EA043655B1 - COMPOUNDS FOR THE TREATMENT OF HUNTINGTON'S DISEASE - Google Patents

Description

One aspect of the present description relates to compounds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof to treat or alleviate Huntington's disease. In particular, another aspect of the present disclosure relates to substituted bicyclic heteroaryl compounds, forms and pharmaceutical compositions thereof, and methods of using such compounds, forms or compositions thereof 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 destruction of brain function. Death, usually caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The incidence of HD is three to seven people per 100,000 people of Western European descent. An estimated 30,000 people in North America have HD, and another 200,000 people are at risk of inheriting the disease from affected parents. The disease is caused by elongation of contiguous repeats of trinucleotide CAG codons in the mutant huntingtin (Htt) gene, resulting in the production of HTT (Htt protein) with an extended polyglutamine (polyQ) chain, also known as a CAG repeat sequence. Currently, there are no small molecule treatments that target the underlying cause of the disease, resulting in a high unmet need for drugs that can be used to treat or alleviate HD. Therefore, there remains a need to identify and provide small molecule compounds for the treatment or alleviation of HD.

All other documents referenced herein are incorporated herein by reference as if set forth in their entirety herein.

Disclosure of the Invention

An aspect of the present description includes compounds containing a compound of formula (I) or a form thereof, wherein R1, R2, W1, _W2 , _W3 , _W4 , W5 and W6 are as defined herein.

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

An aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

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

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the preparation of a medicament for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

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

Carrying out the invention (I)

One aspect of the present description relates to a compound containing a compound of formula or form thereof, wherein

W1, W ₂ , W ₃ , W ₄ , W5 and W6 are independently CR _a , CR _b or N, wherein when one, two or three of W1, W5 and W6 are N, then W ₂ , W ₃ and W4 represent CR _a or CR _b , and wherein when one, two or three of W ₂ , W3 and W4 represent N, then W1, W5 and W6 represent

- 1 043655 are CR _a or CR _b ;

R1 is aryl, heterocyclyl, heterocyclyl-amino, (heterocyclyl)(C _1-8 alkyl)amino or heteroaryl, in each case the heterocyclyl is optionally substituted with one, two or three R3 substituents and optionally with one additional _R4 substituent, or, alternatively, in each case the heterocyclyl is optionally substituted with one, two, three or four R3 substituents;

R2 is aryl, heteroaryl, heteroaryl-amino or (heteroaryl)(C _1-8 alkyl)amino, in each case aryl and heteroaryl is optionally substituted with one, two or three R ₆ substituents and optionally with one additional R ₇ deputy;

Ra is in each case independently selected from hydrogen, halogen or C _1-8 alkyl;

R _{b is} in each case independently selected from hydrogen, halogen or C _1-8 alkyl;

R3 in each case is independently selected from cyano, halogen, hydroxy, C _1-8 alkyl, halo-C _1-8 alkyl, C _1-8 alkyl-carbonyl, C _1-8 alkoxy, halo-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-carbonyl, amino, C _1-8 alkyl-amino, (C _1-8 alkyl)2-amino, amino-C _1-8 alkyl, C _{1 -8} alkyl-amino-C _1-8 alkyl, (C _1-8 alkyl)2amino-C _1-8 alkyl, amino-C _1-8 alkyl-amino, C _1-8 alkyl-amino-C _1-8 alkyl -amino, (C _1-8 alkyl-amino-C _1-8 alkyl) ₂ -amino, (C _1-8 alkyl) ₂ -amino-C _1-8 alkyl-amino, [(C _1-8 alkyl) ₂ -amino-C _1-8 alkyl] ₂ -amino, (C _1-8 alkylamino-C _1-8 alkyl)(C _1-8 alkyl)amino, [(C _1-8 alkyl) ₂ -amino-C _{1- 8} alkyl](C _1-8 alkyl)amino, C _1-8 alkoxy-C _1-8 alkyl-amino, (C _1-8 alkoxy-C _1-8 alkyl) _2- amino, (C _1-8 alkoxy- C _1-8 alkyl)(C _1-8 alkyl) amino, C _1-8 alkyl-carbonylamino, C _1-8 alkoxy-carbonyl-amino, hydroxy-C _1-8 alkyl, hydroxy-C _1-8 alkoxy-C _1-8 alkyl, hydroxy-C _1-8 alkyl-amino, (hydroxy-C _1-8 alkyl) ₂ -amino or (hydroxy-C _1-8 alkyl)(C _1-8 alkyl) amino;

R ₄ is C _3-14 cycloalkyl, C _3-14 cycloalkyl-C _1-8 alkyl, C _3-14 cycloalkyl-amino, aryl-C _1-8 alkyl, aryl-C _1-8 alkoxycarbonyl, aryl- sulfonyloxy-C _1-8 alkyl, heterocyclyl, heterocyclyl C _1-8 alkyl, heteroaryl or heteroaryl-C _1-8 alkyl;

in each case, C _3-14 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R5 substituents;

R5 is in each instance independently selected from halogen, hydroxy, cyano, nitro, _C1-8 alkyl, halo- _C1-8 alkyl, _C1-8 alkoxy, halo- _C1-8 alkoxy, amino, _C1-8 alkyl -amino, (C _1-8 alkyl) ₂ -amino or C _1-8 alkylthio;

R ₆ is in each case independently selected from halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, cyano-C _1-8 alkyl, halo-C _1-8 alkyl, hydroxy-C _1-8 alkyl, C _1-8 alkoxy, halo-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkoxy, amino, C _1-8 alkyl-amino, (C _1-8 alkyl) ₂ -amino, C _1-8 alkoxy, C _1-8 alkyl-amino, (C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkyl) amino or C _1-8 alkyl- too; And

R ₇ is C _3-14 cycloalkyl, C _3-14 cycloalkoxy, aryl, heterocyclyl, heteroaryl or heteroaryl-C _1-8 alkoxy;

wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorphic or tautomeric form thereof.

Aspects of Description

Another aspect of the present description includes a compound of formula (I) containing a compound of formula (I.1)

(1.1) or its form, while

W _b W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are independently CR _a , CR _b or N, wherein when one, two or three of Wb W5 and W ₆ are N, then W ₂ W3 and W ₄ are CR _a or CR _b , and when one, two or three of W ₂ , W3 and W ₄ are N, then W ₁ , W5 and W ₆ are CR _a or CR _b ;

R1 is C _1-8 alkyl, amino, C _1-8 alkyl-amino, (C _1-8 alkyl) ₂ -amino, C _1-8 alkoxy-C _1-8 alkylamino, (C _1-8 alkoxy-C _1-8 alkyl) ₂ -amino, (C _1-8 alkoxy-C _1-8 alkyl)(C _1-8 alkyl) amino, amino-C _1-8 alkyl, C _1-8 alkyl-amino-C _{1- 8} alkyl, (C _1-8 alkyl) ₂ -amino-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl-amino-C _1-8 alkyl, (C _1-8 alkoxy-C _{1- 8} alkyl) ₂ -amino-C _1-8 alkyl, (C _1-8 alkoxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkyl, amino-C _1-8 alkyl-amino , (amino-C _1-8 alkyl) ₂ -amino, (amino-C _1-8 alkyl)(C _1-8 alkyl)amino, C _1-8 alkyl-aminoC _1-8 alkyl-amino, (C _{1- 8} alkyl-amino-C _1-8 alkyl) ₂ -amino, (C _1-8 alkyl-amino-C _1-8 alkyl)(C _1-8 alkyl)amino, (C _1-8 alkyl) ₂ -amino- C _1-8 alkyl-amino, [(C _1-8 alkyl) ₂ -amino-C _1-8 alkyl](C _1-8 alkyl)amino, amino-C _1-8 alkoxy, C _1-8 alkyl-amino -C _1-8 alkoxy, (C _1-8 alkyl) ₂ -amino-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl-amino-C _1-8 alkoxy, C _1-8 alkoxy- C _1-8 alkyl-amino-C _1-8 alkoxy, (C _1-8 alkoxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkoxy, amino-C _2-8 alkenyl, C _1-8 alkyl-amino-C _2-8 alkenyl, (C _1-8 alkyl) _2- amino-C _2-8 alkenyl, amino-C _2-8 alkynyl, C _1-8 alkyl-amino-C _{2- 8} alkynyl, (C _1-8 alkyl) ₂ -amino-C _2-8 alkynyl, halo-C _1-8 alkyl-amino, (halo-C _1-8 alkyl) ₂

- 2 043655 amino, (halo-C _1-8 alkyl)(C _1-8 αlkyl)amino, hydroxy-C _1-8 alkyl, hydroxy-C _1-8 alkoxy-C _1-8 alkyl, hydroxyC _1-8 alkyl -amino, (hydroxy-C _1-8 alkyl)2-amino, (hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino, hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl, (hydroxy-C ₁ . ₈ alkyl) ₂ -amino-C ₁ . ₈ alkyl, (hydroxy-C ₁ - ₈ alkyl) (C ₁ . ₈ alkyl) amino-C ₁ . ₈ alkyl, hydroxy-C _1-8 alkyl-amino-C _1-8 alkoxy, (hydroxy-C _1-8 alkyl) _2- amino-C _1-8 alkoxy, (hydroxy-C _1-8 alkyl)(C _{1 -8} alkyl)amino-C _1-8 alkoxy, hydroxy-C _1-8 alkyl-amino-C _{1-8 alkyl-amino, (hydroxy-C 1-8 αlkyl} -amino-C _1-8 alkyl) ₂ -amino , (hydroxy-C _1-8 alkyl) ₂ -amino-C _1-8 alkyl-amino, (hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl)(C _1-8 alkyl) amino, (hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkyl-amino,

[(hydroxy-C _1-8 alkyl) ₂ -amino-C _1-8 alkyl](C _1-8 alkyl)amino, [(hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _{1 -8} alkyl](C _1-8 alkyl)amino, C _3-14 cycloalkyl, aryl, aryl-C _1-8 alkyl-amino, (aryl-C _1-8 alkyl) _2- amino, (aryl-C1-8 alkyl )(C1-8alkyl)amino, aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, (aryl- _C1-8 alkyl)( _C1-8 alkyl )amino-C _1-8 alkyl, heterocyclyl, heterocyclyl-C _1-8 alkyl, heterocyclyl-C _1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C _1-8 alkyl)amino, heterocyclyl-amino-C _{1- 8} alkyl, heterocyclyl-C _1-8 alkyl-amino, (heterocyclyl-C _1-8 alkyl) _2- amino, (heterocyclyl-C _1-8 alkyl)(C _1-8 alkyl)amino, heterocyclyl-C _1-8 alkyl-amino-C _1-8 alkyl, (heterocyclyl-C _1-8 alkyl) ₂ -amino-C _1-8 alkyl, (heterocyclyl-C _1-8 alkyl)(C _1-8 alkyl)amino-C _{1- 8} alkyl, heterocyclyloxy, heterocyclyl-carbonyl, heterocyclyl-carbonyloxy, heteroaryl, heteroaryl-C _1-8 alkyl, heteroaryl-C _1-8 alkoxy, heteroaryl-amino, heteroaryl-C _1-8 alkylamino, (heteroaryl-C _1-8 alkyl) ₂ -amino, (heteroaryl-C _1-8 alkyl)(C _1-8 alkyl)amino, heteroaryl-C _1-8 alkylamino-C _1-8 alkyl, (heteroaryl-C _1-8 alkyl) ₂ -amino -C _1-8 alkyl or (heteroaryl-C _1-8 alkyl)(C _1-8 alkyl)aminoC _1-8 alkyl, in each case C _3-14 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R ₃ substituents and optionally one additional R 4 substituent, or alternatively in each case C _3-14 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one, two, three or four R ₃ substituents;

R2 is aryl, heteroaryl, heteroaryl-amino or (heterocyclyl)(C _1-8 alkyl)amino, in each case aryl and heteroaryl are optionally substituted with one, two or three R6 substituents and optionally with one additional R7 substituent ;

R _{a is} in each case independently selected from hydrogen or C _1-8 αlkyl;

R _b is in each case independently selected from hydrogen or halogen;

R ₃ in each case is independently selected from cyano, halogen, hydroxy, C _1-8 αlkyl, halo-C _1-8 αlkyl, C _1-8 αlkyl-carbonyl, C _1-8 αlkoxy, halo-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-carbonyl, amino, C _1-8 αlkyl-amino, (C _1-8 alkyl) _2- amino, amino-C _1-8 alkyl, C _1-8 αlkyl-amino-C _1-8 alkyl, (C _1-8 alkyl) ₂ amino-C _1-8 alkyl, amino-C _1-8 alkyl-amino, C _1-8 alkyl-amino-C _{1- 8} alkyl-amino, (C _1-8 alkyl-amino-C _1-8 alkyl) _2- amino, (C _1-8 alkyl) _2- amino-C _1-8 alkyl-amino, [(C _1-8 alkyl ) ₂ -amino-C _1-8 alkyl] ₂ -amino, (C _1-8 alkylamino-C _1-8 alkyl)(C _1-8 alkyl)amino, [(C _1-8 αlkyl) ₂ -amino-C _1-8 αlkyl](C _1-8 αlkyl)amino, C _1-8 alkoxy-C _1-8 alkyl-amino, (C _1-8 alkoxy-C _1-8 alkyl) _2- amino, (C _1-8 alkoxy-C _1-8 alkyl)(C _1-8 alkyl)amino, C _1-8 alkyl-carbonylamino, C _1-8 αalkoxy-carbonylamino, hydroxy-C _1-8 αlkyl, hydroxy-C _1-8 alkoxy -C _1-8 alkyl, hydroxy-C _1-8 αlkyl-amino, (hydroxy-C _1-8 alkyl) ₂ -amino or (hydroxy-C _1-8 alkyl)(C _1-8 alkyl) amino;

R4 is C _3-14 cycloalkyl, C _3-14 cycloalkyl-C _1-8 alkyl, C _3-14 cycloalkyl-amino, aryl-C _1-8 alkyl, aryl-C _1-8 alkoxycarbonyl, aryl-sulfonyloxy -C _1-8 alkyl, heterocyclyl, heterocyclylC _1-8 αalkyl, heteroaryl or heteroaryl-C _1-8 alkyl;

in each case, C _3-14 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R ₅ substituents;

R ₅ is in each case independently selected from halogen, hydroxy, cyano, nitro, C _1-8 alkyl, halo-C _1-8 alkyl, C _1-8 alkoxy, halo-C _1-8 alkoxy, hydroxy-C _1-8 alkyl, amino, C _1-8 αlkyl-amino, (C _1-8 alkyl) ₂ amino, (C _1-8 alkyl) ₂ -amino-C _1-8 alkyl, C _1-8 alkyl-thio or heteroaryl-C _1-8 alkyl;

R6 is in each case independently selected from halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, cyano-C _1-8 alkyl, halo-C _1-8 alkyl, hydroxy-C _1-8 alkyl , C _1-8 alkoxy, halo-C _1-8 alkoxy, (C _1-8 alkyl) _2- amino-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy- C _1-8 alkoxy, amino, C _1-8 alkyl-amino, (C _1-8 alkyl) _2- amino, C _1-8 alkoxy-C _1-8 alkyl-amino, (C _1-8 alkoxy-C _{1 -8} alkyl, C _1-8 alkyl)amino or C _1-8 alkylthio; And

R7 is C _3-14 cycloalkyl, C _3-14 cycloalkyl-oxy, aryl, heterocyclyl, heteroaryl or heteroaryl-C _1-8 alkoxy.

One aspect includes a compound of formula (I) wherein W ₁ is N.

Another aspect includes a compound of formula (I) wherein W ₁ is N, W ₄ is CR _b , and W ₂ , W ₃ , W ₅ and W ₆ are CR _a .

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

Another aspect includes a compound of formula (I) wherein W2 is N, W4 is CR _b , and W ₁ , W ₃ , W ₅ and W ₆ are CR _a .

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

Another aspect includes a compound of formula (I) wherein W ₃ is N, W ₄ is CR _b , and W ₁ , W ₂ , W ₅ and W ₆ are CR _a .

- 3 043655

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

Another aspect includes a compound of formula (I) wherein W ₄ is N and W1, W2, W ₃ , W ₅ and W ₆ are independently CR _a .

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

Another aspect includes a compound of formula (I) wherein W ₅ is N, W ₄ is CR _b and W1, W2, W ₃ and W ₆ are CR _a .

One aspect includes a compound of formula (I) wherein W ₆ is N.

Another aspect includes a compound of formula (I) wherein W ₆ is N, W ₄ is CR _b and W1, W2, W ₃ and W ₅ are CR _a .

Another aspect includes a compound of formula (I) wherein R1 is aryl, heterocyclyl, heterocyclyl-amino, (heterocyclyl)( _C1-8 alkyl)amino or heteroaryl.

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

Another aspect includes a compound of formula (I) wherein R1 is aryl.

Another aspect includes a compound of formula (I), wherein R ₁ is heteroaryl.

Another aspect includes a compound of formula (I), wherein R ₁ is heterocyclyl, heterocyclyl-amino or (heterocyclyl)(C _1-8 alkyl)amino.

Another aspect includes a compound of formula (I) wherein R ₁ is heterocyclyl.

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

Another aspect includes a compound of formula (I) wherein R1 is (heterocyclyl)( _C1-8 alkyl)amino.

Another aspect includes a compound of formula (I) wherein Ra is hydrogen or C ₁ . ₈ alc.

Another aspect includes a compound of formula (I) wherein R _b is hydrogen or halogen.

Another aspect includes a compound of formula (I) wherein R ₄ is heterocyclyl-C ₁ . ₈ alkyl or heteroaryl-C ₁ . ₈ alkyl.

Another aspect includes a compound of formula (I) wherein R ₅ is hydroxy-C ₁ . ₈ αlkyl, (C1. ₈ alkyl) ₂ -amino-C1. ₈ alkyl or heteroaryl-C ₁ . ₈ alkyl.

Another aspect includes a compound of formula (I), wherein R6 is halogen, hydroxy, cyano, C ₁ . ₈ alkyl, cyano-C ₁ . ₈ αlkyl, halo-C ₁ . ₈ alkyl, hydroxy-C ₁ . ₈ alkyl, C ₁ . ₈ αlkoxy, (C ₁ . ₈ alkyl) ₂ -amino-C ₁ . ₈ alkoxy-C ₁ . ₈ alkoxy-C ₁ . ₈ alkoxy or _C1 . ₈ alkoxy-C ₁ . ₈ alkyl amino.

Another aspect includes a compound of formula (I) wherein R7 is _C3 . ₁₄ cycloalkyl, heterocyclyl or heteroaryl- _C1-8 alkoxy.

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

Another aspect includes a compound of formula (I), wherein W1 and W ₅ are N, W ₄ is CR _b , and W ₂ , W ₃ and W ₆ are CR _a .

One aspect includes a compound of formula (I), wherein W1 and _W6 are N.

Another aspect includes a compound of formula (I), wherein W1 and W ₆ are N, W ₄ is CR _b , and W ₂ , W ₃ 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 W2 and W3 are N, W ₄ is CR _b , and W1, W ₅ and W ₆ are CR _a .

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

Another aspect includes a compound of formula (I), wherein W2 and W4 are N, and W1, _W3 , _W5 and _W6 are independently CR _a .

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

Another aspect includes a compound of formula (I), wherein W ₃ and W ₄ are N, and W1, W ₂ , W ₅ and W ₆ are independently CR _a .

One aspect includes a compound of formula (I), wherein W ₅ and W ₆ are N.

Another aspect includes a compound of formula (I) wherein W ₅ and W ₆ are N, W ₄ is CR _b and W1, W2 and W ₃ are CR _a .

Another aspect includes a compound of formula (I), wherein W ₅ and W ₆ are N, W2 is CR _b , and W1, W ₃ and W ₄ are CR _a .

Another aspect includes a compound of formula (I) wherein W ₅ and W ₆ are N, W ₃ is CR _b and W1, W2 and W ₄ are CR _a .

One aspect includes a compound of formula (I), wherein W1, _W5 and _W6 are N.

Another aspect includes a compound of formula (I), wherein W1, _W5 and _W6 represent

- 4 043655 fight N, W ₄ represents CR _b and W2 and W ₃ represent CR _a .

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

Another aspect includes a compound of formula (I) wherein W2, _W3 and _W4 are N, and _{Wb W5} and _W6 are independently CR _a .

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

Another aspect includes a compound of formula (I), wherein R ₁ is a heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1- yl, piperidin-4-yl, piperazin-1-yl, azepan-4-yl, 1,4-diazepan-1-yl, 1,2,5,6tetrahydropyridin-5-yl, 1,2,3,6- tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS )-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrole -1(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-5(1H)-yl, (3aR,6aS)hexahydropyrrolo[3 ,4-c]pyrrol-2(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6Hpyrrolo[3,4-b]pyridin-6-yl, (4aR ,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2 -a]pyrrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)- yl, (8aS)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydro-1H-cyclobuta[1 ,2-c:1,4-c']dipyrrol-2(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1, 2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, 3azabicyclo[3.1.0]hexan-3-yl, 8-azabicyclo[3.2.1 ]octan-3-yl, (1R,5S)-8-azabicyclo[3.2.1]octan-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S) -8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]nonan3-yl, (1R,5S)-9-azabicyclo[3.3.1]nonan-3-yl , 2,5-diazabicyclo[2.2.1]heptan-2-yl, (1S,4S)-2,5diazabicyclo[2.2.1]heptan-2-yl, 1,4-diazabicyclo[3.1.1]heptan-4 -yl, 3,6-diazabicyclo[3.2.0]heptan-3yl, 3,6-diazabicyclo[3.2.0]heptan-6-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, 1 ,4diazabicyclo[3.2.1]octan-4-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, (1R,5S)-3,8diazabicyclo[3.2.1]octan-3-yl, 1 ,4-diazabicyclo[3.2.2]nonan-4-yl, azaspiro[3.3]heptan-2-yl, 4,7diazaspiro[2.5]octan-4-yl, 4,7-diazaspiro[2.5]octan-7-yl , 2,6-diazaspiro[3.3]heptanan-2-yl, 2,6diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1,7-diazaspiro[4.4]nonane -1-yl, 1,7,diazaspiro[4.4]nonan-7-yl, 2,6-diazaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.5]nonan-6-yl, 2,7diazaspiro [3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 5,8-diazaspiro[3.5]nonan-8-yl, 2,7diazaspiro[4.4]nonan-2-yl, 2 ,7-diazaspiro[4.5]decan-2-yl, 2,7-diazaspiro[4.5]decan-7-yl or 6,9diazaspiro[4.5]decan-9-yl; in each case, the heterocyclyl is optionally substituted with R3 and R4 substituents.

Another aspect includes a compound of formula (I), wherein R1 is a heterocyclyl selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,2,5,6tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3-azabicyclo [3.1.0]hexyl, 8azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,6-diazaspiro[3.4]octanyl, 2,6diazaspiro[3.5]nonyl, 2,7-diazaspiro [3.5]nonyl.

- 5 043655

Another aspect includes a compound of formula (I), wherein R ₁ is heterocyclyl selected from pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, azepan-4-yl, 1,2, 5,6tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 8azabicyclo[3.2.1]octan-3-yl, 2, 5-diazabicyclo[2.2.1]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2,6diazaspiro[3.4]octan-6-yl, 2,6-diazaspiro[3.5]nonan- 2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, and 2,7diazaspiro[3.5]nonan-7-yl.

Another aspect includes a compound of formula (I) wherein R ₁ is substituted with heterocyclyl selected from

N,N-dimethylpyrrolidin-3-amine, N,N-dimethylpiperidin-4-amine,

N,N-4-trimethylpiperidin-4-amine, 1-methylpiperidin-4-yl,

1-ethylpiperidin-4-yl, 1-(propan-2-yl)piperidin-4-yl,

2-hydroxyethylpiperidin-4-yl, 2-fluoroethylpiperidin-4-yl,

2,2-difluoroethylpiperidin-4-yl, N,N-dimethyl-2-(piperidin-1-yl)ethan-1-amine, N,N-dimethyl-2-(piperidin-1-yl)propan-1- amine, (2S,6S)-2,6-dimethylpiperidin-4-yl, (2R,6S)-2,6-dimethylpiperidin-4-yl, (2S,6S)-2,6-diethylpiperidin-4-yl, (2S,6S)-(2,6-diethyl-1-methyl)piperidin-4-yl, (2S,6S)-1,2,6-trimethylpiperidin-4-yl, (2R,6S)-1,2 ,6-trimethylpiperidin-4-yl, (2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl, (2R,6R)-1-ethyl-2,6-dimethylpiperidin-4-yl, ( 2R,6S)-[1 -(2-fluoroethyl)-2,6-dimethyl]piperidin-4-yl, (ethyl-1-ol)piperidin-1-yl,

2,6-dimethylpiperidin-1 -yl-ethan-1 -ol, 3-(1 H-pyrazol-1 -yl)propyl] piperidin-4-yl,

3-(1 H-benzimidazol-1 -yl)propyl]piperidin-4-yl,

2-(1 H-benzimidazol-1 -yl)ethyl]piperidin-4-yl, 1 -ethyl-1,2,3,6-tetrahydropyridin-4-yl,

2,2,6,6-tetramethylpiperidin-4-yl, 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl, (3R,5S)-3,5-dimethylpiperazin- 1-yl, 1-methylazepan-4-yl, 1-ethylazepan-4-yl, (2-fluoroethyl)azepan-4-yl, azepan-1-yl-ethan-1-ol, 4-methyl-1,4 -diazepan-1-yl, (3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol- 1(2H)-yl, (3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl, (3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-(propan-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)- 1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR )-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6 -yl, (4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a] pyrazin-2(1H)-yl, (8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2( 1H)-yl, (1 R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl,

N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine, (1R,5 S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl,

9-methyl-9-azabicyclo[3.3.1]non-3-yl, (3-hexo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl, (1 R,5S)-9 -methyl-9-azabicyclo[3.3.1]non-3-yl,

5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, (1S,4S )-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl or (1S,4S)-3-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl.

Another aspect includes a compound of formula (I) wherein R ₁ is substituted with heterocyclyl selected from

N,N-dimethylpyrrolidin-3-amine, N,N-dimethylpiperidin-4-amine,

N,N-4-trimethylpiperidin-4-amine, 1-methylpiperidin-4-yl, 1-ethyl-piperidin-4-yl,

-(propan-2-yl)piperidin-4-yl, 2-hydroxyethylpiperidin-4-yl,

2-fluoroethylpiperidin-4-yl, 2,2-difluoroethylpiperidin-4-yl,

N,N-dimethyl-2-(piperidin-1-yl)ethan-1-amine,

N,N-dimethyl-2-(piperidin-1 -yl)propan-1-amine, (2S,6S)-2,6-dimethylpiperidin-4-yl, (2R,6S)-2,6-dimethylpiperidin-4 -yl, (2S,6S)-2,6-diethylpiperidin-4-yl, (2S,6S)-2,6-diethyl-1-methylpiperidin-4-yl,

- 6 043655 (28.68)-1,2,6-trimethylpiperidin-4-yl, (2R,6S)-1,2,6-trimethylnunerudin-4-ylα, (2S,4R,6R)-1,2 ,6-trimethylpiperidin-4-yl, (2R,6R)-1-ethyl-2,6-dimethylpiperidin-4-yl, (2R,6S)-1-(2-fluoroethyl)-2,6-dimethylpiperidin-4 -yl, piperidin-1-yl-ethan-1-ol,

2,6-dimethylpiperidin-1-yl-ethan-1-ol,

3-(1 H-pyrazol-1 -yl)propyl] piperidin-4 -yl,

3-(1 H-benzimidazol-1 -yl)propyl]piperidin-4-yl,

2-(1 H-benzimidazol-1 -yl)ethyl]piperidin-4-yl,

1-ethyl-1,2,3,6-tetrahydropyridin-4-yl,

2,2,6,6-tetramethylpiperidin-4-yl,

2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl, (3R,5S)-3,5-dimethylpiperazin-1-yl,

1-methylazepan-4-yl, 1-ethylazepan-4-yl, 2-fluoroethylazepan-4-yl, azepan-1-yl-ethan-1-ol, K,K-dimethyl-3-azabicyclo[3.1.0] hexane-6-amine,

5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl or (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl.

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

Another aspect includes a compound of formula (I), wherein R1 is heterocyclyl-amino selected from azetidin-3-yl-amino, pyrrolidin-3-yl-amino, piperidin-4-yl-amino, 9-azabicyclo[3.3 .1]non-3-yl-amino, (1 R,5S)-9-azabicyclo[3.3.1]non-3-yl-amino, 9-methyl-9azabicyclo[3.3.1]non-3-yl- amino, (3-hexo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or (1R,5S)-9methyl-9-azabicyclo[3.3.1]non-3-yl- amino; in each case, the heterocyclyl is optionally substituted with R ₃ and R 4 substituents.

One aspect includes a compound of formula (I), wherein R1 is (heterocyclyl)(C1_ ₈ alkyl)amino, wherein the heterocyclyl is selected from pyrrolidinyl or piperidinyl; and in each case the heterocyclyl is optionally substituted with R ₃ and R ₄ substituents.

Another aspect includes a compound of formula (I), wherein R1 is (heterocyclyl)(C1_ ₈ alkyl)amino, wherein heterocyclyl is piperidinyl.

Another aspect includes a compound of formula (I), wherein R1 is (heterocyclyl)(C1_ ₈ alkyl)amino selected from (pyrrolidin-3-yl)(methyl)amino or (piperidin-4yl)(methyl)amino ; in each case, the heterocyclyl is optionally substituted with R3 and R4 substituents.

One aspect includes a compound of formula (I), wherein R ₃ is selected from cyano, halogen, hydroxy, oxo, C ₁ . ₈ αlkyl, halo-C ₁ . ₈ αlkyl, C ₁ . ₈ alkyl carbonyl, C ₁ . ₈ αlkoxy, halo-C1_ ₈ alkoxy, C _{1_ 8} alkoxy-C _{1_ 8} alkyl, C1_ ₈ alkoxy-carbonyl, amino, C ₁ . ₈ alkyl-amino, (C1_ ₈ alkyl) ₂ -amino, amino-C1_ ₈ alkyl, C ₁ _ ₈ alkyl-amino-C ₁ _ ₈ alkyl, (C ₁ . ₈ αlkyl) ₂ -amino-C ₁ . ₈ alkyl, amino-C ₁ . ₈ alkyl-amino, C1_ ₈ alkylamino-C1_ ₈ alkyl-amino, (C ₁ _ ₈ alkyl) _2- amino-C ₁ _ ₈ alkyl-amino, C ₁ _ ₈ alkoxy-C ₁ _ ₈ alkyl-amino, C1_ ₈ alkylcarbonyl-amino, C1. ₈ alkoxy-carbonyl-amino, hydroxy-C ₁ . ₈ alkyl _, hydroxy _{- C1_8} alkoxy- _{C1_8} alkyl, hydroxy- _{C1_8 alkyl} -amino, ₍ hydroxy- _{C1_8} alkyl) _2- amino or (hydroxy- _{C1_8} alkyl)( _{C1_8} alkyl)amino.

Another aspect includes a compound of formula (I), wherein R3 is selected from cyano, halogen, hydroxy, oxo, C ₁ . ₈ alkyl, halo-C ₁ . ₈ alkyl, C ₁ . ₈ alkoxy, C ₁ _ ₈ alkoxy-C ₁ _ ₈ alkyl, C1- ₈ alkoxy-carbonyl, amino, C1- ₈ alkyl-amino, (C1_ ₈ alkyl) _2- amino, amino-C ₁ . ₈ alkyl, C1.8αalkyl-αamino-C1.8αalkylα, ( _C1.8alkyl ) _{2 amino} - _C1 . ₈ alkyl, C1.8alkyl-αamino-C1.8αalkyl-αamino, C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl-amino, C ₁ . ₈ alkoxy-carbonylamino, hydroxy-C ₁ . ₈ alkyl, hydroxy-C1.8αalkoxy-C1.8alkylα, hydroxy-C ₁ . ₈ alkyl-amino, (hydroxy-C1_ ₈ alkyl) ₂ -amino or (hydroxy-C ₁ _ ₈ alkyl)(C ₁ _ ₈ alkyl) amino.

Another aspect includes a compound of formula (I) wherein R ₃ is C ₁ . ₈ αlkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

Another aspect includes a compound of formula (I), R ₃ is C ₁ . ₈ alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

Another aspect includes a compound of formula (I) wherein R3 is halo-C ₁ . ₈ alkyl selected from trihalomethyl, dihalomethyl, halomethyl, trihaloethyl, dihaloethyl, haloethyl, trihalopropyl, dihalopropyl or halopropyl; the halo being selected from fluorine, chlorine, bromine or iodine.

Another aspect includes a compound of formula (I) wherein R3 is halo-C ₁ . ₈ alkyl selected from trihalomethyl, dihalomethyl, halomethyl, trihaloethyl, dihaloethyl, trihalopropyl or dihalopropyl; the halo being selected from fluorine, chlorine, bromine or iodine.

Another aspect includes a compound of formula (I) wherein R ₃ is hydro

- 7 043655 xy- _C1-8 alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

Another aspect includes a compound of formula (I), wherein R ₃ is hydroxy-C ₁ - ₈ alkyl selected from hydroxy-methyl, hydroxy-ethyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

Another aspect includes a compound of formula (I) wherein R ₃ is C ₁ . ₈ alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

Another aspect includes a compound of formula (I) wherein R ₃ is halo-C ₁ . ₈ alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihaloethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; the halo being selected from fluorine, chlorine, bromine or iodine.

Another aspect includes a compound of formula (I) wherein R3 is _{C1_8} alkoxycarbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino , tert-butoxy-carbonyl-amino.

Another aspect includes a compound of formula (I) wherein R ₄ is C ₃ . ₁₄ cycloalkyl, C ₃ . ₁₄ cycloalkyl-C ₁ . ₈ alkyl, C ₃ . ₁₄ cycloalkyl-amino, aryl-C ₁ . ₈ alkyl, aryl-C ₁ . ₈ αalkoxycarbonyl, aryl-sulfonyloxy-C ₁ . ₈ alkyl, heterocyclyl, heterocyclyl-C ₁ . ₈ alkyl or heteroaryl; Moreover, in each case C ₃ . ₁₄ cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one, two or three R ₅ substituents.

Another aspect includes a compound of formula (I), wherein R ₅ is in each instance independently selected from halogen, hydroxy, cyano, nitro, C ₁ . ₈ αlkyl, halo-C ₁ . ₈ alkyl, C ₁ . ₈ alkoxy, halo-C ₁ . ₈ alkoxy, hydroxy-C ₁ . ₈ αlkyl, amino, C ₁ . ₈ αlkyl- _{αmino, (C1.8 alkyl)2-amino, (C1.8 alkyl )} 2-amino- _C1 . ₈ alkyl, C ₁ . ₈ alkyl-thio or heteroaryl-C ₁ . ₈ alkyl.

One aspect includes a compound of formula (I) wherein R2 is aryl, heteroaryl, heteroaryl-amino, (heteroaryl)( _C1-8 alkyl)amino, or (heterocyclyl)( _C1-8 alkyl)amino.

Another aspect includes a compound of formula (I), wherein R ₂ is aryl, heteroaryl, heteroaryl-amino or (heteroaryl)(C1_ ₈ alkyl)amino.

Another aspect includes a compound of formula (I) wherein R ₂ is aryl.

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

Another aspect includes a compound of formula (I) wherein R ₂ is heteroaryl-amino.

Another aspect includes a compound of formula (I) wherein R2 is (heteroaryl)( _C1-8 alkyl)amino.

Another aspect includes a compound of formula (I), wherein R2 is (heterocyclyl)(C _1-8 alkyl)amino.

One aspect includes a compound of formula (I), wherein R2 is a heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl , pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, N-benzimidazolyl, 1,3-benzothiazolyl, 1,3benzoxazolyl, 9H-purinyl, furo[3,2 -b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2 ,3-6]pyridinyl, N-pyrrolo[2,3c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-6]pyridazinyl, pyrazolo[1 ,5-a]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2Hpyrazolo[4,3-c]pyridinyl, pyrazolo[1,5-a]pyrazinyl , imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 3H -imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[ 4,5-b]pyridinyl, [1,3]oxazolo[4,5-c]pyridinyl, [1,3]thiazolo[4,5-c]pyridinyl, [1,3]thiazolo[5,4-b ]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl or quinoxalinyl; in each case, the heteroaryl is optionally substituted with R6 and R7 substituents.

Another aspect includes a compound of formula (I), wherein R ₂ is a heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1Himidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4- oxadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1Hindol-5- yl, 1H-indol-6-yl, 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothien-2-yl, benzothien-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6- yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2- yl, furo[3,2c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d] pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-2-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[3,4-c]pyridin-5-yl, 2H

- 8 043655 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[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl , imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2b]pyridazin-6-yl, imidazo[1,2-a]pyrazine -2-yl, imidazo[1,2-a]pyrazin-6-yl, 3H-imidazo[4,5b]pyridin-5-yl, imidazo[2,1-b][1,3]thiazol-6- yl, imidazo[2,1 -b] [1,3,4]thiadiazol-6-yl,

[1,3]oxazolo[4,5-b]pyridin-2-yl, [1,3]oxazolo[4,5-c]pyridin-2-yl, [1,3]thiazolo[5,4-b ]pyridin-5-yl, [1,3]thiazolo[5,4-c]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl or quinoxalin-2 -ila;

Moreover, in each case, the heteroaryl is optionally substituted with R ₆ and R ₇ substituents.

One aspect includes a compound of formula (I), wherein R ₆ is selected from halogen, hydroxy, cyano, nitro, C _1-8 alkyl, halo-C _1-8 alkyl, hydroxy-C _1-8 alkyl, C _{1 -8} alkoxy, halo-C _1-8 alkoxy, C _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkoxy, (C _1-8 alkyl) ₂ -amino-C _{1- 8} alkoxy, heteroaryl-C _1-8 alkoxy, aryloxy, (C _1-8 alkyl) ₂ -amino, C _1-8 alkoxy-C _1-8 alkyl-amino, C _1-8 alkyl-thio, C _3-14 cycloalkyl;

wherein the halogen and halo are selected from fluorine, chlorine, bromine or iodine. Another aspect includes a compound of formula (I), wherein R ₆ is C _1-8 alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

Another aspect includes a compound of formula (I), wherein R ₆ is C _1-8 alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

Another aspect includes a compound of formula (I), wherein R ₆ is a halo-C _1-8 alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo- ethyl, trihalopropyl, dihalopropyl or halopropyl;

the halo being selected from fluorine, chlorine, bromine or iodine.

Another aspect includes a compound of formula (I), wherein R ₇ is C _3-14 cycloalkyl, C _3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

One aspect includes a compound of formula (I) wherein Ra is hydrogen or C _1-8 alkyl.

One aspect includes a compound of formula (I) wherein Rb is hydrogen or C _1-8 alkyl.

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

One aspect of a compound with formula (I) includes a compound selected from formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Il), formula (Im) or formula (In):

or its shape.

Another aspect of a compound with formula (I) includes a compound selected from formula (Ib), formula (Ic), formula (Ie), formula (If), formula (Ig), formula (Ii), formula (Ij), formulas (Ik), formulas (Im) or formulas (In):

- 9 043655

or its shape.

Another aspect of a compound of formula (I) includes a compound selected from formula (Ia1), formula (Ib1), formula (Ic1), formula (Id1), formula (Ie1), formula (If1), formula (Ig1), formula (Ih1), formula (Ii1), formula (Ij1), formula (Ik1), formula (Il1), formula (Im1) or formula (In1), respectively:

or its shape.

Another aspect of a compound of formula (I) includes a compound selected from formula (Ib1), formula (Ic1), formula (Ie1), formula (If1), formula (Ig1), formula (Ii1), formula (Ij1), formula (Ik1), formula (Il1), formula (Im1) or formula (In1), respectively:

- 10 043655

(Ill) (Im l) or (Ini), or its form.

Another aspect of a compound of formula (I) includes a compound of formula (Ia1):

(1a1) or its form.

Another aspect of a compound of formula (I) includes a compound of formula (Ib1):

(Ibl) or its form.

Another aspect of a compound of formula (I) includes a compound of formula (Ic1):

Ra

^R a ^R b (Icl) or its form.

