisks (* ***) and _IC50 value <0.1 µM are indicated by five asterisks (*****).

- 126 045009

Table 1

Compound 1C ₅₀ Compound IC50 Compound IC50 1 **** 62 4ί 4ί 4ί 4ί 4ί 121 4ί 4ί 4ί 4ί 4ί 2 **** 63 4ί 4ί 4ί 4ί 4ί 122 ** 3 4ί 4ί 64 4=4= 123 4= 4 4ί 4ί 4ί 4ί 4ί 65 *** 124 4ί 4ί 4ί 4ί 4ί 5 4ί 4ί 4ί 4ί 4ί 66 4ί 4ί 4ί 4ί 4ί 125 **** 6 *** 67 4ί 4ί 4ί 4ί 4ί 126 **** 7 4ί 4ί 4ί 4ί 4ί 68 4ί 4ί 4ί 4ί 4ί 127 4ί 4ί 4ί 4ί 4ί 8 4=4= 69 4= 4= 4= 4= 4= 128 4= 4= 4= 4= 4= 9 4=4= 70 4ί 4ί 4ί 4ί 4ί 129 4ί 4ί 4ί 4ί 4ί 10 4ί 4ί 4ί 4ί 4ί 71 **** 130 4ί 4ί 4ί 4ί 4ί eleven ** 72 **** 131 4ί 4ί 4ί 4ί 4ί 12 **** 73 4ί 4ί 4ί 4ί 4ί 132 *** 13 **** 74 **** 133 **** 14 **** 75 **** 134 4ί 4ί 4ί 4ί 4ί 15 4=4= 76 **** 135 4ί 4ί 4ί 4ί 4ί 16 **** 77 4ί 4ί 4ί 4ί 4ί 136 4ί 4ί 4ί 4ί 4ί 17 4ί 4ί 4ί 4ί 4ί 78 ** 137 4ί 4ί 4ί 4ί 4ί 18 4ί 4ί 4ί 4ί 4ί 79 *** 138 **** 19 ** 80 **** 139 **** 20 4ί 4ί 4ί 4ί 4ί 81 ** 140 4ί 4ί 4ί 4ί 4ί 21 ** 82 **** 141 4ί 4ί 4ί 4ί 4ί

- 127 045009

22 4= 4= 4= 4= 4= 83 4= 4= 4= 4= 4= 142 4= 4= 4= 4= 4= 23 4= 4= 4= 4= 4= 84 4=4= 143 4= 4= 4= 4= 4= 24 4= 4= 4= 4= 4= 85 ** 144 4= 4= 4= 4= 4= 25 4= 4= 4= 4= 4= 86 4=4= 145 4=4= 26 4= 4= 4= 4= 4= 87 **** 146 4=4= 27 4= 4= 4= 4= 4= 88 **** 147 4=4= 28 ** 89 **** 148 4= 4= 4= 4= 4= 29 4= 4= 4= 4= 4= 90 **** 149 4=4= thirty *** 91 ** 150 4= 4= 4= 4= 4= 31 4= 4= 4= 4= 4= 92 ** 151 4= 4= 4= 4= 4= 32 **** 93 4= 4= 4= 4= 4= 152 **** 33 94 4=4=4= 153 4= 4= 4= 4= 4= 34 **** 95 **** 154 4= 4= 4= 4= 4= 35 4= 4= 4= 4= 4= 96 4= 4= 4= 4= 4= 155 4= 36 **** 97 4= 4= 4= 4= 4= 156 **** 37 4= 4= 4= 4= 4= 98 4= 4= 4= 4= 4= 157 **** 38 4= 4= 4= 4= 4= 99 4= 4= 4= 4= 4= 158 4= 4= 4= 4= 4= 39 4= 4= 4= 4= 4= 100 ** 159 4= 4= 4= 4= 4= 40 4= 101 *** 160 **** 42 **** 102 4= 4= 4= 4= 4= 161 4= 4= 4= 4= 4= 43 *** 103 **** 162 4= 4= 4= 4= 4= 46 4=4=4= 104 4=4=4=4=4= 163 4=4=4=4=4= 47 4=4= 105 4= 4= 4= 4= 4= 164 4= 4= 4= 4= 4= 48 **** 107 4= 4= 4= 4= 4= 165 4= 4= 4= 4= 4= 49 ** 108 4= 4= 4= 4= 4= 166 **** 50 **** 109 4= 4= 4= 4= 4= 167 ** 51 **** BY **** 168 4= 4= 4= 4= 4= 52 *** 111 4= 4= 4= 4= 4= 169 4= 4= 4= 4= 4= 53 4= 4= 4= 4= 4= 112 4= 4= 4= 4= 4= 170 4=4= 54 4= 4= 4= 4= 4= 113 4= 4= 4= 4= 4= 171 **** 55 **** 114 4=4= 172 **** 56 **** 115 **** 173 4= 4= 4= 4= 4= 57 4= 4= 4= 4= 4= 116 4= 4= 4= 4= 4= 174 4= 4= 4= 4= 4= 58 **** 117 4= 175 *** 59 4= 4= 4= 4= 4= 118 ** 176 4= 4= 4= 4= 4= 60 4=4= 119 **** 61 4=4= 120 ****

Whether or not a document cited in the invention is specifically and individually indicated as being incorporated by reference into the invention, all documents cited in the invention are incorporated by reference in any and all senses, equally as if the full contents of each specific reference have been fully set forth in the invention.

Having read the full description of the subject matter, it should be apparent to those of ordinary skill in the art that the same result can be achieved by a wide range of equivalents without affecting the scope of the subject matter or the specific aspects described in the invention. The appended claims are intended to be construed as including all such equivalents.

- 128 -

Claims (23)

CLAIM 1. A compound of formula (I) (I) or a form thereof, wherein each dotted line represents an optional chemical bond where valence permits; W1 is selected from the group consisting of CR _a , CH-R _a N, N-Rb, O and S when valency-appropriate; W2 is selected from the group consisting of CR _a , CH-R _a and N when valence-appropriate, and W3 is selected from the group consisting of C and N when appropriate from a valency point of view; where at least one of W1, W2 or W3 is N or N-Rb; where when W1 represents S or O, W2 represents CR _a , and W3 represents C; W4 and W5 are independently CR _a or N, R _a in each particular case is independently selected from the group consisting of hydrogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 alkyl-amino; Rb represents hydrogen; R1 is heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 ring heteroatoms independently selected from N and S, and wherein in each case, C _3-10 cycloalkyl and heterocyclyl is unsubstituted or substituted with one, two, three or four R3 substituents; R ₂ is selected from the group consisting of phenyl, heterocyclyl and heteroaryl, where heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatoms per ring, independently selected from N, O or S, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms per ring, independently selected from N , O or S, and wherein, in each case, phenyl, heterocyclyl and heteroaryl is unsubstituted or substituted with one, two or three R5 substituents, and unsubstituted or substituted with one additional R6 substituent; R ₃ in each particular case is independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkyl-amino; R5 in each case is independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, and oxime; R6 is selected from the group consisting of phenyl and heteroaryl, where heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatoms in the ring, independently selected from N, O or S, and wherein, in each case, phenyl and heteroaryl is unsubstituted or substituted with one, two, three or four R8 substituents; And R ₈ in each particular case is independently selected from the group consisting of cyano, halogen, hydroxy, C _1-6 alkyl, deutero-C _1-4 alkyl, halogen-C _1-6 alkyl, C _1-6 alkoxy, halogen- C _1-6 alkoxy, amino, C _1-6 alkyl-amino, (C _1-6 alkyl) ₂ -amino, and C _3-10 cycloalkyl; wherein the form of the compound is selected from the group consisting of its salt and stereoisomeric form. 2. A compound according to claim 1, wherein the compound is a compound of formula (Ibb1) - 129 045009 or its form. 3. A compound according to claim 1 or a form thereof, where R1 represents a heterocyclyl selected from the group consisting of piperidinyl, piperazinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6tetrahydropyridinyl, 3-azabicyclo[3, 1,0]hexyl, (1R,5S)-3-azabicyclo[3,1,0]hexyl, 8-azabicyclo[3,2,1]octyl, (1R,5S)-8-azabicyclo[3,2,1] octyl, 8-azabicyclo[3,2,1]-oct-2-enyl, (1R,5S)-8azabicyclo[3,2,1]-oct-2-enyl, 9-azabicyclo[3,3,1] nonyl, 0(1R,5S)-9-azabicyclo[3,3,1]nonyl, 3-oxa9-azabicyclo[3,3,1]nonyl and 3-oxa-9-azabicyclo[3,3,1] non-6-enyl, where the heterocyclyl is unsubstituted or substituted with one, two, three or four R ₃ substituents. 4. A compound according to claim 1 or a form thereof, wherein R2 is phenyl and is unsubstituted or substituted with one, two or three R5 substituents and unsubstituted or substituted with one additional R6 substituent. 5. A compound according to claim 1, wherein the form of the compound is a salt selected from the group consisting of hydrochloride, hydrobromide, formate, dihydrochloride and dihydrobromide. 6. A compound or form thereof selected from the group consisting of the following compounds: 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazin-5yl]phenol; 5-[2,5-difluoro-4-(III-pyrazol-4-yl)phenyl]-1-(2,2,6,6-tetramethylpiperidin-4-yl)-III-imidazo[4,5b]pyrazine ; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3yl]phenol; 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazine ; 2-[6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4-yl )phenol; 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5 -c]pyridazine; 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[2,3b ]pyrazin-2-yl]phenol; 3-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-6 -ol; 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2yl]phenol; 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3yl]phenol; 2-[7-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol; 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazine; 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazine; 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridazin-3-yl]phenol; 2-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3b]pyrazine ; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2c]pyridazin- 3 -yl]phenol; 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)thieno[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol; 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]-5-(1H-pyrazol-4-yl)phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2с ]pyridazin-3-yl]phenol; 2-[1-(piperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(1H-pyrazol-4-yl)phenol; 5-(III-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-III-pyrazolo[3,4-c]pyridazin-5yl]phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3c]pyridazin-3 -yl]phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)thieno[3,2-c]pyridazin-3-yl]phenol; 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)thieno[3,2-c]pyridazin-3-yl]-5-(1H- pyrazol-4yl)phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3yl]phenol; 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)-5H-pyrrolo-[3,2-c]pyridazin-3-yl]-5-(1H- pyrazol-4yl)phenol; - 130 045009 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5- (1H-pyrazol-4yl)phenol; 2-[7-(8-azabicyclo[3,2,1]oct-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol; 