Another aspect of a compound of formula (I) includes a compound of formula (Id1):

Ra Ra

(Idl) or its form.

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

(lei) or its form.

Another aspect of a compound of formula (I) includes a compound of formula (If1):

- 11 043655

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ig1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ih1):

or its shape.

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

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Ij1):

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 (Il1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (Im1):

or its shape.

Another aspect of a compound of formula (I) includes a compound of formula (In1):

- 12 043655

(Inl) or its form.

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

- 13 043655

- 14 043655

- 15 043655

- 16 043655

- 17 043655

- 18 043655

- 19 043655

wherein the form of the compound is selected from the group consisting of a salt, prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorphic or tautomeric form thereof. An aspect of a compound of formula (I) or a form thereof (wherein the compound number (#1) indicates that the salt form has been isolated) includes a compound selected from the group consisting of:

Connection Name

I ¹ 2-(2-methyl-2/7-indazol-5-yl)-6-(piperidin-4-yl)quinoline

2 ¹ 6-(1-ethylpiperidin-4-yl)-2-(2-methyl-2/7-indazol-5-yl)quinoline

3 ¹ 6-(2-methyl-2/7-indazol-5-yl)-2-(piperidin-4-yl)quinolone

4 ¹ 3-(2-methyl-2/7-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline

- 20 043655

5 ¹ 4-methyl-6-(2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline

6 ¹ 6-(2-methyl-2R-indazol-5-yl)-2-(1-methylpiperidin-4-yl)quinoline

2-(2-methyl-2R-indazol-5-yl)-6-(piperazin-1-yl)quinoline

9 ¹ 2-(1-ethylpiperidin-4-yl)-6-(2-methyl-2R-indazol-5-yl)quinoline

10 ¹ 2-(2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinazoline

6-(2,7-dimethyl-2R-indazol-5-yl)-M-methyl-M-(2,2,6,6-tetramethylpiperidin4-yl)quinolin-2-amine

R-methyl-6-(2-methyl-2R-indazol-5-yl)-M-(2,2,6,6-tetramethylpiperidin-4yl)quinolin-2-amine

6-(2,7-dimethyl-277-indazol-5-yl)-2-(2,2,6,6-tetramethyl-1,2,3,6te1rahydropyridin-4-yl)quinoline

6-(2,7-dimethyl-2R-indazol-5-yl)-2-(2,2,6,6-tetramethylpiperidin-4-yl)quinoline

6-(2,7-dimethyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline

7-(2,7-dimethyl-2R-indazol-5-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine

3-(2,7-dimethyl-2R-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine

6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(piperidin-4-yl)quinoline

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline

6-(2,7-dimethyl-2R-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinoline

6-(2,7-dimethyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinazoline

24 ¹ 6-[2-methyl-7-(trifluoromethyl)-2R-in dazol-5-yl]-2-(piperidin-4-yl)quinoxaline

25 ¹ 3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine

2-methyl-5-[7-(piperidin-4-yl)-1,2,4-benzotriazin-3-yl]-2R-indazol-7carbonitrile

3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-1,2,4benzotriazine

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(piperidin-4-yl)-1,2,4benzotriazine

3-(2,7-dimethyl-2R-indazol-5-yl)-7-(piperidin-4-yl)quinoline

7-(2,7-dimethyl-2R-indazol-5-yl)-3-(piperidin-4-yl)isoquinoline

31 ¹ 6-(2,7-dimethyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoxaline

5-fluoro-7-(7-fluoro-2-methyl-2R-indazol-5-yl)-3-(piperidin-4-yl)-1,2,4benzotriazine

7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine

34 ¹ 6-(2,7-dimethyl-2R-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline

35 ¹ 5-[8-fluoro-2-(piperidin-4-yl)quinazolin-6-yl]-2-methyl-2R-indazole-7-carbonitrile

36 ¹ 8-fluoro-6-(7-fluoro-2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinazoline

- 21 043655

37 ¹ 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4yl)quinazoline

38 ¹ 6-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-2-(piperidin-4-yl)quinazoline

39 ¹ 6-(2,7-dimethyl-2R-indazol-5-yl)-7-fluoro-2-(piperidin-4-yl)quinazoline

3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(piperidin-4-yl)-

1,2,4-benzotriazine

5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-

1,2,4-benzotriazine

7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-M-methyl-M-(piperidin-4-yl)1,2,4-benzotriazin-3-amine

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-1,2,4benzotriazine

3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(piperidin-4-yl)-1,2,4benzotriazine

45 ¹ 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4-yl)quinoline

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

47 ¹ 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(1-methylpiperidin4-yl)quinoline

48 ¹ 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)8-fluoroquinoline

49 ¹ 8-fluoro-6-(7-methoxy-2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline

50 ¹ 8-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4yl)quinoline

51 ¹ 8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin4-yl)quinoline

3-(7-methoxy-2-methyl-2R-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine

53 ¹ 8-fluoro-6-[8-(2-methoxyethoxy)-2-methylimidazo[1,2-b]pyridazin-6-yl]-2(piperidin-4-yl)quinoline

54 ¹ 6-[8-fluoro-2-(piperidin-4-yl)quinolin-6-yl]-M-(2-methoxyethyl)2-methylimidazo[1,2-b]pyridazin-8-amine

55 ¹ 7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(1,2,3,6-tetrahydropyridin-4yl)cinnoline

56 ¹ 7-(8-azabicyclo[3.2.1]oct-3-yl)-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)1,2,4-benzotriazine

57 ¹ 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)-

1,2,4-benzotriazine

58 ¹ 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)-

1,2,4-benzotriazine

- 22 043655

59 ¹ 7-(8-ethoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

60 ¹ 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

61 ¹ 5-fluoro-7-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-3-(piperidin4-yl)-1,2,4-benzotriazine

62 ¹ 7-(2,4-dimethyl-1,3-benzoxazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4benzotriazine

63 ¹ 7-(2,4-dimethyl-1R-benzimidazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4benzotriazine

64 ¹ 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

65 ¹ 7-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

66 ¹ 7-(2,7-dimethyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

67 ¹ 7-(2,7-dimethyl-2R-pyrazolo[3,4-c]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-

1,2,4-benzotriazine

5-fluoro-7-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-3-(piperidin-4-yl)-

1,2,4-benzotriazine

69 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin4-yl)-1,2,4-benzotriazine

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluoro1,2,4-benzotriazine

71 ¹ 7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline

72 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4yl)isoquinoline

73 ¹ 7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

74 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]piperidin-1-yl}ethanol

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-propylpiperidin4-yl)cinnoline

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(propan-2yl)piperidin-4-yl]cinnoline

- 23 043655

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin4-yl)cinnoline

80 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperazin-1 yl)cinnoline

81 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(37?, 55)-3,5-dimethylpiperazin-1 yl]-5-fluorocinnoline

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4yl)quinoxaline

83 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1 -(2fluoroethyl)piperidin-4-yl]cinnoline

84 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)cinnoline

1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]-M,Mdimethylpyrrolidin-3-amine

87 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(25.65)-2,6-dimethylpiperidin-4yl]-5-fluorocinnoline

1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]M,M-dimethylpiperidin-4-amine (37?)-1-[ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]N,N-dimethylpyrrolidin-3-amine

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(27?,4g,65)-2,6dimethylpiperidin-4-yl]-5-fluorocinnoline

91 ¹ 5-fluoro-7-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-3-(piperidin-4-yl)cinnoline

92 ¹ 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4yl)cinnoline

93 ¹ 6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-a]pyridin8-carbonitrile

94 ¹ 5-fluoro-7-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(piperidin-4yl)cinnoline

95 ¹ 5-fluoro-7-(2-methyl-277-indazol-5-yl)-3-(piperidin-4-yl)cinnoline

96 ¹ 5-fluoro-7-(7-fluoro-2-methyl-277-indazol-5-yl)-3-(piperidin-4-yl)cinnoline

97 ¹ 5-fluoro-7-(6-fluoro-2-methyl-277-indazol-5-yl)-3-(piperidin-4-yl)cinnoline

98 ¹ 3-[1-(2,2-difluoroethyl)piperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6yl)-5-fluorocinnoline

99 ¹ 5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline

100 ¹ 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6yl)cinnoline

101 ¹ 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

- 24 043655

102 ¹ 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin6-yl)cinnoline

103 ¹ 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

104 ¹ 5-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methyl-277-indazole-7-carbonitrile

105 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

106 5-fluoro-7-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin4-yl)cinnoline

107 {6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin8-yl} methanol

108 6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin8-carbonitrile

109 ¹ 5-fluoro-7-(4-fluoro-2-methyl-277-indazol-5-yl)-3-(piperidin-4-yl)cinnoline

110 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)8-fluoroquinoxaline

111 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-methoxy-2-methylimidazo[1,2-b]pyridazin6-yl)cinnoline

112 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin4-yl)cinnoline

113 {6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]2-methylimidazo[1,2-b]pyridazin-8-yl}methanol

114 6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-carbonitrile

115 ¹ 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3 -(1-ethylpiperidin-4yl)-5-fluorocinnoline

116 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

117 ¹ 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6tetrahydropyridin-4-yl)cinnoline

118 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

119 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-3 -(1-ethylpiperidin-4-yl)-5fluorocinnoline

120 ¹ 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline

121 ¹ 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

122 ¹ 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin4-yl)cinnoline

123 ¹ 2-{4-[7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-

-yl] piperidin-1 -yl} ethan-1 -ol

- 25 043655

124 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro3-[(25.65)-1,2,6-trimethylpiperidin-4-yl]cinnoline

125 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2K,6K)-1-ethyl-,6-dim ethylpiperidin-4-yl]-5-fluorocinnoline

126 7-(2,7-dimethyl-377-imidazo[4,5-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

127 ¹ 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]piperidin-1-yl}-M,M-dimethylethane-1 -amine

128 ¹ 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4yl)cinnoline

129 3-(azepan-4-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline

130 3-[(25.65)-2,6-diethylpiperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6yl)-5-fluorocinnoline

131 3-[(25.65)-2, b-diethyl-1-methylpyridin-4-yl]-7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluorocinnoline

132 7-(2,7-dimethyl-37/-imidazo[4,5-b]pyridin-5-yl)-3 -(1-ethylpiperidin-4-yl)5-fluorocinnoline

133 ¹ 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

134 ¹ 5-fluoro-3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin4-yl)cinnoline

135 ¹ 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

136 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

137 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

138 ¹ 2-({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}oxy)-LG,N- dimethylethane-1-amine

139 ¹ 3 -({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}oxy)-LG,N- dimethylpropan-1-amine

140 ¹ 5-fluoro-7-{2-methyl-8-[2-(1R-pyrazol-1-yl)ethoxy]imidazo[1,2-b]pyridazin-6-yl}3 -(piperidin-4- yl)cinnoline

141 ¹ 5-fluoro-7-{2-methyl-8-[3-(1R-pyrazol-1-yl)propoxy]imidazo[1,2-b]pyridazin-6yl} -3 -(piperidin-4-yl )cinnoline

142 ¹ 5-fluoro-7-{8-[3-(177-imidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6yl} -3 -(piperidin-4-yl) cinnoline

143 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(pyrrolidin-3yl)cinnoline

- 26 043655

144 7-(1-ethylpiperidin-4-yl)-5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin6-yl)cinnoline

145 ¹ 3- {1 -[3-(1 R-benzimidazol-1 -yl)propyl]piperidin-4-yl} 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)- 5-fluorocinnoline

146 ¹ 7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline

147 7-(4,6-dimethyl[1,3]thiazolo[4,5-с]pyridin-2-yl)-3 -(1-ethylpiperidin-4-yl)5-fluorocinnoline

148 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

149 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

150 ¹ 7-{8-[3-(1R-benzimidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6yl} - 5-fluoro-3 -(nip erydin-4- yl)cinnoline

151 ¹ 5-fluoro-3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(piperidin-4-yl)cinnoline

152 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

153 ¹ 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2R-indazol5-yl)cinnoline

154 7-(1-ethylpiperidin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2R-indazol-5-yl)cinnoline

155 2-{(25.65)-4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]-2,6-dimethylpiperidin-1 - yl}ethan-1-ol

156 ¹ 3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin 4-yl)cinnoline

157 ¹ 3-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4yl)cinnoline

158 3-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]piperidin-1-yl}-LG,M-dimethylpropan-1- amine

159 3-{1-[2-(1R-benzimidazol-1-yl)ethyl]piperidin-4-yl}7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5- fluorocinnoline

160 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-{1-[3-(1R-pyrazol-

-yl)propyl]piperidin-4-yl}cinnoline

161 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro3-[(2A,65)-1,2,6-trimethylpiperidin-4-yl]cinnoline

162 7-(2,7-dimethyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

163 ¹ 5-fluoro-7-(7-methoxy-2-methyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-3-(piperidin4-yl)cinnoline

164 7-(2,7-dimethyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

- 27 043655

165 ¹ 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin4-yl)quinazoline

166 ¹ 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin4-yl)quinoline

167 ¹ 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(1,2,3,6te1rahydropyridin-4-yl)cinnoline

168 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(27?, 65)-1-ethyl-2,6dimethylpiperidin-4-yl]-5-fluorocinnoline

169 3-[(1R,3,55)-8-azabicyclo[3.2.1]octan-3-yl]-7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluorocinnoline

170 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[(27?,65)-1-(2-fluoroethyl)2,6-dimethylpiperidin- 4-yl]cinnoline

171 ¹ 5-fluoro-3-(7-fluoro-2-methyl-2R-benzotriazol-5-yl)-7-(1,2,3,6-tetrahydropyridin4-yl)cinnoline

172 7-(7-ethyl-2-methyl-277-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin4-yl)cinnoline

173 ¹ 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(7-methoxy-2-methyl-2R-pyrazolo[4,3b]pyridin-5-yl)cinnoline

174 7-(7-ethyl-2-methyl-2Npyrazolo[4,3-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

175 ¹ 5-[5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-3-yl]-2-methyl-2Rindazol-7-carbonitrile

176 ¹ 6-[5-fluoro-3-(1-methylpiperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-carbonitrile

177 ¹ 3 -(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline

178 ¹ 6-{5-fluoro-3-[1-(2-hydroxyethyl)piperidin-4-yl]cinnolin-7-yl}2-methylimidazo[1,2-b]pyridazin-8-carbonitrile

179 ¹ 6-{5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}2-methylimidazo[1,2-b]pyridazin-8-carbonitrile

180 {6-[5-fluoro-3-(1 -methylpiperidin-4-yl)cinnolin-7-yl]2-methylimidazo[1,2-b]pyridazin-8-yl} methanol

181 ¹ 2-(4-{5-fluoro-7-[8-(hydroxymethyl)-2-methylimidazo[1,2-b]pyridazin-6yl]cinnolin-3-yl}piperidin-1-yl)ethan-1 -ol

182 ¹ (6-{5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}2-methylimidazo[1,2-b]pyridazin-8-yl)methanol

183 3-(2,7-dimethyl-2R-indazol-5-yl)-7-(1-ethylpiperidin-4-yl)-5-fluorocinnoline

184 ¹ 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol5-yl)quinoline

- 28 043655

185 ¹ 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4yl)cinnoline

186 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(1-ethylpiperidin-4-yl)5-fluorocinnoline

187 {6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin8-yl}acetonitrile

188 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylazepan4-yl)cinnoline

189 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylazepan-4-yl)-5fluorocinnoline

190 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]azepan1-yl}ethan-1-ol

191 ¹ 7-(5,7-dimethyl-1R-pyrrolo[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

192 ¹ 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinoline

193 ¹ 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2/7-indazol-5-yl)quinoline

194 ¹ 5-fluoro-7-[8-(1/7-imidazol-1-yl)-2-methylimidazo[1,2-b]pyridazin-6-yl]-3(piperidin-4-yl)cinnoline

195 ¹ 5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin4-yl)cinnoline

196 ¹ 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline

197 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline

198 3-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-7-(2,3,6,7-tetrahydro-1R-azepin4-yl)cinnoline

199 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(2-fluoroethyl)azepan4-yl]cinnoline

200 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin6-yl)cinnoline

201 ¹ 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol5 -yl)quinazoline

202 ¹ 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)quinazoline

203 (3X,45)-4-[3-(2,7-dimethyl-2/7-indazol-5-yl)-5-fluorocinnolin-7-yl]piperidin-3,4diol

204 5-fluoro-7-(2-methyl-8-propylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4yl)cinnoline

205 ¹ {6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl} acetonitrile

- 29 043655

206 2-{6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]2-methylimidazo[1,2-b]pyridazin-8-yl}ethan-1-ol

207 2-{6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}ethan-1-ol

208 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(2,2,6,6-tetramethyl1,2,3,6-tetrahydropyridin-4- yl)cinnoline

209 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(5-methyl2,5-diazabicyclo[2.2.1]heptan-2-yl)cinnoline

210 ¹ 5-fluoro-7-(2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline

211 5-fluoro-7-[2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-6-yl]-3-(piperidin4-yl)cinnoline

212 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methyl-8-propylimidazo[1,2-b]pyridazin6-yl)cinnoline

213 2-{4-[7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluorocinnolin-3yl]piperidin-1-yl}ethan-1 -ol

214 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(1-methylpiperidin4-yl)cinnoline

215 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[(15,4Х)-5-methyl2,5-diazabicyclo[2.2.1]heptane- 2-yl]cinnoline

216 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-3yl)cinnoline

217 ¹ 3-(2,6-diazaspiro[3.4]octan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline

218 ¹ 3-(2,6-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline

219 ¹ 3-(2,7-diazaspiro[3.5]nonan-7-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline

220 ¹ 3-(2,6-diazaspiro[3.4]octan-6-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline

221 ¹ 3-(2,7-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline

222 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-[2-methyl-8-(propan-2-yl)imidazo[1,2b]pyridazin-6-yl]cinnoline

223 (17?,5X,b5)-3-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]-M,M-dimethyl-3- azabicyclo[3.1.0]hexane-6-amine

224 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]M,M,4-trimethylpiperidin-4-amine

225 ¹ 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1,2,3,6tetrahydropyridin-4-yl)cinnoline

226 5-(5-fluoro-3-((2X,47?,67?)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7-yl)2,7-dimethyloxazolo[5,4-b ]pyridine

227 7-(2,7-dimethyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro3-((2X,47?,67?)-1,2,6-trimethylpiperidin- 4-yl)cinnoline and

228 7-(4,6-dimethyloxazolo[4,5-с]pyridin-2-yl)-5-fluoro-3((2Х,47?,67?)-1,2,6-trimethylpiperidin-4-yl )cinnoline;

wherein the form of the compound is selected from the group consisting of a salt, prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorphic or tautomeric form thereof.

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

- 30 043655

Connection Name

2-(2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinoline hydrochloride

6-(1-ethylpiperidin-4-yl)-2-(2-methyl-2R-indazol-5-yl)quinoline hydrochloride

6-(2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride

3 -(2-methyl-2R-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride

4-methyl-6-(2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride

6-(2-methyl-2R-indazol-5-yl)-2-(1-methylpiperidin-4-yl)quinoline hydrochloride

2-(1-ethylpiperidin-4-yl)-6-(2-methyl-2R-indazol-5-yl)quinoline hydrochloride

2-(2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinazoline hydrochloride

6-[2-methyl-7-(trifluoromethyl)-2R-yne dazol-5-yl]-2-(piperidin-4-yl)quinoxaline hydrochloride

3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine dihydrochloride

6-(2,7-dimethyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoxaline hydrochloride

6-(2,7-dimethyl-2R-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride

5-[8-fluoro-2-(piperidin-4-yl)quinazolin-6-yl]-2-methyl-2R-indazole-7carbonitrile dihydrochloride

8-fluoro-6-(7-fluoro-2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinazoline dihydrochloride

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4yl)quinazoline dihydrochloride

6-(2,7-dimethyl-2//-indazol-5-yl)-5-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride

6-(2,7-dimethyl-2R-indazol-5-yl)-7-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4yl)quinoline hydrochloride

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(1-methylpiperidin4-yl)quinoline hydrochloride

6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)8-fluoroquinoline hydrochloride

8-fluoro-6-(7-methoxy-2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride

8-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4yl)quinoline hydrochloride

8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin4-yl)quinoline hydrochloride

8-fluoro-6-[8-(2-methoxyethoxy)-2-methylimidazo[1,2-b]pyridazin-6-yl]-2(piperidin-4-yl)quinoline hydrochloride

6-[8-fluoro-2-(piperidin-4-yl)quinolin-6-yl]-M-(2-methoxyethyl)2-methylimidazo[1,2-b]pyridazin-8-amine hydrochloride

7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(1,2,3,6-tetrahydropyridin-4yl)cinnoline hydrochloride

7-(8-azabicyclo[3.2.1]oct-3-yl)-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)1,2,4-benzotriazine hydrochloride

3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

7-(8-ethoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

5-fluoro-7-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-3-(piperidin4-yl)-1,2,4-benzotriazine hydrochloride

7-(2,4-dimethyl-1,3-benzoxazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4benzotriazine hydrochloride

7-(2,4-dimethyl-1R-benzimidazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4benzotriazine hydrochloride

7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

- 31 043655

7-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine hydrochloride

7-(2,7-dimethyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine dihydrochloride

7-(2,7-dimethyl-2R-pyrazolo[3,4-c]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)1,2,4-benzotriazine dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)1,2,4-benzotriazine dihydrochloride

7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline hydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4yl)isoquinoline hydrochloride

7-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline hydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4yl)cinnoline dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperazin-1yl)cinnoline dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(37?, 55)-3,5-dimethylpiperazin-1 yl]-5-fluorocinnoline dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(2fluoroethyl)piperidin-4-yl]cinnoline dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride

7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(25.65)-2,6-dimethylpiperidin-4yl]-5-fluorocinnoline hydrochloride

5-fluoro-7-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-3-(piperidin-4-yl)cinn oline dihydrochloride

5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4yl)cinnoline dihydrochloride

6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-a]pyridine8-carbonitrile dihydrochloride

5-fluoro-7-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(piperidin-4yl)cinnoline dihydrochloride

5-fluoro-7-(2-methyl-2R-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride

5-fluoro-7-(7-fluoro-2-methyl-2R-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride

5-fluoro-7-(6-fluoro-2-methyl-2R-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride

- 32 043655

3-[1-(2,2-difluoroethyl)piperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6yl)-5-fluorocinnoline dihydrochloride

5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride

100 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6yl)cinnoline dihydrochloride

101 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride

102 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin6-yl)cinnoline dihydrochloride

103 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride

104 5-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methyl-2R-indazole-7carbonitrile hydrochloride

109 5-fluoro-7-(4-fluoro-2-methyl-2R-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride

115 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3 -(1-ethylpiperidin-4yl)-5-fluorocinnoline formate

117 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6tetrahydropyridin-4-yl)cinnoline hydrochloride

120 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline formate

121 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline dihydrochloride

122 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin4-yl)cinnoline dihydrochloride

123 2-{4-[7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin3 -yl] piperidin-1 -yl} ethan-1 -ol dihydrochloride

127 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3yl]piperidin-1-yl}-M,M-dimethylethane-1- amine trihydrochloride

128 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4yl)cinnoline dihydrochloride

133 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4yl)cinnoline formate

134 5-fluoro-3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin4-yl)cinnoline hydrochloride

135 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)5-fluorocinnoline formate

- 33 043655

138 2-({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}oxy)-LG,LG-dimethylethane -1-amine trihydrochloride

139 3-({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}oxy)-LG,LG-dimethylpropane -1-amine trihydrochloride

140 5-fluoro-7-{2-methyl-8-[2-(1R-pyrazol-1-yl)ethoxy]imidazo[1,2-b]pyridazin-6-yl}3 -(piperidin-4-yl )cinnoline dihydrochloride

141 5-fluoro-7-{2-methyl-8-[3-(1R-pyrazol-1-yl)propoxy]imidazo[1,2-b]pyridazin-6yl}-3-(piperidin-4-yl) cinnoline trihydrochloride

142 5-fluoro-7-{8-[3-(1R-imidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6yl}-3-(piperidin-4-yl)cinnoline trihydrochloride

145 3-{1-[3-(1R-benzimidazol-1-yl)propyl]piperidin-4-yl} 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5- fluorocinnoline trihydrochloride

146 7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline hydrochloride

150 7-{8-[3-(1R-benzimidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6yl} - 5-fluoro-3 -(piperidin-4-yl) cinnoline trihydrochloride

151 5-fluoro-3-(7-fluoro-2-methyl-2R-indazol-5-yl)-7-(piperidin-4-yl)cinnoline hydrochloride

153 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2R-indazol5-yl)cinnoline hydrochloride

156 3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin4-yl)cinnoline hydrochloride

157 3-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4yl)cinnoline hydrochloride

163 5-fluoro-7-(7-methoxy-2-methyl-2R-pyrazolo[4,3-b]pyridin-5-yl)-3-(piperidin4-yl)cinnoline formate

165 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin4-yl)quinazoline hydrochloride

166 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin4-yl)quinoline hydrochloride

167 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(1,2,3,6tetrahydropyridin-4-yl)cinnoline hydrochloride

171 5-fluoro-3-(7-fluoro-2-methyl-2R-benzotriazol-5-yl)-7-(1,2,3,6-tetrahydropyridin4-yl)cinnoline hydrochloride

173 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(7-methoxy-2-methyl-2R-pyrazolo[4,3b]pyridin-5-yl)cinnoline formate

175 5-[5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-3-yl]-2-methyl-2Rindazole-7-carbonitrile hydrochloride

- 34 043655

176 6-[5-fluoro-3-(1-methylpiperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-carbonitrile trihydrochloride

177 3-(2,7-dimethyl-2R-indazol-5-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline hydrochloride

178 6-{5-fluoro-3-[1-(2-hydroxyethyl)piperidin-4-yl]cinnolin-7-yl}2-methylimidazo[1,2-b]pyridazin-8-carbonitrile trihydrochloride

179 6-{5-fluoro-3-[1 -(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl} 2-methylimidazo[1,2-b]pyridazin-8-carbonitrile trihydrochloride

181 2-(4-{5-fluoro-7-[8-(hydroxymethyl)-2-methylimidazo[1,2-b]pyridazin-6yl]cinnolin-3-yl}piperidin-1-yl)ethane-1- ol trihydrochloride

182 (6-{5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}2-methylimidazo[1,2-b]pyridazin-8-yl)methanol trihydrochloride

184 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol5-yl)quinoline hydrochloride

185 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4yl)cinnoline hydrochloride

191 7-(5,7-dimethyl-1R-pyrrolo[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline dihydrochloride

192 8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinoline hydrochloride

193 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol-5-yl)quinoline hydrochloride

194 5-fluoro-7-[8-(177-imidazol-1-yl)-2-methylimidazo[1,2-b]pyridazin-6-yl]-3(piperidin-4-yl)cinnoline formate

195 5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin4-yl)cinnoline formate

196 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4yl)cinnoline formate

201 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2R-indazol5-yl)quinazoline hydrochloride

202 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-277-indazol-5-yl)quinazoline hydrochloride

205 {6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2b]pyridazin-8-yl}acetonitrile formate

210 5-fluoro-7-(2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride

216 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-3yl)cinnoline dihydrochloride

217 3-(2,6-diazaspiro[3.4]octan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline trihydrochloride

218 3-(2,6-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline trihydrochloride

219 3-(2,7-diazaspiro[3.5]nonan-7-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline ditrifluoroacetate

220 3-(2,6-diazaspiro[3.4]octan-6-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline ditrifluoroacetate

221 3-(2,7-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)5-fluorocinnoline ditrifluoroacetate and

225 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1,2,3,6tetrahydropyridin-4-yl)cinnoline dihydrochloride;

wherein the salt form of the compound is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorphic or tautomeric form thereof.

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

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

Another aspect of the present disclosure includes a method of treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

An aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof

- 35 043655 position.

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

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

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

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the preparation of a medicament for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

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

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

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

Chemical definitions

Chemical terms used above and throughout the description herein, unless specifically stated otherwise, will be understood by one skilled in the art to have the following defined meanings.

As used herein, the term C ₁ . ₈ αlkyl generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n -butyl (also called butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also called pentyl or pentanyl), n-hexyl (also called hexyl or hexanyl), n-heptyl (also referred to as heptyl or heptanyl), n-octyl and the like. In certain aspects, O^alkyl includes, but is not limited to, O^alkyl, Omalkyl, and the like. Radical _C1 . ₈ alkyl is optionally substituted with the types of substituents as described herein if available valences allow.

As used herein, the term _{C2_8} alkenyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration, and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also called vinyl), allyl, propenyl and the like. In certain aspects, _C2-8 alkenyl includes, but is not limited to, _C2.6alkenyl , _C2.4alkenyl , and the like. The C ₂ - ₈ alkenyl radical is optionally substituted with the types of substituents as described herein as available valences permit.

As used herein, the term C ₂ _ ₈ alkynyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration, one or more carbon-carbon triple bonds therein, including, but not limited to , ethynyl, propynyl, butynyl and the like. In certain aspects, C _{2_8 alkynyl} includes, but is not limited to, C ₂ . _{6 alkynyl} , C _{2_4} alkynyl and the like. The C ₂ _ ₈ alkynyl radical is optionally substituted with the types of substituents as described herein as available valences permit.

As used herein, the term C _1-8 alkoxy generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, with the formula: -O-C _1-8 alkyl, including but not limited to , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In certain aspects C ₁ . ₈ alkoxy includes, but is not limited to, C ₁ . ₆ alkoxy, C ₁ . ₄ αlkoxy and the like. Radical _C1 . ₈ alkoxy is optionally substituted with the types of substituents as described herein as available valences allow.

As used herein, the term C ₃ . ₁₄ cycloalkyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon

- 36 043655 to the native radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, N-indanyl, indenyl, tetrahydronaphthalenyl and the like. In certain aspects C ₃ . ₁₄ cycloalkyl includes, but is not limited to, C ₃ . ₈ cycloalkyl, C _5-8 cycloalkyl, C ₃ . ₁₀ cycloalkyl and the like. Radical _C3 . ₁₄ cycloalkyl is optionally substituted with the types of substituents as described herein if available valences allow.

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 the like. The aryl radical is optionally substituted with the types of substituents as described herein as available valences allow.

As used herein, the term heteroaryl generally refers to a radical with a monocyclic, bicyclic or polycyclic aromatic carbon ring structure in which one or more carbon ring members are replaced, if structural stability permits, by one or more heteroatoms such as an O, S atom or N, including, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2- diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, N-pyrrolo[2,3-c]pyridinyl, 1Hpyrrolo[3,24e]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H- imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2a]pyrazinyl, imidazo[ 2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5a]pyridinyl, [1,2, 4]triazolo[4,3-a]pyridinyl and the like.

The heteroaryl radical is optionally substituted on the carbon or nitrogen element of the atomic ring with the types of substituents as described herein, as available valences permit.

In certain aspects, the nomenclature of the heteroaryl radical may differ, for example, in non-limiting examples, where furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl, and 1,3-benzoxazolyl may also be referred to as 1 ,3-benzooxazolyl.

In some other aspects, the term heteroaryl radical may also include other regioisomers, for example, in non-limiting examples where the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and the like, the term pyrazolyl may also include 1H-pyrazolyl and the like likewise, the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl and the like, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term indazolyl may also include itself 1H-indazolyl, 2H-indazolyl and the like, the term benzoimidazolyl may also include 1H-benzoimidazolyl, and the term purinyl may also include 9H-purinyl and the like.

As used herein, the term heterocyclyl generally refers to a saturated or partially unsaturated radical with a monocyclic, bicyclic or polycyclic ring structure of carbon atoms, in which one or more members of the ring atoms are replaced, if structural stability allows, by a heteroatom, such as an O, S or N, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidine yl, triazolinyl, triazolidinil, oxadiazolinil, oxadiazolidinil , thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorph olinyl , 1,4-diazepanyl, 1,3benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxynyl, hexahydropyrrolo[3,4-b]pyrrol(1H)-yl, (3aS,6aS)- hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H) -yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3 ,4-c]pyrrol-(1H)-yl, (3aR,6aS)hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol- (1H)-yl, octahydro5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6Hpyrrolo[3,44e]pyridinyl, (4aS ,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2- 37 043655

a]pyrazin-(1H)-yl, a]pyrazin-(1H)-yl, a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-( 1H)-yl, (8aS)-hexahydropyrrolo[1,2(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2(8aR)-octahydropyrrolo[1 ,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin (2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0] hexyl, (1R,5S)-3azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[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, 2 ,5-diazabicyclo[2.2.1]heptyl, (1R,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl , (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro [3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl and the like.

The heterocyclyl radical is optionally substituted on the carbon or nitrogen element of the atomic ring with the types of substituents as described herein, as available valences permit.

In certain aspects, the nomenclature of the heterocyclyl radical may differ, as in non-limiting examples, where 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxolyl, and 2,3-dihydro-1,4-benzodioxinyl may also be referred to as 2 ,3-dihydrobenzo[b][1,4]dioxynyl.

As used herein, the term heteroaryl-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ alkyl-heteroaryl.

As used herein, the term C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl refers to a radical with the formula: -C ₁ _ ₈ alkyl-O-C ₁ _ ₈ alkyl.

As used herein, the term C _{1_8} alkoxy-C _{1_8} alkyl-amino refers to a radical with _the formula: _-NH -C ₁ . ₈ alkyl-O-C ₁ . ₈ αlkyl.

As used herein, the term (C ₁ _ ₈ alkoxy-C ₁ _ ₈ alkyl) ₂ -amino refers to a radical with the formula: -N (C ₁ _ ₈ alkyl-O-C ₁ _ ₈ alkyl) ₂ .

As used herein, the term C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl-amino-C ₁ . ₈ alkoxy refers to the radical with the formula: -O-C ₁ . ₈ alkyl-NH-C ₁ . ₈ alkyl-O-C ₁ . ₈ alkyl.

As used herein, the term (C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl) ₂ -amino-C ₁ . ₈ alkoxy refers to the radical with the formula: -O-C ₁ . ₈ αlkyl-N(C ₁ . ₈ alkyl-O-C ₁ . ₈ αlkyl) ₂ .

As used herein, the term (C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl)(C ₁ . ₈ alkyl) amino-C ₁ . ₈ alkoxy refers to the radical with the formula: -O-C ₁ . ₈ alkyl-N(C ₁ . ₈ alkyl)(C ₁ . ₈ alkyl-O-C ₁ . ₈ alkyl).

As used herein, the term C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl-amino-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ αlkyl-NH-C ₁ . ₈ αlkyl-O-C ₁ . ₈ αlkyl.

As used herein, the term (C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl) ₂ -amino-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ alkyl-N(C ₁ . ₈ alkyl-O-C ₁ . ₈ alkyl) ₂ .

As used herein, the term (C ₁ . ₈ alkoxy-C ₁ . ₈ alkyl)(C ₁ . ₈ alkyl) amino-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ alkyl-N(C ₁ . ₈ alkyl)(C ₁ . ₈ alkyl-O-C ₁ . ₈ alkyl).

As used herein, the term _{C1_8} alkoxycarbonyl refers to a radical with the formula: -C(O)-O- _{C1_8} alkyl.

In the context of this document, the term C1. ₈ alkoxy-carbonyl-C ₂ . ₈ alkenyl refers to the radical with the formula: -C ₂ . ₈ alkenyl-C(O)-O-C1. ₈ alkyl.

As used herein, the term C1_ ₈ alkoxy-carbonyl-amino refers to a radical with the formula: -NH-C(O)-O-C ₁ . ₈ alc.

As used herein, the term heteroaryl- _C1-8 alkoxy refers to a radical with the formula: -O- _{C1_8} alkyl-heteroaryl.

As used herein, the term _{C1_8} alkyl-amino refers to a radical with the formula: -NH- _C1 . ₈ αlkyl.

As used herein, _the term ( _{C1_8alkyl} ) ₂ -amino refers to a radical with the formula: -N( _{C1_8alkyl} ) ₂ .

As used herein, the term C ₁ . ₈ αlkyl-amino-C ₂ . ₈ alkenyl refers to the radical with the formula: -C ₂ . ₈ alkenyl-NH-C ₁ . ₈ αlkyl.

As used herein, the term ( _C1.8 alkyl) _2- amino- _C2 . ₈ alkenyl refers to the radical with the formula: -C ₂ . ₈ alkenyl-N (C ₁ . ₈ αlkyl) ₂ .

As used herein, the term C _{1_8} alkyl-amino-C _{1_8} alkoxy refers to _a radical with _the formula: -O-C ₂ . ₈ alkyl-NH-C ₁ . ₈ alk.

As used herein, the term (C ₁ _ ₈ alkyl) ₂ -amino-C ₁ _ ₈ alkoxy refers to a radical with the formula: -O-C ₁ . ₈ alkyl-N (C1_ ₈ alkyl) ₂ .

As used herein _, the term C _{1_8} alkyl-amino-C _{1_8} alkyl refers to a radical with the formula: -C _{1 . 8} alkyl-NH-C 1 - ₈ alkyl.

As used herein, the term (C ₁ _ ₈ alkyl) ₂ -amino-C ₁ _ ₈ alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-N (C1_ ₈ alkyl) ₂ .

As used herein, the term C _{1_8} alkyl-amino-C _{1_8} alkyl-amino refers to a radical with _the formula: _-NH -C ₁ . ₈ alkyl-NH-C ₁ . ₈ alc.

- 38 043655

As used herein, the term (C^alkyl^-amino-C^alkyl-amino) refers to a radical with the formula: -MH- _C1-8 alkyl-M( _C1-8 alkyl)2.

As used herein, the term (C ₁ _ ₈ alkyl-amino-C ₁ _ ₈ alkyl)2-amino refers to a radical with the formula: -N(C ₁ _ ₈ alkyl-NH-C ₁ _ ₈ alkyl) ₂ .

As used herein, the term [( _{C1_8alkyl} )2-amino- _{C1_8alkyl ] 2-} amino refers _{to the radical with the formula: -N[C1_8alkyl - N ( C1_8alkyl} ) ₂ ] ₂ .

As used herein _, the term ( _{C1_8alkyl} -amino- _{C1_8alkyl} ) _{( C1_8alkyl} )amino refers _to the radical with the _{formula : -N(C1_8alkyl )} ( _{C1_8alkyl-} NH-C ₁ _ ₈ alkyl).

As used herein, the term [(C1.8alkyl) _2- amino-C1.8alkyl](C1.8alkyl) _{amino refers to the radical with the formula: -N(C1.8alkyl )} [ _C1 . ₈ alkyl-N(C ₁ . ₈ alkyl) ₂ ].

As used herein, the term C1-8alkyl-amino-C2-8alkynyl refers to a radical with the formula: _-C2 . ₈ alkynyl-NH-C ₁ . ₈ alkyl.

As used herein, the term (C ₁ _ ₈ alkyl) ₂ -amino-C ₂ _ ₈ alkynyl refers to a radical with the formula: -C ₂ . ₈ alkynyl-N (C _1-8 alkyl) ₂ .

As used herein _, the term C _1-8 alkyl-carbonyl refers to a radical with the formula: -C(O)-C _1-8 alkyl.

As used herein, the term C ₁ - ₈ alkyl-carbonyl-amino refers to a radical with the formula: -NH-C(O)-C ₁ - ₈ alkyl.

As used herein, the term C _1-8 alkyl-thio refers to a radical with the formula: -SC ₁ . ₈ alkyl.

As used herein, the term amino-C ₂ - ₈ alkenyl refers to a radical with the formula: -C ₂ . ₈ alkenyl-NH ₂ .

As used herein, the term amino-C _1-8 alkoxy refers to a radical with the formula: -O-C ₁ . ₈ alkyl-NH ₂ .

As used herein, the term amino-C _1-8 alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-NH ₂ .

As used herein, the term amino-C ₁ - ₈ alkyl-amino refers to a radical with the formula: -NH-C ₁ - ₈ alkyl-NH ₂ .

As used herein, the term (amino-C ₁ - ₈ alkyl) ₂ -amino refers to a radical with the formula: -N(C ₁ - ₈ alkyl-NH ₂ ) ₂ .

_As used herein, the term (amino- _{C1_8alkyl} )( _{C1_8alkyl} ) _amino refers to _a radical with the _formula : -N( _{C1_8alkyl} )( _{C1_8alkyl} - _NH2 ).