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-7-yl)-5H-pyrrolo-[3,2-c]pyridazin-3-yl]-5-(1H- pyrazol-4yl)phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3yl]phenol; 3-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5Hpyrrolo[2 ,3-c]pyridazine; 4-fluoro-2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 4-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 7-[(3-exo)-8-azabicyclo[3,2,1]oct-3-yl]-3-[2,3-di-fluoro-4-(1H-pyrazol-4-yl)phenyl] -6,7-dihydro-5Hpyrrolo[2,3-c]pyridazine; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1-methylpyridin-2(1H)-one; 4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]biphenyl-3,4' diol; 5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 2-[6-methoxy-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4-yl )phenol; 2-[6-(methylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4 -yl)phenol; 2-[7-(piperazin-1-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5 -(1H-pyrazol-4-yl)phenol; 5-(1-ethyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1-propyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1H-pyrazol-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 2-[6-(ethylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5 -(1Hpyrazol-4 -yl)phenol; 5-(1-methyl-1H-pyrazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1-methyl-1H-pyrazol-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 2-[3-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-( 1Hpyrazol-4-yl)phenol; 6-fluoro-4-[3 -(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl] [1 ,1'biphenyl]-3,4'-diol; 2-fluoro-3-(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 4-{2-fluoro-5-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine6 -yl]-phenyl}-1-methylpyridin-2(1H)-oh; 2-[3-(2,2-dimethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H-pyrazol-4yl) phenol; 2-{3-[(1R,5S)-1,5-dimethyl-8-azabicyclo[3,2,1]octan-3-yl]-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl}-5-(1H-pyrazol-4-yl)phenol; 2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]benzene-1,4-diol; 3-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(pyrazin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 5-(pyridin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol; - 131 045009 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(III- 1,2,4triazol-1-yl)phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(4H- 1,2,4triazol-4-yl)phenol; 5-(pyridin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyridin-3-ol; 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyrimidin-5-ol; 5-[1-( ² H ₃ )methyl-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3 ]triazolo[4,5c]pyridazin-6-yl]phenol; 5-(1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 5-[1-(difluoromethyl)-III-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H- 1,2,3triazol-1-yl)phenol; 5-(2-methylpyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-[2( trifluoromethyl)pyridin-4-yl]phenol; 5-(pyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 5-(pyridazin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 5-(2-methoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol; 5-(pyrimidin-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyridazin-3-ol; 5-(1H-pyrrol-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin-6yl]phenol; 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol; (3E)-3-(hydroxyimino)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6- yl]-2,3-dihydro-1H-inden-5-ol; 4-chloro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-[6-(dimethylamino)pyridin-3-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol; 5-(imidazo[1,2-a]pyrazin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 1-cyclopropyl-4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin-6 -yl]-phenyl}pyridin-2(1H)-one; 4-fluoro-5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c] pyridazin-6-yl]phenol; 5-(imidazo[1,5-a]pyridin-7-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(thiophene- 3yl)phenol; 5-(imidazo[1,2-a]pyridin-7-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 5-(1H-imidazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 1-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1Hbenzimidazole -6-ol; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyridin-2(1H)-one; 5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1H-indazol-6 - 132 045009 ol; 5-(furan-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3-thiazol-2yl)phenol; 2-methyl-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-1Hbenzimidazole -6-ol; 