As used herein, the term amino-C ₂ - ₈ alkynyl refers to a radical with the formula: -C ₂ . ₈ alkynyl-NH ₂ .

As used herein, the term aryl-C ₁ - ₈ alkoxycarbonyl refers to a radical with the formula: -C(O)-O-C ₁ - ₈ alkyl-aryl.

As used herein _, the term aryl-C _1-8 alkyl refers to a radical with the formula: -C _1-8 alkyl-aryl.

As used herein, the _term aryl-C _1-8 alkyl-amino refers to a radical with the formula: -NH-C _{1_8} alkyl-aryl.

As used herein, the term (aryl-C _1-8 alkyl) ₂ -amino refers to a radical with _the formula: -N(C _{1_8} alkyl-aryl) ₂ .

_As used herein, _the term (aryl- _{C1_8alkyl} )( _{C1_8alkyl} )amino refers to _a radical _with the formula: -N( _{C1_8alkyl} )( _{C1_8alkyl} -aryl).

As used herein _{, the term aryl-C 1_8 alkyl-amino-C 1_8 alkyl refers} to a radical with the formula: -C ₁ . ₈ alkyl-NH-C ₁ . ₈ alkyl-aryl.

As used herein, the term (aryl-C ₁ _ ₈ alkyl) ₂ -amino-C ₁ _ ₈ alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-N(C ₁ . ₈ alkyl-aryl) ₂ .

As _{used herein, the term (aryl-C1.8alkyl ) ( C1.8alkyl} )amino- _C1 . ₈ alkyl refers to a radical with the formula: -C ₁ _ ₈ alkyl-N(C ₁ _ ₈ alkyl)(C ₁ _ ₈ alkyl-aryl).

As used herein, the term aryl-amino refers to a radical with the formula: -NHaryl.

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

As used herein, the term aryl-sulfonyloxy-C ₁ - ₈ alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-O-SO ₂ -aryl.

As used herein, the term benzoxycarbonyl refers to a radical with the formula: -C(O)-O-CH ₂ -phenyl.

As used herein _{, the term C3_14cycloalkyl - C1_8alkyl} refers to a _{radical with} the _formula : _{-C1_8alkyl} - _{C3_14cycloalkyl} .

As used herein _, the term C _{3_14} cycloalkyl-amino refers to a radical with the formula: -NH-C3_ ₁₄ cycloalkyl.

- 39 043655

As used herein, the term '^-cycloalkyloxy' refers to a radical with the formula: -O-C ₃ . ₁₄ cycloalkyl.

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

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

As used herein, the term halo-C ₁ . ₈ alkoxy refers to a radical with the formula: -O-C ₁ - ₈ alkyl halo, wherein C ₁ . ₈ αlkyl is partially or completely substituted with one or more halogen atoms as available valences permit.

As used herein, the term halo-C ₁ . ₈ alkyl refers to a radical with the formula: -C ₁ - ₈ alkyl halo, wherein C ₁ . ₈ alkyl is partially or completely substituted with one or more halogen atoms if available valences permit.

As used herein, the term halo-C ₁ - ₈ alkyl-amino refers to a radical with the formula: -NH-C ₁ . ₈ αlkyl-halo.

As used herein, the term (halo-C ₁ _ ₈ alkyl)(C ₁ _ ₈ alkyl)amino refers to a radical with the formula: -N(C ₁ _ ₈ αlkyl)(C ₁ _ ₈ αlkyl-halo).

As used herein, the term (halo-C ₁ - ₈ alkyl)2-amino refers to a radical with the formula: -N(C ₁ - ₈ αalkyl-halo) ₂ .

As used herein, the term heteroaryl-C ₁ _ ₈ alkoxy refers to a radical with the formula: -O-C ₁ . ₈ αlkyl-heteroaryl.

As used herein, the term heteroaryl-C ₁ _ ₈ alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-heteroaryl.

As used herein, the term heteroaryl-C ₁ . ₈ alkyl-amino refers to the radical with the formula: -NH-C ₁ . ₈ alkyl-heteroaryl.

As used herein, the term (heteroaryl-C ₁ - ₈ alkyl)2-amino refers to a radical with the formula: -N (C ₁ - ₈ alkyl-heteroaryl)2.

_As used herein, the term (heteroaryl _{- C1_8alkyl} )( _{C1_8alkyl} ) _amino refers to a radical with the _formula : -N( _{C1_8alkyl} )( _{C1_8alkyl} -heteroaryl).

As used herein, the term heteroaryl-C ₁ . ₈ alkyl-amino-C ₁ . ₈ alkyl refers to a radical with _{the formula} : -C _{1_8} αlkyl-NH-C _{1_8} αlkyl-heteroaryl.

As used herein _{, the term (heteroaryl-C1.8alkyl )} 2-amino- _C1 . ₈ alkyl refers to the radical with the formula: -C ₁ _ ₈ alkyl-N(C ₁ _ ₈ alkyl-heteroaryl) ₂ .

As used herein, the term (heteroaryl-C1.8alkyl)(C1.8alkyl)amino-C1.8alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-N(C ₁ . ₈ alkyl)(C ₁ . ₈ αlkyl-heteroaryl).

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

As used herein, _the term heterocyclyl-C _1-8 alkoxy refers to a radical with the formula: -O-C _1-8 alkyl-heterocyclyl.

As used herein, the term heterocyclyl-C _1-8 alkyl _{refers to a radical with the formula: -C 1-8 alkyl} -heterocyclyl.

As used herein, the term heterocyclyl-C ₁ - ₈ alkyl-amino refers to a radical with the formula: -NH-C ₁ - ₈ alkyl-heterocyclyl.

As used herein, the term (heterocyclyl-C ₁ - ₈ alkyl) ₂ -amino refers to a radical with the formula: -N(C _{1 8} αlkyl-heterocyclyl) ₂ .

As used herein, the term (heterocyclyl- _{C1_8alkyl} )( _{C1_8alkyl} ) _amino refers to a radical with the formula: -N( _C1.8alkyl )(C1.8alkyl-heterocyclyl).

As used herein, the term heterocyclyl-C ₁ . ₈ alkyl-amino-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ alkyl-NH-C ₁ . ₈ alkyl-heterocyclyl.

As used herein _{, the term (heterocyclyl-C1.8alkyl ) 2-} amino- _C1 . ₈ alkyl refers to a radical with the formula: -C ₁ _ ₈ αlkyl-N(C ₁ _ ₈ αlkyl-heterocyclyl) ₂ .

As used herein, the term (heterocyclyl- _C1.8alkyl )( _C1.8alkyl )amino- _C1 . ₈ alkyl refers to a radical with the formula: -C ₁ _ ₈ alkyl-N(C ₁ _ ₈ alkyl)(C ₁ _ ₈ alkyl-heterocyclyl).

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

As used herein, the term (heterocyclyl)(C _1-8 alkyl)amino refers to a radical with the formula: -N(C _{1 8} alkyl)(heterocyclyl).

As used herein, the term heterocyclyl-amino-C ₁ . ₈ alkyl refers to the radical with the formula: -C ₁ . ₈ alkyl-NH-heterocyclyl.

As used herein, the term heterocyclylcarbonyl refers to a radical with the formula: -C(O)-heterocyclyl.

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

As used herein, the term heterocyclyl-hydroxy refers to a radical with the formula:

- 40 043655

-O-heterocyclyl.

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

As used herein, the term hydroxy-C _1-8 alkoxy-C _1-8 alkyl refers to a radical with the formula: -C ₁ . ₈ alkyl-O-C ₁ . ₈ alkyl-OH.

As used herein, the term hydroxy-C _1-8 αlkyl refers to a radical with the formula: -Cl. ₈ alkyl-OH, with Cl. ₈ αlkyl is partially or completely substituted by one or more hydroxy radicals as available valences permit.

As used herein, the term hydroxy-C _1-8 alkyl-amino refers to a radical with the formula: -NH-C ₁ . ₈ alkyl-OH.

As used herein, the term (hydroxy-C _1-8 alkyl)2-amino refers to a radical with the formula: -K(C _{1 8} alkyl-OH) ₂ .

As used herein, the term (hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino refers to a radical with the formula: -K(C _1-8 alkyl)(C _1-8 alkyl-OH).

As used herein, the term hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl refers to a radical with the formula: -C _1-8 alkyl-NH-C _1-8 αlkyl-OH.

As used herein, the term (hydroxy-C _1-8 alkyl) ₂ -amino-C _1-8 alkyl refers to a radical with the formula: -C _1-8 alkyl-K(C _1-8 alkyl-OH) ₂ .

As used herein, the term (hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkyl refers to a radical with the formula: -C _1-8 alkyl-N(C _1-8 alkyl)( C _1-8 alkyl-OH).

As used herein, the term hydroxy-C _1-8 alkyl-amino-C _1-8 alkoxy refers to a radical with the formula: -O-C _1-8 alkyl-NH-C _1-8 alkyl-OH.

As used herein, the term (hydroxy-C _1-8 alkyl) ₂ -amino-C _1-8 alkoxy refers to a radical with the formula: -O-C _1-8 alkyl-K(C _1-8 alkyl-OH) ₂ .

As used herein, the term (hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkoxy refers to a radical with the formula: -O-C _1-8 alkyl-K(C _1-8 alkyl )(C _1-8 alkyl-OH).

As used herein, the term hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl-amino refers to a radical with the formula: -NH-C _1-8 αlkyl-NH-C _1-8 alkyl-OH.

As used herein, the term (hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl) ₂ -amino refers to a radical with the formula: -N(C _1-8 αlkyl-NH-C _1-8 alkyl-OH) ₂ .

As used herein, the term (hydroxy-C _1-8 alkyl) _2- amino-C _1-8 alkyl-amino refers to a radical with the formula: -NH-C _1-8 αlkyl-N(C _1-8 alkyl-OH) ₂ .

As used herein, the term (hydroxy-C _1-8 alkyl-amino-C _1-8 alkyl)(C _1-8 alkyl)amino refers to a radical with the formula: -N(C _1-8 alkyl)(C _1-8 alkyl-NH-C _1-8 alkyl-OH).

As used herein, the term [(hydroxy-C _1-8 alkyl) ₂ -amino-C _1-8 alkyl](C _1-8 alkyl)amino refers to a radical with the formula: -K(C _1-8 alkyl)[C _1-8 alkyl-K(C _1-8 alkyl-OH) ₂ ].

As used herein, the term (hydroxy-C1-8alkyl)(C1-8alkyl)amino-C1-8alkyl-amino refers to a radical with the formula: -NH-C _1-8 alkyl-N(C _1-8 αlkyl,C _{1- 8} αlkyl-OH).

As used herein, the term [(hydroxy-C _1-8 alkyl)(C _1-8 alkyl)amino-C _1-8 alkyl] (C _1-8 alkyl) amino refers to the radical with the formula: -K(C _{1- 8} alkyl)[C _1-8 alkyl-K(C _1-8 alkyl)(C _1-8 alkylOH)].

As used herein, the term substituent means a substitution of the position of the atoms of the parent molecule that are replaced at the position of a specific atom by replacing one or more hydrogen atoms with a specific atom, provided that the normal valency of the specified atom is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or substitutions are permitted only if such combinations result in stable compounds. One skilled in the art will note that any carbon, as well as heteroatom, with valences that are found to be unsaturated as described or shown herein is assumed to have a sufficient number of hydrogen atoms to saturate the valencies described or shown. In some examples, one or more substituents may be described having a double bond (e.g., oxo or =O) as the point of attachment shown or listed herein in a group of substituents, wherein the structure may only show a single bond as the point of attachment to the basic structure of formula (I). One skilled in the art will appreciate that although only a single bond is shown, a double bond is intended for these substituents.

As used herein, the term and the like, with respect to the definitions of chemical terms provided herein, means that variations in chemical structures expected by one skilled in the art include, but are not limited to, isomers (including branched chain or spatial structural isomers ), hydration of ring systems (including saturation or partial saturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations allowed by the available valencies that result in a stable compound.

For the purposes of this description, if one or more substituent options for connection with

- 41 043655 of formula (I) or forms thereof contains functional groups included in the compound of formula (I), each functional group appearing at any position in the disclosed compound can be independently selected and, if necessary, independently and/or further substituted .

As used herein, the term independently selected or each selected refers to functional variants in a list of substituents that may appear more than once in the structure of formula (I), the substitution pattern in each occurrence being independent of the pattern in any other occurrence. In addition, the use of a generic substituent replaced with in any formula or structure for a compound described herein should be understood to include the replacement of the generic substituent with specific substituents that are included in a particular genus, for example, aryl may be substituted with phenyl or naphthalenyl and the like, and that the resulting compound should be included within the scope of the compounds described herein.

As used herein, the terms each example and in each case, when used before a phrase such as C ₃ . ₁₄ cycloalkyl, C ₃ . ₁₄ cycloalkyl-C ₁ . ₄ alkyl, aryl, aryl-C ₁ . ₄ alkyl, heteroaryl, heteroaryl-C ₁ . ₄ alkyl, heterocyclyl and heterocyclyl-C ₁ . ₄ alkyl is intended to refer to C ₃ ring systems. ₁₄ cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which occurs either alone or as a substituent.

As used herein, the term optionally substituted means the optional substitution of specified options for substituents, groups, radicals or components.

Forms of connections

As used herein, the term form means a compound of formula (I) having a form selected from the group consisting of a free acid, a free base, a prodrug, a salt, a hydrate, a solvate, a clathrate, an isotopologue, a racemate, a stereoisomer, a diastereomer, a stereoisomer, its polymorphic and tautomeric forms.

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

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

In some aspects described herein, the form of a compound of Formula (I) is its isotopologue.

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

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

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

In certain aspects described herein, the compound of formula (I) or 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 it has been isolated and/or purified from a synthetic process (e.g., a reaction mixture) or a natural source, or a combination thereof, in accordance with the isolation or purification process or processes described herein or well known to one of ordinary skill in the art (eg, chromatography, recrystallization, and the like) with sufficient frequency to be characterized by standard analytical techniques described herein or well known to one of ordinary skill 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 eliminate unwanted side reactions at the protected site when the compound reacts. Suitable protecting groups will be determined by those skilled in the art and also by reference to standard reference literature such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarialkylsilyl (eg t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol and the like. Suitable protecting groups for amino, amidino and guanidino include tbutoxycarbonyl, benzyloxycarbonyl and the like. Suitable carboxylic acid protecting groups include alkyl, aryl or arylalkyl ethers. In certain cases, the protecting group may also be a polymer resin such as Wang's resin or 2-chlorotrityl chloride resin. Protecting groups can be added or removed according to standard techniques that are well known to those skilled in the art and described herein. It will also be appreciated by those skilled in the art that, although such protected derivatives of the compounds described herein may not themselves have pharmacological activity, they may be administered to a subject and subsequently metabolized in the body to form the compounds described herein, which have pharmacological activity. Thus, such derivatives can be described as prodrugs. All prodrugs of the compounds described herein are included within the scope of use described herein.

As used herein, the term prodrug means a form of the immediate compound (eg, a drug precursor) that is converted in vivo to produce the active compound of formula (I) or a form thereof. The transformation can occur through various mechanisms (eg, through metabolic and/or non-metabolic chemical processes), such as, for example, hydrolysis and/or metabolism in the blood, liver and/or other organs and tissues. For a description of the use of prodrugs, see T. Higuchi and W. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 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 a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug may contain an ester formed by replacing a hydrogen atom in the acidic group with a functional group such as an alkyl or the like. In another example, when a compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form can be prepared by replacing the hydrogen atom in the hydroxyl group with another functional group such as an alkyl, alkylcarbonyl or phosphonate ester and the like. In another example, when a compound of formula (I) or a form thereof contains an amine functional group, the prodrug form may be prepared by replacing one or more hydrogen atoms with a functional group such as an alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of formula (I) or forms thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters, and mono-, di- or triphosphate esters or alkyl substituents, if applicable. As described herein, one skilled in the art will appreciate that one or more such substituents may be used to provide 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 the like, and the description herein is intended to cover both solvated, and unsolvated forms.

As used herein, the term solvate means the physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bond formation, including hydrogen bonds. In certain cases the solvate will be capable of isolation, for example when one or more solvent molecules are included in the crystal lattice of the crystalline solid. As used herein, solvate includes both solution phase solvates and isolated solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like.

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

Compounds of formula (I) may form salts, which are intended to be included within the scope of this specification. Reference herein to a substance of formula (I) or a form thereof is understood to include its salt forms unless otherwise indicated. The term salt(s) as used herein means acid salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula (I) or a form thereof contains both a basic component, such as, but not limited to, an amine component, and an acidic component, such as, but not limited to, a carboxylic acid, zwitterions (internal salts) can be formed. , which are included in the concept of salt in the context of this document.

The term pharmaceutically acceptable salt(s) as used herein means those salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals, and that are biologically stable, although other salts are also suitable. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with an amount of acid or base, such as an equivalent amount, in such an environment in which the salt precipitates, or in an aqueous environment with subsequent lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in the compounds described herein. Certain aspects of acid addition salts include, but are not limited to, acetate salts, ascorbates, benzoates, benzenesulfonates, bisulfates, bitartrates, borates, bromides, butyrates, chlorides, citrates, camphorates, camphorsulfonates, ethanesulfonates, formates, fumarates, gentisinates, gluconates, glucaronates, glu

- 43 043655 tamates, iodides, isonicotinates, lactates, maleates, methanesulfonates, naphthalene sulfonates, nitrates, oxalates, pamoates, pantothenates, phosphates, propionates, saccharates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), trifluoroacetate you etc. Certain specific aspects of acid addition salts include chlorides or dichlorides.

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

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

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

Compounds of formula (I) and forms thereof may also exist in tautomeric form. All such tautomeric forms are intended and intended to be included within the scope of compounds of formula (I) or the forms thereof described herein.

Compounds of formula (I) and their forms may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present specification 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 thus may exist as racemic mixtures (R/S) or as substantially pure enantiomers or diastereomers. Also, compounds can exist as essentially pure enantiomers (R) or (S) (when there is a single chiral center). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially containing only the (S) isomer. In another specific aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially containing only the (R) isomer. As one skilled in the art will appreciate, when there is more than one chiral center, the compounds described herein may also exist as an (R,R), (R,S), (S,R) or (S, S), as defined by the IUPAC Rules of Nomenclature.

As used herein, the term substantially pure refers to compounds consisting essentially of one 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 equal to 98%, in an amount greater than or equal to 99%, or in an amount greater than or equal to 100% of one isomer.

In one aspect of this specification, the compound of formula (I) or form thereof is a substantially pure form of the enantiomer (S) 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 greater than or equal to 100%.

In one aspect of this specification, the compound of formula (I) or form thereof is a substantially pure form of the enantiomer (R) 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 greater than or equal to 100%.

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

In addition, the present description 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, the scope of the present disclosure extends to both cis and trans forms, as well as mixtures. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by using a chiral HPLC column or other chromatography techniques known to those skilled in the art. Also, enantiomers can be separated by converting an enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as

- 44 043655 chiral alcohol or Mosher acid chloride), separating diastereomers and converting (eg hydrolysis) individual diastereomers into the corresponding pure enantiomers. Also, some of the compounds of formula (I) may be atropisomers (eg, substituted biaryls) and are considered part of this specification.

All stereoisomers (e.g., geometric isomers, optical isomers, and the like) of the present compounds (including isomers of salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), such as those that may exist due to the asymmetry of the carbon atoms in various substituents, including enantiomeric forms (which can exist even in the absence of carbon asymmetry), rotameric forms, atropoisomers and diastereomeric forms, are intended to be included within the scope of this description, as well as positional isomers (such as, for example, 4-pyridyl and 3- pyridil). The individual stereoisomers of the compounds described herein may, for example, be substantially free from other isomers or may be present in a racemic mixture as described above.

The use of the terms salt, solvate, ester, prodrug and the like is intended to apply equally to the salt, solvate, ether and prodrug of enantiomers, stereomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the immediate compounds.

The term isotopologue refers to isotopically enriched compounds described herein that are identical to the compounds described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be included in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^2H , ^3H , ^13C , ^14C , ^15N , 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 description.

Certain isotopically enriched compounds described herein (eg, labeled ^3H and ^14C ) are useful for compound and/or tissue substrate distribution studies. Tritium (ie ³ H) isotopes and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and their detectability. Additionally, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide some therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred under some circumstances.

Polymorphic crystalline and amorphous forms of compounds of formula (I) and salts, solvates, hydrates, esters and prodrugs of compounds of formula (I) are also intended to be included herein.

Applications of connections

Within the intended scope of the present disclosure, aspects of the present disclosure include compounds that have been identified and demonstrated to be useful for selectively preventing, treating, or ameliorating HD, and that have been proposed for use in preventing, treating, or ameliorating HD.

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

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

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

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

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

Another aspect of the present disclosure includes a method of treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

An aspect of the present disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or alleviate HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

Another aspect of the present disclosure includes a method of using a salt of a compound of the form

- 45 043655 loy (I) or a form or composition thereof for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of formula (I) or a form thereof.

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

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

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for the preparation of a medicament for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of the medicament.

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

An aspect of the present disclosure includes in vitro or in vivo use of a compound of formula (I) or a form thereof having activity against HD.

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in combination therapy to provide additive or synergistic activity, thereby allowing the development of a combination product for the treatment or relief of HD.

Another aspect of the present disclosure includes a combination therapy containing the compounds described herein in combination with one or more known drugs or one or more known therapies that can be used to treat HD regardless of whether the HD is affected by a known medicine.

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

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

In an aspect of the use or method provided herein, compounds of formula (I) or forms thereof, used in combination with one or more active substances, can be administered to a subject or brought into contact with the cell(s) of the subject or patient before, simultaneously, or after administering to a subject or patient or bringing a cell into contact with additional active substance(s). The compound(s) of formula (I) or a form thereof and additional active substance(s) may be administered to a subject or contacted with a cell in the same composition or in different compositions. In particular aspects, the compound(s) of Formula (I) or forms thereof are used in combination with gene therapy to inhibit HTT expression (using, for example, viral delivery vectors) or the administration of another small molecule HTT inhibitor. In another specific aspect, the compound(s) of formula (I) or a form thereof are used in combination with cell replacement using differentiated non-mutant HTT stem cells. In another specific aspect, the compound(s) of formula (I) or a form thereof is used in combination with cell replacement using differentiated HTT stem cells.

In one aspect, the present document provides for the use of compounds of formula (I) or a form thereof in combination with standard supportive care, 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 for treating or alleviating HD in a subject in need thereof, containing a compound of Formula (I) or a form thereof and instructions for administering an effective amount of a compound of Formula (I) or its forms.

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in the preparation of a kit for treating or alleviating HD in a subject in need thereof, containing a compound of formula (I) or a form thereof and instructions for administering an effective amount of a compound of formula (I) (I) or forms thereof; and, if necessary, for administering to a subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents.

An aspect of the present disclosure includes the use of a compound of Formula (I) or a form thereof in the preparation of a kit for treating or alleviating HD in a subject in need thereof, containing a compound of Formula (I) or a form thereof and instructions for administering an effective amount

- 46 043655 compounds with formula (I) or forms thereof; and, if necessary, for administering to the subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents; and, if necessary, for administering to the subject an effective amount of a compound of formula (I) or a form thereof in a combination product with an effective amount of one or more therapeutic agents in combination with standard supportive care, wherein the standard supportive care is palliative therapy.

In one respect, for each of these aspects, the subject has not previously received therapy. In another respect, for each of these aspects, the subject has previously received therapy.

As used herein, the term prevention refers to preventing the onset of a disease, disorder, or condition in a subject who may be predisposed to said disease, disorder, and/or condition, but who has not yet been diagnosed as having said disease, disorder, and/or condition.

As used herein, the term treatment refers to inhibiting the progression of a disease, disorder or condition in a subject already exhibiting symptoms of the disease, disorder and/or condition, i.e. to stop the progression of a disease, disorder and/or condition that has already affected the subject.

As used herein, the term relief refers to the alleviation of symptoms of a disease, disorder and/or condition in a subject already exhibiting symptoms of the disease, disorder and/or condition, i.e. providing regression of a disease, disorder and/or condition that has already affected the subject.

In the context of this document, the term subject refers to an animal or any living organism that has sensitivity and the ability to move voluntarily, and which requires oxygen and organic food. Non-limiting examples include human species, primates, horses, pigs, cows, mice, rats, dogs and cats. In certain aspects, the subject is a mammal or warm-blooded vertebrate. In other aspects the subject is human. 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 means the amount of a compound of formula (I) or a form thereof, composition or drug thereof that achieves a target plasma concentration that is effective for treating or alleviating HD as described herein. and thus providing the desired therapeutic, relieving, inhibitory or prophylactic effect to the subject in need thereof. In one aspect, the effective amount may be the amount needed to treat HD in a subject or patient, more particularly in a human.

In another aspect, the concentration-biological effect relationships observed for a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from about 0.001 to about 50 μg/mL, from about 0.01 to about 20 μg/ml, about 0.05 to about 10 μg/ml, or about 0.1 to about 5 μg/ml. To achieve such plasma concentrations, the compounds described herein can be administered in doses ranging from, for example, but not limited to, 1.0 ng to 10,000 mg.

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

- 47 043655 or from about 0.1 to about 1500 mg/kg/day, or from about 0.1 to about 1000 mg/kg/day, or from about 0.1 to about 500 mg/kg/day, or from about 0.1 to about 250 mg/kg/day, or about 0.1 to about 200 mg/kg/day, or about 0.1 to about 150 mg/kg/day, or about 0.1 to about 100 mg/kg/day, or about 0.1 to about 75 mg/kg/day, or about 0.1 to about 50 mg/kg/day, or about 0.1 to about 25 mg/kg /day, or from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day, or from about 0.1 to about 1 mg/kg/day, or from about 0.1 to about 0.5 mg/kg/day.

Effective amounts for a given subject can be determined by routine experimentation that is within the skill and judgment of the physician or specialist in the art in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be taken into account include genetic screening, severity of disease, disease progression status, general health of the subject, ethnicity, age, weight, sex, diet, time of day and frequency of administration, combination of drug(s) ), allergic reactions, experience with other treatments and tolerance/response to therapy.

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

In certain aspects, the dose administered to achieve an effective target plasma concentration may also be administered as a single, divided, or continuous dose to a patient or subject weighing in the range of about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly for children weighing less than 40 kg). The average weight of a typical adult subject is expected to be around 70 kg. Long-acting pharmaceutical compositions may be administered 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 route of drug administration known in the art. Non-limiting examples include oral, ophthalmic, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral and pulmonary routes of administration.

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

For any compound, the effective amount can be initially assessed either in cell culture assays or in animal models, such as mouse, guinea pig, chimpanzee, marmoset or tamarin animal models. Suitable animal models can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine doses and routes of administration for humans. Therapeutic efficacy and toxicity can be determined using standard pharmaceutical techniques in cell culture or experimental animals, for example, ED50 (dose that is therapeutically effective in 50% of the population) and LD ₅₀ (dose that is lethal in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio LD ₅₀ /ED ₅₀ . In certain aspects, the effective amount is such that it provides a high therapeutic index. In other specific aspects, the dosage is within a circulating concentration range that includes the ED50 with little or no toxicity. Dosage may vary within this range depending on the dosage form used, patient sensitivity and route of administration.

In one aspect, provided herein are methods of modulating HTT (huntingtin protein) content comprising the step of contacting a human cell with a compound of formula (I) or a form thereof. In a specific aspect, provided herein are methods of modulating HTT content, comprising the step of contacting a human cell with a compound of formula (I) or a form thereof that modulates HTT expression. A human cell can 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 human. In a particular embodiment, the human cell is from or located in a human. In another specific aspect, the human cell is taken from a person with HD or is located in a person with HD. In another specific

- 48 043655 aspect, the human cell is taken from or located in a person with HD caused by a CAG repeat in the Htt gene, which leads to loss of HTT expression and/or function. In another aspect, a human cell is taken from a person with HD. In another aspect, the human cell is in a person with HD. In one aspect, the compound is a form of the compound of Formula (I).

In a specific aspect, provided herein is a method of enhancing inhibition of a mutant HTT transcribed from the Htt gene, comprising the step of contacting a human cell with a compound of formula (I) or a form thereof. A human cell can 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 human. In a particular aspect, the human cell is taken from or located in a human. In another specific aspect, the human cell is taken from a person with HD or is located in a person with HD. In another specific aspect, the human cell is from or located in an individual with HD caused by a CAG repeat in the Htt gene caused by loss of normal wild-type HTT expression and/or function. In another aspect, a human cell is taken from a person with HD. In another aspect, the human cell is in a person with HD. In one aspect, the compound is a form of the compound of Formula (I).

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

In another aspect, provided herein is a method for reducing mutant HTT, comprising the step of contacting a human cell with a compound of formula (I) or a form thereof. In a specific aspect, provided herein is a method of reducing mutant HTT, comprising the step of contacting a human cell with a compound of formula (I) that inhibits transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific aspect, provided herein is a method of reducing HTT content, comprising the step of contacting a human cell with a compound of formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. A human cell can 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 human. In a particular aspect, the human cell is taken from or located in a human. In another specific aspect, the human cell is taken from a person with HD or is located in a person with HD. In another specific aspect, the human cell is from or located in an individual with HD caused by a CAG repeat in the Htt gene resulting in loss of HTT expression and/or function. In another aspect, a human cell is taken from a person with HD. In another aspect, the human cell is in a person with HD. In another aspect, the compound is a form of the compound of formula (I).

In certain aspects, treating or alleviating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional active agent) provides a therapeutic effect and/or a beneficial effect. In a particular aspect, treatment of HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional active agent) results in one, two or more of the following effects: (i) reduces or alleviates the severity of HD; (ii) delays the onset of HD; (iii) inhibits the progression of HD; (iv) reduces the need for hospitalization of the subject; (v) reduces the length of hospitalization of the subject; (vi) improves subject survival; (vii) improves the subject's quality of life; (viii) reduces the number of symptoms associated with HD; (ix) reduces or alleviates the severity of symptom(s) associated with HD; (x) reduces the duration of symptoms associated with HD; (xi) prevents recurrence of symptoms associated with HD; (xii) inhibits the development or onset of HD symptoms; and/or (xiii) inhibits the progression of symptoms associated with HD.

Metabolites

In another aspect, the use of in vivo metabolic products of the compounds described herein is included within the scope of the present disclosure. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, mainly due to fermentation processes. Accordingly, the present description includes the use of compounds produced by the process of bringing a compound described herein into contact with tissue of a mammal or with a mammal for a period of time sufficient to obtain the product of its metabolism.

Typically, such products are identified by preparing a radiolabeled isotopologue (e.g., ¹⁴ C or ³ H) of the compound described herein, administering the radiolabeled compound at a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal, such as a rat, mouse, guinea pig, dog, monkey or human, allow sufficient time for

- 49 043655 passage of metabolism (usually from 30 s to about 30 h), and identification of metabolic transformation processes from urine, bile, blood or other biological samples. The transformation products are easily isolated because they are labeled with a radioisotope due to the fact that they are enriched in the isotope (others are isolated through the use of antibodies capable of binding epitopes retained in the metabolite). The structures of metabolites are determined in the usual way, for example, by MS or NMR analysis. In general, metabolite analysis can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products, because they are not otherwise detectable in vivo, are useful in diagnostic studies to determine the therapeutic dosage of the compounds described herein, even if they themselves do not have biological activity.

Pharmaceutical compositions

Within the intended scope of the present disclosure, aspects of the present disclosure include compounds that have been identified and demonstrated to be useful for selectively preventing, treating, or ameliorating HD, and that have been proposed for use as one or more pharmaceutical compositions for preventing, treating, or ameliorating HD.

An aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in the preparation of a pharmaceutical composition for treating or alleviating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof in admixture with one or a more pharmaceutically acceptable excipient.

An aspect of the present disclosure includes the use of a pharmaceutical composition of a compound of formula (I) or a form thereof in the preparation of a kit for treating or alleviating HD in a subject in need thereof, containing a pharmaceutical composition of a compound of formula (I) or a form thereof and instructions for administering the pharmaceutical compositions.

As used herein, the term composition means a product containing the specified ingredients in the specified amounts, as well as any product that is obtained, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

The pharmaceutical composition can be formulated to achieve a physiologically compatible pH level, in the range of a pH of about 3 to a pH of about 11. In some aspects, the pharmaceutical composition has a dosage form to achieve a pH level of from about pH 3 to about pH 7. In other aspects, the pharmaceutical composition has dosage form to achieve a pH of about pH 5 to about pH 8.

The term pharmaceutically acceptable excipient refers to an excipient for administration with a pharmaceutical active ingredient, such as the compounds described herein. The term refers to any pharmaceutical excipient that can be administered without unwanted toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition to be administered, as well as the particular mode of administration and/or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, diluents, stabilizers, adjuvants, diluents and the like. Accordingly, there is a wide variety of suitable dosage forms of pharmaceutical compositions for the immediate compounds described herein (see, for example, Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include long, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (eg hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerin and ethanol; wetting or emulsifying agents; pH buffering substances; etc. Liposomes are also included in the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be in any dosage form suitable for the purpose described herein. Suitable dosage forms for oral administration include solid forms, liquid solutions, emulsions and suspensions, while suitable inhaled dosage forms for pulmonary administration include liquids and powders. Alternative dosage forms include syrups, creams, ointments, tablets, and lyophilized solid forms, which can be reconstituted with a physiologically compatible solvent prior to administration.

When prescribed, for example, for oral administration, tablets, troches, lozenges, aqueous or oily solutions, anhydrous solutions, dispersible powders or gras may be prepared.

- 50 043655 zeros (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral administration may be prepared in accordance with any method of making pharmaceutical compositions known in the art, and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents and preservatives to provide a pleasant to the taste of the drug.

Pharmaceutically acceptable excipients suitable for use with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegration agents such as croscarmellose sodium, cross-linked povidone, corn starch or alginic acid; binders such as povidone, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action over a longer period. For example, a retarding material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be used.

Oral dosage 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 an anhydrous or oily medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

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

Excipients suitable for use in connection with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic, dispersing or wetting agents such as naturally occurring phosphatide (e.g. lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethylene oxcetanol), a condensation product of ethylene oxide with a partial ester derivative of a fatty acid and hexitol anhydride (for example, polyoxyethylene sorbitan monooleate); and thickening agents 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 phydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums such as gum arabic and gum tragacanth; phosphatides of natural origin, such as soy lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be in dosage form with sweetening agents such as glycerin, sorbitol or sucrose. Such dosage forms may also contain an emollient, preservative, flavoring or coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such an emulsion or suspension may be in a dosage form known in the art using those suitable dispersing or wetting agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable preparation can also be prepared as a lyophilized powder. Acceptable carriers and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils can be used as a solvent or suspension medium. Any light fatty oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, in a similar way when preparing injectable drugs

- 51 043655 fatty acids such as oleic acid can be used.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium chain fatty acids (eg, caprylic and capric acids) or triglycerides and propylene glycol ethers medium chain fatty acids. Thus, provided herein are compounds that have been modified by substitutions or additions of chemical or biochemical moieties that make them more suitable for administration (e.g., increase solubility, bioactivity, improve palatability, reduce adverse reactions, etc.), e.g. by esterification, glycosylation, PEGylation, etc.

In some aspects, a compound described herein is in an oral dosage form in a lipid-based composition suitable for compounds with low solubility. Lipid-based dosage forms may generally increase the oral bioavailability of such compounds. Thus, the pharmaceutical compositions described herein may contain an effective amount of a compound of Formula (I) or a form thereof together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol ethers thereof (e.g., propylene glycol fatty acid ethers marketable acids such as caprylic and capric acids), and pharmaceutically acceptable surfactants such as polysorbate 20 or 80 (also called Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

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

In alternative aspects, the pharmaceutical composition may further comprise one or more 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 some aspects, the pharmaceutical composition further contains HPBC in the range of from about 0.1 to about 20%, from about 1 to about 15%, 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

As disclosed herein, general methods for preparing compounds of formula (I) or forms thereof as described herein are available using standard, well known synthetic methodology. Many of the starting materials are commercially available, or when not available, can be prepared using the methods described below using techniques known to those skilled in the art. The synthesis schemes presented herein contain multiple reaction steps, each of which is designed to stand alone and can be carried out together or without any preceding or subsequent step(s). In other words, each of the individual reaction steps is considered in the synthesis schemes presented separately herein. Scheme A.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme A below.

Compound A1 (in which X1 and X2 are independently bromine, chlorine, and the like) is converted to compound A2 by nucleophilic substitution using a primary or secondary amine in the presence of a suitable base (such as K2CO3 and the like) in a suitable solvent (such as DMF etc). Alternatively, compound A1 is converted to compound A2 by cross-coupling with a primary or secondary amine (ie R ₁ substituted base) in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and base (such as tert- sodium butoxide and the like) in a suitable solvent (that

- 52 043655 com as 1,4-dioxane and the like). Compound A2 is converted to compound A3 through a Suzuki coupling reaction with an aryl or heteroaryl boric acid (or pinacol boric acid ester) (i.e. R ₂ substituted boric acid or ester) in the presence of a catalyst (such as Pd(dppf) Cl ₂ and the like) and a base (such as an aqueous solution of K ₂ CO ₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like).

Scheme B.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme B below.

^r - _N h (ROhB-R ₂ >yR ₂ ^ _1у

Χι^ννΓγ^^ ^А3

_Rb

IN 1

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

Scheme C.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme C below.

group, and P represents a protecting group such as Boc and the like) (i.e., R1 protected by a boric acid ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as aqueous a solution of K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound B1 is converted to compound C1 by a Negishi coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkyl zinc halide (i.e. R1 substituted zinc halide) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like the like) in a suitable solvent (such as 1,4-dioxane and the like). After treatment with a deprotecting agent suitable for the protecting group (such as HCl in dioxane for the Boc protecting group), compound C1 is converted to compound C2. Compound C2 is converted to compound C3 by reductive amination with a suitable aldehyde and a reducing agent (such as NaBH(OAc) ₃ and the like) in a suitable solvent (such as 1,2-dichloroethane and the like). Alternatively, compound C2 is converted to compound C3 by alkylation with an alkyl halide (such as 2-iodopropane and the like) in the presence of a suitable base (such as K ₂ CO ₃ and the like). In cases where unsaturation exists in the ring containing the basic amino group, the compound can be converted to its fully saturated counterpart under an H ₂ atmosphere in a suitable solvent (such as methanol and the like) and in the presence of a catalyst (such as 10% Pd/C and the like).

Scheme D.

Compounds of formula (I) in which R ₁ and R 2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme D below.

- 53 043655

Following the general conditions described

C, connection D1 can be converted into connection diagram D5.

Scheme E.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme E below.

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

Scheme F.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme F below.

Compound F1 (in which X represents bromine, chlorine and the like) is converted to compound F2 by condensation with an optionally substituted N-Boc-piperidine-4-aldehyde (in which Y represents hydrogen or an optionally substituted alkyl group, and P represents a protecting group such as Boc and the like) in a suitable solvent (such as EtOH and the like). Compound F2 is converted to compound F3 by reduction of the nitro group with H ₂ in the presence of a catalyst (such as PtO ₂ and the like) in a suitable solvent (such as EtOH and the like). Compound F3 is converted to compound F4 through a ring formation/oxidation reaction with a suitable oxidizing agent (such as DDQ and the like) in a suitable solvent (such as CH3CN and the like). Compound F4 is converted to compound F5 via a Suzuki coupling reaction with an aryl or heteroaryl boric acid (or pinacol boric acid ester) (i.e. R2 substituted boric acid or

- 54 043655 ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, compound F4 is converted to compound F5 by treatment with pinacolatodiborone and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) in a suitable solvent (such as 1,4-dioxane and the like), followed by the addition of an aryl or heteroaryl halide (ie R2 substituted halide). Compound F5 is converted to compound F6 by treatment under conditions suitable for removing the protecting group (eg TFA or HCl in dioxane for the Boc protecting group). Additional modification of the basic amino group can be achieved according to the methods described in Scheme C.

Scheme G.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme G below.