5-(1-methyl-1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4c]pyridazin-5 -yl ]phenol; 5-(2-aminopyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с]pyridazin- 6-yl]phenol; 5-[2-(dimethylamino)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol; 5-(3-fluoropyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с]pyridazin- 6-yl]phenol; 5-[1-( ^2H3 )methyl-1H-pyrazol-4-yl]-2-[1-(2,2,6,6-tetramethylpiperidin-4 _- yl)-1H-pyrazolo[3,4с] pyridazin-5-yl]phenol; 5-[5-(difluoromethoxy)pyridin-2-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol; 5-[2-(methylamino)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с ]pyridazin-6-yl]phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)furo[3,2c]pyridazin- 3 -yl]phenol; 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3-thiazol-5yl)phenol; 5-(3-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1 H-pyrazole-3-carbonitrile; 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1,3-thiazol-5-car bonitrile; 5-(1,3-oxazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H- 1,2,3triazol-4-yl)phenol; 5-(6-methoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol; 5-[2-(difluoromethoxy)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol; 5-(1H-imidazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3,4thiadiazol-2-yl)phenol; 6-[4-(1H-pyrazol-4-yl)-1H-benzotriazol-7-yl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2, 3]triazolo[4,5-c]pyridazine; 5-(III-pyrrolo[2,3-b]pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol; 5-(2-methoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol; 5-(1,2-oxazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl]phenol; 5-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol; 5-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5c]pyridazin-6-yl]phenol; 5-(2-ethoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с]pyridazin- 6-yl]phenol; 5-(6-ethoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5- 133 045009 ( [1,2,3]triazolo[1,5-a]pyridin-5-yl)phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5([ 1, 2,4]triazolo[1,5-a]pyridin-7-yl)phenol; 5-(3-chloro-1-methyl-III-pyrazol-4-yl)-2-[3-(2,2,6,6-tetra-ethylpiperidin-4-yl)-3H[1,2,3 ]triazolo[4,5-c]pyridazin-6-yl]phenol; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyrimidin-4(3H)-one; 5-(3-chloro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(3-fluoro-1-methyl-III-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol; 5-(3-methoxy-III-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1 -methyl-1H-pyrazole-3-carbonitrile; 5-(5-methyl-1,3-thiazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 2,4thiadiazol-5-yl)phenol; 5-(4-fluoro-1H-benzotriazol-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3yl]pyridin-3 -ol; 5-(3-bromo-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(1-methyl-1H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2, 3]triazolo[4,5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-[3( trifluoromethyl)-1 H-pyrazol-4-yl]phenol; 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]pyridin-3-ol; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3yl]pyridin-3 -ol; 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(4-methyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H[ 1,2,3]triazolo[4,5-b]pyridin-6-yl)phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(3H[ 1,2,3]triazolo[4,5-c]pyridin-6-yl)phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H[ 1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol; 5-(3-fluoro-1 -methyl-1 H-pyrazol-4-yl)-2-[ 1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4c] pyridazin-5-yl]phenol; 5-(2,4-dimethyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 5-(2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2, 3]triazolo[4,5c]pyridazin-6-yl]phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5([1, 2,4]triazolo[4,3-b]pyridazin-6-yl)phenol; 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5c]pyridazin-6-yl]phenol; 5-(4-fluoro-2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3 ]triazolo[4,5-c]pyridazin-6-yl]phenol; 5-(5-methyl-1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol; 5-(4-methyl-1H-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5 - 134 045009 c]pyridazin-6-yl)phenol; 5-(3-methyl-III-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl)phenol; 5-(2-methyl-1,3-oxazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol; 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(3-(2,2,6,6-tetramethylpiperide in-4-yl)-3H-[1,2,3 ]triazolo[4,5c]pyridazin-6-yl)phenol; 