Compound G1 (in which X is bromine, chlorine, and the like; Y is hydrogen or optionally substituted alkyl; and P is a suitable protecting group) is converted to compound G2 via a condensation/ring formation sequence in the presence of a catalyst (such as CuI and the like), a ligand (such as 1,10-phenanthroline and the like) and a base (such as NaOt-Bu and the like) in a suitable solvent (such as DMF and the like). Compound G2 is converted to compound G3 by treatment with a strong acid (conc. HCl and the like) in the presence of oxygen. Compound G3 is converted to compound G4 via a Suzuki coupling reaction with an aryl or heteroaryl boric acid (or pinacol boric acid ester) (i.e. R2 substituted boric acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as an aqueous solution of 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 treatment with pinacolatodiborone and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) in a suitable solvent (such as 1,4-dioxane and the like), followed by the addition of an aryl or heteroaryl halide (ie R2 substituted halide). Compound G4 is converted to compound G5 by treatment under conditions suitable for removing the protecting group (eg TFA or HCl in dioxane for the Boc protecting group). Additional modification of the basic amino group can be achieved according to the methods described in Scheme C.

Scheme N.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme H below.

- 55 043655

Compound H1 (in which X2 represents bromine, chlorine and the like; and P represents a protecting group such as tert-butyl and the like) is converted to compound H2 through a Suzuki coupling reaction with an aryl or heteroaryl boric acid or ester (i.e. R2 substituted with boric acid or ester) in the presence of a catalyst (such as Pd(dppf)Cl ₂ and the like) and a base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4 -dioxane and the like). By treatment with an acid (such as TFA or HCl in dioxane and the like), the H2 compound is converted to the H3 compound. Compound H3 is converted to compound B1 (in which X1 is a triflate and the like) by treatment with an activated triflate (such as Tf ₂ O or Tf2NPh and the like) in the presence of a base (such as K2CO3 or NaH and the like) in a suitable solvent (such as THF or DMF and the like). Alternatively, compound H3 can be converted to compound B1 (where X1 is Cl and the like) by treatment with a dehydrogenating halogenating agent (such as POCl3 and the like). Additional modification of the basic amino group can be achieved according to the methods described in Scheme C.

Scheme I.

Compounds of formula (I) in which R1 and R2 are monocyclic or bicyclic heterocyclyl or heteroaryl ring systems can be prepared as described in Scheme I below.

Compound I1 (where X1 is bromine, chlorine and the like; and P is a protecting group such as methyl and the like) is converted to compound I2 through a Suzuki coupling reaction with an optionally substituted and suitably protected amine-containing cycloalkyl/cycloalkenyl pinacol complex boric acid ester (in which Y is hydrogen or an optionally substituted alkyl group, and P is a protecting group such as Boc and the like) (i.e. R1 is a substituted boric acid ester) in the presence of a catalyst (such as Pd (dppf)Cl ₂ 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 I2 is converted to compound E2 (in which X2 is a triflate and the like) by treatment with an activated triflate (such as Tf2O or Tf2NPh and the like) in the presence of a base (such as K2CO3 or NaH and the like) in a suitable solvent (such as THF or DMF and the like). Additional modification of the basic amino group can be achieved according to the methods described in Scheme C.

Specific examples of synthesis

For more detailed description and ease of understanding, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein and should not be construed as specifically limiting their scope. It is believed that such variations of the compounds described herein, which may be currently known or later developed, as may be determined by one skilled in the art, are within the scope of the compounds described herein and hereinafter claimed. These examples illustrate the preparation of certain compounds. Those skilled in the art will appreciate that the methods described in these examples are methods described by those skilled in the art that work well in synthetic practice, and as such represent preferred methods for carrying them out. It should be understood, however, that those skilled in the art will appreciate in light of the present disclosure that many changes can be made to the specific methods disclosed and still obtain a similar or similar result without departing from the spirit and scope of the present disclosure.

- 56 043655

Except for the following examples of embodiments, unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, experimental data, etc., used in the description and claims are to be understood as being modified by the term about. Accordingly, all such numbers represent approximations that may vary depending on the desired properties to be obtained by the reaction or as a result of varying experimental conditions. Therefore, within the expected range of experimental reproducibility, the term approximately in the context of the data obtained refers to the range of data provided that it can vary according to a standard deviation from the mean. Additionally, for experimental results provided, final data may be rounded up or down to present data consistently without losing significant figures. At the very least, and not as an attempt to limit the application of the basic principles of equivalents to 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 setting forth the broad scope of this disclosure are approximate, the numerical values set forth in the examples described below are reported to the greatest possible accuracy. However, any numerical value by its nature contains certain errors that inevitably arise from the standard deviation found in the corresponding experimental measurements.

Connection examples

Above and throughout this description, the following abbreviations, unless otherwise indicated, should be understood to have the following meanings:

Reduction Meaning Δ heating (chemistry) or removal (biology) AcOH or HO Ac acetic acid Ac ₂ O acetic anhydride _Ag2SO4 silver sulfate Ag argon ACN or CH ₃ CN acetonitrile atm atmosphere(s) В2Р1П2 bis(pinacolato)diborone Vos tert-butoxycarbonyl Vosgo di-tert-butyl dicarbonate Vg ₂ bromine nBuLi n-butyl lithium iBuNO isobutyl nitrite BuOH //-butanol Bu ₃ SnCl Tributylchlorostannane or tributyltin chloride °C degrees Celsius Celite® or Celite diatomite

- 57 043655

_CO2C12 oxalyl chloride CerSOz cesium carbonate Cui copper(I) iodide d/h/hour/hours/min/s days(d)/hour(s, hour or hours)/minute(s)/second(s) DCM or CH2CI2 dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIEA or DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine or Ν,Νdimethylpyridin-4-amine DMF dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol Et ₂ O diethyl ether Fe(acac)32 iron(III) acetylacetonate H ₂ hydrogen HC1 hydrochloric acid HI hydroiodic acid H2SO4 sulfuric acid K2CO3 potassium carbonate KOAc potassium acetate KOtBu /n-potassium butoxide KOH potassium hydroxide K ₂ OsO ₄ 2H ₂ 0 potassium osmate(U1) dihydrate LAH or LiA1H ₄ Lithium aluminum hydride Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane- 2,4-disulfide LC/MS, LCMS or LC-MS liquid chromatography-mass spectrometry LiOH lithium hydroxide MeOH methanol _MeSO3H methanesulfonic acid

- 58 043655

_MgSO4 magnesium sulfate _MnO2 manganese dioxide MS mass spectroscopy MsCl methanesulfonyl chloride N.B.S. A-bromosuccinimide NEts triethylamine NH ₄ C1 ammonium chloride _NH4OAc ammonium acetate NaBH ₄ sodium borohydride NaBH(OAc) ₃ sodium triacetoxyborohydride NaH sodium hydride _NaHCO3 bicarbonate of soda NaHMDS sodium bis(trimethylsilyl)amide or sodium hexamethyldisilazide NaH sodium hydride NaOH sodium hydroxide NaOMe sodium methoxide _NaNO2 sodium nitrite _{Na2SO4 _} sodium sulfate n ₂ nitrogen NH4CI ammonium chloride NMO 4-methylmorpholine N-oxide NMP methylpyrrolidone NMR nuclear magnetic resonance NOBF4 nitrosonium tetrafluoroborate or nitrosyl tetrafluoroborate Pb(OAc) ₄ lead acetate (1U) or lead tetraacetate Pd palladium Pd/C palladium on coal Pd(dppf)Cl ₂ or complex [1,Г- Pd(dppf)Cl ₂ -CH ₂ Cl ₂ bis(diphenylphosphino)ferrocene]dichloropalladium(P) with dichloromethane PHBu ₃ BF ₄ or tri-tert-butylphosphonium tetrafluoroborate /BmPHBF4

- 59 043655

PhCH ₃ toluene Phi iodobenzene PhI(OTFU) ₂ [bis(trifluoroacetoxy)iodine] benzene PhMe toluene Ph-N(Tf) ₂ or PhN(Tf) ₂ N-phenyl triflimide, also called Nphenyl-bis(trifluoromethanesulfonimide) ROVgs phosphoryl bromide or phosphorus(U) oxybromide _{P2O5 _} Phosphorus pentoxide or phosphorus(V) oxide ROS1z phosphoryl chloride or phosphorus(V) oxychloride PhMe toluene Psi pressure in pounds per square inch _Pt2O platinum(IV) oxide Rt or rt room temperature SEMC1 2-(trimethylsilyl)ethoxymethyl chloride _SnCl2 tin(II) chloride or tin chloride SOC1 ₂ thionyl chloride S-Phos, SPhos or Sphos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G2 chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,Gbiphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(P) TBAF Tetrabutylammonium fluoride TBSC1 tert-butyldimethylsilyl chloride TEA, EHN or NEt3 triethyl amine TFU trifluoroacetic acid THF tetrahydrofuran UPS triisopropylsilane TLC thin layer chromatography TMEDA tetr am eti le ti l e n d i a m i n TMS trimethylsilyl TMSCCH trimethylsilylacetylepe t-Bu tert-butyl Zn(CN) ₂ zinc cyanide ZnMe ₂ dimethyl zinc

Example 1.

Receiving connection 11

Step A: 6-Bromo-2-chloroquinoline (121 mg, 0.5 mmol) was combined with N,2,2,6,6-pentamethylpiperidin4-amine (170 mg, 0.95 mmol) and Cs ₂ CO ₃ (325 mg, 1.0 mmol) in DMF (2 ml), and the mixture was stirred at 100°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-5% MeOH in CH ₂ Cl ₂ to give 6-bromo-N-methyl-N-(2,2,6,6tetramethylpiperidin-4-yl)quinolin-2-amine (480 mg, 65%). MS m/z 375.9, 377.9 [M+H]+.

Step B. 6-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine (40 mg, 0.11 mmol), 2,7-dimethyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (51 mg, 0.15 mmol) and [1,1'-bis(diphenylphosphino)ferrocene complex ]dichloropalladium(P) with dichloromethane (8 mg, 0.01 mmol) was combined with an aqueous solution of 1 M K ₂ CO ₃ (0.5 ml, 0.5 mmol) and 1,4-dioxane (1 ml). The mixture was stirred at 80°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 6-(2,7-dimethyl-2Hindazol-5-yl)-N-methyl-N-(2, 2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine (40 mg, 85%) as

- 60 043655 almost white solid.

MS m/z 442.1 [M+H]+; 1H NMR (DMSO^) δ: 8.35 (s, 1H), 8.11 (d, J=9.4 Hz, 1H), 8.01 (m, 1H), 7.89 (dd, J= 9.0, 1.5 Hz, 1H), 7.83 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.46 (s, 1H), 7.13 ( d, J=8.9 Hz, 1H), 5.24 (br, 1H), 4.20 (s, 3H), 2.99 (s, 3H), 2.59 (s, 3H), 1, 69-1.01 (m, 16H).

Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate boric acid in Step B, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Example 2.

Receiving connection 15

Step A: 6-Bromo-2-chloroquinoline (242 mg, 1.0 mmol) was complexed with

1,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (45 mg, 0.05 mmol), 2,7-dimethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-2H-indazole (350 mg, 1.0 mmol), 1,4-dioxane (5 ml) and aqueous 1 M K2CO3 (2.5 ml, 2.5 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexane to give 2-chloro-6-(2,7-dimethyl-2H-indazol-5-yl)quinoline (150 mg, 49%). MS m/z 308.0, 310.0 [M+H]+.

Step B: 2-Chloro-6-(2,7-dimethyl-2H-indazol-5-yl)quinoline (135 mg, 0.30 mmol) was combined with pinacol ester N-Boc-1,2,5,6 -tetrahydropyridine-4-borinic acid (193 mg, 0.61 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (40 mg, 0.05 mmol), 1,4-dioxane (2.5 ml) and an aqueous solution of 1 M K2CO3 (1.2 ml, 1.2 mmol). The mixture was stirred at 90°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH in EtOAc to give tert-butyl 4-[6-(2,7dimethylindazol-5-yl)-2-quinolyl]-3,6-dihydro-2H-pyridin- 1-carboxylate (135 mg, 61%). MS m/z 455.1 [M+H]+.

Step C. tert-Butyl 4-[6-(2,7-dimethylindazol-5-yl)-2-quinolyl]-3,6-dihydro-2H-pyridine-1carboxylate (35 mg, 0.08 mmol) was combined with 10% Pd/C (10 mg) in MeOH (3 ml). The mixture was stirred under H2 (1 atm) for 18 hours. The mixture was filtered through Celite®. The filtrate was concentrated to give tert-butyl 4-[6-(2,7-dimethylindazol-5-yl)-2-quinolyl]piperidine-1-carboxylate (35 mg, 99%). MS m/z 457.2 [M+H] ⁺ .

Step D: tert-Butyl 4-[6-(2,7-dimethylindazol-5-yl)-2-quinolyl]piperidine-1-carboxylate from Step C (35 mg, 0.077 mmol) was combined with TFA (1 mL). The solution was left for 20 min before volatiles were removed using a stream of N2. The residue was partitioned between EtOAc and an aqueous solution of 1 M K2CO3. The organic layer was collected and concentrated to give 6-(2,7-dimethyl-2H-indazol-5-yl)-2(piperidin-4-yl)quinoline (25 mg, 91%).

- 61 043655

MS m/z 357.1 [M+H]+; 1H NMR (DMSO-d ₆ ) δ: 8.40 (s, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H) , 8.09 (dd, J=8.8, 2.2 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.93-7.97 (m, 1H), 7.50-7.57 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 4.21 (s, 3H), 3.05-3.11 (m, 2H) , 2.92-2.99 (m, 1H), 2.61-2.68 (m, 2H), 2.61 (s, 3H), 1.81-1.88 (m, 2H), 1 ,69-1.79 (m, 2H), The proton corresponding to NH was not observed.

Using the procedure described above for Example 2, additional compounds described herein were prepared by substituting suitable starting material, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Example 3.

Receiving connection 13

Step A: 2,2,6,6-Tetramethylpiperidin-4-one (3.1 g, 20 mmol) was dissolved in THF (100 ml) and cooled to -78°C. NaHMDS (21 mL, 21 mmol, 1.0 M in THF) was added to the solution. The mixture was stirred for 15 minutes at -78°C. N,N-bis(trifluoromethylsulfonyl)aniline (7.8 g, 22 mmol) was added to the mixture in solid form. The mixture was allowed to warm to room temperature before quenching with saturated aqueous NaHCO ₃ solution. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with aqueous 2 M KOH, dried over Na ₂ SO ₄ , filtered and concentrated to give 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (6.0 g , 100%).

1H NMR (acetone) δ: 10.28 (br s, 1H), 6.13 (s, 1H), 2.85 (br s, 2H), 1.76 (s, 6H), 1.68 (s , 6H).

Step B: (2,2,6,6-Tetramethyl-1,3-dihydropyridin-4-yl) trifluoromethanesulfonate (100 mg, 0.35 mmol) was combined with bis(pinacolato)diborone (125 mg, 0.50 mmol) , potassium acetate (100 mg, 1.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (12 mg, 0.015 mmol) and 1,4-dioxane (2.4 ml) . The mixture was stirred at 90°C for 2 hours. The mixture was cooled to room temperature. An aqueous solution of 1 M K ₂ CO ₃ (1 ml, 1 mmol), 2-chloro-6-(2,7dimethylindazol-5-yl)quinoline (100 mg, 0.30 mmol, prepared according to example 2, step) was added to the mixture A) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (12 mg, 0.015 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH (2N NH ₃ ) in CH ₂ Cl ₂ to give 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(2,2 ,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)quinoline (90 mg, 46%).

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

Example 4.

Receiving connection 14

6-(2,7-Dimethylindazol-5-yl)-2-(2,2,6,6-tetramethyl-1,3-dihydropyridin-4-yl)quinoline (20 mg, 0.05

- 62 043655 mmol) was combined with 10% Pd/C (10 mg) in MeOH (2 ml). The mixture was stirred under H ₂ (1 atm) at room temperature for 6 hours. The mixture was then filtered through celite. The filtrate was concentrated to give 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(2,2,6,6-tetramethylpiperidin-4-yl)quinoline (20 mg, 99%).

MS m/z 413.5 [M+H]+; ¹ H NMR (DMSO-d ₆ ) δ: 8.40 (s, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H ), 8.09 (dd, J=8.8, 2.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93-7.95 (m, 1H) , 7.49-7.53 (m, 2H), 4.21 (s, 3H), 2.61 (s, 3H), 1.73-1.79 (m, 2H), 1.47-1 .55 (m, 2H), 1.27 (s, 6H), 1.11 (s, 6H), The proton corresponding to NH was not observed.

Example 5.

Receiving connection 20

Step A: 6-Bromo-2-chloro-8-fluoroquinoline (52 mg, 0.2 mmol) was combined with 1,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloride dichloromethane complex (8 mg, 0. 01 mmol), 2,7-dimethyl-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (54 mg, 0.2 mmol), 1,4-dioxane (1 ml) and an aqueous solution of 1 M K2CO3 (0.5 ml, 0.5 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexane to give 2-chloro-6-(2,7-dimethyl-2H-indazol-5-ul)-8-fluoroquinoline (25 mg, 38%). MS m/z 326.2, 328.2 [M+H]+.

Step B: Zinc powder (5 g, 76 mmol) was suspended in N,N-dimethylacetamide (10 ml) under argon. A mixture of 1,2-dibromoethane (520 μL, 6.02 mmol) and chlorotrimethylsilane (730 μL, 5.74 mmol) was added dropwise over 10 min. During the addition, the internal temperature increased to 50°C. The reaction mixture was allowed to cool to room temperature. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (16.5 g, 53.0 mmol) in N,N-dimethylαcetamide (26 ml) was added dropwise over 20 min. The reaction mixture was filtered through Celite on a Schlenk filter to obtain approximately 50 ml of ~1 M (1-tert-butoxycarbonyl-4-piperidyl)-iodo-zinc solution. 2-Chloro-6-(2,7-dimethyl2H-indazol-5-yl)-8-fluoroquinoline (25 mg, 0.077 mmol) was combined with a solution of 1-tert-butoxycarbonylpiperidin-4-ylzinc iodide (0.25 ml, 0.25 mmol), chloro(2-dicyclohexylphosphino2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(P) (4 mg, 0.005 mmol) and 1,4dioxane (1 ml). The mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH in EtOAc to give tert-butyl 4-[6-(2,7-dimethylindazol-5-yl)-8fluoro-2-quinolyl]piperidine-1-carboxylate (30 mg, 82%). MS m/z 475.4 [M+H]+.

Step C. tert-Butyl 4-[6-(2,7-dimethylindazol-5-yl)-8-fluoro-2-quinolyl]piperidine-1-carboxylate (30 mg, 0.06 mmol) was combined with TFA (1 ml). After 10 min, volatile substances were removed. The mixture was partitioned between CH ₂ Cl ₂ and an aqueous solution of 1 M K2CO3. The organic layers were loaded onto silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 6-(2,7-dimethyl-2H-indazol-5-yl)-8-fluoro-2(piperidine -4-yl)quinoline (20 mg, 85%).

MS m/z 375.3 [M+H]+; 1H NMR (acetone^) δ: 8.22 (dd, J=8.7, 1.7 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.79-7.81 (m, 1H), 7.70 (dd, J=12.5, 2.0 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H ), 7.36-7.40 (m, 1H), 4.12 (s, 3H), 2.99-3.06 (m, 2H), 2.87-2.93 (m, 1H), 2.58-2.65 (m, 2H), 2.52 (s, 3H), 1.67-1.81 (m, 4H), No proton corresponding to NH was observed.

- 63 043655

Using the procedure described above for Example 5, additional compounds described herein were prepared by substituting the specified starting material in Step A, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Source material and data

Starting material: 6-bromo-2-chloroquinazoline ^MS m/z 358.3 [M+H]+; Ή NMR (DMSO-ί/ό) δ: 9.59 (s, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.98 - 8.02 (m, 2H), 7.54 (s, 1H), 4.22 (s, 3H), 3.29 - 3.35 (m, 2H ), 2.86 - 2.94 (m, 1H), 3.01 - 3.09 (m, 2H), 2.61 (s, 3H), 1.90 - 1.96 (m, 2H), 1.75 - 1.84 (m, 2H), The proton corresponding to ΝΉ was not observed.

Starting material: 7-bromo-3-chloroisoquinoline

MS m/z 357.3 [M+H]+; Ή NMR (DMSO-7,) δ: 9.32 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.13 (dd, J = 8.5, 1 .9 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.96 - 7.97 (m, 1H), 7.64 (s, 1H), 7.54 (t , J = 1.6 Hz, 1H), 4.21 (s, 3H), 3.09 - 3.15 (m, 2H), 2.86 - 2.94 (m, 1H), 2.66 - 2.74 (m, 2H), 2.61 (s, 3H), 1.87 - 1.93 (m, 2H), 1.69 - 1.78 (m, 2H), Proton corresponding to NH, not observed.

Example 6.

Receiving connection 72

Step A: Methyl cyanoacetate (5.71 g, 57.6 mmol) was added to a mixture of DMSO (30 ml) and NaH (60 wt%) in mineral oil (2.3 g, 57.6 mmol) at 0°C . The mixture was stirred at 0°C for 15 minutes. 5Chloro-2,3-difluorobenzonitrile (5.0 g, 28.8 mmol) in DMSO (5 ml) was added to the mixture. The mixture was stirred at room temperature for 30 minutes, and then heated to 90°C for 4 hours. The mixture was cooled to room temperature and diluted with H ₂ O (200 ml), brine (100 ml) and EtOAc (200 ml). A precipitate formed and was collected by vacuum filtration. The solid was washed with H ₂ O and dried to obtain methyl 2-(4-chloro-2-cyano-6-fluorophenyl)-2-cyano-acetate (6 g, 82%) in the form of a brownish powder. MS m/z 251.1, 253.1 [M-H]-.

Step B: Methyl 2-(4-chloro-2-cyano-6-fluorophenyl)-2-cyano-acetate (5.5 g, 22 mmol) was combined with concentrated aqueous HCl (40 ml) and 1.4 -dioxane (20 ml). The mixture was heated at 80°C for 4 hours. The mixture was cooled to room temperature and filtered. The solid was washed with H2O and CH3CN, and then dried to give 7-chloro-5-fluoro-4H-isoquinoline-1,3-dione (3.0 g, 65%) as an off-white solid. MS m/z 214.1, 216.1 [M+H]+.

Step C: 7-Chloro-5-Fluoro-4H-isoquinoline-1,3-dione (3.0 g, 14.0 mmol) was combined with POCl ₃ (20 ml, 212 mmol). The mixture was heated at 110°C for 2 hours, and then at 90°C overnight. The mixture was cooled to room temperature and then poured onto ice with vigorous stirring. Hard material

- 64 043655 was collected by vacuum filtration, dried and chromatographed on silica gel, eluting with CH2C12 to give 1,3,7-trichloro-5-fluoro-isoquinoline (1.3 g, 37%) in the form of a white powder. MS m/z 250.2, 252.2, 254.2 [M+H]+.

Step D: 1,3,7-Trichloro-5-fluoro-isoquinoline (1.3 g, 5.2 mmol) was combined with [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (210 mg , 0.26 mmol, TMEDA (0.77 ml, 5.2 mmol and THF (20 ml). Sodium borohydride (378 mg, 10 mmol) was added to the mixture. The mixture was stirred at room temperature for 30 min, and then separated between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% EtOAc in CH2Cl2 to give 3,7-dichloro-5-fluoro-isoquinoline (870 mg, 78%) as a white solid.

MS m/z 216.2, 218.2, 220.2 [M+H]+; ^1H NMR (acetone^) δ: 9.26 (m, 1H), 8.16 (m, 1H), 8.00 (s, 1H), 7.72 (dd, J=9.8, 1, 9 Hz, 1H).

Step E: 3,7-Dichloro-5-fluoro-isoquinoline (432 mg, 2.0 mmol) was combined with N-Boc-1,2,5,6-tetrahydropyridine-4-borinic acid pinacol ester (610 mg, 2.4 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (50 mg, 0.06 mmol), 1,4-dioxane (6 ml) and an aqueous solution of 1 M K2CO3 (4 ml, 4 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in hexane to give tert-butyl 4-(7chloro-5-fluoro-3-isoquinolyl)-3,6-dihydro-2H-pyridine-1-carboxylate (370 mg , 51%) in the form of an almost white solid. MS m/z 362.2, 364.2 [M+H] ⁺ .

Step F: 6-Chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine hydrochloride (62 mg, 0.28 mmol, prepared according to the procedure of Example 11) was combined with KOAc (83 mg, 0.85 mmol ), 1,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (23 mg, 0.03 mmol), bis(pinacolato)diborone (91 mg, 0.36 mmol) and 1,4-dioxane ( 1.5 ml). The mixture was stirred under N2 at 100°C for 2 hours. 1 M K2CO3 (aq) (0.75 mL, 0.75 mmol) was added to the mixture, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene complex -nalladium(II)dichloride dichloromethane (11 mg, 0.014 mmol) and tert-butyl 4-(7-chloro-5-fluoro-3-isoquinolyl)-3,6-dihydro-2H-pyridine-1carboxylate (100 mg, 0 .28 mmol). The mixture was stirred under N ₂ atmosphere for 1 hour at 80°C. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in CH2Cl2 then 5% MeOH in EtOAc to give tert-butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl )-5-fluoro-3-isoquinolyl]-3,6-dihydro2H-pyridine-1-carboxylate (90 mg, 69%) as a white solid. MS m/z 474.5 [M+H] ⁺ .

Step G. tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-isoquinolyl]-3,6dihydro-2H-pyridin-1- carboxylate (90 mg, 0.19 mmol) was combined with 10% Pd/C (20 mg) in MeOH (3 ml). The mixture was stirred under H2 atmosphere (1 atm) for 2 hours at 40°C. The mixture was filtered through a syringe filter. The filtrate was concentrated. The residue was chromatographed on silica gel, eluted with 40-100% EtOAc in hexane to give tert-butyl 4-[7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluoro-3-isoquinolyl ]piperidine-1-carboxylate (52 mg, 57%) in the form of an off-white solid. MS m/z 476.3 [M+H] ⁺ .

Step H. tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3isoquinolyl]piperidine-1-carboxylate (52 mg, 0.11 mmol ) combined with 4n. HCl in 1,4-dioxane (2 ml, 8 mmol). The mixture was stirred and treated with ultrasound at room temperature. After 1 hour, volatiles were removed. The residue was suspended in CH3CN, sonicated and filtered. The solids were dried to give 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4piperidyl)isoquinoline hydrochloride (36 mg, 46%) as a yellow solid .

MS m/z 376.5 [M+H]+; 1H NMR (DMSO^) δ: 9.58 (s, 1H), 9.14-9.22 (br, 1H), 8.96-9.05 (br, 1H), 8.89 (s, 1H ), 8.48-8.53 (m, 2H), 8.34 (dd, J=11.6, 1.5 Hz, 1H), 7.84 (s, 1H), 3.39-3, 45 (m, 2H), 3.25-3.31 (m, 1H), 3.02-3.12 (m, 2H), 2.79 (s, 3H), 2.60 (s, 3H) , 2.07-2.17 (m, 4H).

Using the procedure described above for Example 6, additional compounds described herein were prepared by substituting the appropriate boric acid in Step F, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 71 MS m/z 375.4 [M+H] ⁺ ; Ή NMR (DMSO-D ₆ ) δ: 9.56 (s, 1H), 9.12 - 9.20 (br, 1H), 8.89 - 8.98 (br, 1H), 8.89 (s , 1H), 8.43 - 8.48 (m, 2H), 8.34 (d, J= 12.2 Hz, 1H), 7.84 (s, 1H), 7.58 (s, 1H) , 4.22 (s, 3H), 3.39 - 3.46 (m, 2H), 3.27 - 3.34 (m, 1H), 3.02 - 3.12 (m, 2H), 2 .61 (s, 3H), 2.05 - 2.20 (m, 4H).

Using the procedure described above for Example 6, Steps E-H, additional compounds described herein were prepared by substituting suitable starting material in Step E, suitable boric acid in Step F, suitable reagents and reaction conditions to obtain the compounds, such as selected from:

- 65 043655

Source material and data

Starting material: 6-bromo-2-chloroquinoline

MS m/z 343.2 [M+H] ⁺ ; Ή NMR (DMSO-<7 ₆ ) δ: 8.75 - 8.80 (br, 2H), 8.64 (s, 1H), 8.54 (s, 1H), 8.47 - 8.50 ( m, 1H), 8.22 - 8.26 (m, 2H), 8.07 - 8.10 (m, 1H), 7.83 (s, 1H), 7.70 - 7.76 (m, 1H), 2H), 4.22 (s, 3H), 3.42 - 3.48 (m, 2H), 3.05 - 3.14 (m, 3H), 2.07 - 2.12 (m, 2H) , 1.87 - 1.95 (m, 2H).

Starting material: 6-bromo-2-chloroquinazoline

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

Example 7.

Receiving connection 74

1) nobf ₄ , ch ₂ ci ₂

2) SnCI ₂ , HCI

Pb(OAc)4

CH ₂ CI ₂ , rt, 16 h

Step A: 1,2-Difluoro-3-nitro-benzene (23 g, 145 mmol) was combined with Ag ₂ SO ₄ (45.2 g, 145 mmol) in H2SO4 (150 ml). The mixture was stirred for 5 minutes at room temperature. Br ₂ (11.2 ml, 217 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hours, and then poured into ice water (800 ml). The mixture was extracted with Et ₂ O (3 times 500 ml). The combined organic parts were dried, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-30% CH ₂ Cl ₂ in hexane to give 5-bromo-1,2-difluoro-3-nitro-benzene (18.8 g, 55%) as a white crystalline solid .

1H NMR (acetone^) δ: 8.20 (ddd, J=5.8, 2.4, 2.2 Hz, 1H), 8.12 (ddd, J=9.2, 6.5, 2, 2 Hz, 1H).

Step B. 5-Bromo-1,2-difluoro-3-nitro-benzene (15 g, 63 mmol), dimethyl malonate (12.5 g, 95 mmol), Cs ₂ CO ₃ (41.1 g, 126 mmol ) and DMF (63 ml) were stirred at room temperature for 6 hours. The reaction mixture was partitioned between an aqueous solution of 1 M HCl and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was combined with AcOH (30 ml) and conc. HCl (30 ml) and heated at 110°C for 16 hours. The mixture was diluted with H2O to form a precipitate. The solid was collected by vacuum filtration, washed with H2O, washed with 1:1 hexane/ether and dried to give 2-(4-bromo-2-fluoro-6-nitro-phenyl)acetic acid (14.5 g, 83 %) in the form of a white solid.

- 66 043655 ¹ H NMR (acetone-d ₆ ) δ: 11.28 (br s, 1H), 8.16 (t, J=1.5 Hz, 1H), 7.92 (dd, J=9, 0, 1.5 Hz, 1H), 4.06 (s, 2H).

Step C: 2-(4-Bromo-2-fluoro-6-nitro-phenyl)acetic acid (14.5 g, 52 mmol) was suspended in CH ₂ Cl ₂ (250 ml). Oxalyl chloride (7 mL, 79 mmol) was added to the mixture, followed by DMF (0.1 mL, 1 mmol). The mixture was stirred at room temperature for 1 hour, and then added dropwise to MeOH at 0°C. Volatiles were removed in vacuo to give methyl 2-(4-bromo-2-fluoro-6nitro-phenyl)acetate (15 g, 98%) as an off-white solid.

1H NMR (acetone-d6) δ: 8.16 (t, J=1.5 Hz, 1H), 7.93 (dd, J=9.0, 1.5 Hz, 1H), 4.05 (s , 2H), 3.71 (s, 3H).

Step D: Methyl 2-(4-bromo-2-fluoro-6-nitro-phenyl)acetate (15 g, 51 mmol) was suspended in a mixture of MeOH (200 ml) and NH ₄ Cl (55 g, 1.03 mol) at 0°C. Zinc powder (16.8 g, 257 mmol) was added in one part. The mixture was stirred at room temperature for 4 hours and then filtered through celite. The filtrate was concentrated and then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give methyl 2-(2-amino-4-bromo-6-fluorophenyl) acetate (12.6 g, 94%) as a white solid. MS m/z 262.0, 264.0 [M+H]+.

Step E Methyl 2-(2-amino-4-bromo-6-fluorophenyl)acetate (12.6 g, 48 mmol) was suspended in CH ₂ Cl ₂ (150 ml) at 0°C. Nitrosonium tetrafluoroborate (8.4 g, 72 mmol) was added to the mixture in one portion. The mixture was stirred at 0°C for 1 hour. The mixture was added directly to a vigorously stirred mixture of SnCl ₂ dihydrate (43.8 g, 194 mmol) in conc. HCl (200 ml) at 0°C. The mixture was allowed to slowly warm to room temperature while stirring. After 24 hours the mixture was filtered. The solid was washed with H2O and ether, and then dried to give 1-amino-6-bromo-4-fluoro-indolin-2-one (9.0 g, 76%) as a white solid. MS m/z 244.9, 246.9 [M+H] ⁺ .

Step F: 1-Amino-6-bromo-4-fluoro-indolin-2-one (9.0 g, 37 mmol) was suspended in CH ₂ Cl ₂ (500 ml) at 0°C. Pb(OAc) ₄ (22.8 g, 51.4 mmol) was added to the mixture in one portion. The mixture was stirred at room temperature for 16 hours. MeOH (50 ml) was added to the mixture, and the mixture was eluted through a pad of silica gel. The filtrate was concentrated and chromatographed on silica gel, eluted with 0-100% EtOAc in CH ₂ Cl ₂ to give 7-bromo-5-fluoro-cinnolin-3-ol (3.5 g, 39%) as a yellow powder. MS m/z 241.1, 243.1 [M-H] ^- .

Step G: 7-Bromo-5-fluoro-cinnolin-3-ol (3.5 g, 14 mmol) was suspended in POCl ₃ (28 ml, 300 mmol). The mixture was stirred at 100°C for 4 hours in a hermetically sealed tube. The mixture was cooled to room temperature and quenched on ice. Ice water was extracted with CH ₂ Cl ₂ (2 times). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% EtOAc in CH ₂ Cl ₂ to give 7bromo-3-chloro-5-fluorocinnoline (2.6 g, 69%) as an off-white powder. MS m/z 261.1, 263.1, 265.1 [M+H] ⁺ .

Step H: 7-Bromo-3-chloro-5-fluoro-cinnoline (785 mg, 3.00 mmol) was combined with (2,8dimethylimidazo[1,2-b]pyridazin-6-yl)boric acid (3.6 mmol, obtained according to the procedure from example 11), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2yl) palladium(P) (108 mg, 0.15 mmol), 1,4-dioxane and an aqueous solution of 1 M K2CO3 (10 ml, 10 mmol). The mixture was stirred at 50°C for 2 hours. The mixture was partitioned between EtOAc and H2O, then filtered through celite. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 40-100% EtOAc in hexanes followed by 5% MeOH in EtOAc to give 3-chloro-7(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)- 5-fluoro-cinnoline (605 mg, 62%) in the form of a brownish solid. MS m/z 328.2, 330.2 [M+H] ⁺ .

Step I: 3-Chloro-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnoline (400 mg, 1.2 mmol) was combined with complex 1,1' -bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (50 mg, 0.06 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-borinic acid pinacol ester (462 mg, 1. 47 mmol), 1,4-dioxane (6 ml) and an aqueous solution of 1 M K2CO3 (3 ml, 3.0 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 40-100% EtOAc in hexanes followed by 5% MeOH in EtOAc to give tert-butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin6-yl)- 5-fluoro-cinnolin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (430 mg, 74%) as a brownish solid. MS m/z 475.5 [M+H] ⁺ .

Step J. tert-Butyl 4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnolin-3-yl]-3,6dihydro-2H-pyridin- 1-Carboxylate (430 mg, 0.91 mmol) was combined with 10% Pd/C (500 mg) in MeOH:EtOAc (1:1) (25 ml). The mixture was stirred under H ₂ (1 atm) for 3 hours at 40°C. The mixture was filtered through a syringe filter and the filtrate was concentrated. The residue was dissolved in CH ₂ Cl ₂ (2 ml). MnO ₂ (20 eq.) was added to the solution. The mixture was stirred at room temperature for 30 minutes, and then filtered through celite. The filtrate was concentrated. The residue was chromatographed on silica gel, eluted with 40-100% EtOAc in hexane to give tert-butyl 4-[7-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnoline-3 -yl]piperidine-1-carboxylate (200 mg, 46%) as an off-white solid. MS m/z 477.5 [M+H] ⁺ .

- 67 043655

Step K: tert-Butyl 4-[7-(2,8-gimethylimigazo[1,2-b]pyrigazin-6-yl)-5-fluoro-cinnolin-3yl]piperidine-1-carboxylate (200 mg, 0. 42 mmol) was combined with 4n. HCl in 1,4-dioxane (1 ml, 4 mmol). The mixture was stirred at room temperature for 1 hour. Volatiles were removed with a stream of N2. The residue was suspended in CH ₃ CN, sonicated and filtered. The solids were dried to give 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4-piperidyl)cinnoline hydrochloride (190 mg, quant.) in the form of almost white solid.

MS m/z 377.3 [M+H]+; ^1H NMR (DMSO^) δ: 9.13 (s, 1H), 8.84 (br, 1H), 8.58 (br, 1H), 8.32-8.41 (m, 3H), 8 .20 (s, 1H), 3.55-3.62 (m, 1H), 3.47-3.53 (m, 2H), 3.11-3.20 (m, 2H), 2.71 (s, 3H), 2.52 (s, 3H), 2.16-2.30 (m, 4H).

Using the procedure described above for Example 7, additional compounds described herein were prepared by substituting suitable boric acid or boric acid equivalent in Step H or I, suitable reagents and reaction conditions to produce compounds such as those selected from:

Conn. Data 73 MS m/z 376.4 [M+H] ⁺ ; Ή NMR (DMSO-b/ ₆ ) δ: 9.02 - 9.10 (br, 1H), 8.75 - 8.84 (br, 1H), 8.64 (s, 1H), 8.48 ( s, 1H), 8.34 (dd, J= 11.4, 1.4 Hz, 1H), 8.16 - 8.19 (m, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 4.23 (s, 3H), 3.51 - 3.59 (m, 1H), 3.43 - 3.50 (m, 2H), 3.08 3.18 (m, 2H), 2.62 (s, 3H), 2.18 - 2.28 (m, 4H). 84 MS m/z 359.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.26 (s, 1H), 8.71 (dd, J= 8.5, 1.5 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.32 (d, J= 8.5 Hz, 1H), 3.61 - 3.69 (m, 3H), 2.45 - 2, 55 (m, 2H - overlap with residual solvent peak), 2.88 (s, 3H), 2.72 (s, 3H), 2.30 - 2.50 (m, 4H). The proton corresponding to NH was not observed. 87 MS m/z 405.3 [M+H] ⁺ ; Ή NMR (methanol- _g74 ) δ: 9.13 (s, 1H), 8.59 (s, 1H), 8.40-8.45 (m, 2H), 8.32 (s, 1H), 4.04 (m, 1H), 3.91 (t, J= 12.5 Hz, 1H), 3.79 (br s, 1H), 2.87 (s, 3H), 2.70 (s, 3H), 2.38 - 2.50 (m, 2H), 2.24 (d, J = 14 Hz, 1H), 2.06 (q, J = 14 Hz, 1H), 1.65 (d, J= Ί Hz, ZN), 1.45 (d, J= 6 Hz, ZN). Protons corresponding to NH and HC1 were not observed. 90 MS m/z 405.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.88 (s, 1H), 8.28 (d, J= 10 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 3.48 (tt, J= 10, 3 Hz, 1H), 2.98 - 3.04 (m, 2H), 2.71 (s, 3H), 2.51 (s, 3H), 2.13 (d, J= 15 Hz, 2H), 1.55 (q, J= 12 Hz, 2H), 1.26 (d, J= 7 Hz, 6H). The proton corresponding to NH was not observed. 129 MS m/z 391.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.96 (s, 1H), 8.36 (dd, J= 11 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 3.60 - 3.71 (m, 2H), 3.37 - 3.52 (m, 3H), 2.74 (s, 3H), 2.42 - 2, 55 (m, 5H), 2.30 - 2.40 (m, 1H), 2.05 - 2.30 (m, ZH), The proton corresponding to NH was not observed. 130 MS m/z 433.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.91 (s, 1H), 8.30 (dd, J= 11, 1.5 Hz, 1H), 8.18 (s, 1H), 8.00 (s , 1H), 7.88 (s, 1H), 3.62 - 3.71 (m, 1H), 3.16 - 3.20 (m, 1H), 2.95 - 3.02 (m, 1H ), 2.73 (s, 3H), 2.51 (s, 3H), 2.21 (d, J= 12.5 Hz, 1H), 2.07 2.16 (m, 2H), 1, 89 (pentet, J= 7.5 Hz, 2H), 1.46 - 1.60 (m, 3H), 1.00 - 1.08 (m, 6H). The proton corresponding to NH was not observed. 143 MS m/z 363.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.00 (s, 1H), 8.39 (d, J= 11 Hz, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 4.24 (septet, J= 7.5 Hz, 1H), 3.91 (d, J= 7.5 Hz, 2H), 3.68 - 3.75 (m , 1H), 3.54 - 3.61 (m, 1H), 2.70 - 2.78 (m, 4H), 2.53 (s, 3H), 2.45 - 2.52 (m, 1H ), The proton corresponding to NH was not observed. 169 MS m/z 403.5 [M+H] ⁺ ; Ή NMR (methanol- _g74 ) δ: 9.13 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.40 (m, 2H), 4.18 ( br s, 2H), 3.87 (m, 1H), 3.12 (d, J= 15 Hz, 2H), 2.85 (s, 3H), 2.60 - 2.70 (m, 5H) , 1.96 (m, 2H), 1.80 - 1.84 (m, 2H). 210 MS m/z 362.3 [M+H] ⁺ ; Ή NMR (methanol- _g74 ) δ: 9.76 (s, 1H), 8.88 (s, 1H), 8.83 8.86 (m, 1H), 8.30 (s, 1H), 8 .14 (s, 1H), 8.07 (d, J= 9.5 Hz, 1H), 7.72 (d, J= 9.5 Hz, 1H), 3.61 - 3.64 (m, 2H), 3.23 - 3.31 (m, 3H), 2.63 (s, 3H), 2.28 - 2.35 (m, 2H), 2.07 2.18 (m, 2H), No protons corresponding to NH and HCl were observed. 216 MS m/z bP,b [M+H] ⁺ ; Ή NMR (methanol-d) δ 9.15 (s, 1 Η), 8.55 (s, 1 Η), 8.44 (br d, J= 10.8 Hz, 1 Η), 8.41 ( s, 1 Η), 8.39 (s, 1 Η), 3.83 - 3.45 (m, 5 Η), 2.86 (s, 3 Η) 2.69 (s, 3 Η) 2, 33 - 2.42 (m, 1 Η) 2.02 - 2.19 (m, 3 H), Protons corresponding to NH and HCl were not observed.

Boric acid or boric acid equivalents for use in step H or I were prepared according to the following procedures.

Example 7-1.

rac-(2R,6R)-1-Benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate and rac(2S,6R)-1-benzyl-2,6-dimethyl- 1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate

Step A: 3-oxopentanedioic acid (20.5 g, 140 mmol) and acetaldehyde (15.7 ml, 279 mmol) were suspended in H ₂ O (50 ml). The mixture was stirred with a powerful stirrer at room temperature for 10 minutes. The mixture was then cooled in an ice bath. Benzylamine (15.3 mL, 140 mmol) was added dropwise. The mixture became thick. Stirring was continued at room temperature for 5 days. An aqueous solution of 6N was added. HCl. The mixture was stirred at room temperature for 1

- 68 043655

h. The mixture was then made alkaline with an aqueous solution of K2CO3 and washed three times with CH2C12. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by silica gel chromatography (10-20% EtOAc in hexanes) provided 6.6 g (17% overall yield) of a mixture of rac-(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-one and (2S ,6R)-1-benzyl-2,6-dimethylpiperidin-4-one. These two components easily transform into each other.

Step B. Approximately 2:3 ratio of rac-(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-one and (2S,6R)-1benzyl-2,6-dimethylpiperidin-4-one (4, 45 g, 18.4 mmol) were dissolved in THF (12.8 ml) at -78°C. NaHMDS (2 M in THF, 13.1 mL, 26.2 mmol) was added dropwise. The mixture was stirred at -78°C for 3 hours. N,N-Bis(trifluoromethylsulfonyl)aniline (9.25 g, 25.9 mmol) was added to the mixture in one portion. The mixture was slowly warmed to room temperature over 15 hours. THF was removed from the mixture under vacuum. The product mixture was diluted with CH2Cl2 and filtered through a pad of silica to remove solid impurities. The filtrate was concentrated under vacuum. The residue was dissolved in EtOAc. The solution was washed with dilute aqueous NaOH (approximately 800 ml), and then with saline. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50-100% CH ₂ Cl ₂ in hexane) to obtain the trans isomer rac(2R,6R)-1-benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridine-4 -yl trifluoromethanesulfonate (1.5 g, 23%) as the higher Rf component. 1H NMR (acetone- _d4 ) δ: 7.37-7.40 (m, 2H), 7.30-7.35 (m, 2H), 7.227.27 (m, 1H), 5.87 (s , 1H), 3.76 (d, J=14.5 Hz, 1H), 3.58 (d, J=14.5 Hz, 1H), 3.30-3.42 (m, 2H), 2 .41-2.50 (m, 1H), 2.24-2.30 (m, 1H), 1.20-1.25 (m, 6H). The cis-isomer rac-(2S,6R)-1-benzyl-2,6-dimethyl-1,2,3,6tetrahydropyridin-4-yl trifluoromethanesulfonate (2.1 g, 33%) was collected as the lower Rf component .

^1H NMR (acetone- _d4 ) δ: 7.37-7.40 (m, 2H), 7.30-7.35 (m, 2H), 7.20-7.25 (m, 1H), 5.85 (s, 1H), 3.87 (d, J=16 Hz, 1H), 3.82 (d, J=16 Hz, 1H), 3.50-3.57 (m, 1H), 3.16-3.22 (m, 1H), 2.49-2.57 (m, 1H), 2.24-2.30 (m, 1H), 1.22 (d, J=7 Hz, 3H), 1.17 (d, J=6.5 Hz, 3H).

Example 7-2.

(2R,6R)-1-Benzyl-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6tetrahydropyridine

Potassium acetate (1.8 g, 18 mmol) was dried under Ar at 180°C for 30 min, and then cooled to room temperature. To the solid was added rac-(2S,6R)-1-benzyl-2,6-dimethyl1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.5 g, 4.3 mmol) prepared according to Example 36 ), Pd(dppf)Cl ₂ (146 mg, 0.175 mmol), dppf (110 mg, 0.19 mmol), bis(pinacolato)diborone (1.2 g, 4.7 mmol) and 1,4-dioxane ( 14.5 ml). The mixture was heated at 80°C for 15 hours. The reaction mixture was then diluted in EtOAc and filtered through celite. The filtrate was concentrated under vacuum. The residue was dissolved in EtOAc and washed with 800 ml of dilute aqueous NaHCO ₃ solution and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in ether and filtered through celite to remove brown insoluble impurities. The filtrate was concentrated to give (2S,6R)-1-benzyl-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1,2,3 ,6-tetrahydropyridine (1.43 g, 80% pure, 81% yield) as a crude black oil.

1H NMR (acetone- _d4 ) δ: 7.40-7.45 (m, 2H), 7.25-7.32 (m, 2H), 7.16-7.21 (m, 1H), 6 .31 (s, 1H), 3.80 (m, 2H), 3.20-3.28 (m, 1H), 2.73-2.79 (m, 1H), 2.12-2.19 (m, 1H), 1.90-1.98 (m, 1H), 1.35 (s, 12H), 1.22 (d, J=5.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 3H).

Example 7-3 (2R,6R)-1-Benzyl-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2, 3,6tetrahydropyridine was prepared from rac-(2R,6R)-1-benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate according to Example 7-2.

1H NMR (acetone- _d4 ) δ: 7.40-7.45 (m, 2H), 7.25-7.32 (m, 2H), 7.16-7.21 (m, 1H), 6 .38 (s, 1H), 3.62 (m, 2H), 3.12-3.21 (br s, 1H), 3.00-3.08 (m, 1H), 2.12-2, 21 (m, 1H), 1.90-1.98 (m, 1H), 1.27 (s, 12H), 1.22 (m, 6H).

Example 7-4. (2R,6R)-1-Benzyl-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6tetrahydropyridine was prepared by substituting the appropriate acetaldehyde in step A of Example 7-1.

1H NMR (acetone- _d4 ) δ: 7.40-7.45 (m, 2H), 7.25-7.32 (m, 2H), 7.16-7.21 (m, 1H), 6 .38 (s, 1H), 3.62 (m, 2H), 3.12-3.21 (br s, 1H), 3.00-3.08 (m, 1H), 2.12-2, 21 (m, 1H), 1.90-1.98 (m, 1H), 1.27 (s, 12H), 1.22 (m, 6H).

Example 8.

Receiving connection 34

- 69 043655 o

Step A: 2-Amino-5-bromo-3-fluorobenzoic acid (1.0 g, 4.27 mmol) was dissolved in THF (20 ml). LAH (8.5 mL, 8.5 mmol, 1.0 M in THF) was added to the solution at 0°C. The mixture was warmed to room temperature. After 1 hour, the mixture was quenched with an aqueous solution of 2N. NaOH at 0°C. After vigorous stirring for 30 minutes, the mixture was filtered through celite. The filter cake was washed with THF and MeOH. The combined filtrate was concentrated to give (2-amino-5-bromo-3-fluorophenyl)methanol (900 mg, 96%). MS m/z 220.2, 222.2 [M+H]+.

Step B: (2-Amino-5-bromo-3-fluorophenyl)methanol (900 mg, 4.09 mmol) was combined with MnO ₂ (6.9 g, 79 mmol) in CH ₂ Cl ₂ (20 ml) . The mixture was stirred at room temperature for 1 hour. The mixture was filtered through celite. The filtrate was concentrated to give 2-amino-5-bromo-3-fluorobenzaldehyde (650 mg, 73%). MS m/z 218.1, 220.1 [M+H] ⁺ .

Step C: 2-Amino-5-bromo-3-fluorobenzaldehyde (650 mg, 3.0 mmol) was combined with urea (3.6 g, 60 mmol) and DMSO (3 ml). The mixture was stirred at 180°C for 2 hours. The mixture was cooled to room temperature, after which H ₂ O (10 ml) was added. The precipitate was collected, washed with H ₂ O and dried to obtain 6-bromo-8-fluoro-quinazolin-2-ol (615 mg, 85%). MS m/z 243.1, 245.1 [M+H] ⁺ .

Step D: 6-Bromo-8-fluoroquinazolin-2-ol (615 mg, 2.53 mmol) was combined with POCl ₃ (5 ml, 53 mmol). The mixture was stirred at 110°C for 2 hours. The mixture was cooled to room temperature and poured onto ice. After vigorous stirring for 15 minutes, the solids were collected, dried and chromatographed on silica gel, eluting with 0-20% EtOAc in CH ₂ Cl ₂ to give 6bromo-2-chloro-8-fluoroquinazoline (345 mg, 52%). MS m/z 261.1, 263.1, 265.1 [M+H] ⁺ .

Steps E-G: The following procedures are the same as those in Example 5 (Steps A-C), 6-bromo-2-chloro-8-fluoroquinazoline was converted to 6-(2,7-dimethyl-2H-indazol-5-yl)-8 -fluoro-2-(piperidin-4yl)quinazoline hydrochloride.

MS m/z 376.3 [M+H] ⁺ ; ^1H NMR (DMSO^) δ: 9.70 (s, 1H), 8.86-8.93 (br, 1H), 8.54-8.63 (br, 1H), 8.46 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.32 (dd, J=12.10, 1.9 Hz, 1H), 8.07 (s, 1H), 7, 57 (s, 1H), 4.22 (s, 3H), 3.36-3.44 (m, 3H), 3.08-3.16 (m, 2H), 2.61 (s, 3H) , 2.22-2.28 (m, 2H), 2.08-2.15 (m, 2H).

Using the procedure described above for Example 8, additional compounds described herein were prepared by substituting the appropriate boric acid in Step E, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 35 MS m/z 387.3 [M+H] ⁺ ; Ή NMR (DMSO-b/ ₆ ) δ: 9.69 (d, J= 1.6 Hz, IH), 8.79 - 8.85 (br, IH), 8.78 (s, IH), 8 .67 (d, J= 1.9 Hz, IH), 8.49 - 8.55 (br, IH), 8.48 (d, J = 1.7 Hz, IH), 8.47 (d, J = 1.8 Hz, IH), 8.43 (dd, J = 12.2, 1.8 Hz, IH), 4.30 (s, 3H), 3.37 3.46 (m, 3H) , 3.07 - 3.17 (m, 2H), 2.22 - 2.28 (m, 2H), 2.07 - 2.16 (m, 2H). 36 MS m/z 380.3 [M+H] ⁺ ; Ή NMR (DMSO-cC) δ: 9.69 (s, IH), 8.73 - 8.79 (br, IH), 8.63 (d, J= 1.9 Hz, IH), 8.43 - 8.52 (br, IH), 8.40 (d, J= 1.8 Hz, IH), 8.37 (dd, J= 12.3, 1.8 Hz, IH), 8.13 ( d, J= 1.8 Hz, IH), 7.65 (dd, J= 12.2, 1.9 Hz, IH), 4.25 (s, 3H), 3.37 - 3.46 (m , 3H), 3.08 - 3.18 (m, 2H), 2.22 - 2.28 (m, 2H), 2.05 - 2.14 (m, 2H). 37 MS m/z 377.3 [M+H] ⁺ ; Ή NMR (DMSOh/b) δ: 9.83 (s, IH), 8.85 - 8.91 (br, IH), 8.83 (d, J= 1.9 Hz, IH), 8.59 - 8.64 (br, IH), 8.56 (dd, J= 12.3, 1.8 Hz, IH), 8.42 (s, IH), 8.31 (s, IH), 3, 58 (s, 3H), 3.39 - 3.47 (m, 3H), 3.08 - 3.18 (m, 2H), 2.74 (s, 3H), 2.23 2.30 (m , 2H), 2.07 - 2.15 (m, 2H).

- 70 043655

Using the procedure described above for Example 8, additional compounds described herein were prepared by substituting the indicated starting material, suitable reagents and reaction conditions to obtain compounds such as those selected from:

Conn. Source material and data 38 Starting material: 6-amino-3-bromo-2-fluorobenzoic acid MS m/z 376.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.70 (s, 1H), 7.94 (s, 1H), 7.81 7.86 (m, 1H), 7.58 - 7.61 (m, 1H ), 7.47 (d, J = 8.5 Hz, 1H), 6.37 (s, 1H), 4.40 (s, 3H), 3.63 - 3.70 (m, 3H), 3 .21 - 3.29 (m, 2H), 2.69 (s, 3H), 2.29 - 2.40 (m, 4H) The proton corresponding to NH was not observed. 39 Starting material: 2-amino-5-bromo-4-fluorobenzoic acid MS m/z 376.3 [M+H]+; Ή NMR (DMSO-Jr,) δ: 8.77 (s, 1H), 7.98 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.63 - 7, 68 (m, 1H), 7.43 (d, J = 10.4 Hz, 1H), 6.27 (s, 1H), 4.42 (s, 3H), 3.63 - 3.70 (m , 3H), 3.24 - 3.31 (m, 2H), 2.69 (s, 3H), 2.28 - 2.45 (m, 4H), No proton corresponding to NH was observed.

Example 9.

Receiving connection 17

Step A: 4-Bromo-2-nitroaniline (3.7 g, 17 mmol), cyanamide (5.72 g, 135 mmol) and Et ₂ O (3 ml) were combined in a 75 ml test tube. The mixture was stirred at 100°C for 30 minutes. The mixture was cooled to 50°C. Concentrated aqueous HCl solution (7.2 ml) was slowly added to the mixture. The resulting mixture was stirred for 1 hour at 110°C. The reaction mixture was again cooled to 50°C before adding an aqueous solution of 7.5 M NaOH (16 ml). The mixture was again heated to 110°C for 1 hour. After cooling to room temperature, 20 ml of H ₂ O was added to the mixture. The solid material was collected, washed with H ₂ O and dried to obtain 7-bromo-1-oxido-1, 2,4-benzotriazine-1-ium-3-amine (3.2 g, 79%). MS m/z 240.8, 242.8 [M+H]+.

Step B: NaNO ₂ (2.76 g, 40.0 mmol) in small parts at room temperature. The mixture was stirred at room temperature for 30 minutes. H ₂ O (75 ml) was added to the mixture to obtain a white precipitate. The solids were collected, washed with H ₂ O and dried. The solids were combined with POCl ₃ (30 ml, 318.6 mmol). The mixture was stirred at 110°C for 2 hours. After cooling to room temperature, the mixture was poured onto ice with vigorous stirring. After stirring for 10 minutes, CH ₂ Cl ₂ (400 ml) was added. The organic phase was collected and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% EtOAc in CH ₂ Cl ₂ to give 7-bromo-3-chloro-1-oxido-1,2,4-benzotriazine-1-ium (2.37 g, 54 %). MS m/z 259.9, 261.9, 264.0 [M+H] ⁺ .

Step C: 7-Bromo-3-chloro-1-oxido-1,2,4-benzotriazine-1-ium (520 mg, 2.0 mmol) was combined with N-Boc-1,2,5 pinacol ester. 6-tetrahydropyridine-4-boric acid (773 mg, 2.45 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane dichloride complex (80 mg, 0.10 mmol), 1,4- dioxane (10 ml), and an aqueous solution of 1 M K ₂ CO ₃ (5 ml, 5.0 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with saline

- 71 043655 solution, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexane to give tert-butyl 4-(3-chloro-1oxido-1,2,4-benzotriazin-1-ium-7-yl)-3,6- Dihydro-2H-pyridine-1-carboxylate (540 mg, 75%). MS m/z 307.1, 309.1 [M+H-tBu] ⁺ (the molecule ionizes as M+H minus tBu).

Step D. tert-Butyl 4-(3-chloro-1-oxido-1,2,4-benzotriazin-1-ium-7-yl)-3,6-dihydro-2H-pyridine-1carboxylate (72 mg, 0 .20 mmol) was combined with 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indazole (80 mg, 0.30 mmol), complex 1,1 '-bis(diphenylphosphino)ferrocene palladium(P)dichloromethane dichloride (8 mg, 0.01 mmol), 1,4-dioxane (1 ml), and aqueous solution of 1 M K ₂ CO ₃ (0.5 ml, 0.5 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 5% MeOH in EtOAc to give tert-butyl 4-[3-(2,7-dimethylindazol-5-yl)-1-oxido-1,2,4-benzotriazine-1-ium -7-yl]-3,6dihydro-2H-pyridin-1-carboxylate (72 mg, 77%). MS m/z 473.4 [M+H] ⁺ .

Step E. tert-Butyl 4-[3-(2,7-dimethylindazol-5-yl)-1-oxido-1,2,4-benzotriazin-1-ium-7-yl]-3,6dihydro-2H- Pyridine-1-carboxylate (60 mg, 0.13 mmol) was combined with 10% Pd/C (10 mg) and MeOH (3 ml). The mixture was stirred under H2 atmosphere (1 atm) for 2 hours at 30°C. The mixture was filtered through a 0.2 μm syringe filter to obtain tert-butyl 4-[3-(2,7-dimethylindazol-5-yl)-1,2,4-benzotriazin-7yl]piperidine-1-carboxylate (58 mg, 99%). MS m/z 459.4 [M+H] ⁺ .

Step F. tert-Butyl 4-[3-(2,7-dimethylindazol-5-yl)-1,2,4-benzotriazin-7-yl]piperidine-1carboxylate (58 mg, 0.13 mmol) was dissolved in TFA ( 1 ml). After 20 minutes, volatile substances were removed from the mixture. The residue was partitioned between EtOAc and an aqueous solution of 1 M K2CO3. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 3-(2,7dimethyl-2H-undazol-5-yl)-7-(piperidin-4-yl) benzo[e][1,2,4]triazine (20 mg, 44%).

MS m/z 359.3 [M+H] ⁺ ; ^1H NMR (DMSO-Y6) δ: 9.01 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.068.12 ( m, 2H), 4.24 (s, 3H), 3.11-3.19 (m, 2H), 2.94-3.01 (m, 1H), 2.68-2.76 (m, 2H), 2.64 (s, 3H), 1.88-1.94 (m, 2H), 1.66-1.76 (m, 2H), No proton corresponding to NH was observed.

Using the procedure described above for Example 9, additional compounds described herein were prepared by substituting suitable boric acid in steps B and/or C, suitable reagents and reaction conditions to produce compounds such as those selected from:

Conn. Data 25 MS m/z 363.3 [Μ+Η] ⁺ ; Ή NMR (DMSO%>) δ: 9.03 (s, 1H), 8.76 (d, J= 2.7 Hz, 1H), 8.31 (s, 1H), 8.16 (dd, J = 13.0, 1.2 Hz, 1H), 8.10 - 8.14 (m, 2H), 4.24 (s, 3H), 3.14 3.20 (m, 2H), 2.97 - 3.05 (m, 1H), 2.71 - 2.79 (m, 2H), 1.90 - 1.97 (m, 2H), 1.69 1.79 (m, 2H), Proton, corresponding NH was not observed. 26 MS m/z 370.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.48 (d, J = 1.6 Hz, 1H), 9.05 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.09 - 8.17 (m, 2H), 4.36 (s, 3H), 3.35 - 3.42 (m, 2H), 3.11 - 3, 20 (m, 1H), 2.97 - 3.05 (m, 2H), 2.11 - 2.19 (m, 2H), 1.89 - 1.99 (m, 2H), Proton corresponding to NH , was not observed. 27 MS m/z 359.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.52 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.01 - 8.07 (m, 2H), 7 .73 (s, 1H), 3.27 - 3.32 (m, 2H), 3.03 - 3.10 (m, 1H), 2.88 2.94 (m, 2H), 2.63 ( s, 3H), 2.45 (s, 3H), 2.04 - 2.09 (m, 2H), 1.81 - 1.91 (m, 2H), No proton corresponding to NH was observed. 43 MS m/z 363.3 [M+H] ⁺ ; Ή NMR (DMSO%>) δ: 9.78 (s, 1H), 8.36 (s, 1H), 8.10 - 8.17 (m, 3H), 8.04 (dd, J= 12, 2, 1.3 Hz, 1H), 3.09 - 3.15 (m, 2H), 2.94 - 3.01 (m, 1H), 2.66 - 2.72 (m, 2H), 2 .42 (s, 3H), 1.87 - 1.93 (m, 2H), 1.64 - 1.74 (m, 2H), The proton corresponding to NH was not observed. 52 MS m/z 375.4 [M+H] ⁺ ; Ή NMR (DMSO%>) δ: 8.78 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.07 - 8.12 (m, 2H), 7 .82 (s, 1H), 4.21 (s, 3H), 4.07 (s, 3H), 3.10 - 3.17 (m, 2H), 2.93 - 2.99 (m, 1H ), 2.66 - 2.73 (m, 2H), 1.87 - 1.93 (m, 2H), 1.65 - 1.75 (m, 2H), The proton corresponding to NH was not observed. 56 MS m/z 389.2 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 10.01 (s, 1H), 8.88 - 8.92 (m, 1H), 8.75 (s, 1H), 8.36 (dd, J= 9, 0, 2.2 Hz, 1H), 8.30 - 8.33 (m, 1H), 8.24 - 8.27 (m, 1H), 4.18 - 4.28 (m, 2H), 3 .61 - 3.69 (m, 1H), 2.58 - 2.74 (m, 5H), 2.20 - 2.33 (m, 4H), 2.08 - 2.13 (m, 2H) ,The proton corresponding to NH was not observed.

- 72 043655

Example 10.

Obtaining connection 28 o

_NH4OAc

Bu ₃ SnCI

AcOH, 120 °C

Pd(dppf)CI ₂ K ₂ CO ₃

1,4-dioxane:H ₂ O 80 °C, 2 h

MeOH:EtOAc, rt

Step A: 1-(1H-Pyrrol-2-yl)ethanone (1.09 g, 10.0 mmol) was dissolved in 50 ml CH ₂ Cl ₂ and cooled to 78°C. A solution of Br ₂ (620 µl, 12.1 mmol) in 12 ml CH ₂ Cl ₂ was added dropwise to the solution. The reaction mixture was poured onto ice. The organic layer was washed with aqueous 1 M NaOH, dried over MgSO ₄ , filtered and concentrated to give 1-(4-bromo-1H-pyrrol-2-yl)ethanone (1.42 g, 76%).

^1H NMR (acetone^) δ: 11.08 (br s, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 2.34 (s, 3H).

Step B: 1-(4-Bromo-1H-pyrrol-2-yl)ethanone (1.36 g, 7.2 mmol) was dissolved in DMF (15 ml) and cooled to 0°C. NaH (60 wt% in mineral oil) (316 mg, 7.9 mmol) was added to the solution. The mixture was warmed to room temperature for 30 minutes. Chloroacetone (0.6 ml, 7 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between H ₂ O and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 30% EtOAc in hexane to give 1-(2-acetyl-4-bromopyrrol-1-yl)propan-2-one (1.2 g, 68%) as a white solid.

1H NMR (acetone^) δ: 7.13 (d, J=2 Hz, 1H), 7.10 (d, J=2 Hz, 1H), 5.17 (s, 2H), 2.36 (s , 3H), 2.18 (s, 3H).

Step C: 1-(2-Acetyl-4-bromo-pyrrol-1-yl)propan-2-one (1.15 g, 4.7 mmol), acetic acid (40 ml) and ammonium acetate (7.2 g, 93 mmol) was heated at 120°C for 16 hours. Volatiles were removed under reduced pressure. The residue was partitioned between an aqueous solution of 1 M NaOH and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-50% EtOAc in CH ₂ Cl ₂ to give 7-bromo-1,3-dimethyl-pyrrolo[1,2a]pyrazine (975 mg, 92%).

1H NMR (acetone^) δ: 7.86 (s, 1H), 7.63 (s, 1H), 6.84 (s, 1H), 2.56 (s, 3H), 2.31 (s, 3H).

Step D: 7-Bromo-1,3-dimethylpyrrolo[1,2-a]pyrazine (2.0 g, 8.9 mmol) was dissolved in THF (90 ml). The solution was cooled to -78°C, after which n-butyllithium (6.7 ml, 13.3 mmol, 2 M solution in cyclohexane) was added. The mixture was stirred at -78°C for 30 minutes. Tributylchlorostannane was added to the mixture. The mixture was left to warm slowly to 0°C. The excess reagent was quenched with a saturated aqueous solution of NH ₄ Cl. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tributyl-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)stannane (1.3 g, 30%).

1H NMR (chloroform-d) δ: 7.53 (s, 1H), 7.20 (s, 1H), 6.72 (s, 1H), 2.65 (s, 3H), 2.37 (s , 3H), 1.52-1.58 (m, 6H), 1.30-1.38 (m, 6H), 1.04-1.08 (m, 6H), 0.88-0.94 (m, 9H).

Step E. tert-Butyl 4-(3-chloro-1-oxido-1,2,4-benzotriazin-4-ium-7-yl)-3,6-dihydro-2H-pyridine-1carboxylate (72 mg, 0 .20 mmol prepared according to the procedure of Example 9, Step C) was combined with tributyl-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)stannane (140 mg, 0.32 mmol), complex 1 ,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloride dichloromethane (12 mg, 0.015 mmol), 1,4dioxane (1.5 ml) and an aqueous solution of 1 M K ₂ CO ₃ (0.75 ml, 0.75 mmol). The mixture was stirred at 80°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 50-100% EtOAc in CH ₂ Cl ₂ then EtOAc containing 5% MeOH to give

- 73 043655 tert-butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-1-oxido-1,2,4-benzotriazin-1-ium-7-yl ]-3,6dihydro-2H-pyridine-1-carboxylate (50 mg, 53%). MS m/z 473.5 [M+H]+.

Step F. tert-Butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-1-oxido-1,2,4-benzotriazin-1ium-7-yl]- 3,6-Dihydro-2H-pyridine-1-carboxylate (30 mg, 0.06 mmol) was combined with 10% Pd/C (10 mg) in EtOAc:MeOH (1:1.2 ml). The mixture was stirred under H ₂ (1 atm) for 2 hours at 40°C. The mixture was filtered through a 2 μm syringe filter. The filtrate was concentrated to give tert-butyl 4-(3(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)benzo[e][1,2,4]triazin-7-yl)-3, 6-dihydropyridine-1(2H)carboxylate (25 mg, 86%). MS m/z 457.5 [M+H] ⁺ .

Step G. tert-Butyl 4-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-1,2,4-benzotriazin-7yl]piperidine-1-carboxylate (25 mg, 0.05 mmol) was dissolved in TFA (1 ml). After 15 min, volatiles were removed. The residue was partitioned between CH ₂ Cl ₂ and an aqueous solution of 1 M K ₂ CO ₃ . The organic layer was loaded onto silica gel, eluted with 0-10% MeOH (2N NH ₃ ) in CH ₂ Cl ₂ to give 3-(1,3dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1 ,2,3,6-tetrahydropyridin-4-yl)benzo[e][1,2,4]triazine (8 mg, 43%).

^1H NMR (DMSO-d6) δ: 8.34 (s, 1H), 8.25 (s, 1H), 8.23 (dd, J=9.0, 2.0 Hz, 1H), 7, 90 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 6.62 (s, 1H), 3.58-3.62 (m , 2H), 3.15-3.19 (m, 2H), 2.64-2.70 (m, 5H), 2.35 (s, 3H), The proton corresponding to NH was not observed.

Example 11.

Obtaining connection 44 o

? ^r ZnMe ₂ I ^yNH ₂ Pd(PPh ₃ ) ₄ * ^yNH ₂ NEt ₃ *

ClA^ ^N DMF, 50°CLN EtOH, 150°C h Cl N _{45 m} . _n

IB ₂ pin ₂ , KOAc I ___ Pd(dppf)CI ₂ ___ ri 1,4-dioxane , _μΓη ^C| N ₉₀ o _{C 2 h} (HO) ₂ BN

Step A: 4-Bromo-6-chloro-pyridazin-3-amine (5.2 g, 25 mmol) was combined with tetrakis(triphenylphosphine)palladium(0) (700 mg, 0.61 mmol) and DMF (50 ml) . Dimethylzinc in heptane (50 mL, 50 mmol, 1.0 M) was added to the mixture at room temperature. The mixture was heated at 50°C for 2 hours, then 70°C for 1 hour. The mixture was cooled to 0°C and the excess reagent was quenched by adding H ₂ O. The mixture was filtered through celite and concentrated. The residue was chromatographed on silica gel and eluted with 0-10% MeOH in CH2Cl2. MS m/z 144.2, 146.2 [M+H] ⁺ .

Step B: 6-Chloro-4-methyl-pyridazin-3-amine (3.5 g, 24 mmol) was combined with ethanol (40 ml), triethylamine (8.7 ml, 62 mmol) and chloroacetone (4 ml, 49 mmol) in 100 ml in a high pressure flask. The flask was sealed and heated behind an explosion-proof shield at 150°C for 45 min. The mixture was concentrated and chromatographed on silica gel, eluting with 30-80% EtOAc in CH ₂ Cl ₂ to give 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine (2.2 g, 49%). MS m/z 182.3, 184.3 [M+H] ⁺ .

Step C: 6-Chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (54 mg, 0.30 mmol) was combined with potassium acetate (87 mg, 0.89 mmol), complex 1,1' -bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (12 mg, 0.015 mmol) and bis(pinacolato)diborone (94 mg, 0.37 mmol) in 1,4-dioxane (1 ml). The mixture was stirred under N2 atmosphere at 95°C for 2 hours to obtain (2,8-dimethylimidazo[1,2b]pyridazin-6-yl)borinic acid. MS m/z 192.4 [M+H] ⁺ . The crude mixture was used directly in the next step.

Step D. To the crude mixture from Step C was added an aqueous solution of 1 M K ₂ CO ₃ (0.75 ml, 0.75 mmol), tert-butyl 4-(3-chloro-1-oxido-1,2,4- benzotriazin-1-ium-7-yl)-3,6-dihydro-2H-pyridine-1carboxylate (72 mg, 0.20 mmol, prepared according to the procedure of Example 9, Step C), and complex 1,1'bis( diphenylphosphino)ferrocene-palladium(11)dichloromethane dichloride (8 mg, 0.01 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-80% EtOAc in CH2Cl2 to give tert-butyl 4-[3(2,8-dimethylimidazo[1,2-b]pyridαzin-6-yl)-1-oxido-1, 2,4-benzotriazin-1-ium-7-yl]-3,6-dihydro-2Hpyridine-1-carboxylate (69 mg, 73%). MS m/z 474.4 [M+H]+.

Stage E. tert-Butyl 4-[3-(2,8-dimethylumidazo[1,2-b]pyridazin-6-yl)-1-oxido-1,2,4-benzotriazin-1ium-7-yl]- 3,6-Dihydro-2H-pyridine-1-carboxylate (69 mg, 0.15 mmol) was combined with 10% Pd/C (20 mg) in MeOH (2 ml). The mixture was stirred under H2 atmosphere (1 atm) for 2 hours at 40°C. The mixture was filtered. The filtrate was concentrated and chromatographed on silica gel, eluting with 20-100% EtOAc in hexane to give tert-butyl 4-[3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1-oxido1, 2,4-benzotriazin-1-ium-7-yl]-3,6-dihydro-2H-pyrudin-1-carboxylate (69 mg, 97%). MS m/z 460.4 [M+H] ⁺ .

Stage F. tert-Butyl 4-[3-(2,8-dimethylumidazo[1,2-b]pyridazin-6-yl)-1-oxido-1,2,4-benzotriazin-1ium-7-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (69 mg, 0.15 mmol) was suspended in 4N. HCl in 1,4dioxane (1 ml, 4 mmol). Volatiles were removed after 30 min. The residue was divided between CH ₂ Cl ₂ and an aqueous solution of 1 M K2CO3. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 3-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(piperidin- 4-yl)benzo[e][1,2,4]triazine.

MS m/z 360.4 [M+H]+; 1H NMR (DMSO^) δ: 8.47 (s, 1H), 8.32 (s, 1H), 8.18-8.25 (m, 2H), 8.10 (s, 1H), 3, 35-3.40 (m, 2H), 3.15-3.22 (m, 1H), 2.96-3.04 (m, 2H), 2.78 (s, 3H), 2.56 ( s, 3H), 2.12-2.18 (m, 2H), 1.891.99 (m, 2H), The proton corresponding to NH was not observed.

Example 12.

Receiving connection 16

I

About Pd(dppf)CI ₂

K ₂ CO ₃

SK N

H ₂ , Pd/C

Pd(dppf)CI ₂ K ₂ CO ₃

MeOH: EtOAc 40 °C, 2 h rt, 20 min

Step A: 7-Bromo-3-chloro-1-oxido-1,2,4-benzotriazine-1-ium (260 mg, 1.0 mmol, prepared in Example 9 Step B) was combined with 2,7-dimethyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (360 mg, 1.06 mmol), 1,G-bis(diphenylphosphino)ferrocene complex palladium(P)dichloride dichloromethane (45 mg, 0.05 mmol), 1,4-dioxane (5 ml) and an aqueous solution of 1 M K2CO3 (2.5 ml). The mixture was stirred at 70°C for 1 hour. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-90% EtOAc in hexane to give 3-chloro-7-(2,7dimethyl-2H-undazol-5-yl)benzo[e][1,2,4]triazin-1 -oxide (200 mg, 54%). MS m/z 326.0, 328.0 [M+H]+.

Step B: 3-Chloro-7-(2,7-dimethyl-2H-indazol-5-yl)benzo[e][1,2,4]triazine-1-oxide (200 mg, 0.54 mmol) was combined with N-Boc-1,2,5,6-tetrahydroniridine-4-borinic acid pinacol ester (250 mg, 0.80 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane dichloride complex (40 mg, 0.05 mmol), 1,4-dioxane (3 ml) and an aqueous solution of 1 M K2CO3 (1.5 ml, 1.5 mmol). The mixture was stirred at 80°C for 2 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexane to give tert-butyl 4-[7-(2,7-dimethylindazol-5-yl)-1-oxido-1,2,4-benzotriazine-1-ium -3-yl]-3,6-dihydro-2Hpyridin-1-carboxylate (200 mg, 78%). MS m/z 473.1 [M+H] ⁺ .

- 75 043655

Step C. tert-Butyl 4-[7-(2,7-dimethylindazol-5-yl)-1-oxido-1,2,4-benzotriazin-1-ium-3-yl]-3,6dihydro-2H- Pyridine-1-carboxylate (200 mg, 0.085 mmol) was combined with 10% Pd/C (40 mg) in MeOH (5 ml). The mixture was stirred under H2 atmosphere (1 atm) for 2 hours at 40°C. The mixture was filtered through a 2 μm syringe filter. The filtrate was concentrated and chromatographed on silica gel, eluted with 10-100% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-[7-(2,7-dimethylindazol-5-yl)-1,2,4benzotriazin-3-yl ]piperidine-1-carboxylate (100 mg, 50%). MS m/z 459.1 [M+H]+.

Step D: tert-Butyl 4-[7-(2,7-dimethylindazol-5-yl)-1,2,4-benzotriazin-3-yl]piperidine-1carboxylate (50 mg, 0.11 mmol) was dissolved in TFA (1 ml). After 20 min, volatile substances were removed from the reaction mixture. The residue was divided between CH ₂ Cl ₂ and an aqueous solution of 1 M K2CO3. The organic layer was loaded directly onto silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 7-(2,7-dimethyl-2H-indazol-5-yl)-3-(piperidin-4 -yl)benzo[e][1,2,4]triazine (30 mg,

77%).

MS m/z 359.1 [M+H]+; ¹ H NMR (DMSO-d ₆ ) δ: 8.77 (d, J=2.5 Hz, 1H), 8.56 (dd, J=9.0, 1.9 Hz, 1H), 8.47 (s, 1H), 8.12-8.18 (m, 2H), 7.66 (s, 1H), 4.23 (s, 3H), 3.40-3.47 (m, 1H), 3.08-3.15 (m, 2H), 2.69-2.76 (m, 2H), 2.63 (s, 3H), 2.00-2.07 (m, 2H), 1, 83-1.92 (m, 2H), No proton corresponding to NH was observed.

Example 13.

Receiving connection 46

Step A: 5-Bromo-1,3-difluoro-2-nitro-benzene (9.52 g, 40.0 mmol) was dissolved in EtOH (50 ml). Hydrazine monohydrate (16.6 mL, 160 mmol) was added to the solution. The solution was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in hexane to give (5-bromo-3-fluoro-2-nitrophenyl)hydrazine (8.5 g, 85%). MS m/z 250.2, 252.2 [M+H]+.

Step B: (5-Bromo-3-fluoro-2-nitrophenyl)hydrazine (1.25 g, 5.0 mmol) and tert-butyl 4formylpiperidine-1-carboxylate (3.2 g, 15 mmol) were combined in EtOH ( 25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in CH2Cl2 to give tert-butyl (E)-4-((2-(5-bromo-3-fluoro-2-nitrophenyl)hydrazono)methyl)piperidine-1 -carboxylate (2.2 g, 99%) MS m/z 443.1, 445.4 [M-H] ^- .

Step C. tert-Butyl (E)-4-((2-(5-bromo-3-fluoro-2-nitrophenyl)hydrazono)methyl)piperidine-1carboxylate (2.2 g, 4.9 mmol) was suspended in EtOH (50 ml) with PtO ₂ (100 mg, 0.4402 mmol). The mixture was stirred under H ₂ (1 atm, balloon) at room temperature for 3 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain tert-butyl (E)-4-((2-(2-amino-5-bromo-3-fluorophenyl)hydrazono)methyl)piperidine-1-carboxylate (2.03 g, 98%). MS m/z 413.3, 415.3 [M-H] ^- .

Step D. tert-Butyl 4-(7-bromo-5-fluoro-1,2,3,4-tetrahydro-1,2,4-benzotriazin-3-yl)piperidine-1carboxylate (2.03 g, 4. 9 mmol) was dissolved in CH ₃ CN (40 ml, 765 mmol). 2,3-Dichloro5,6-dicyano-1,4-benzoquinone (3.41 g, 15.0 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was suspended in CH2Cl2 and filt

- 76 043655 trolled. The filtrate was concentrated and chromatographed on silica gel, eluting with 030% EtOAc in hexanes to give tert-butyl 4-(7-bromo-5-fluorobenzo[e][1,2,4]triazin-3-yl)piperidine 1-carboxylate (805 mg, 39%). MS m/z 411.2, 413.2 [M+H]+.