5-(imidazo[1,2-a]pyrimidin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl)phenol; 5-(3-fluoro-1H-pyrazol-4-yl)-2-(1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin5- yl)phenol; 5-(imidazo[1,2-b]pyridazin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl)phenol; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H- 1,2,3triazol-2-yl)phenol; 2-{3-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6-yl}5-(1H-pyrazol-4-yl)phenol; 5-(pyridin-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol; 5-(pyridin-3-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol; 5-(pyrimidin-5-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol; 2-{3-[(3S,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6-yl}5-(1H-pyrazol-4-yl)phenol; 5-(1 -methyl-1 H-pyrazol-3 -yl)-2-[1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1 H-pyrazolo[3,4c]pyridazin-5 -yl]phenol; 2-{3-[3-(tert-butylamino)cyclobutyl]-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4yl)phenol ; 4-(4-{3-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylnineridin-4-yl]-3H-[1,2,3]triazolo[4,5-c ]niridazin-6yl}-3-hydroxy-phenyl)-1-methylpyridin-2(1H)-one; 6-(4-{3-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c ]pyridazin-6yl}-3-hydroxy-phenyl)-3-methylpyrimidin-4(3H)-one; 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H[1 ,2,3]triazolo[4,5-c]pyridazin-6-yl}phenol; 2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(2H-1,2,3-triazole -2yl)phenol; 2-{3-[3-(tert-butylamino)cyclopentyl]-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4yl)phenol ; And 2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo-[2,3-c]pyridazin-3-yl]-5-(2H-1,2,3- triazol-2yl)phenol; wherein the form of the compound is selected from the group consisting of its salt and stereoisomeric form. 7. A salt of the compound according to claim 6 or a form thereof selected from the group consisting of the following salts of the compounds 5-(1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazin-5yl]phenol hydrochloride; 5-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-imidazo[4,5b]pyrazine hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3yl]phenol hydrochloride; 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazine hydrochloride; 2-[6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo-[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4- yl)phenol hydrochloride; 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7Nimidazo[4,5 -c]pyridazine hydrochloride; 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[2,3b ]pyrazin-2-yl]phenol hydrochloride; 3-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5c]pyridazin-6 -ol hydrochloride; - 135 045009 5-(1H-pyrazol-4-yl)-2-[5-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2yl]phenol hydrochloride; 5-(III-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3yl]phenol hydrochloride; 2-[7-(piperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride; 6-[2,3-difluoro-4-(III-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazine hydrochloride; 6-[2,5-difluoro-4-(III-pyrazol-4-yl)phenyl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazine hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridazin-3-yl]phenol hydrochloride; 2-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-5-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[2,3b]pyrazine hydrochloride; 5-(III-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2с] pyridazin-3-yl]phenol hydrochloride; 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)thieno[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol hydrochloride; 2-[1-(piperidin-4-yl)-III-pyrazolo[3,4-b]pyrazin-5-yl]-5-(III-pyrazol-4-yl)phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3 ,2c]pyridazin-3-yl]phenol hydrochloride; 2-[1-(piperidin-4-yl)-III-pyrazolo[3,4-c]pyridazin-5-yl]-5-(III-pyrazol-4-yl)phenol hydrochloride; 5-(III-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-III-pyrazolo[3,4-c]pyridazin-5yl]phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3c]pyridazin-3 -yl]phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)thieno[3,2-c]pyridazin-3-yl]phenol hydrochloride; 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)thieno[3,2-c]pyridazin-3-yl]-5-(1H- pyrazol-4yl)phenol hydrochloride; 5-(III-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3yl]phenol hydrochloride; 2-[7-(8-azabicyclo[3,2,1]oct-2-en-3-yl)-5H-pyrrolo-[3,2-c]pyridazin-3-yl]-5-(1H- pyrazol-4yl)phenol hydrochloride; 