Step E. tert-Butyl 4-(7-bromo-5-fluorobenzo[e][1,2,4]triazin-3-yl)piperidine-1-carboxylate (500 mg, 1.22 mmol) was combined with KOAc ( 358 mg, 3.65 mmol), complex of [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) with dichloromethane (100 mg, 0.12 mmol), bis(pinacolato)diborone (386 mg, 1.52 mmol ) and 1,4-dioxane (3 ml). The mixture was stirred at 100°C for 2 hours. After the mixture cooled to room temperature, an aqueous solution of 1 M K ₂ CO ₃ (1.5 ml, 1.5 mmol), 6-chloro-2,8-dimethylimidazo[1, 2-b]pyridazine (270 mg, 1.22 mmol, prepared according to the procedure in example 11), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(I) complex with dichloromethane (100 mg, 0.12 mmol ). The mixture was stirred at 80°C for 2 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 20-80% EtOAc in hexane to give tert-butyl 4-(7-(2,8-dnmethylimdazo[1,2-b]pyridazin-6-nl)-5fluorobenzo[e][ 1,2,4]triazin-3-yl)piperidin-1-carboxylate (550 mg, 94%). MS m/z 478.6 [M+H] ⁺ .

Step F. tert-Butyl 4-(7-(2,8-dimethyllimndazo[1,2-b]pnrndaznn-6-nl)-5-fluorobenzo[e][1,2,4]triazin3-yl)piperidin- 1-carboxylate (67 mg, 0.14 mmol) was suspended in 4N. HCl in 1,4-dioxane (2 ml, 8 mmol). The mixture was stirred vigorously for 1 hour. The solids were collected, washed with CH3CN, and dried to give 7-(2,8-dnmethylnmdazo[1,2-b]pyrnazin-6-nl)-5-fluoro-3(piperidine -4-yl)benzo[e][1,2,4]triazine hydrochloride (46 mg, 73%).

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

Using the procedure described above for Example 13, additional compounds described herein were prepared by replacing the appropriate aryl halide in Step E, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 32 MS m/z 381.1 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.67 - 8.69 (m, 1H), 8.49 (d, J= 2.8 Hz, 1H), 8.34 (dd, J= 11.0, 1.9 Hz, 1H), 8.12 (d,J= 1.6 Hz, 1H), 7.63 (dd, J= 12.6, 1.6 Hz, 1H), 4.31 (s, 3H), 3.83 - 3.90 (m, 1H), 3.60 - 3.67 (m, 2H), 3.32 - 3.38 (m, 2H), 2.52 - 2.59 ( m, 2H), 2.32 - 2.42 (m, 2H), The proton corresponding to NH was not observed. 33 MS m/z 3ΊΊ,3 [M+H] ⁺ ; Ή NMR (DMSO-s/ ₆ ) δ: 8.69 (d, J= 1.9 Hz, 1H), 8.47 - 8.52 (m, 2H), 8.20 - 8.23 (m, 1H), 7.69 - 7.71 (m, 1H), 4.23 (s, 3H), 3.44 - 3.51 (m, 1H), 3.10 - 3.15 (m, 2H) , 2.69 - 2.77 (m, 2H), 2.62 (s, 3H), 2.03 - 2.08 (m, 2H), 1.83 - 1.92 (m, 2H), Proton , corresponding to NH, was not observed. 58 MS m/z 381.3 [M+H] ⁺ ; Ή NMR (DMSO-g7 ₆ ) δ: 9.42 (s, 1H), 9.02 - 9.09 (br, 1H), 8.95 (s, 1H), 8.74 - 8.82 (br , 1H), 8.58 (dd, J = 13.0, 1.2 Hz, 1H), 8.30 - 8.37 (m, 1H), 8.07 (s, 1H), 3.77 - 3.84 (m, 1H), 3.43 - 3.49 (m, 2H), 3.14 - 3.24 (m, 2H), 2.51 (s, 3H), 2.33 - 2, 39 (m, 2H), 2.17 - 2.27 (m, 2H).

- 77 043655

59 MS m/z 408.2 [M+H] ⁺ ; Ή NMR (DMSO-ίΖβ) δ: 9.35 (s, IH), 8.94 - 9.01 (br, IH), 8.65 - 8.75 (m, 2H), 8.26 (s, IH), 7.82 (s, IH), 4.64 (q, J= 7.3 Hz, 2H), 3.78 - 3.86 (m, IH), 3.43 - 3.50 (m , 2H), 3.15 - 3.25 (m, 2H), 2.46 (s, 3H), 2.34 - 2.41 (m, 2H), 2.18 2.27 (m, 2H) , 1.54 (t, J = 6.9 Hz, 3H). 60 MS m/z 377.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.23 (s, IH), 8.86 (d, J= 1.7 Hz, IH), 8.37 (dd, J= 10.5, 1.5 Hz , IH), 8.31 (s, IH), 8.08 (s, IH), 3.88 - 3.93 (m, IH), 3.68 - 3.61 (m, 2H), 3, 32 - 3.39 (m, 2H), 2.78 (s, 3H), 2.65 (s, 3H), 2.54 - 2.60 (m, 2H), 2.34 - 2.43 ( m, 2H), The proton corresponding to NH was not observed. 61 MS m/z 431.3 [M+H] ⁺ ; Ή NMR (DMSO-^ ₆ ) δ: 9.61 (s, IH), 9.02 (br, IH), 8.98 (s, IH), 8.72 (br, IH), 8.63 ( dd, J = 11.8, 2.0 Hz, IH), 8.40 (s, IH), 8.00 (s, IH), 3.77 3.83 (m, IH), 3.42 - 3.49 (m, 2H), 3.15 - 3.24 (m, 2H), 2.47 (s, 3H), 2.33 - 2.39 (m, 2H), 2.16 - 2, 27 (m, 2H). 62 MS m/z 378.4 [M+H] ⁺ ; Ή NMR (DMSO-b7 ₆ ) δ: 8.84 (s, IH), 8.56 (dd, J = 11.6, 1.9 Hz, IH), 8.20 (s, IH), 7, 89 (s, IH), 3.75 - 3.82 (m, IH), 3.44 - 3.49 (m, 2H), 3.16 3.23 (m, 2H), 2.68 (s , 3H), 2.62 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H), No proton corresponding to NH was observed. 63 MS m/z 377.4 [M+H] ⁺ ; Ή NMR (DMSO-^b) δ: 14.98 (br, IH), 9.05 (br, IH), 8.87 (s, IH), 8.77 (br, IH), 8.60 ( dd, J = 11.5, 1.9 Hz, IH), 8.17 (s, IH), 8.02 (s, IH), 3.77 3.83 (m, IH), 3.44 - 3.49 (m, 2H), 3.16 - 3.23 (m, 2H), 2.85 (s, 3H), 2.70 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 64 MS m/z 377.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.89 - 8.92 (m, IH), 8.86 (d, J= 1.6 Hz, IH), 8.46 (dd, J= 10.7, 1.9 Hz, IH), 8.37 - 8.42 (m, 2H), 3.85 - 3.91 (m, IH), 3.61 - 3.67 (m, 2H), 3.35 - 3.39 (m, 2H), 3.05 (s, 3H), 2.53 - 2.60 (m, 5H), 2.33 - 2.44 (m, 2H), Proton corresponding to NH, was not observed. 65 MS m/z 377.3 [M+H] ⁺ ; Ή NMR (DMSO-c7 ₆ ) δ: 8.95 (br, IH), 8.90 (s, IH), 8.59 - 8.66 (m, 2H), 8.26 (s, IH), 7.53 (s, IH), 6.60 (s, IH), 3.77 - 3.83 (m, IH), 3.44 - 3.49 (m, 2H), 3.16 - 3, 23 (m, 2H), 2.77 (s, 3H), 2.48 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H) . 66 MS m/z 378.3 [M+H] ⁺ ; Ή NMR (DMSO-e/b) δ: 9.17 (s, IH), 9.08 (br, IH), 8.82 (dd, J = 11.5, 1.9 Hz, IH), 8 .78 (s, IH), 8.76 (br, IH), 8.21 (s, IH), 4.28 (s, 3H), 3.75 - 3.83 (m, IH), 3, 43 - 3.49 (m, 2H), 3.15 - 3.23 (m, 2H), 2.69 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15- 2.25 (m, 2H). 67 MS m/z 378.1 [M+H] ⁺ ; Ή NMR (DMSO-b7 ₆ ) δ: 9.17 (s, IH), 8.79 - 8.86 (m, 2H), 8.64 (s, IH), 8.58 (s, IH), 8.52 (br, IH), 4.31 (s, 3H), 3.77 - 3.83 (m, IH), 3.44 - 3.51 (m, 2H), 3.15 - 3, 23 (m, 2H), 2.89 (s, 3H), 2.32 - 2.38 (m, 2H), 2.15 - 2.25 (m, 2H). 68 MS m/z 382.0 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.68 (s, IH), 8.27 (d, J = 13.0, IH), 8.01 (s, IH), 7.72 (d, J = 13.0, IH), 3.58 - 3.67 (m, IH), 3.26 - 3.30 (m, 2H), 2.87 2.96 (m, 2H), 2.72 (s , 3H), 2.20 - 2.28 (m, 2H), 2.05 - 2.16 (m, 2H), The proton corresponding to NH was not observed.

Example 14.

Receiving connection 57

NHoCI

Step A. 5-Bromo-1,2-difluoro-3-nitro-benzene (11.7 g, 49 mmol, prepared according to the procedure from

- 78 043655 example 7, step A) was combined with guanidine hydrochloride (23.5 g, 246 mmol), K2CO3 (34 g, 246 mmol) and DMSO (75 ml). The mixture was vigorously stirred at 120°C for 30 minutes. The mixture was cooled to room temperature. An aqueous solution of 7.5 N was added to the mixture. NaOH (100 ml). The mixture was stirred at 60°C for 30 minutes. AcOH (75 ml) and H2O (400 ml) were added to the mixture. The mixture was filtered. The collected solids were dried to give 7-bromo-5-fluoro-1-oxido-1,2,4-benzotriazine-1-ium-3amine (9.6 g, 76%). MS m/z 259.1, 261.1 [M+H]+.

Step B: 7-Bromo-5-fluoro-1-oxido-1,2,4-benzotriazine-1-ium-3-amine (9.6 g, 37 mmol) was dissolved in TFA (66 ml). NaNO ₂ (13.1 g, 190 mmol) was added to the mixture in small portions at 0°C. The mixture was stirred at room temperature for 20 minutes, and then cooled to 0°C. Ice water (20 ml) was slowly added to the mixture. The resulting solid was collected, washed with H2O and dried. The solid was suspended in CH3CN, collected by filtration and dried to give 7-bromo-5-fluoro-1-oxido-1,2,4-benzotriazin-1-ium-3-ol (5.3 g, 55%). MS m/z 260.1, 262.1 [M+H] ⁺ .

Step C: 7-Bromo-5-fluoro-1-oxido-1,2,4-benzotriazin-1-ium-3-ol (2.9 g, 11 mmol) was combined with POCl ₃ (30 ml, 320 mmol) . The mixture was stirred at 110°C for 2 hours. The mixture was cooled to room temperature, and then added to ice. The mixture was partitioned into CH ₂ Cl ₂ and H ₂ O. The organic layer was collected and loaded onto silica gel, eluted with 0-10% EtOAc in CH ₂ Cl ₂ to give 7-(2,7dimethyl-2H-indazol-5-yl)- 5-fluoro-N-methyl-N-(piperidin-4-yl)benzo[e][1,2,4]triazin-3-amine (490 mg, 16%). MS m/z 277.9, 279.9, 281.9 [M+H] ⁺ .

Step D: 7-Bromo-3-chloro-5-fluoro-1-oxido-1,2,4-benzotriazine-1-ium (78 mg, 0.28 mmol) was combined with (2,8-dimethylimidazo[1, 2-b]pyridazin-6-yl)boric acid (53 mg, 0.28 mmol, prepared according to the procedure of Example 11), 1,1'-bis(diphenylphosphino)ferrocene-palladium(P)dichloride dichloromethane complex (11 mg , 0.014 mmol), 1,4-dioxane (1.5 ml) and an aqueous solution of 1 M K2CO3 (0.75 ml). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in CH ₂ Cl ₂ to give 7-bromo-3(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-1 -(λ1-oxidanyl)-1λ4-benzo[e][1,2,4]triazine (69 mg, 63%). MS m/z 389.0, 391.0 [M+H] ⁺ .

Step E. 7-Bromo-3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-1-(λ1-oxidanyl)-1λ4benzo[e][1,2, 4]triazine (20 mg, 0.051 mmol) was combined with N-Boc-1,2,5,6tetrahydropyridine-4-borinic acid pinacol ester (19 mg, 0.062 mmol), 1,1'bis(diphenylphosphino)ferrocene-complex palladium(P)dichloride dichloromethane (4 mg, 0.005 mmol), 1,4-dioxane (1 ml) and an aqueous solution of 1 M K2CO3 (0.5 ml). The mixture was heated at 80°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-(3-(2,8dimetulumidazo[1,2-b]niridazin-6-ul)-5-fluoro- 1-(λ1-oxidanyl)-1λ4-benzo[e][1,2,4]triazin-7-yl)-3,6dihydropyridin-1(2H)-carboxylate (2θ mg, 79%). MS m/z 492.3 [M+H] ⁺ .

Stage F. tert-Butyl 4-(3-(2,8-dimethylumidazo[1,2-b]niridazin-6-yl)-5-fluoro-1-(λ1-oxidanyl)-1λ4benzo[e][1, 2,4]triazin-7-yl)-3,6-dihydropyridin-1(2H)-carboxylate (20 mg, 0.04 mmol) was combined with 10% Pd/C (5 mg) in MeOH (2 ml). The mixture was stirred under H ₂ (1 atm) for 2 hours at 40°C. The mixture was filtered through celite. The filtrate was concentrated and chromatographed on a C18 reverse phase column, eluting with 40-100% CH3CN in H2O to give tert-butyl 4-(3-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-5- fluorobenzo[e][1,2,4]triazin-7-yl)piperidine-1-carboxylate (17 mg, 87%). MS m/z 478.5 [M+H] ⁺ .

Step G. tert-Butyl 4-(3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorobenzo[e][1,2,4]triazin7-yl)piperidin- 1-carboxylate (17 mg, 0.036 mmol) was suspended in 4N. HCl in 1,4-dioxane (1 ml, 4 mmol HCl). Volatiles were removed from the mixture after 30 min. The residue was suspended in CH3CN. The solids were collected and dried to give 3-(2,8-dimethylumidazo[1,2-b]nuridazin-6-yl)-5-fluoro-7(piperidin-4-yl)benzo[e][1,2. 4]triazine hydrochloride (8 mg, 54%).

^1H NMR (methanol- _d4 ) δ: 8.89 (d, J=1.6 Hz, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.51 (d, J =1.3 Hz, 1H), 8.08 (dd, J=10.6, 1.7 Hz, 1H), 3.61-3.67 (m, 2H), 3.35-3.43 ( m, 1H), 3.25-3.33 (m, 2H), 2.92 (s, 3H), 2.73 (s, 3H), 2.322.38 (m, 2H), 2.09-2 ,19 (m, 2H), No protons corresponding to NH were observed.

Using the procedure described above for Example 14, additional compounds described herein were prepared by substituting the appropriate arylboronic acid in Step D, suitable reagents, and reaction conditions to produce compounds such as those selected from:

- 79 043655

Conn. Data 40 MS m/z 377.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.84 - 8.86 (m, 1H), 8.64 - 8.67 (m, 1H), 8.25 (dd, J= 11.0, 1.9 Hz, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 3.63 - 3.70 (m, 1H), 3.32 - 3.38 (m, 2H), 2 .94 - 3.02 (m, 2H), 2.66 (s, 3H), 2.48 (s, 3H), 2.25 - 2.32 (m, 2H), 2.10-2.19 (m, 2H), The proton corresponding to NH was not observed. 41 Starting material: 2-amino-5-bromo-4-fluorobenzoic acid MS m/z 381.4 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 8.89 (d, J= 1.6 Hz, 1H), 8.65 - 8.68 (m, 1H), 8.25 (dd, J= 10.8, 1.9 Hz, 1H), 7.83 (dd, J= 2.8, 0.6 Hz, 1H), 7.70 (dd, J= 12.0, 1.6 Hz, 1H), 3, 60 - 3.68 (m, 1H), 3.27 - 3.32 (m, 2H), 2.89 - 2.97 (m, 2H), 2.48 (s, 3H), 2.21 - 2.29 (m, 2H), 2.06 - 2.16 (m, 2H), No proton corresponding to NH was observed.

Example 15.

Receiving connection 4

Step A: 7-Bromo-3-chloro-5-fluoro-1-oxido-1,2,4-benzotriazine-1-ium (60 mg, 0.22 mmol, prepared according to the procedure of Example 14, Step C) was combined with Cs ₂ CO ₃ (104 mg, 0.32 mmol) and 1-Boc-4methylaminopiperidine (56 mg, 0.26 mmol) in DMF (2 ml). The mixture was stirred at 60°C for 2 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-80% EtOAc in CH ₂ Cl ₂ to give 7-bromo-3-((1-(tert-butoxycarbonyl)piperidin-4yl)(methyl)amino)-5-fluorobenzo[e ][1,2,4]triazine 1-oxide (64 mg, 65%). MS m/z 356.2, 358.2 [M+H-Boc]+.

Step B. 7-bromo-3-(( 1 -(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-5 fluorobenzo[e][1,2,4]triazine 1-oxide (64 mg, 0.14 mmol) and 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indazole (46 mg, 0.17 mmol) were combined with complex 1, 1'bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (0.05 eq., 0.007 mmol) and 1,4dioxane (1 ml). An aqueous solution of 1 M K2CO3 (0.5 ml) was added to the mixture. The mixture was stirred at 80°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 10-90% EtOAc in CH ₂ Cl ₂ to give 3((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-7-(2,7-dimethyl -2H-indazol-5-yl)-5fluorobenzo[e][1,2,4]triazine 1-oxide (74 mg, 100%). MS m/z 522.4 [M+H]+.

Step C. 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-7-(2,7-dimethyl-2H-indazol-5yl)-5-fluorobenzo[e][1 ,2,4]triazine 1-oxide (74 mg, 0.14 mmol) was combined with 10% Pd/C (20 mg) in MeOH (2 ml). The mixture was stirred under H2 (1 atm) at room temperature for 1 hour. The mixture was filtered through celite. The filtrate was concentrated to give tert-butyl 4-[[7-(2,7-dimethylindazol-5yl)-5-fluoro-1,2,4-benzotriazin-3-yl]-methyl-amino]piperidine-1-carboxylate ( 70 mg, 97%). MS m/z 506.3 [M+H] ⁺ .

Step D. tert-butyl 4-[[7-(2,7-dimethylindazol-5-yl)-5-fluoro-1,2,4-benzotriazin-3-yl]-methylamino]piperidine-1-carboxylate (70 mg, 0.14 mmol) suspended in 4N. HCl in 1,4-dioxane (1 ml, 4 mmol HCl). The mixture was stirred at room temperature for 1 hour. Volatiles were removed from the reaction mixture with a stream of N ₂ . The residue was separated in CH ₂ Cl ₂ and an aqueous solution of 1 M K ₂ CO ₃ . The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-N-methyl -N(piperidin-4-yl)benzo[e][1,2,4]triazin-3-amine (43 mg, 77%).

MS m/z 406.4 [M+H]+; 1H NMR (DMSO^) δ: 8.42 (s, 1H), 8.37 (s, 1H), 8.15-8.19 (m, 1H), 8.04-8.07

- 80 043655 (m, 1H), 7.60 (s, 1H), 4.24-4.30 (m, 1H), 4.21 (s, 3H), 3.22 (br s, 3H), 3.06-3.11 (m, 2H), 2.61-2.66 (m, 2H), 2.60 (s, 3H), 1.72-1.81 (m, 2H), 1, 64-1.70 (m, 2H), No proton corresponding to NH was observed.

Example 17.

Receiving connection 50

Step A: 6-Bromo-2-chloro-8-fluoroquinoline (260 mg, 1.0 mmol) was combined with 1,1'bis(diphenylphosphino)ferrocene-palladium(P)dichloride dichloromethane complex (80 mg, 0. 10 mmol) and 1,4dioxane (4 ml). A solution of 1-tert-butoxycarbonylpiperidin-4-ylzinc iodide in N,N-dimethylacetamide (2 ml, 2 mmol, prepared according to the procedure of Example 5, Step B) was added to the mixture at room temperature. The mixture was stirred at 70°C for 1 hour. Volatiles were removed from the mixture with a stream of N2. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in hexane to give tert-butyl 4-(6-bromo-8-fluoro-2-quinolyl)piperidine-1-carboxylate (235 mg, 58%).

1H NMR (DMSO-d6) δ: 8.36 (dd, J=8.8, 1.6 Hz, 1H), 8.10-8.14 (m, 1H), 7.85 (dd, J= 10.3, 2.2 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 4.04-4.16 (m, 2H), 3.07-3.14 (m , 1H), 2.89 (br s, 2H), 1.88-1.96 (m, 2H), 1.64-1.74 (m, 2H), 1.44 (s, 9H).

Step B: tert-butyl 4-(6-bromo-8-fluoro-2-quinolyl)piperidine-1-carboxylate (40 mg, 0.10 mmol) was combined with (8-fluoro-2-methyl-imidazo[1, 2-a]pyridin-6-yl)boric acid (40 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(H)dichloromethane dichloride complex (4 mg, 0.005 mmol), 1, 4-dioxane (1.5 ml) and an aqueous solution of 1 M K ₂ CO ₃ (0.75 ml). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-80% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-[8-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6 -yl)-2-quinolyl]piperidine-1-carboxylate (45 mg, 96%). MS m/z 479.4 [M+H]+.

Step C. tert-Butyl 4-[8-fluoro-6-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-2quinolyl]piperidine-1-carboxylate (45 mg, 0.09 mmol) suspended in 4N. HCl in 1,4-dioxane (1 ml, 4 mmol HCl). Volatiles were removed from the reaction mixture after 30 min. The residue was partitioned between CH2Cl2 and an aqueous solution of 1 M K2CO3. The organic layer was concentrated and chromatographed on silica gel, eluting with 0-10% MeOH (2N NH ₃ ) in CH ₂ Cl ₂ . The collected material was dissolved in 1.25 M HCl in MeOH. Volatiles were removed to give 8-fluoro-6-(8-fluoro-2-methylimidazo[1,2a]pyridin-6-yl)-2-(piperidin-4-yl)quinoline hydrochloride (35 mg, 90%).

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

Using the procedure described above for Example 17, additional compounds described herein were prepared by replacing the specified starting material in step A, suitable boric acid in step B, suitable reagents and reaction conditions, to obtain compounds such as those selected from:

- 81 043655

Conn. Source material and data 29 Starting material: 7-bromo-3-chloroquinoline MS m/z 357.4 [M+H] ⁺ ; ^1H NMR (DMSO-yb) δ: 9.26 (d, J = 2.5 Hz, IH), 8.59 (d, J = 2.5 Hz, IH), 8.43 (s, IH) , 8.01 - 8.03 (m, IH), 7.98 (d, J = 8.5 Hz, IH), 7.81 - 7.83 (m, IH), 7.53 - 7.58 (m, 2H), 4.22 (s, 3H), 3.06 - 3.11 (m, 2H), 2.79 - 2.86 (m, IH), 2.63 2.69 (m, 2H), 2.61 (s, 3H), 1.80 - 1.86 (m, 2H), 1.59 - 1.69 (m, 2H), No proton corresponding to NH was observed. 45 Starting material: 6-bromo-2-chloro-8-fluoroquinoline MS m/z 376.1 [M+H] ⁺ ; Ή NMR (methanol-D ₄ ) δ: 8.63 - 8.68 (m, 2H), 8.48 (s, IH), 8.38 (s, IH), 8.35 (d, J= 11 .5 Hz, IH), 7.80 (d, J= 8.0 Hz, IH), 3.60 - 3.65 (m, 2H), 3.46 - 3.50 (m, IH), 3 .25 - 3.33 (m, 2H), 2.86 (s, 3H), 2.70 (s, 3H), 2.27 - 2.33 (m, 4H), Proton corresponding to NH was not observed . 49 Starting material: 6-bromo-2-chloro-8-fluoroquinoline MS m/z 391.4 [M+H] ⁺ ; Ή NMR (DMSO-D ₆ ) δ: 9.11 (br, IH), 8.77 (br, IH), 8.46 (d, J = 8.5 Hz, IH), 8.41 (s, IH), 8.17 - 8.20 (m, IH), 8.05 (dd, J= 12.7, 2.1, IH), 7.73 (d, J = 1.3 Hz, IH) , 7.61 (d, J = 8.5 Hz, IH), 7.06 - 7.08 (m, IH), 4.18 (s, 3H), 4.05 (s, 3H), 3, 39 - 3.45 (m, 2H), 3.24 - 3.31 (m, IH), 3.02 - 3.12 (m, 2H), 2.04 - 2.18 (m, 4H).

Example 18.

Receiving connection 51

Step A: 8-Bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine (250 mg, 1.01 mmol) was combined with Cs ₂ CO ₃ (700 mg, 2.15 mmol in CH3CN ( 5 ml). MeOH (0.2 ml) was added to the mixture. The mixture was stirred at room temperature for 4 hours. Volatiles were removed from the reaction mixture. The residue was partitioned between EtOAc and H ₂ O. The organic layer was collected, concentrated and chromatographed on silica gel , eluted with 20-100% EtOAc in hexane to give 6-chloro-8-methoxy-2-methylimidazo[1,2-b]pyridazine (180 mg, 90%) MS m/z 198.2, 202.2 [M+N]+.

Step B: 6-Chloro-8-methoxy-2-methyl-imidazo[1,2-b]pyridazine (39 mg, 0.20 mmol) was combined with KOAc (59 mg, 0.60 mmol), complex 1, D -bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride (8 mg, 0.01 mmol) and bis(pinacolato)diborone (63 mg, 0.25 mmol) in 1,4-dioxane (1 ml). The mixture was stirred under N ₂ atmosphere at 95°C for 1 hour. An aqueous solution of 1 M K2CO3 (0.75 ml), tert-butyl 4-(6-bromo-8-fluoro-2-quinolyl)piperidine- 1-carboxylate (40 mg, 0.10 mmol, prepared in Example 17, Step A) and 1,1'-bis(diphenylphosphino)ferrocene palladium(11)dichloromethane dichloride complex (4 mg, 0.005 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-80% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-[8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6 -yl)-2-quinolyl]piperidine-1-carboxylate (38 mg, 79%). MS m/z 492.4 [M+H] ⁺ .

Step C. tert-Butyl 4-[8-fluoro-6-(8-methoxy-2-methyl-imidazo[1,2-b]pyridazin-6-yl)-2quinolyl]piperidine-1-carboxylate (38 mg, 0.08 mmol) suspended in 4N. HCl in 1,4-dioxane (1 ml, 4 mmol HCl). Volatiles were removed from the reaction mixture with a stream of N ₂ after 30 minutes. The residue was suspended in CH3CN, collected by filtration and dried to give 8-fluoro-6-(8-methoxy-2methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline hydrochloride ( 26 mg, 79%).

MS m/z 392.4 [M+H]+; 1H NMR (DMSO-yb) δ: 9.22 (br, 1H), 8.95 (br, 1H), 8.77-8.80 (m, 1H), 8.60 (d,

- 82 043655

J=8.6 Hz, 1H), 8.47 (s, 1H), 8.37 (dd, J=12.0, 2.0 Hz, 1H), 7.99 (s, 1H), 7, 73 (d, J=8.5 Hz, 1H), 4.35 (s, 3H), 3.39-3.45 (m, 2H), 3.29-3.37 (m, 1H), 3 .02-3.12 (m, 2H), 2.53 (s, 3H), 2.06-2.20 (m, 4H).

Using the procedure described above for Example 18, additional compounds described herein were prepared by substituting the appropriate reagent in Step A, suitable reagents, and reaction conditions to produce compounds such as those selected from:_________________

Conn. Data 53 MS m/z 436.3 [M+H] ⁺ ; Ή NMR (DMSO-b/ ₆ ) δ: 8.97 (br, 1H), 8.71 (br, 1H), 8.68 (s, 1H), 8.57 (d, J= 8.6 Hz , 1H), 8.28 - 8.35 (m, 2H), 7.76 (br s, 1H), 7.71 (d, J= 8.5 Hz, 1H), 4.70 - 4.74 (m, 2H), 3.84 - 3.88 (m, 2H), 3.42 - 3.47 (m, 2H), 3.39 (s, 3H), 3.29 3.37 (m, 1H), 3.05 - 3.14 (m, 2H), 2.48 (s, 3H), 2.06 - 2.20 (m, 4H). 54 MS m/z 435.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.59 - 8.64 (m, 2H), 8.30 (dd, J= 12.0, 1.7 Hz, 1H), 8.18 (d, J= 1.3 Hz, 1H), 7.76 (d, J= 8.5 Hz, 1H), 7.41 (s, 1H), 3.78 - 3.84 (m, 4H), 3.60 - 3.65 (m, 2H), 3.49 (s, 3H), 3.43 - 3.49 (m, 1H), 3.24 - 3.31 (m, 2H), 2.64 (s, 3H), 2.24 - 2.36 (m, 4H), No protons corresponding to NH were observed.

Example 19.

Receiving connection 70

7-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4-piperidyl)-1,2,4-benzotriazine dihydrochloride (36 mg, 0.08 mmol , obtained according to the procedure of example 13) was combined with 1,2dichloroethane (1 ml), EtOH (0.2 ml) and triethylamine (22 μl, 0.16 mmol). Acetaldehyde (18 μL, 0.32 mmol) was added to the mixture. The mixture became homogeneous. The mixture was stirred for 5 minutes. Sodium triacetoxyborohydride (36 mg, 0.16 mmol) was added to the mixture. After 20 minutes stirring at room temperature, the mixture was loaded directly onto silica gel and chromatographed, eluting with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 7-(2,8-dimethylimidazo[1,2-b] pyridazin6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorobenzo[e][1,2,4]triazine (32 mg, 84%) in the form of a yellow powder.

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

Using the reductive amination procedure described above for Example 19, additional compounds described herein were prepared by substituting the indicated starting materials, aldehyde, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Source material and data 2 Starting material: 2-(2-methyl-2R-indazol-5-yl)-6-(piperidin-4-yl)quinoline (obtained according to the procedure from example 6) and acetaldehyde MS m/z 371.1 [M+H ] ⁺ ; 1H NMR (methanolD4) δ: 8.99 (br s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.34 - 8.40 (m, 2H), 8, 15 - 8.20 (m, 1H), 8.04 - 8.10 (m, 2H), 7.19 (d, J = 9.5 Hz, 1H), 4.33 (s, 3H), 3 .76 - 3.82 (m, 2H), 3.49 - 3.56 (m, 1H), 3.26 (q, J = 7.5 Hz, 2H), 3.19 - 3.24 (m , 2H), 2.31 - 2.36 (m, 2H), 2.18 - 2.23 (m, 2H), 1.44 (t, J = 7.5 Hz, 3H).

- 83 043655

6 Starting material: 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2(piperidin-4-yl)quinoline (prepared according to the procedure of Example 17) and formaldehyde MS m /z 357.2 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 8.95 (br s, IH), 8.57 (s, IH), 8.51 (s, IH), 8.44 - 8.50 (m, 2H), 8.24 (s, IH), 7.86 (d, J= 8.5 Hz, IH), 7.76 - 7.78 (m, 2H), 4.22 (s, 3H), 4.00 - 4.07 (m, 2H), 3.22 - 3.28 (m, IH), 3.14 - 3.20 (m, 2H), 2.81 (s, 3H), 2.27 - 2 .33 (m, 4H). 9 Starting material: 6-(2-methyl-2R-indazol-5-yl)-2-(piperidin-4-yl)quinoline (obtained according to the procedure from example 2) and acetaldehyde MS m/z 371.2 [M+H ] ⁺ ; Ή NMR (DMSO-de) δ: 9.11 (d, J= 8.5 Hz, IH), 8.58 - 8.64 (m, 2H), 8.48 - 8.54 (m, 2H) , 8.23 (s, IH), 7.96 (d, J = 8.5 Hz, IH), 7.74 - 7.78 (m, 2H), 4.23 (s, 3H), 3, 75 - 3.80 (m, IH), 3.63 - 3.67 (m, 2H), 3.08 - 3.18 (m, 4H), 2.32 2.46 (m, 4H), 1 .32 (t, J= 7.5 Hz, 3H). 47 Starting material: 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2(piperidin-4-yl)quinoline (prepared according to the procedure of Example 17) and formaldehyde MS m /z 390.2 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 8.67 (s, IH), 8.57 (d, J = 8.0 Hz, IH), 8.47 (s, IH), 8.42 (s, IH ), 8.27 (d, J= 12.0 Hz, IH), 7.73 (d, J= 8.0 Hz, IH), 3.54 3.57 (m, IH), 3.14 - 3.25 (m, 4H), 2.80 (s, 3H), 2.76 (s, 3H), 2.58 (s, 3H), 2.20 - 2.25 (m, 4H). 48 Starting material: 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2(piperidin-4-yl)quinoline (prepared according to the procedure of Example 17) and acetaldehyde MS m /z 404.2 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 8.67 (s, IH), 8.57 (d, J = 8.0 Hz, IH), 8.47 (s, IH), 8.42 (s, IH ), 8.27 (d, J = 12.0 Hz, IH), 7.73 (d, J = 8.0 Hz, IH), 3.60 3.64 (m, IH), 3.27 - 3.32 (m, 2H), 3.07 - 3.16 (m, 4H), 2.77 (s, 3H), 2.59 (s, 3H), 2.22 - 2.26 (m, 4H), 1.30 (t, J= 7.5 Hz, 3H). 69 Starting Material: 7-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4piperidyl)-1,2,4-benzotriazine (prepared according to the procedure of Example 13) and formaldehyde MS m/z 392.2 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 9.27 (s, IH), 8.70 (dd, J= 11.0, 1.7 Hz, IH), 8.54 (s, IH), 8.45 (s, IH), 3.70 - 3.77 (m, IH), 3.59 - 3.65 (m, 2H), 3.21 3.30 (m, 2H), 2.84 (d, J= 4.7 Hz, 3H), 2.76 (s, 3H), 2.56 (s, 3H), 2.41 - 2.47 (m, 2H), 2.25 - 2.35 (m , 2H).

- 84 043655

75 Starting Material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 7) and 1,4dioxane -2,5-diol MS m/z 421.5 [M+H] ⁺ ; 1HNMR (methanol-44) δ: 9.17 (s, 1H), 8.61 (d, J = 1.0 Hz, 1H), 8.42 - 8.47 (m, 2H), 8.35 (s, 1H), 3.98 - 4.01 (m, 2H), 3.88 - 3.94 (m, 2H), 3.63 3.70 (m, 1H), 3.35 - 3, 42 (m, 4H), 2.88 (s, 3H), 2.71 (s, 3H), 2.44 - 2.52 (m, 4H), No proton corresponding to OH was observed. 76 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline and acetaldehyde (prepared according to the procedure of Example 7) MS m /z 405.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.17 (s, 1H), 8.60 (d, J = 1.0 Hz, 1H), 8.42 - 8.47 (m, 2H), 8.35 (s, 1H), 3.81 - 3.87 (m, 2H), 3.63 - 3.70 (m, 1H), 3.25 3.38 (m, 4H), 2.88 (s, 3H), 2.71 (s, 3H), 2.38 - 2.52 (m, 4H), 1.47 (t, J= 7.4 Hz, 3H). 77 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 7) MS m/ z 419.5 [M+H] ⁺ ; Ή NMR (DMSO-<7b) δ: 9.02 (s, 1H), 8.32 (dd, J= 11.0, 1.3 Hz, 1H), 8.15 (s, 1H), 8, 14 (d, J= 0.6 Hz, 1H), 8.05 (d, J= 0.9 Hz, 1H), 3.10 - 3.22 (m, 3H), 2.94 - 3.07 (m, 2H), 2.65 (d, J= 0.9 Hz, 3H), 2.43 (d, J= 0.6 Hz, 3H), 2.02 2.14 (m, 4H), 1.52 - 1.61 (m, 2H), 1.12 - 1.18 (m, 2H), 0.92 (t, J= 7.4 Hz, 3H), No protons corresponding to HCl were observed. 79 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 7) MS m/ z 391.4 [M+H] ⁺ ; Ή NMR (DMSO-<7 ₆ ) δ: 9.05 (s, 1H), 8.36 (dd, J= 10.9, 1.4 Hz, 1H), 8.19 (s, 1H), 8 .15 (d, V=0.6Hz, 1H), 8.07 (d, V=0.9Hz, 1H), 3.36-3.48 (m, 3H), 2.80 - 2.94 ( m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.44 (d, J= 0.6 Hz, 3H), 2.18 - 2.28 (m, 4H ), Protons corresponding to HCl were not observed. 85 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 7) MS m/z 387.3 [ M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.01 (s, 1H), 8.57 (dd, J= 9, 1.5 Hz, 1H), 8.13 (m, 2H), 8.00 (s , 1H), 7.85 (s, 1H), 3.26 - 3.33 (m, 3H), 2.74 (s, 3H), 2.65 (q, J= 7.5 Hz, 2H) , 2.52 (s, 3H), 2.35 - 2.41 (m, 2H), 2.20 - 2.24 (m, 2H), 2.06 - 2.18 (m, 2H), 1 .23 (t, J= 7.5 Hz, 3H).

- 85 043655

100 Starting material: 5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS m/z 391 .5 [M+N] ⁺ ; Ή NMR (methanol-^) δ: 9.14 (s, 1H), 8.58 (d, J= 9.5 Hz, 1H), 8.43 - 8.48 (m, 2H), 8.40 (s, 1H), 8.32 (s, 1H), 3.82 - 3.86 (m, 2H), 3.61 - 3.68 (m, 1H), 3.24 - 3.33 (m , 4H), 2.67 (s, 3H), 2.38 - 2.52 (m, 4H), 1.46 (t, J= 7.6 Hz, 3H), No protons corresponding to HO were observed. 102 Starting Material: 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3(piperidin-4-yl)cinnoline hydrochloride (prepared according to the procedure of Example 29) MS m/z 408.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.28 (d, J= 1.2 Hz, 1H), 8.78 (s, 1H), 8.47 (dd, J= 11.0, 1.2 Hz , 1H), 8.33 (s, 1H), 8.21 (d, J= 1.2 Hz, 1H), 8.12 (dd, J = 10.5, 1.7 Hz, 1H), 3 .84 (br d, J= 12.5 Hz, 2H), 3.61 - 3.69 (m, 1H), 3.24 - 3.35 (m, 4H), 2.66 (d, J= 0.9 Hz, 3H), 2.38 - 2.51 (m, 4H), 1.46 (t, J= 7.3 Hz, ZH), Protons corresponding to HC1 were not observed. BUT Starting material: 6-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-8-fluoro-2(piperidin-4-yl)quinoxaline hydrochloride (prepared according to the procedure of Example 38) MS m/ z 405.5 [M+N] ⁺ ; Ή NMR (methanol-^) δ: 8.88 (s, 1H), 8.26 (d, J= 0.9 Hz, 1H), 8.03 (dd, J= 11.3, 1.8 Hz , 1H), 7.81 (s, 1H), 7.57 (d, J= 1.2 Hz, 1H), 3.17 (d, J= 11.3 Hz, 2H), 3.06 (spt , J= 4.9 Hz, 1H), 2.59-2.61 (m, 1H), 2.60 (s, 2H), 2.54 (q, J= 7.3 Hz, 2H), 2 .60 (s, 3H), 2.21 (td, J= 11.3, 3.7 Hz, 2H), 2.03-2.12 (m, 4H), 1.18 (t, J = 7 ,3 Hz, 3H). 111 Starting material: 5-fluoro-7-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6yl)-3-(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS m /z 421.0 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.80 (s, 1H), 8.21 (d, J= 12 Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H) , 7.00 (s, 1H), 4.23 (s, 3H), 3.37 - 3.42 (m, 1H), 3.21 (d, J = 11.3 Hz, 2H), 2, 52 - 2.55 (m, 5H), 2.19 - 2.25 (m, 4H), 2.01 - 2.09 (m, 2H), 1.17 (t, J= 7.2 Hz, 3H). 113 Starting material: (6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)methanol dihydrochloride (prepared according to the procedure of Example 29 ) MS m/z 421.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.13 (s, 1H), 8.61 (s, 1H), 8.46 (d, J = 0.9 Hz, 1H), 8.43 (dd, J = 10.6, 1.3 Hz, 1H), 8.33 (s, 1H), 5.17 (d, J = 1.1 Hz, 2H), 3.82 (br d, J = 12.2 Hz, 2H), 3.61 - 3.70 (m, 1H), 3.23 - 3.30 (m, 4H), 2.69 (s, 3H), 2.39 - 2.50 (m, 4H), 1.45 (t, J= 7.3 Hz, ZH), Protons corresponding to HC1 and OH were not observed.