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-6-en-7-yl)-5H-pyrrolo-[3,2-c]pyridazin-3-yl]-5 -(1H-pyrazol4-yl)phenol hydrochloride; 2-[7-(8-azabicyclo[3,2,1]oct-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazol-4-yl )phenol hydrochloride; 2-[7-(3-oxa-9-azabicyclo[3,3,1]non-7-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(1H-pyrazole -4yl)phenol hydrochloride; 5-(III-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-5H-pyrrolo[3,2-c]pyridazin-3yl]phenol hydrochloride; 3-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-7-(2,2,6,6-tetramethylpiperidin-4-yl)-6,7-dihydro-5Hpyrrolo[2 ,3-c]pyridazine hydrochloride; 4-fluoro-2-(III-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 4-fluoro-5-(III-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrobromide; 7-[(3-exo)-8-azabicyclo[3,2,1]oct-3-yl]-3-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6 ,7-dihydro-5Hpyrrolo-[2,3-c]pyridazine hydrochloride; 4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]biphenyl-3,4' diol hydrobromide; 5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrobromide; 2-[6-methoxy-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4-yl )phenol hydrochloride; 2-[6-(methylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5-(1Hpyrazol-4 -yl)phenol hydrochloride; 2-[6-(ethylamino)-7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3-yl]-5 -(1Hpyrazol-4 -yl)phenol hydrochloride; 2-[3-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-( 1Hpyrazol-4-yl)phenol dihydrochloride; - 136 045009 6-fluoro-4-[3 -(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl] [1 ,1'biphenyl]-3,4'-diol hydrobromide; 2-fluoro-3-(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrochloride; 4-{2-fluoro-5-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine6 -yl]-phenyl}-1-methylpyridin-2(1H)-one hydrochloride; 2-[3-(2,2-dimethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H-pyrazol-4yl) phenol hydrochloride; 2-{3-[(1R,5S)-1,5-dimethyl-8-azabicyclo[3,2,1]octan-3-yl]-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride; 2-(1H-pyrazol-4-yl)-5-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]benzene-1,4-diol dihydrochloride; 3-fluoro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrochloride; 5-(pyrazin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol dihydrochloride; 5-(pyridin-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol dihydrochloride; 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H- 1,2,4triazol-1-yl)phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(4H- 1,2,4triazol-4-yl)phenol hydrochloride; 5-(pyridin-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol dihydrochloride; 5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol dihydrochloride; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]traazolo[4,5-c]pyrudazin-6yl]phenyl }pyridin-3-ol dihydrochloride; 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyrimidin-5-ol dihydrochloride; 5-[1-( ² H ₃ )methyl-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3 ]triazolo[4,5c]pyridazin-6-yl]phenol dihydrochloride; 5-(1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]phenol hydrochloride; 5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4 ,5-c]pyridazin-6-yl]phenol dihydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H- 1,2,3triazol-1-yl)phenol hydrochloride; 5-(2-methylpyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-[2( trifluoromethyl)pyridin-4-yl]phenol dihydrochloride; 5-(pyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol dihydrochloride; 5-(pyridazin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol hydrochloride; 5-(2-methoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol dihydrochloride; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyridazin-3-ol hydrochloride; 6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]quinolin-7-ol hydrobromide ; 4-chloro-5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrobromide; 4-fluoro-5-(pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с] pyridazin-6-yl]phenol dihydrobromide; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(thiophene- 3yl)phenol hydrochloride; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyridin-2(1H)-one hydrochloride; - 137 045009 5-(furan-3-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3-thiazol-2yl)phenol hydrochloride; 5-(1-methyl-1H-pyrazol-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4c]pyridazin-5 -yl ]phenol dihydrochloride; 5-[1-( ² H ₃ )methyl-III-pyrazol-4-yl]-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-III-pyrazolo[3,4с] pyridazin-5-yl]phenol