- 86 043655

114 Starting material: 6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazine-8-carbonitrile dihydrochloride (prepared according to the procedure of Example 29) MS m /z 416.0 [M+H] ⁺ ; Ή NMR (chloroform-D) δ: 8.53 (s, 1H), 8.23 (dd, J= 10.8, 1.5 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J= 0.4 Hz, 1H), 7.95 (s, 1H), 3.36 - 3.43 (m, 1H), 3.19 (br d, J= 11 Hz, 2H), 2.64 (s, 3H), 2.52 - 2.54 (m, 2H), 2.21 - 2.23 (m, 4H), 1.98 - 2.08 (m, 2H), 1, 17 (t, J = 7.2 Hz, 3H). 115 Starting Material: 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)5-fluoro-3-(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 29) MS m /z 431.1 [M+H] ⁺ ; Ή NMR (chloroform-D) δ: 8.78 (s, 1H), 8.19 (d, J= 12 Hz, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 3.28 - 3.42 (m, 1H), 3.29 (br d, J= 12 Hz, 2H), 2.60 - 2.72 (m, 3H), 2.56 (s, 3H), 2.24 - 2.27 (m, 2H), 2.09 - 2.13 (m, 4H), 1.33 1.37 (m, 2H), 1.19 - 1.25 (m, 5H). 119 Starting Material: 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-3(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 41) MS m/z 405.1 [M+H] ⁺ ; Ή NMR (chloroform-D) δ: 8.86 (s, 1H), 8.56 (s, 1H), 8.21 (m, 3H), 4.59 (s, 1H), 3.28 (s , 2H), 2.90 (s, 3H), 2.65 (dd, J= 14.4, 7.1 Hz, 2H), 2.48 (s, 3H), 2.39 (t, J= 11.8 Hz, 2H), 2.27 - 2.06 (m, 4H), 1.23 (t, J= 7.2 Hz, 3H). 120 Starting material: 6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2,4dimethylbenzo[th]thiazole (prepared according to the procedure of Example 29) MS m/z 421.1 [M +H] ⁺ ; Ή NMR (chloroform-D) δ: 8.58 (s, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.90 (s, 1H), 7.71 (dd, J = 10.6, 1.2 Hz, 1H), 7.63 (d, J= 0.8 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.20 (d, J= 11.2 Hz, 2H), 2.89 (s, 3H), 2.83 (s, 3H), 2.51 - 2.56 (m, 2H), 2.08 - 2.24 (m, 4H ), 2.01 - 2.05 (m, 2H), 1.23 (t, J= 7.2 Hz, 3H). 121 Starting Material: 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS m/z 419.5 [M+H] ⁺ ; Ή NMR (methanol-D ₄ ) δ: 9.18 (s, 1H), 8.54 (s, 1H), 8.40 8.50 (m, 2H), 8.33 (s, 1H), 3 .84 (br d, J= 12.5 Hz, 2H), 3.61 - 3.70 (m, 1H), 3.16 3.31 (m, 6H), 2.71 (s, 3H), 2.38 - 2.52 (m, 4H), 1.58 (t, J= 7.6 Hz, 3H), 1.46 (t, J= 7.6 Hz, 3H), Protons corresponding to HC1, were not observed. 122 Starting Material: 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS m/z 405.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.16 (s, 1H), 8.47 (s, 1H), 8.45 (d, J = 10.4 Hz, 1H), 8.40 (s, 1H ), 8.33 (s, 1H), 3.75 - 3.80 (m, 2H), 3.59 - 3.69 (m, 1H), 3.32 - 3.38 (m, 2H), 3.23 (q, J= 7.5 Hz, 2H), 3.02 (s, 3H), 2.69 (s, 3H), 2.37 - 2.49 (m, 4H), 1.57 (t, J= 7.5 Hz, SI) Protons corresponding to HC1 were not observed.

- 87 043655

123 Starting Material: 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS mz 435.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.17 (s, 1H), 8.50 (s, 1H), 8.45 (d, J = 10.7 Hz, 1H), 8.42 (s, 1H ), 8.33 (s, 1H), 3.98 - 4.02 (m, 2H), 3.88 - 3.94 (m, 2H), 3.62 - 3.68 (m, 1H), 3.35 - 3.42 (m, 4H), 3.23 (q, J = 7.5 Hz, 2H), 2.70 (s, 3H), 2.44 2.51 (m, 4H), 1.58 (t, J= 7.5 Hz, ZN), Protons corresponding to HC1 and OH were not observed. 124 Starting material: gas-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3((2K,6K)-2,6-dimethylpiperidin-4-yl)-5-fluorocinnoline dihydrochloride (obtained according to the method from example 7) MS m/z 419.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.92 (s, 1H), 8.32 (d, J= 10 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.76 (tt, J= 12.5, 3.5 Hz, 1H), 3.43 (m, 1H), 3.00 (m, 1H), 2.73 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 2.30 - 2.36 (dd, J= 13.5 Hz, 1H), 2.05 - 2, 15 (m, 2H), 1.8 (q, J= 12.5 Hz, 1H), 1.32 (d, J= 7 Hz, 3H), 1.23 (d, J= 6 Hz, 3H) . 125 Starting material: rac-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3((2K,6K)-2,6-dimethylpiperidin-4-yl)-5-fluorocinnoline hydrochloride (obtained according to the method from example 7) MS m/z 433.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.91 (s, 1H), 8.31 (d, J= I Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 3.65 - 3.80 (m, 2H), 3.13 - 3.27 (m, 2H), 2.73 (s, 3H), 2.64 (m, 1H), 2.51 (s, 3H), 2.31 (m, 1H), 2.13 (t, J = 13.5 Hz, 2H), 1.90 (q, J - 12.5 Hz, 1H), 1.34 (d, J= 6.5 Hz, 3H), 1.21 - 1.30 (m, 6H). 131 Starting material: gas-3-((2K,6K)-2,6-diethylpiperidin-4-yl)-7-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline (obtained according to the method from example 7) MS m/z 447.6 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.94 (s, 1H), 8.33 (d, J= 11 Hz, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 3.71 (m, 1H), 3.32 (m, 1H), 3.18 (br s, 1H), 2.73 (s, 3H), 2.66 ( s, 3H), 2.52 (s, 3H), 2.28 - 2.35 (m, 1H), 2.16-2.23 (m, 2H), 1.80 2.00 (m, 4H ), 1.51 (m, 1H), 1.08 (t, J= 7.5 Hz, 3H), 1.02 (t, J= 7.5 Hz, 3H). 132 Starting material: 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29 ) MS m/z 405.2 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 9.30 (s, 1H), 8.50 (d, J= 12 Hz, 1H), 7.99 (s, 1H), 7.37 (s, 1H), 3.37 (t, J= 13.2, 1H), 3.20 (d, J= 11.2, 2H), 2.93 (s, 3H), 2.69 (s, 3H), 2, 56 - 2.51 (m, 2H), 2.22 - 2.04 (m, 6H), 1.17 (t, J= 8 Hz, 3H), The proton corresponding to NH was not observed.

- 88 043655

135 Starting material: 5-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2,7dimethylthiazolo[5,4-b]pyridine dihydrochloride (prepared according to the procedure of Example 29) MS m/z 422.3 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.90 (s, 1H), 8.34 (dd, J = 11, 1.2 Hz, 1H), 7.93 (s, 2H), 3.42 (m , 1H), 3.33 (d, J= 12.4 Hz, 2H), 2.90 (s, 3H), 2.84 (s, 3H), 2.65 - 2.71 (m, 2H) , 2.37 - 2.39 (m, 2H), 2.24 - 2.29 (m, 2H), 2.13 - 2.20 (m, 2H), 1.23 (t.7=7, 4 Hz, 3H). 136 Starting Material: 2-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-4,6dimethyloxazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure of Example 29) MS m/z 406.2 [M+H] ⁺ ; Ή NMR (methanol- ₇₄ ) δ: 9.11 (s, 1H), 8.35 (dd, J = 9.9, 1.2 Hz, 1H), 8.25 (s, 1H), 7, 57 (s, 1H), 3.41 - 3.56 (m, 1H), 3.28 - 3.25 (m, 2H), 2.86 (s, 3H), 2.69 (s, 3H) , 2.61 (q, J= 7.2 Hz, 2H), 2.34 (td, J= 11.6, 2.1 Hz, 2H), 2.24 - 2.10 (m, 4H), 1.22 (t, J= 7.3 Hz, 3H). 147 Starting Material: 2-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-4,6dimethylthiazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure of Example 29) MS m/z 422.3 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 8.89 (s, 1H), 8.32 (dd, J = 10.1.2 Hz, 1H), 7.94 (s, 1H), 7.59 (s , 1H), 3.40 (m, 1H), 3.22 (d, J= 12.4 Hz, 2H), 3.04 (s, 3H), 2.68 (s, 3H), 2.54 - 2.57 (m, 2H), 2.21 - 2.25 (br s, 4H), 2.04 - 2.11 (m, 2H), 1.18 (t, J= 14.4 Hz, 3H). 152 Starting material: 5-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2,7dimethyloxazolo[5,4-b]pyridine dihydrochloride (prepared according to the procedure of Example 29) MS m/z 406.2 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 8.89 (s, 1H), 8.29 (dd, J = 10.6, 1.6 Hz, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 3.35 - 3.39 (m, 1H), 3.21 (d, J= 10.4 Hz, 2H), 2.70 (s, 6H), 2.55 (d, J= 6.8 Hz, 2H), 2.18 - 2.21 (m, 4H), 2.03 - 2.07 (m, 2H), 1.18 (t, 7= 7.2 Hz, 3H ). 155 Starting material: gas-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3((2K,6K)-2,6-dimethylpiperidin-4-yl)-5-fluorocinnoline hydrochloride (obtained according to the method from example 7) MS m/z 449.5 [M+H] ⁺ ; Ή NMR (DMSO-7 ₆ ) δ: 8.96 (s, 1H), 8.26 (d, 7= 11.5 Hz, 1H), 8.06 (m, 2H), 7.88 (s, 1H), 3.68 (m, 1H), 3.52 (t, 7= 6.5 Hz, 2H), 3.43 (m, 1H), 3.09 (br s, 1H), 2.83 (m, 1H), 2.60 - 2.70 (m, 4H), 2.47 (s, 3H), 2.22 (td, 7= 12.5, 5.5 Hz, 1H), 1, 98 (d, 7= 12 Hz, 1H), 1.90 (d, 7= 11.5 Hz, 1H), 1.70 (q, 7= 12.5 Hz, 1H), 1.26 (d, 7= 6.5 Hz, 3H), 1.13 (d, 7= 6.5 Hz, ZN), The proton corresponding to OH was not observed.

- 89 043655

161 Starting material: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3((28.4g,6K)-2,6-dimethylpiperidin-4-yl)-5-fluorocinnoline dihydrochloride (obtained according to the method from example 7) MS m/z 419.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.92 (s, 1H), 8.32 (d, J= 11 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.51 (m, 1H), 2.8 (br s, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 2.52 ( s, 3H), 2.20 (d, J= 11.5 Hz, 2H), 1.96 (q, J= 12.5 Hz, 2H), 1.37 (d, J= 6.5 Hz, 6H). 164 Starting Material: 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29 ) MS m/z 405.2 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.88 (s, 1H), 8.38 (dd, J= 10.8, 1.2 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.78 (d, J= 0.8 Hz, 1H), 4.32 (s, 3H), 3.32 3.44 (m, 3H), 2.86 (s, 3H ), 2.66 - 2.71 (m, 2H), 2.25 - 2.29 (m, 4H), 2.20 (s, 3H), 1.25 - 1.29 (m, 2H). 173 Starting material: 5-fluoro-7-(7-methoxy-2-methyl-2H-pyrazolo[4,3-b]pyridin5-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure in Example 29) MS m/z 421.1 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.84 (s, 1H), 8.37 (dd, J= 10.8, 1.2 Hz, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.29 (s, 1H), 4.29 (s, 3H), 4.22 (s, 3H), 3.34 3.41 (m, 1H), 3.20 (br d, J= 12 Hz, 2H), 2.50 - 2.55 (m, 2H), 2.17 - 2.23 (m, 4H), 1.98 - 2.08 (m, 2H) 1, 21 (t, J = 6.4 Hz, 3H). 174 Starting Material: 7-(7-ethyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5fluoro-3-(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 29 ) MS m/z 419.1 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.89 (s, 1H), 8.38 (dd, J= 10.9, 1.3 Hz, 1H), 8.24 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 4.31 (s, 3H), 3.39 (t, J= 11.9 Hz, 1H), 3.27 - 3.13 (m, 4H), 2.56 (dd, J= 14.0, 7.5 Hz, 2H), 2.24 (d, J= 10.5 Hz, 4H), 2.07 (dd, J= 24.6 , 12.5 Hz, 2H), 1.52 (t, J= 7.6 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H). 176 Starting Material: 6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazine-8-carbonitrile dihydrochloride (prepared according to the procedure of Example 29) MS m /z 402.4 [M+H] ⁺ ; ΉNMR (methanol^) δ: 9.22 (s, 1H), 9.17 (s, 1H), 8.58 (s, 1H), 8.43 (dd, J= 10.8, 0.9 Hz , 1H), 8.37 (s, 1H), 3.76 (br d, J= 12.5 Hz, 2H), 3.64 (tt, J= 10.6, 6.2 Hz, 1H), 3.35 (dd, J= 12.0, 4.4 Hz, 2H), 3.00 (s, 3H), 2.71 (s, 3H), 2.49 - 2.34 (m, 4H) ,Protons corresponding to HCl were not observed.

- 90 043655

178 Starting Material: 6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazine-8-carbonitrile dihydrochloride (prepared according to the procedure of Example 29) MS m /z 432.5 [Μ+Η] ⁺ ; Ή NMR (methanol-^) δ: 9.16 (s, 2H), 8.55 (s, 1H), 8.43 (br d, J= 10.22 Hz, 1H), 8.34 (s, 1H), 3.96 - 4.02 (m, 2H), 3.89 (br d, J= 12.51 Hz, 2H), 3.58 - 3.71 (m, 2H), 3.35 - 3.40 (m, 3H), 2.69 (s, 3H), 2.41 - 2.51 (m, 4H), No protons corresponding to OH and HCl were observed. 179 Starting material: 6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazine-8-carbonitrile (prepared according to the procedure of Example 29) MS m/ z 434.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.16 (s, 1H), 9.14 (s, 1H), 8.54 (s, 1H), 8.42 (d, J= 10.0 Hz, 1H ), 8.35 (s, 1H), 4.98 - 5.02 (m, 1H), 4.89 - 4.93 (m, 1H), 3.90 (br d, J= 12.5 Hz , 2H), 3.62 - 3.71 (m, 3H), 3.39 - 3.50 (m, 2H), 2.69 (s, 3H), 2.44 - 2.52 (m, 4H ), Protons corresponding to HCl were not observed. 180 Starting Material: (6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)methanol (prepared according to the procedure of Example 29) MS m/z 407.5 [M+H] ⁺ ; ΉNMR (methanol-^) δ: 8.94 (s, 1H), 8.33 - 8.39 (m, 1H), 8.25 (s, 1H), 8.04 (d, J= 1.98 Hz, 2H), 5.10 (s, 2H), 3.48 - 3.63 (m, 3H), 3.11 (br s, 2H), 2.87 (s, 3H), 2.50 ( s, 3H), 2.31 - 2.40 (m, 4H), The proton corresponding to OH was not observed. 181 Starting material: (6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)methanol dihydrochloride (prepared according to the procedure of Example 29 ) MS m/z 437.5 [M+H] ⁺ ; Ή NMR (methanol-J ₄ ) δ: 9.14 (s, 1 Η), 8.62 (s, 1 Η), 8.46 (s, 1 Η), 8.44 (d, J = 10, 1 Hz, 1 Η), 8.36 (s, 1 Η), 5.17 (s, 2 Η), 3.96 - 4.01 (m, 2 Η), 3.89 (br d, J= 12.7 Hz, 2 Η), 3.35 - 3.40 (m, 3 Η), 3.20 - 3.27 (m, 2 Η), 2.69 (s, 3 Η), 2.43 2.50 (m, 4 H), No protons corresponding to OH and HC1 were observed. 182 Starting material: (6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)methanol dihydrochloride MS m/z 439.5 [M+N] ⁺ ; Ή NMR (methanol-^) δ: 9.14 (s, 1H), 8.62 (s, 1H), 8.45 8.49 (m, 1H), 8.43 (d, J= 10 Hz, 1H), 8.33 - 8.37 (m, 1H), 5.17 (s, 2H), 4.91 - 5.06 (m, 2H), 3.90 (br d, J= 12.21 Hz, 2H), 3.61 - 3.72 (m, 3H), 3.37 - 3.47 (m, 2H), 2.69 (s, 3H), 2.43 - 2.54 (m, 4H), Protons corresponding to OH and HCl were not observed.

- 91 043655

188 Starting material: 3-(azepan-4-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6yl)-5-fluorocinnoline dihydrochloride (prepared according to the procedure of Example 7) MS m/z 405 ,3 [M+N] ⁺ ; Ή NMR (methanol-^) δ: 8.92 (s, 1H), 8.32 (d, J= 11.5 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H ), 7.89 (s, 1H), 3.62 (septet, J= 5 Hz, 1H), 3.03 - 3.09 (m, 1H), 2.85 - 2.92 (m, 3H) , 2.73 (s, 3H), 2.52 (s, 3H), 2.51 (s, 3H), 2.28 - 2.40 (m, 1H), 2.20 - 2.28 (m , 2H), 2.03-2.20 (m, 2H), 1.90 - 1.99 (m, 1H). 189 Starting material: gas-3-(azepan-4-yl)-7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluorocinnoline (prepared according to the procedure from example Ό MS m/z 419 ,3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.87 (s, 1H), 8.27 (d, J= 11 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 3.60 (septet, J= 5 Hz, 1H), 3.09 - 3.15 (m, 1H), 2.83 - 3 .00 (m, 3H), 2.75 (q, J= 7 Hz, 2H), 2.71 (s, 3H), 2.51 (s, 3H), 2.20 - 2.35 (m, 3H), 2.00 - 2.20 (m, 2H), 1.90 - 1.98 (m, 1H), 1.20 (t, J= 7 Hz, 3H). 190 Starting material: quench-3-(azepan-4-yl)-7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluorocinnoline (prepared according to the procedure of Example 7) MS m/z 435.3 [M+H] ⁺ ; W NMR (methanol- _J4 ) δ: 8.91 (s, 1H), 8.31 (d, J= 11 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H) , 7.87 (s, 1H), 3.76 (t, J= 6 Hz, 2H), 3.60 (m, 1H), 3.17 3.21 (m, 1H), 2.99-3 .07 (m, 3H), 2.88 (t, J = 6 Hz, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.00 - 2.34 (m, 5 H), 1.91-1.98 (m, 1H), The proton corresponding to OH was not observed. 197 Starting material: 2-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-4,6dimethylthiazolo[5,4-c]pyridine (prepared according to the procedure of Example 29) MS m/z 422 ,1 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.93 (s, 1H), 8.21 (dd, J= 9.9, 1.4 Hz, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 3.38-3.29 (m, 1H), 3.16 (d, J= 11.2 Hz, 2H), 2.79 (s, 3H), 2.64 (s, 3H), 2.49 (q, J= 7.2 Hz, 2H), 2.25 - 2.09 (m, 4H), 2.06 - 1.93 (m, 2H), 1.12 (t , J = 7.2 Hz, 3H). 200 Starting material: 5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6yl)-3-(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 29) MS m/ z 483.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.59 (s, 1H), 8.25 (dd, J= 10.8, 1.2 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.61 - 7.65 (m, 2H), 7.42 - 7.49 (m, 3H), 6.95 (s, 1H), 3.33 - 3.34 (m , 1H), 3.23 - 3.32 (m, 2H), 2.54 - 2.62 (m, 2H), 2.54 (s, 3H), 2.28 2.34 (m, 2H) , 2.07 - 2.19 (m, 4H), 1.20 (t, J= 7.2 Hz, 3H).

- 92 043655

205 Starting material: 2-(6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)acetonitrile dihydrochloride (prepared according to the procedure from example 29) MS m/z 430.2 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.00 (s, 1H), 8.39 (dd, J= 11, 1.6 Hz, 1H), 8.26 (s, 1H), 8.15 (s , 1H), 8.09 (s, 1H), 3.49 - 3.52 (m, 3H), 2.91 - 2.94 (m, 2H), 2.70 - 2.79 (br s, 2H), 2.56 (s, 3H), 2.22 - 2.35 (m, 6H), 1.32 (t, J= 7.2 Hz, 3H). 206 Starting material: 2-(6-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-2methylimidazo[1,2-b]pyridazin-8-yl)ethan-1-ol dihydrochloride ( obtained according to the method from example 29) MS m/z 435.2 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.96 (s, 1H), 8.36 (dd, J= 11.6, 1.2 Hz, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 4.09 (t, 7= 6.2 Hz, 2H), 3.34 - 3.37 (br s, 3H), 3.25 - 3 .28 (m, 2H), 2.61 - 2.63 (m, 2H), 2.53 (s, 3H), 2.34 (m, 2H), 2.14 2.20 (m, 4H) , 1.22 (t, J= 7.2 Hz, ZN), The proton corresponding to OH was not observed. 212 Starting material: 5-fluoro-7-(2-methyl-8-propylimidazo[1,2-b]pyridazin-6yl)-3-(piperidin-4-yl)cinnoline dihydrochloride (prepared according to the procedure of Example 29) MS m /z 433.1 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 8.84 (s, 1H), 8.22 (dd, 7= 10.4 Hz, 1.2 Hz, 1H), 7.95 (s, 1H), 7, 81 (s, 1H), 7.51 (s, 1H), 3.43 (t, 7=12 Hz, 1H), 3.26 (d, 7= 10.8 Hz, 2H), 3.12 ( t, 7 = 7.6, 2H), 2.60 (d, J= 7.2 Hz, 2H), 2.56 (s, 3H), 2.27 1.91 (m, 8H), 1, 21 (t, 7 = 7.2 Hz, 3H), 1.11 (1.7 = 7.2 Hz, ZN). 213 Starting Material: 2-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-4,6dimethyloxazolo[4,5-c]pyridine dihydrochloride (prepared according to the procedure of Example 29) MS m/z 422.1 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 9.11 (s, 1H), 8.22 (dd, 7= 9.6, 1.2 Hz, 1H), 7.90 (s, 1H), 7.25 (s, 1H), 3.80 - 3.66 (m, 2H), 3.46 - 3.27 (m, 3H), 2.87 2.70 (m, 5H), 2.64 - 2, 50 (m, 5H), 2.30 - 2.18 (m, 4H), No proton corresponding to OH was observed. 214 Starting material: 2-(5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl)-4,6dimethyloxazolo[4,5-c]pyridine (prepared according to the procedure of Example 29) MS m/z 392 ,1 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 9.17 (s, 1H), 8.26 (dd, J= 9.7, 1.3 Hz, 1H), 7.93 (s, 1H), 7.32 (s, 1H), 3.40 - 3.29 (m, 1H), 3.10 (d, 7= 11.7 Hz, 2H), 2.89 (s, 3H), 2.71 (s, 3H), 2.39 (s, 3H), 2.30 - 2.15 (m, 4H), 2.11 - 1.98 (m, 2H). 222 Starting material: 5-fluoro-7-(8-isopropyl-2-methylimidazo[1,2-b]pyridazin-6yl)-3-(piperidin-4-yl)cinnoline (prepared according to the procedure of Example 29) MS m/ z 433.2 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.97 (s, 1H), 8.36 (dd, 7= 10.9, 1.3 Hz, 1H), 8.22 (s, 1H), 8, 04 (s, 1H), 7.84 (s, 1H), 3.76 - 3.69 (m, 1H), 3.39 (d, 7= 11.7 Hz, 2H), 3.28 (s , 1H), 2.65 (dd, 7= 14.4, 7.2 Hz, 2H), 2.54 (s, 3H), 2.38 (t, 7= 11.0 Hz, 2H), 2 .27 - 2.10 (m, 4H), 1.54 (d, 7= 6.9 Hz, 6H), 1.23 (t, 7= 7.3 Hz, ZN).

Example 20

Receiving connection 18

1,4-dioxane:H ₂ O, 80 °C

Step A: 6-Bromo-2-chloroquinoline (300 mg, 1.2 mmol) was dissolved in THF (7.5 ml). A solution of KOtBu in THF (2.5 mL, 2.5 mmol, 1.0 M) was added to the solution. The mixture was heated at 40°C for 2 hours. The mixture was

- 93 043655 was divided between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in hexane to give 6-bromo-2-tert-butoxyquinoline (310 mg, 89%). MS m/z 224.2, 226.2 [M+H-tBu] ⁺ .

Step B: 6-Bromo-2-tert-butoxy-quinoline (310 mg, 1.11 mmol) was combined with bis(pinacolato)diborone (375 mg, 1.46 mmol), a 1,1'-bis(diphenylphosphino) complex ferrocenepalladium(P)dichloride dichloromethane (40 mg, 0.048 mmol), KOAc (300 mg, 3.03 mmol) and 1,4-dioxane (4 ml). The mixture was stirred at 90°C for 2 hours to obtain 2-tert-butoxy-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)quinoline as a crude mixture, which was used without cleaning. MS m/z 272.3 [M+H-tBu] ⁺ .

6-Bromo-2,8-dimethyl-imidazo[1,2-a]pyrazine (100 mg, 0.44 mmol) and 2-tert-butoxy-6-(4,4,5,5tetramethyl-1,3, 2-Dioxaborolan-2-yl)quinoline (164 mg, 0.50 mmol, prepared above) was combined with 1,G-bis(diphenylphosphino)ferrocene-palladium(P)dichloromethane dichloride complex (20 mg, 0.024 mmol), 1. 4-dioxane (2.5 ml) and an aqueous solution of 1 M K ₂ CO ₃ (1.5 ml). The mixture was heated at 80°C for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in hexane to give 2-tert-butoxy-6-(2,8dimethylimidazo[1,2-a]pyrazin-6-yl)quinoline (140 mg, 73%) . MS m/z 347.3 [M+H] ⁺ .

Step C: 2-tert-Butoxy-6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)quinoline (130 mg, 0.38 mmol) was suspended in 4N. HCl in 1,4-dioxane (1 ml, 4 mmol). The mixture was stirred at room temperature for 1 hour. Volatiles were removed. The residue was suspended in DMF (1 ml) with Cs ₂ CO ₃ (325 mg, 1.0 mmol). N,N-bis(trifluoromethylsulfonyl)aniline (107 mg, 0.30 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexanes to give [6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-quinolyl]trifluoromethanesulfonate (90 mg, 56 %). MS m/z 423.3 [M+H] ⁺ .

Step D: [6-(2,8-Dimethylimidazo[1,2-a]pyrazin-6-yl)-2-quinolyl]trifluoromethanesulfonate (90 mg, 0.21 mmol) was combined with 1-tert-butoxycarbonylpiperidine-4- ylzinc iodide (0.25 ml, 0.25 mmol, prepared according to the procedure of example 5, step B), 1,1'-bis(diphenylphosphino)ferrocene palladium(P)dichloromethane dichloride complex (8 mg, 0.01 mmol), 1,4-dioxane (2 ml). The mixture was heated at 80°C for 20 minutes. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-100% EtOAc in hexanes followed by 5% MeOH in EtOAc to give tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl) -2-quinolyl]piperidine-1-carboxylate (60 mg, 62%). MS m/z 458.4 [M+H] ⁺ .

Step E. tert-Butyl 4-[6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-quinolyl]piperidine-1carboxylate (60 mg, 0.1311 mmol) was dissolved in TFA (1 ml). After 20 min, volatiles were removed. The residue was partitioned between CH ₂ Cl ₂ and an aqueous solution of 1 M K ₂ CO ₃ . The organic layer was loaded directly onto silica gel, eluted with 0-20% MeOH (2 M NH3) in CH2Cl2 to give 6(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(piperidin-4 -yl)quinoline in the form of a white powder (15 mg, 32%).

MS m/z 358.4 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 9.17 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H ), 8.36 (dd, J=8.8, 2.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 3.11-3.17 (m, 2H), 2.98-3.05 (m, 1H), 2.83 (s, 3H), 2, 69-2.77 (m, 2H), 2.44 (s, 3H), 1.87-1.95 (m, 2H), 1.75-1.85 (m, 2H).

Using the procedure described above for Example 20, additional compounds described herein were prepared by substituting the appropriate arylboronic acid in Step B, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data

G 19 MS m/z 358.4 [M+H] ⁺ ; Ή NMR (DMSO-7 ₆ ) δ: 8.67 (d, J= 2.2 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.42 (dd.7= 8.8, 2.0 Hz, 1H), 8.11 (s, 1H), 8.08 (d, 7= 8.8 Hz, 1H), 7.82 (d, 7= 1.3 Hz, 1H), 7.57 (d, 7= 8.5 Hz, 1H), 3.24 - 3.30 (m, 2H), 3.09 - 3.15 (m, 1H), 2.84 -2 .91 (m, 2H), 2.65 (s, 3H), 2.43 (s, 3H), 1.87 - 1.95 (m, 2H), 1.75 - 1.85 (m, 2H ).______________________________________________________________________________

Example 21.

Receiving connection 55

- 94 043655 tert-Butyl 4-(7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluorocinnolin-3-yl)-3,6-dihydropyridin-1 (2H)carboxylate (25 mg , 0.053 mmol obtained according to example 7, step I) was stirred in the presence of HCl in dioxane (4 M, 1 ml, 4 mmol) for 1 hour. The reaction mixture was filtered and the solids were washed with ether, then 9:1 CH ₂ Cl ₂ :MeOH to give 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride (19 mg, 88 %).

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

Using the procedure described above for Example 2, additional compounds described herein were prepared by substituting suitable starting material, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 225 MS m/z 375.3 [M+H] ⁺ ; Ή NMR (chloroform-D) δ: 8.70 (s, IH), 8.08 (dd, J= 10.7, 1.0 Hz, IH), 7.86 (s, IH), 7.73 - 7.67 (m, IH), 7.40 (s, IH), 7.11 (br s, IH), 4.23 (dd, J = 6.8, 2.2 Hz, 2H), 3 .73 (dd, J= 5.2 Hz, 2H), 2.79 (br s, 2H), 2.69 (s, 3H), 2.48 (s, 3H), Protons corresponding to NH and HCl, were not observed. 208 MS m/z 431.5 [M+H] ⁺ ; Ή NMR (chloroform-D) δ: 8.81 - 8.89 (m, IH), 8.21 (d, J= 10.1 Hz, IH), 8.00 (s, IH), 7.82 (s, IH), 7.54 (d, J= 0.9 Hz, IH), 7.13 (br s, IH), 2.78 (s, 3H), 2.59 - 2.73 (br m, 2H), 2.53 - 2.57 (m, 3H), 1.43 (br s, 12H).

Example 22.

Receiving connection 4

Step A: 7-Bromocinnolin-3-ol (100 mg, 0.44 mmol, prepared according to the procedure used for 7-bromo-5-fluoro-cinnolin-3-ol in Example 7), tert-butyl 4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.65 mmol), Pd(dppf)Cl ₂ -CH _2Cl2 (50 mg, 0.061 mmol), DMF (2.5 ml) and aqueous K2CO3 ( ₂ M, 0.825 ml, 1.65 mmol) were heated at 80°C for 1 hour. The mixture was then partitioned between H2O and EtOAc. The organic layer was washed with H2O, and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by chromatography on silica gel (5% MeOH in CH ₂ Cl ₂ ) followed by trituration with ether gave tert-butyl 4-(3-hydroxycinnolin-7-yl)-3,6-dihydropyridine 1(2H)-carboxylate (110 mg) in the form of a yellow solid. MS m/z 328.0 [M+H] ⁺ .

Step B. tert-Butyl 4-(3-hydroxycinnolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (108 mg, 0.33 mmol), 1,1,1-trifluoro-N- Phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (143 mg, 0.4 mmol), Cs ₂ CO ₃ (175 mg, 0.54 mmol) and DMF (1 ml) were stirred at room temperature for 30 min. The mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with H ₂ O and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-5% EtOAc in CH ₂ Cl ₂ ) gave tert-butyl 4-(3-(((trifluoromethyl)sulfonyl)oxy)cinnolin-7-yl)-3,6-dihydropyridin- 1(2H)carboxylate (109 mg, 54% in two steps) as a white solid.

1H NMR (acetone^) δ: 8.53 (s, 1H), 8.43 (s, 1H), 8.28 (dd, J=9 Hz, 2 Hz, 1H), 8.23 (d, J =9 Hz, 1H), 6.69 (br s, 1H), 4.22 (s, 2H), 3.75 (m, 2H), 2.79 (m, 2H), 1.51 (s, 9H).

Step C. Mixture of tert-butyl 4-(3-(((trifluoromethyl)sulfonyl)oxy)cinnolin-7-yl)-3,6dihydropyridine-1(2H)-carboxylate (85 mg, 0.18 mmol), (2 -methyl-2H-indazol-5-yl)boric acid (51 mg, 0.29 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (40 mg, 0.05 mmol), dioxane (1.05 ml ) and an aqueous solution of K ₂ CO ₃ (2M, 220 µl, 0.44 mmol) were heated at 80°C for 90 min. The mixture was partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (20% acetone in CH2Cl2, then 5% MeOH in CH2Cl2). The resulting mate

- 95 043655 rial was triturated with 2:1 hexane:CH ₂ C1 ₂ . The solid material was collected and dried to give tert-butyl 4-(3(2-methyl-2H-indazol-5-yl)cinnolin-7-yl)-3,6-dihydropyridin-1(2H)-carboxylate (51 mg, 64%) in the form of a yellow solid.

1H NMR (DMSO-d6) δ: 8.72 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.21 (dd , J=9 Hz, 2 Hz, 1H), 8.11 (dd, J=9 Hz, 2 Hz, 1H), 8.06 (d, J=9 Hz, 1H), 7.80 (d, J =9 Hz, 1H), 6.61 (br s, 1H), 4.23 (s, 3H), 4.13 (s, 2H), 3.64 (t, J=5.5 Hz, 2H) , 2.72 (s, 2H), 1.46 (s, 9H).

Step D: Tert-Butyl 4-(3-(2-methyl-2H-indazol-5-yl)cinnolin-7-yl)-3,6-dihydropyridine1(2H)-carboxylate solution (51 mg, 0.12 mmol in CH ₂ Cl ₂ (1 ml) and TFA (0.3 ml) were stirred at room temperature for 1 hour. Volatiles were removed with a stream of N2. The solid material was triturated with 1N HCl in ether for 1 hour and volatiles were removed stream of N2 The residue was washed with 4:1 CH ₂ Cl ₂ :MeOH and dried to give 3-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4yl )cinnoline hydrochloride (42 mg, 100%) in the form of a light brown solid.

MS m/z 342.0 [M+H]+; 1H NMR (DMSOL) δ: 9.25 (br s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.22 (dd, J=9 Hz, 1.5 Hz, 1H), 8.14 (dd, J=9 Hz, 2 Hz, 1H), 8.10 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 1H), 6.65 (br s, 1H), 4.24 (s, 3H), 3.88 (s, 2H), 3.41 (m , 2H), 2.95 (s, 2H).

Example 23.

Receiving connection 24

Step A. Quinoxalin-2-ol (2.0 g, 13.7 mmol), concentrated H2SO4 (14 ml), Ag ₂ SO ₄ (2.12 g, 6.8 mmol) and Br ₂ (0.7 ml , 13.6 mmol) was stirred at room temperature for 15 hours. The mixture was filtered to remove AgBr. The solid was washed with sulfuric acid. The combined filtrate was poured onto ice. The white solid was collected by filtration, washed with H ₂ O, EtOH, and ether, and then dried to give 6-bromoquinoxalin-2-ol (2.7 g, 87%) as a light brown solid containing 10% unreacted starting material.

1H NMR (DMSO-d6) δ: 12.54 (br s, 1H), 8.21 (s, 1H), 7.99 (d, J=2 Hz, 1H), 7.73 (dd, J= 9 Hz, 2 Hz, 1H), 7.27 (d, J=9 Hz, 1H).

Step B. 6-Bromoquinoxalin-2-ol (200 mg, 0.88 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-7- (trifluoromethyl)-2H-indazole (300 mg, 1.09 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (50 mg, 0.061 mmol), DMF (5 ml), and aqueous K ₂ CO ₃ ( 2 M, 1.65 ml, 3.3 mmol) was heated at 90°C for 2 hours. A dilute aqueous solution of HCl was added to the mixture. The solid material was collected by filtration, washed with H ₂ O, EtOH and ether, and then dried to give crude 6-(2methyl-7-(trifluoromethyl)-2H-indazol-5-yl)quinoxalin-2-ol (231 mg). MS m/z 345.2 [M+H]+.

Step C. 6-(2-Methyl-7-(trifluoromethyl)-2H-indazol-5-yl)quinoxalin-2-ol (231 mg, 0.67 mmol), CH3CN (3 ml) and POBr3 (1.2 g, 4.18 mmol) was heated at 90°C for 15 hours. The mixture was diluted in ether and filtered. The solid material was washed with CH ₂ Cl ₂ . The mixture was dissolved in CH ₂ Cl ₂ :MeOH and filtered through a pad of silica to remove major impurities. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (30% EtOAc in CH ₂ Cl ₂ ). The product was triturated with CH2Cl2. The solids were collected and dried to give 2-bromo-6-(2-methyl-7-(trifluoromethyl)2H-indazol-5-yl)quinoxaline (117 mg, 32% in two steps) as an off-white solid.

1H NMR (acetone-d6) δ: 9.02 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.46 (d, J=2 Hz, 1H), 8.37 (dd, J=8.5 Hz, 2 Hz, 1H), 8.14-8.17 (m, 2H), 4.36 (s, 3H).

- 96 043655

Step D. 2-Bromo-6-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)quinoxaline (85 mg, 0.21 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(P) (10 mg, 0.013 mmol, 1,4-dioxane (0.5 ml), and (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1M in DMA, 0.5 ml, 0.5 mmol, prepared according to Example 5) was heated at 80°C for 2 hours. The mixture was partitioned between EtOAc and saturated aqueous NH ₄ Cl. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:1 CH ₂ Cl ₂ : EtOAc, then 20% acetone in CH ₂ Cl ₂ The collected material was triturated with 1:1 hexane:ether. The solid material was collected by vacuum filtration and dried to give tert-butyl 4-(6-(2-methyl-7(trifluoromethyl)-2H-indazol-5-yl)quinoxalin- 2-yl)piperidine-1-carboxylate (41 mg, 38%) as a pink solid.

1H NMR (acetone-06) δ: 8.97 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.39 (d, J=2 Hz, 1H), 8.26 (dd, J=8.5 Hz, 2 Hz, 1H), 8.14-8.17 (m, 2H), 4.36 (s, 3H), 4.25-4.34 (m , 2H), 3.42 (m, 1H), 2.90-3.15 (br s, 2H), 2.05-2.10 (m, 2H), 1.91 (qd, J=12, 5 Hz, 4 Hz, 2H), 1.50 (s, 9H).