dihydrochloride; 5-[5-(difluoromethoxy)pyridin-2-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol formate; 5-(III-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)furo[3,2c] pyridazin-3-yl]phenol hydrochloride; 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3-thiazol-5yl)phenol hydrochloride; 5-(3-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }-1H-pyrazole-3-carbonitrile hydrochloride; 2-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1,3-thiazole-5-carbonitrile hydrochloride; 5-(1,3-oxazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl]phenol formate; 5-[2-(difluoromethoxy)pyridin-4-yl]-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5- c]pyridazin-6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 3,4thiadiazol-2-yl)phenol hydrochloride; 6-[4-(1 H-pyrazol-4-yl)-1 H-benzotriazol-7-yl]-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2, 3]triazolo[4,5-c]pyridazine trifluoroacetate; 5-(III-pyrrolo[2,3-b]pyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol hydrochloride; 5-(2-methoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol hydrochloride; 5-(1,2-oxazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6yl]phenol hydrochloride; 5-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol hydrochloride; 5-(1-ethyl-5-fluoro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5c]pyridazin-6-yl]phenol hydrochloride; 5-(2-ethoxypyridin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5с]pyridazin- 6-yl]phenol hydrochloride; 5-(6-ethoxypyrimidin-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5c]pyridazin- 6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5([1, 2,3]triazolo[1,5-a]pyridin-5-yl)phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5([1, 2,4]triazolo[1,5-a]pyridin-7-yl)phenol hydrochloride; 5-(3-chloro-1-methyl-III-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol hydrochloride; 6-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl }pyrimidin-4(3H)-one hydrochloride; 5-(3-chloro-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo [4,5-c]pyridazin-6-yl]phenol hydrochloride; 5-(3-methoxy-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 4-{3-hydroxy-4-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6yl]phenyl } -1-methyl-1H-pyrazole-3-carbonitrile hydrochloride; 5-(5-methyl-1,3-thiazol-2-yl)-2-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol hydrochloride; - 138 045009 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1, 2,4thiadiazol-5-yl)phenol hydrochloride; 5-(4-fluoro-1H-benzotriazol-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3yl]pyridin-3 -ol dihydrochloride; 5-(3-bromo-1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol hydrochloride; 5-(1-methyl-III-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2, 3]triazolo[4,5c]pyridazin-6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-[3( trifluoromethyl)-1H-pyrazol-4-yl]phenol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c] pyridazin6-yl]pyridin-3-ol hydrochloride; 5-(1H-pyrazol-4-yl)-2-[7-(2,2,6,6-tetramethylpiperidin-4-yl)-7H-imidazo[4,5-c]pyridazin-3yl]pyridin-3 -ol dihydrochloride; 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol hydrochloride; 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrochloride; 5-(4-methyl-1H-imidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H[ 1,2,3]triazolo[4,5-b]pyridin-6-yl)phenol dihydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(3H[ 1,2,3]triazolo[4,5-c]pyridin-6-yl)phenol dihydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(1H[ 1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol dihydrochloride; 5-(2,4-dimethyl-1H-umidazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol dihydrochloride; 5-(2-methyl-1,3-thiazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl]phenol dihydrochloride; 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-[3-(2,2,6,6-tetramethylpiperudin-4-yl)-3H-[1,2, 3]triazolo[4,5c]pyridazin-6-yl]phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5([1, 2,4]triazolo[4,3-b]pyridazin-6-yl)phenol hydrochloride; 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5c]pyridazin-6-yl]phenol hydrochloride; 5-(5-methyl-1H-pyrazol-1-yl)-2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl]phenol dihydrochloride; 5-(3-methyl-1H-pyrazol-1-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5c]pyridazin-6-yl)phenol dihydrochloride; 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(3-(2,2,6,6-tetramethylpiperide in-4-yl)-3H-[1,2,3 ]triazolo[4,5c]pyridazin-6-yl)phenol dihydrochloride; 5-(imidazo[1,2-a]pyrimidin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl)phenol hydrochloride; 5-(3-fluoro-1H-pyrazol-4-yl)-2-(1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin5- yl)phenol hydrochloride; 5-(imidazo[1,2-b]pyridazin-6-yl)-2-(3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[ 4,5c]pyridazin-6-yl)phenol hydrochloride; 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H- 1,2,3triazol-2-yl)phenol hydrochloride; 2-{3-[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6-yl}5-(1H-pyrazol-4-yl)phenol dihydrochloride; 5-(pyridin-4-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol hydrochloride; 5-(pyridin-3-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol hydrochloride; 5-(pyrimidin-5-yl)-2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5yl]phenol hydrochloride; 2-{3-[(3S,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c]pyridazin- 6-yl}5-(1H-pyrazol-4-yl)phenol dihydrochloride; - 139 045009 5-(1 -methyl-1 H-pyrazol-3 -yl)-2-[ 1 -(2,2,6,6-tetramethylpiperidin-4-yl)-1 H-pyrazolo[3,4c]pyridazin-5 -yl]phenol hydrochloride; 2-{3-[3-(tert-butylamino)cyclobutyl]-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4yl)phenol dihydrochloride; 4-(4-{3-[(38,48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c ]pyridazin-6yl} -3 -hydroxyphenyl)-1 -methylpyridin-2(1H)-one hydrochloride; 6-(4-{3-[(38,48)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]-3H-[1,2,3]triazolo[4,5-c ]pyridazin-6yl}-3-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one dihydrochloride; 2-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(2H-1,2,3-triazole -2yl)phenol hydrochloride and 2-{3-[3-(tert-butylamino)cyclopentyl]-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl}-5-(1H-pyrazol-4yl)phenol dihydrochloride; wherein the form of the compound is a stereoisomeric form. 8. A method of treating or alleviating Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or form thereof according to any one of claims 1 to 7. 9. The method of claim 8, wherein the effective amount of the compound or form thereof is in the range of 0.001 mg/kg/day to 500 mg/kg/day. 10. Use of a compound or form thereof according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment or alleviation of Huntington's disease in a subject in need thereof. 11. Use of a compound or form thereof according to any one of claims 1 to 7 in admixture with one or more pharmaceutically acceptable excipients in a pharmaceutical composition for treating or alleviating Huntington's disease in a subject. 12. Use according to claim 11, wherein the effective amount of the compound in the pharmaceutical composition is in the range from 0.1 ng to 10,000 mg. 13. A pharmaceutical composition comprising a compound or form thereof according to any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient. 14. A pharmaceutical composition comprising a compound or form thereof according to claim 6 and at least one pharmaceutically acceptable excipient. 15. A pharmaceutical composition comprising a salt of the compound or form thereof according to claim 7 and at least one pharmaceutically acceptable excipient. 16. A compound where the compound is 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H[1,2,3]triazolo[4,5-c]pyridazin-6-yl ]-5-(2H-1,2,3-triazol-2-yl)phenol. 17. A compound where the compound is a salt of the compound, wherein the salt of the compound is 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4, 5-c]pyridazin-6-yl]-5-(2H1,2,3-triazol-2-yl)phenol hydrochloride. 18. A method of treating or alleviating Huntington's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 16 or 17. 19. The method of claim 18, wherein the effective amount of the compound is in the range from 0.1 ng to 10,000 mg. 20. Use of a compound according to claim 16 or 17 for the preparation of a medicament for treating or alleviating Huntington's disease in a subject in need thereof. 21. Use of a compound according to claim 16 or 17 in admixture with one or more pharmaceutically acceptable excipients in a pharmaceutical composition for treating or alleviating Huntington's disease in a subject. 22. Use according to claim 21, wherein the effective amount of the compound in the pharmaceutical composition is in the range from 0.1 ng to 10,000 mg. 23. A pharmaceutical composition containing a compound according to claim 16 or 17 and at least one pharmaceutically acceptable excipient. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 140 -