Step E. tert-Butyl 4-(6-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)quinoxalin-2-yl)piperidine 1carboxylate (25 mg, 0.049 mmol) and 4N. HCl in dioxane (1 ml, 4 mmol) was heated at 80°C for 1 hour. The mixture was diluted in ether. The solid material was collected by vacuum filtration and dried to give 6-(2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoxaline hydrochloride as a yellow solid (20 mg , 91%).

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

Using the procedure described for Example 23, additional compounds described herein were prepared by substituting the appropriate boric acid in Step B, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 31 MS m/z 358.2 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.98 (s, 1H), 8.86 (s, 1H), 8.39 (d, J = 2 Hz, 1H), 8.27 (dd, J = 9 Hz, 2 Hz, 1H), 8.23 (s, 1H), 8.21 (d, J= 8.5 Hz, 1H), 8.00 (s, 1H), 4.46 (s, 3H) , 3.60 -3.69 (m, 2H), 3.46 - 3.54 (m, 1H), 3.24 - 3.33 (m, 2H), 2.75 (s, 3H), 2 ,33 - 2.40 (m, 2H), 2.21 - 2.31 (m, 2H), The proton corresponding to NH was not observed.

Example 24.

Receiving connection 5

- 97 043655

Step A: 4-Bromaniline (5.0 g, 29.1 mmol) was dissolved in EtOAc (60 ml) and Et ₃ N (5.25 ml, 37.5 mmol) at 0°C. Methyl 3-chloro-3-oxopropanoate (3.95 mL, 31.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and dilute HCl solution. The organic layer was washed with an aqueous NaHCO ₃ solution and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with 2:1 hexane:ether. The solid material was collected by vacuum filtration and dried to give ethyl 3-((4-bromophenyl)amino)-3-oxopropanoate (6.23 g, 75%) as a white solid.

'H NMR (acetone-d6) δ: 9.50 (br s, 1H), 7.64 (m, 2H), 7.49 (m, 2H), 4.19 (q, J=7 Hz, 2H ), 3.48 (s, 2H), 1.26 (t, J=7 Hz, 3H).

Step B: Ethyl 3-((4-bromophenyl)amino)-3-oxopropanoate (6.23 g, 22.1 mmol) was dissolved in THF (60 ml) and MeOH (15 ml) at 0°C. An aqueous solution of 2N was added dropwise to the mixture. NaOH (15 ml, 30 mmol). The mixture was stirred at 0°C for 1 hour, after which the excess reagent was quenched with an aqueous solution of 6N. HCl (7.5 ml). The mixture was concentrated under vacuum. The residue was suspended in H2O. The solid material was collected by vacuum filtration and dried to give 3-((4-bromophenyl)amino)-3-oxopropanoic acid (5.7 g, 100%) as a white solid.

1H NMR (acetone^) δ: 9.63 (br s, 1H), 7.64 (m, 2H), 7.49 (m, 2H), 3.50 (s, 2H), no CO2H proton observed.

Step C: Methanesulfonic acid (28 ml), 3-((4-bromophenyl)amino)-3-oxopropanoic acid (5.7 g, 22.1 mmol), and P ₂ O ₅ (9 g, 63.4 mmol ) were combined and heated at 80°C for 6 hours. The mixture was poured onto ice and the resulting solid was collected by suction filtration. The solid was washed with EtOH and ether and dried to give 6-bromo-2-hydroxyquinolin-4(1H)-one (3.48 g, 65%) as a brownish solid. MS m/z 240.0, 242.0 [M+H]+.

Step D: 6-Bromo-2-hydroxyquinolin-4(1H)-one (3.48 g, 14.5 mmol) and POCl ₃ (25 ml) were heated at 100°C for 15 hours. The mixture was poured into ice water . The resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (30% hexane in CH ₂ Cl ₂ ) to give 6-bromo-2,4-dichloroquinoline (2.9 g, 72%) as a white solid.

1H NMR (acetone^) δ: 8.42 (d, J=2 Hz, 1H), 8.06 (dd, J=9 Hz, 2 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 7.85 (s, 1H).

Step E: 6-Bromo-2,4-dichloroquinoline (2.82 g, 10.2 mmol) and 0.5 M NaOMe in MeOH (21.2 mL, 10.6 mmol) were combined and refluxed for 2 hours. The mixture was partitioned between H ₂ O and CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. Remainder

- 98 043655 was purified by silica gel chromatography (50-70% CH2C12 in hexane) to give 6-bromo-4-chloro-2methoxyquinoline (1.02 g, 37%).

1H NMR (acetone-d6) δ: 8.25 (d, J=2 Hz, 1H), 7.88 (dd, J=9.2 Hz, 1H), 7.80 (d, J=9 Hz, 1H), 7.22 (s, 1H), 4.06 (s, 3H).

Step F. 6-Bromo-4-chloro-2-methoxyquinoline (210 mg, 0.77 mmol), (2-methyl-2H-indazol-5yl)boric acid (161 mg, 0.91 mmol), Pd(PPh ₃ ) ₄ (90 mg, 0.078 mmol), 2 M aqueous K ₂ CO ₃ (1.4 ml, 2.8 mmol) and 1,4-dioxane (4.2 ml) were combined and heated at 80°C in for 1 hour. The reaction mixture was divided between CH ₂ Cl ₂ and H2O. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (30% EtOAc in CH ₂ Cl ₂ ). The collected product was ground in ether. The solid material was collected by vacuum filtration and dried to give 4-chloro-2-methoxy-6-(2-methyl-2H-indazol-5-yl)quinoline (182 mg, 73%) as a white solid.

^1H NMR (acetone- _d6 ) δ: 8.37 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.14 (dd, J=9 Hz, 2 Hz, 1H) , 8.11 (m, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.76-7.80 (m, 1H), 7.72 (dd, J=8.5 Hz, 1.5 Hz, 1H), 7.20 (s, 1H), 4.27 (s, 3H), 4.08 (s, 3H).

Step G: 4-Chloro-2-methoxy-6-(2-methyl-2H-indazol-5-yl)quinoline (120 mg, 0.37 mmol) was combined with Pd(dppf)Cl ₂ -CH ₂ Cl ₂ ( 35 mg, 0.043 mmol) in 1,4-dioxane (0.5 ml). Dimethylzinc (1.2 M in toluene, 1 ml, 1.2 mmol) was added to the mixture. The mixture was heated at 80°C for 4 hours. The reaction mixture was cooled to room temperature, after which the excess reagent was carefully quenched with MeOH. The mixture was partitioned between NH4OH and CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by silica gel chromatography (30% EtOAc in CH ₂ Cl ₂ ) followed by trituration with ether gave 2-methoxy-4-methyl-6-(2-methyl-2H-indazol-5-yl)quinoline (102 mg , 91%) in the form of a white solid.

1H NMR (acetone-d6) δ: 8.31 (s, 1H), 8.23 (d, J=2 Hz, 1H), 8.08 (t, J=1.5 Hz, 1H), 8, 02 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.89 (d, J=9 Hz, 1H), 7.74 (m, 2H), 6.88 (s, 1H) , 4.27 (s, 3H), 4.03 (s, 3H), 2.76 (s, 3H).

Step H. 2-Methoxy-4-methyl-6-(2-methyl-2H-indazol-5-yl)quinoline (100 mg, 0.33 mmol) and 4N. HCl in 1,4-dioxane (1.5 ml, 6 mmol) was heated at 110°C for 3 hours. The mixture was diluted in ether and filtered. The solid was dried to give 4-methyl-6-(2-methyl-2H-indazol-5-yl)quinolin-2-ol (82 mg, 84%) as a light brown solid. MS m/z 289.9 [M+H]+.

Step I: 4-Methyl-6-(2-methyl-2H-indazol-5-yl)quinolin-2-ol (82 mg, 0.28 mmol) and POCl ₃ (1.5 ml) were heated at 120°C for 2 hours. The mixture was poured onto ice. A saturated aqueous solution of NaHCO ₃ was added to ice to neutralize the mixture. The aqueous mixture was washed with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (5% MeOH in CH ₂ Cl ₂ ). The collected product was triturated with 1:1 acetone:CH ₂ Cl ₂ . The solids were collected and dried to give 2-chloro-4-methyl-6-(2-methyl-2H-indazol-5-yl)quinoline (84 mg, 100%) as an orange solid.

1H NMR (DMSO-d6) δ: 8.46 (s, 1H), 8.32 (d, J=2 Hz, 1H), 8.17-8.23 (m, 2H), 8.01 (d , J=9 Hz, 1H), 7.79 (dd, J=9 Hz, 1.5 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 7.52 (s, 1H) , 4.22 (s, 3H), 2.80 (s, 3H).

Step J. 2-Chloro-4-methyl-6-(2-methyl-2H-indazol-5-yl)quinoline (75 mg, 0.24 mmol), tert-butyl 4(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (93 mg, 0.3 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy -1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(P) (10 mg, 0.014 mmol), aqueous solution of 2 M K2CO3 (0.45 ml, 0.9 mmol) and DMF (1.35 ml) were combined and heated at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (30-50% EtOAc in CH ₂ Cl ₂ ). The collected product was triturated with ether. The solids were collected and dried to yield tert-butyl 4-(4-methyl-6-(2-methyl-2H-indazol-5yl)quinolin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate ( 73 mg, 67%) in the form of a white solid.

1H NMR (acetone-d6) δ: 8.32 (s, 1H), 8.31 (s, 1H), 8.14 (t, J=1.5 Hz, 1H), 8.06-8.12 (m, 2H), 7.75-7.80 (m, 2H), 7.73 (s, 1H), 6.86 (br s, 1H), 4.27 (s, 3H), 4.20 (s, 2H), 3.69 (t, J=5.5 Hz, 2H), 2.88 (m, 2H), 2.83 (s, 3H), 1.51 (s, 9H).

Step K: tert-Butyl 4-(4-methyl-6-(2-methyl-2H-indazol-5-yl)quinolin-2-yl)-3,6-dihydropyridine1(2H)-carboxylate (70 mg, 0 .15 mmol) was combined with 4:1 CH ₂ Cl ₂ :MeOH (1.5 ml) and 10% Pd/C (35 mg). The mixture was stirred at room temperature under H2 (1 atm) for 4 hours. The mixture was filtered through celite. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (1:1 CH2Cl2:EtOAc, then 20% acetone in CH2Cl2). The collected material was ground in ether. The solids were collected and dried to give tert-butyl 4-(4-methyl-6-(2-methyl-2H-indazol-5-yl)quinolin-2yl)piperidine-1-carboxylate (55 mg, 79%) as white solid.

1H NMR (acetone-d6) δ: 8.32 (s, 1H), 8.30 (s, 1H), 8.12 (t, J=1.5 Hz, 1H), 8.04-8.11 (m, 2H), 7.73-7.78 (m, 2H), 7.37 (s, 1H), 4.27 (m, 5H), 3.03-3.14 (m, 1H), 2.85-3.01 (m, 2H), 2.82 (s, 3H), 1.95-2.03 (m, 2H), 1.821.92 (m, 2H), 1.49 (s, 9H).

Step L. tert-Butyl 4-(4-methyl-6-(2-methyl-2H-indazol-5-yl)quinolin-2-yl)piperidine-1-carboxylate

- 99 043655 (53 mg, 0.12 mmol) and 4n. HCl in 1,4-dioxane (1 ml, 4 mmol) was combined and heated at 50°C for 1 hour. The mixture was diluted with ether. The solid material was collected by vacuum filtration, washed with 9:1 CH ₂ Cl ₂ :MeOH and dried to give 4-methyl-6-(2-methyl-2H-indazol-5-yl)-2-(piperidin-4yl)quinoline hydrochloride (46 mg, 100%) in the form of a yellow solid.

MS m/z 357.0 [M+H]+; ^1H NMR (DMSO-de) δ: 9.11-9.23 (br s, 1H), 8.95-9.10 (br s, 1H), 8.38-8.53 (m, 4H) , 8.28 (s, 1H), 7.83 (dd, J=9 Hz, 1.5 Hz, 1H), 7.72-7.80 (m, 2H), 4.23 (s, 3H) , 3.50-3.60 (m, 1H), 3.41-3.49 (m, 2H), 3.09 (m, 2H), 3.00 (s, 3H), 2.20-2 .38 (m, 4H).

Example 25.

Receiving connection 7

Step A: 6-Bromoquinolin-2-ol (670 mg, 3.0 mmol) was combined with piperazine (504 mg, 6.0 mmol), potassium tert-butoxide (840 mg, 7.5 mmol), 2-dicyclohexylphosphino- 2',6'-diisopropoxybiphenyl (280 mg, 0.6 mmol) and tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.3 mmol) in 1,4-dioxane (10 ml). The mixture was heated at 100°C for 16 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% MeOH in CH2C12 to give 6(piperazin-1-yl)quinolin-2-ol (575 mg, 84%). MS m/z 230.1 [M+H] ⁺ .

Step B: 6-(Piperazin-1-yl)quinolin-2-ol (575 mg, 2.5 mmol) was suspended in POC13 (4.6 ml, 50 mmol). The mixture was heated at 100°C for 16 hours. The mixture was slowly added to a vigorously stirred mixture of CH2C12 (100 ml), H2O (100 ml) and 10 g (NaHCO ₃ ). The organic layer was collected and concentrated. The residue was chromatographed on silica gel, eluted with 0-15% MeOH in CH2C12 to give 2-chloro-6-(piperazin-1-yl)quinoline (280 mg, 45%). MS m/z 248.1, 250.1 [M+H]+.

Step C: 2-Chloro-6-(piperazin-1-yl)quinoline (280 mg, 1.1 mmol) was combined with 2-methylindazole-5boric acid (387 mg, 1.5 mmol), a 1,1'- complex bis(diphenylphosphino)ferrocenepalladium(11)dichloromethane dichloride (80 mg, 0.10 mmol), 1,4-dioxane (10 ml), and aqueous 1 M K2CO3 (5 ml, 5 mmol). The mixture was stirred at 100°C for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-15% MeOH in CH2C12 to give 2-(2-methyl-2H-indazol-5-yl)-6-(piperazin-1-yl)quinoline (51 mg, 20%) .

MS m/z 344.1 [M+H]+; 1H NMR (DMSO-de) δ: 8.52 (s, 1H), 8.46 (s, 1H), 8.18-8.22 (m, 2H), 8.05 (d, J=8, 5 Hz), 7.88 (d, J=9.0 Hz), 7.69 (d, J=9.0 Hz), 7.60 (d, J=8.5 Hz), 7.18 ( s, 1H), 4.20 (s, 3H), 3.19-3.22 (m, 4H), 2.88-2.91 (m, 4H), No proton corresponding to NH was observed.

Example 26.

Receiving connection 117

Step A. Mixture of 7-bromo-3-chloro-5-fluorocinnoline (120 mg, 0.46 mmol, prepared according to example 7), tert-butyl 4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

- 100 043655 (153 mg, 0.49 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,G-biphenyl)(2'-amino-1,Gbiphenyl-2-yl) palladium (P ) (25 mg, 0.034 mmol) in 1,4-dioxane (3.5 ml) and an aqueous solution of 2 M K ₂ CO ₃ (0.7 ml, 1.4 mmol) was heated to 80°C for 2 hours. The crude reaction mixture was cooled to room temperature, filtered through celite and concentrated. The residue was chromatographed on silica gel, eluted with 10-50% EtOAc in hexanes to give tert-butyl 4-(3chloro-5-fluorocinnolin-7-yl)-3,6-dihydropyridin-1(2H)-carboxylate (120 mg, 72%) in the form of a brownish solid. MS m/z 364.4, 366.4 [M+H]+.

Step B. Mixture of 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2a]pyridine (69 mg, 0. 25 mmol), tert-butyl 4-(3-chloro-5-fluorocinnolin-7-yl)-3,6-dihydropyridine-1(2H)carboxylate (60 mg, 0.16 mmol) and chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)(2'amino-1,1'-biphenyl-2-yl) palladium(P) (12 mg, 0.016 mmol) in 1,4-dioxane (1 .5 ml) and an aqueous solution of 2 M K2CO3 (0.25 ml, 0.5 mmol) was heated to 90°C for 2 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated. The residue was chromatographed on silica gel, eluted with 5-10% MeOH in CH ₂ Cl ₂ to give tert-butyl 4-(5-fluoro-3-(8-fluoro-2methylimidazo[1,2-a]pyridin-6-yl )cinnolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (54 mg, 69%) as a brown solid. MS m/z 478.5 [M+H] ⁺ .

Step C. To a solution of tert-butyl 4-(5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnolin7-yl)-3,6-dihydropyridin-1 (2H)-carboxylate (54 mg, 0.11 mmol) in CH ₂ Cl ₂ (1.5 ml) was added trifluoroacetic acid (1.5 ml). The reaction mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was dissolved in HCl in MeOH (1.25 M) and concentrated. This procedure was repeated once again to obtain 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6tetrahydropyridin-4-yl) cinnoline hydrochloride (26 mg, 56%) in the form of a yellow solid.

MS m/z 378.4 [M+H] ⁺ ; 1H NMR (DMSO) δ: 9.82 (s, 1H), 9.35-9.42 (br s, 2H), 8.92 (s, 1H), 8.64 (d, J=11.9 Hz, 1H), 8.43 (s, 1H), 8.21-8.25 (br s, 1H), 8.13 (d, J=11.6 Hz, 1H), 6.74-6, 77 (br s, 1H), 3.87-3.92 (br s, 2H), 3.39-3.44 (m, 2H), 2.92-2.97 (m, 2H), 2, 53 (s, 3H).

Using the procedure described for Example 26, additional compounds described herein were prepared by substituting the appropriate boric acid in Step B, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 134 MS m/z 378.4 [M+H] ⁺ ; Ή NMR (DMSO-g7 ₆ ) δ: 9.21 - 9.26 (br s, 2H), 8.77 (s, 1H), 8.65 - 8.74 (m, 2H), 8.38 ( s, 1H), 8.12 (d, J= 13.4 Hz, 1H), 8.06 (d, J= 11.9 Hz, 1H), 6.70 - 6.74 (br s, 1H) , 4.27 (s, 3H), 3.85 - 3.90 (m, 2H), 3.35 - 3.44 (m, 2H), 2.90 2.95 (m, 2H).

- 101 043655

156 MS m/z 374.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.65 (s, IH), 8.89 (d, J= 1.0 Hz, IH), 8.69 (t, J= 1.2 Hz, IH), 8.46 (s, IH), 8.14 (d, J= 0.9 Hz, IH), 8.00 (dd, J= 11.1, 1.4 Hz, IH), 6.67 (dt , J= 3.4, 1.8 Hz, IH), 4.02 (d, J= 3.1 Hz, 2H), 3.61 (t, J= 6.1 Hz, 2H), 3.01 - 3.11 (m, 2H), 2.81 (s, 3H), 2.65 (s, ZH), Protons corresponding to NH and HCl were not observed. 157 MS m/z 374.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.82 (s, IH), 8.58 - 8.61 (m, 2H), 8.38 (s, IH), 8.14 (s, IH), 7 .97 (d, J= 10.4 Hz, IH), 6.64 - 6.67 (m, IH), 4.36 (s, 3H), 4.01 - 4.03 (m, 2H), 3.60 (t, J= 6.1 Hz, 2H), 3.04 - 3.08 (m, 2H), 2.75 (s, 3H), No protons corresponding to NH and HCl were observed. 165 MS m/z 378.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.73 (d, J= 2.4 Hz, IH), 8.37 (s, IH), 7.66 - 7.72 (m, IH), 7.62 (s, IH), 7.50 (d, J= 11.4 Hz, IH), 6.37 - 6.43 (m, IH), 6.24 - 6.28 (m, IH), 4, 34 - 4.39 (s, 3H), 3.92 - 3.97 (m, 2H), 3.51 - 3.55 (m, 2H), 2.84 - 2.93 (m, 2H), No protons corresponding to NH and HCl were observed. 166 MS m/z 377.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.70 (d, J= 9.8 Hz, IH), 8.57 (dd, J = 2.4, 1.4 Hz, IH), 8.44 (s , IH), 8.31 (d, J= 8.9 Hz, IH), 7.99 (s, IH), 7.94 (m, 2H), 6.52 (br s, IH), 4, 29 - 4.36 (m, 3H), 3.98 (d, J= 2.1 Hz, 2H), 3.58 (dd, J= 7.8, 6.1 Hz, 2H), 2.96 - 3.04 (m, 2H), No protons corresponding to NH and HCl were observed. 167 MS m/z 375.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.08 (s, IH), 8.86 (s, IH), 8.39 (s, IH), 8.32 (s, IH), 7.91 (d , J= 11.0 Hz, IH), 6.57 - 6.59 (br s, IH), 3.87 - 3.95 (m, 2H), 3.49 (t, J= 6.1 Hz , 2H), 2.94 - 2.98 (m, 2H), 2.78 (s, 3H), 2.59 (s, 3H), No protons corresponding to NH were observed. 171 MS m/z 379.4 [M+H] ⁺ ; Ή NMR (DMSO-D,) δ: 9.20 - 9.25 (br s, 2H), 8.96 (s, IH), 8.88 (s, IH), 8.41 (s, IH) , 8.36 (d,J = 12.5 Hz, IH), 8.11 (d, J= 11.6 Hz, IH), 6.73 6.76 (br s, IH), 4.62 ( s, 3H), 3.87 - 3.91 (m, 2H), 3.39 - 3.44 (m, 2H), 2.92 - 2.97 (m, 2H). 175 MS m/z 385.4 [M+H] ⁺ ; Ή NMR (DMSO-D,) δ: 9.25 (s, IH), 9.05 - 9.10 (br s, 2H), 8.90 (s, IH), 8.94 (s, IH) , 8.84 (s, IH), 8.41 (s, IH), 8.09 (d, J= 11.0 Hz, IH), 6.72 6.75 (m, IH), 4.32 (s, 3H), 3.88 - 3.92 (m, 2H), 3.40 - 3.45 (m, 2H), 2.91 - 2.96 (m, 2H). 198 MS m/z 388.3 [M+H] ⁺ . Ή NMR (DMSO-D,) δ: 8.67 (s, IH), 8.65 (s, IH), 8.52 (s, IH), 8.37 (s, IH), 8.08 ( s, IH), 7.86-7.88 (d, J= I Hz, IH), 6.45 (t, J= 6.5 Hz, IH), 4.34 (s, 3H), 3, 97 (m, 2H), 3.00 (m, 2H), 2.65 (s, 3H), 2.37 (m, 2H), 2.02, (m, 2H). The proton corresponding to NH was not observed.

Example 27.

Receiving connection 128

Suspension of 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4yl)cinnoline hydrochloride (22 mg, 0.05 mmol) and Pd/C (20 mg) in MeOH (2 ml) were stirred under H ₂ (1 atm) at room temperature for 12 hours. The mixture was filtered through celite and concentrated. The residue was dissolved in DMF (1 ml). MnO ₂ (45 mg, 0.5 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour, then filtered through celite. The filtrate was concentrated. The residue was dissolved in 1.25 M HCl in MeOH. After concentration, 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)cinnoline hydrochloride (15 mg, 62%) was obtained in the form of yellow solid matter.

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

Using the procedure described above for Example 27, additional compounds described herein were prepared by substituting suitable reagents and reaction conditions to produce compounds such as those selected from:

- 102 043655

Conn. Data 151 MS m/z 380.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.71 (s, 1H), 8.47 - 8.57 (m, 2H), 8.23 (s, 1H), 8.02 (d, J= 12, 2 Hz, 1H), 7.64 (d, J= 10.1 Hz, 1H), 4.31 (s, 3H), 3.62 (d, J= 11.6 Hz, 2H), 3.21 - 3.29 (m, 3H), 2.32 (d, J = 13.4 Hz, 2H), 1.97-2.15 (m, 2H), No protons corresponding to NH and HC1 were observed. 177 MS m/z 376.4 [M+H] ⁺ ; Ή NMR (DMSO-g7 ₆ ) δ: 9.00 - 9.07 (br s, 1H), 8.87 - 8.95 (br s, 1H), 8.60 - 8.66 (m, 2H) , 8.51 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.68 (d, J= 10.5 Hz, 1H), 4.23 (s, 3H), 3.46 - 3.55 (m, 1H), 3.15 - 3.22 (m, 2H), 3.01 - 3.10 (br s, 2H), 2.64 (s, 3H ), 2.12 - 2.19 (m, 2H), 1.98 - 2.07 (m, 2H). 185 MS m/z 377.3 [M+H] ⁺ ; Ή NMR (methanol-s/ ₄ ) δ: 9.21 (s, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.78 (d, J= 9.5 Hz, 1H), 3.63 (d, J= 12.5 Hz, 2H), 3.23 - 3.40 (m, 3H), 2.90 (s, 3H) , 2.71 (s, 3H), 2.34 (d, J= 14.0 Hz, 2H), 2.06 - 2.17 (m, 2H), Protons corresponding to NH and HC1 were not observed. 192 MS m/z 379.4 [M+H] ⁺ ; Ή NMR (methanol-D ₄ ) δ: 8.46 (d, J= 2.4 Hz, 1H), 8.35 - 8.40 (m, 2H), 8.16 (d, J= 8.9 Hz, 1H), 8.03 (dd, J= 13.2, 1.1 Hz, 1H), 7.61 (s, 1H), 7.48 (dd, J= 11.9, 1.5 Hz , 1H), 4.29 (s, 3H), 3.30 (br s, 2H), 2.88 - 3.01 (m, 3H), 2.04 (d, J = 12.5 Hz, 2H ), 1.80 - 1.90 (m, 2H), The proton corresponding to NH was not observed.

Example 28.

Receiving connection 144

To a suspension of 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)cinnoline hydrochloride (175 mg, 0.42 mmol) and sodium triacetoxyborohydride (900 mg, 4.2 mmol) in CH ₂ Cl ₂ (4 ml) and EtOH (1 ml), a solution of acetaldehyde (0.25 ml, 4.4 mmol) in EtOH (1 ml) was added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with a saturated aqueous solution of K ₂ CO ₃ . The mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The aqueous layer was extracted once with CH ₂ Cl ₂ . The combined organic parts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was subjected to silica gel chromatography and eluted with 0-20% 1.4N. NH ₃ /MeOH in CH ₂ Cl ₂ to give 7-(1-ethylpiperidin-4-yl)-5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6yl)cinnoline ( 120 mg, 70%) in the form of a light orange solid.

MS m/z 408.5 [M+H]+; 1H NMR (methanol^) δ: 9.29 (d, J=1.2 Hz, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 8.01 (dd, J= 12.2, 1.2 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.65 (d, J=10.7 Hz, 1H), 3.36-3, 39 (m, 2H), 2.98-3.09 (m, 1H), 2.76 (q, J=7.2 Hz, 2H), 2.44-2.55 (m, 5H), 2 .16 (d, J=13.1 Hz, 2H), 1.95-2.03 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).

Using the procedure described above for Example 28, additional compounds described herein were prepared by substituting suitable reagents and reaction conditions to produce compounds such as those selected from:

- 103 043655

Conn. Data 153 MS m/z 406.5 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.83 (s, 1H), 8.55 (d, J= 1.5 Hz, 2H), 8.38 (s, 1H), 8.01 (dd, J= 12.8, 1.2 Hz, 1H), 7.97 (dd, J= 11.3, 1.2 Hz, 1H), 6.63 - 6.67 (br s, 1H), 4, 32 (s, 3H), 4.25 (d, J= 13.1 Hz, 1H), 3.88 - 4.01 (m, 2H), 3.38 3.50 (m, 3H), 3, 10-3.18 (m, 2H), 1.49 (t, J = Ί.3 Hz, ZN), the proton corresponding to HC1 was not observed. 154 MS m/z 408.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.66 - 8.71 (m, 1H), 8.48 - 8.54 (m, 2H), 8.21 (s, 1H), 8.01 (dd, J= 12.8, 1.2 Hz, 1H), 7.63 (d, J= 10.7 Hz, 1H), 4.31 (s, 3H), 3.42 - 3.55 (m, 2H ), 3.12 (t, J= 12.4 Hz, 1H), 2.91 - 2.97 (m, 2H), 2.70 - 2.78 (m, 2H), 2.23 (d, J = 13.1 Hz, 2H), 1.98-2.14 (m, 2H), 1.33 (t, J = 7.3 Hz, 3H). 183 MS m/z 404.4 [M+H] ⁺ ; Ή NMR (DMSO-7 ₆ ) δ: 8.63 (d, J= 6.4 Hz, 2H), 8.51 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.74 (d, J= 10.4 Hz, 1H), 4.23 (s, 3H), 3.12 - 3.25 (m, 3H), 2.86 - 2.96 (m , 2H), 2.64 (s, 3H), 2.45 - 2.55 (m, 2H), 1.97 - 2.05 (m, 2H), 1.84 - 1.91 (m, 2H ), 1.06-1.17 (m, 3H). 184 MS m/z 405.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.83 (d, J= 9.5 Hz, 1H), 8.61 (d, J= 2.3 Hz, 1H), 8.45 (s, 1H), 8.35 (d, 7= 8.5 Hz, 1H), 8.07 (s, 1H), 8.02 (d, J= 11.7 Hz, 1H), 7.91 (d, J= 12 .4 Hz, 1H), 6.54 (br s, 1H), 4.33 (s, 3H), 4.22 (d, J= 15.4 Hz, 1H), 3.81 - 3.99 ( m, 2H), 3.37 - 3.49 (m, 3H), 3.04 - 3.15 (m, 2H), 1.48 (t, J= 7.2 Hz, 3H). 186 MS m/z 405.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.04 (d, J= 0.9 Hz, 1H), 8.39 (d, J= 1.2 Hz, 1H), 8.27 (s, 1H) , 8.05 (d, J= 0.9 Hz, 1H), 7.66 - 7.73 (m, 1H), 3.47 (d, J= 11.9 Hz, 2H), 3.07 - 3.17 (m, 1H), 2.90 (q, J= 7.2 Hz, 2H), 2.76 (d, J= 0.9 Hz, 3H), 2.69 (t, J= 11 .6 Hz, 2H), 2.54 (s, 3H), 2.23 (d, J= 13.7 Hz, 2H), 2.04 (qd, J= 12.9, 3.5 Hz, 2H ), 1.32 (t, J= 7.3 Hz, 3H). 193 MS m/z 407.5 [M+Hp^HNMR (methanol-7 ₄ ) δ: 8.47 (d, J= 2.4 Hz, 1H), 8.37 - 8.41 (m, 2H), 8.18 (d, J= 8.7 Hz, 1H), 8.04 (d, 7= 13.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, 7 = 12 .2 Hz, 1H), 4.30 (s, 3H), 3.42 - 3.52 (m, 2H), 2.87 - 3.01 (m, 3H), 2.59 - 2.76 ( m, 2H), 2.15 (d, 7= 16.6 Hz, 2H), 2.00 (m, 2H), 1.32 (t, 7= 7.3 Hz, 3H). 201 MS m/z 406.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.58 (s, 1H), 8.89 (s, 1H), 8.50 (d, 7 = 2.6 Hz, 1H), 8.24 (d, 7= 14.3 Hz, 1H), 7.97 (d.7= 11.6 Hz, 1H), 7.91 (s, 1H), 6.50 (br s, 1H), 4.29 (s , 3H), 2.92 (t, 7= 6.7 Hz, 2H), 2.77 - 2.83 (m, 2H), 2.70 (d, 7= 7.3 Hz, 2H), 1 .31 (br s, 2H), 1.25 (t, 7= 7.2 Hz, 3H). 202 MS m/z 408.3 [M+H] ⁺ ; Ή NMR (methanol- ₇₄ ) δ: 9.59 (br s, 1H), 8.91 (br s, 1H), 8.51 (br s, 1H), 8.25 (d, 7 = 13, 1 Hz, 1H), 7.82 (br s, 1H), 7.74 (d, 7= 12.4 Hz, 1H), 4.30 (br s, 3H), 3.68 (d, 7= 9.3 Hz, 2H), 3.20 (br s, 3H), 3.08 (br s, 2H), 2.28 (d, 7 = 14.8 Hz, 2H), 1.99 - 2.12 (m, 2H), 1.35 - 1.44 (t, 7 = 7.2 Hz, 3H).

Example 29.

Receiving connection 108

Step A: 1-Bromo-2,3-difluoro-5-nitrobenzene (10.0 g, 42.0 mmol, prepared in Example 7, Step A) was combined with tert-butyl 4-(3-ethoxy-3-oxo -propanoyl)piperidine-1-carboxylate (13.8 g, 46.2 mmol) in DMF (100 ml). Cs ₂ CO ₃ (27.4 g, 84.0 mmol) was added to the solution. Once added, the mixture turned dark red. The mixture was stirred at 60°C for 4 hours. The mixture was partitioned between EtOAc and water

- 104 043655 with a solution of 0.5 M HCl. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 4-[2-(2-bromo-6-fluoro-4-nitro-phenyl)-3-ethoxy3-oxo-propanoyl] piperidine-1-carboxylate (21.5 g) in the form of a crude oil. MS m/z 515.5, 517.5 [M-H] ^- .

Step B. The crude material from Step A was suspended in AcOH (40 ml) and an aqueous solution of conc. HCl (37 wt.%, 40 ml). The mixture was heated at 120°C for 4 hours, then 100°C for 16 hours. Volatiles were removed under reduced pressure. The residue was dissolved in MeOH (100 ml) and triethylamine (23.4 ml, 168.0 mmol). Di-tert-butyl dicarbonate (13.7 g, 63.0 mmol) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. Volatile material was removed from the mixture under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-[2-(2-bromo-6-fluoro-4-nitro-phenyl)acetyl]piperidine-1-carboxylate (10.2 g, 55%). MS m/z 443.5, 445.5 [M-H] ^- .

Step C. tert-Butyl 4-[2-(2-bromo-6-fluoro-4-nitro-phenyl)acetyl]piperidine-1-carboxylate (10 g, 22.5 mmol) was combined with Zn (73.2, 112 mmol), NH ₄ Cl (24.1 g, 450 mmol) and MeOH (100 ml). The mixture was stirred at 40°C for 3 hours. The mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated to give tert-butyl 4-[2-(4-amino-2-bromo-6-fluorophenyl)acetyl]piperidine-1-carboxylate (9.5 g, 100%). MS m/z 315.2, 317.2 [M-Boc+H]+.

Step D: tert-Butyl 4-[2-(4-amino-2-bromo-6-fluorophenyl)acetyl]piperidine-1-carboxylate (9.5 g, 23 mmol) was combined with CuCl (4.6 g , 46 mmol), CuCl ₂ (9.3 g, 69 mmol) and CH3CN (100 ml). Isoamyl nitrite (9.3 mL, 69 mmol) was added dropwise to the mixture at 0°C. The mixture was stirred at 60°C for 2 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-40% EtOAc in hexanes to give tert-butyl 4-[2-(2-bromo-4-chloro-6-fluorophenyl)acetyl]piperidine-1-carboxylate (7.5 g , 75% yield). 1H NMR (acetone-d ₆ ) δ: 7.56 (t, J=1.7 Hz, 1H), 7.34 (dd, J=9.1, 1.9 Hz, 1H), 4.15 (d, J=1.9 Hz, 2H), 4.11 (br d, J=12.0 Hz, 2H), 2.78-2.96 (m, 3H), 1.98 (br d, J=12 .3 Hz, 2H), 1.48-1.58 (m, 2H), 1.46 (s, 9H).

Step E. tert-Butyl 4-[2-(2-bromo-4-chloro-6-fluorophenyl)acetyl]piperidine-1-carboxylate (7.5 g, 17 mmol) was combined with benzoyl hydrazide (3.6 g, 26 mmol), CuI (0.32 g, 1.7 mmol), 1,10-phenanthroline (0.31 g, 1.7 mmol) and sodium tert-butoxide (3.36 g, 35 mmol) in DMF (50 ml). The mixture was stirred under N2 at 70°C for 1 hour. The mixture was partitioned between EtOAc and 0.25 M HCl (aq). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-40% EtOAc in hexane to give tert-butyl 4-(1-benzoyl-7-chloro-5-fluoro-2H-cinnolin-3-yl)piperidin-1-carboxylate (6 .4 g, 79%). MS m/z 470.6, 472.6 [M-H] ^- .

Step F: tert-Butyl 4-(1-benzoyl-7-chloro-5-fluoro-2H-cinnolin-3-yl)piperidin-1-carboxylate (6.2 g, 13 mmol) was suspended in conc. aqueous solution of HCl (37 wt.%, 30 ml) and EtOH (20 ml). The mixture was heated at 100°C for 24 hours. The mixture was cooled to 60°C. Air was bubbled through the mixture for 5 hours. Volatile material was removed with a stream of N2. To the crude residue was added MeOH (50 mL), triethylamine (7.4 mL, 53 mmol), and then di-tert-butyl dicarbonate (5.7 g, 26 mmol). The mixture was stirred at room temperature for 30 minutes. Volatiles were removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-60% EtOAc in hexanes to give tert-butyl 4-(7-chloro-5-fluoro-cinnolin-3-yl)piperidine-1-carboxylate (3.0 g, 62% ).

MS m/z 310.2, 312.2 [M-tBu+H] ⁺ . ¹ H NMR (acetone-d6) δ: 8.38 (s, 1H), 8.09 (s, 1H), 7.71 (dd, J=9.5, 1.9 Hz, 1H), 4, 26-4.38 (m, 2H), 3.49 (tt, J=12.0, 3.7 Hz, 1H), 3.00 (br s, 2H), 2.10-2.15 (m , 2H) 1.95 (qd, J=12.6, 4.4 Hz, 2H), 1.49 (s, 9H).

Step G: Powdered tert-butyl 4-(7-chloro-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (1.00 g, 2.73 mmol) was weighed into a 50 mL screw cap tube. then anhydrous 1,4dioxane (27 ml), then (Bpin) ₂ (0.76 g, 3.0 mmol), pre-catalyst SPhos Pd G2 (0.20 g, 0.27 mmol) and lastly powdered potassium acetate ( 1.02 g, 10.4 mmol). Argon was then passed through the yellow mixture for 2 min, the vapor phase was purged, and the tube was capped and hermetically sealed. The test tube was placed in an aluminum thermostat and vigorously stirred at 90°C for 3 hours. Then the reaction mixture was cooled to room temperature. The dark brown reaction mixture was filtered through celite. Celite was washed with EtOAc (60 ml). The brown filtrate was then washed with water (60 ml), 50% aq. NaHCO ₃ (2 times 60 ml), and brine (60 ml), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain tert-butyl 4-[5-fluoro-7-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-3yl]piperidine-1-carboxylate in the form of a crude dark brown powder without further purification.

MS m/z 490.5 [M+MeOH+H]+; 1H NMR (chloroform-d) δ: ppm 8.84 (s, 1H), 7.87 (s, 1H), 7.72 (d, J=9.5 Hz, 1H), 4.37 (br s , 2H), 3.45 (tt, 1H), 2.98 (br s, 2H), 2.16 (br d, J=13.6 Hz, 2H), 1.93 (qd, J=12, 6, 4.0, 2H), 1.52 (s, 12H), 1.42 (s, 9H).

- 105 043655

Step H: Solid 6-chloro-2-methyl-imidazo[1,2b]pyridazine-8-carbonitrile (0.14 g, 0.72 mmol) and anhydrous 1,4-dioxane (6, 56 ml), then tert-butyl 4[5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-3-yl]piperidine-1-carboxylate (0.30 g, 0.66 mmol), SPhos Pd G2 precatalyst (0.047 g, 0.065 mmol), granulated K ₂ CO ₃ (0.27 g, 1.96 mmol) and water (0.33 ml). The brown mixture was purged with argon for 5 min, then closed with a screw cap. The reaction mixture was vigorously stirred at 90°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with water (2 times 100 ml) and saline (100 ml), then dried over anhydrous Na ₂ SO ₄ was filtered and concentrated under reduced pressure. The dark brown crude material was purified by silica gel column chromatography (hexane/EtOAc gradient elution) to give tert-butyl 4-[7-(8-cyano-2-methyl-imidazo[1,2-b]pyridazin-6-yl) -5-fluoro-cinnolin-3-yl]piperidine-1-carboxylate (0.182 g, 57%) in the form of a yellow powder.

MS m/z 488.5 [M+H]+; ¹ H NMR (chloroform-d) δ: 8.87 (s, 1H), 8.18 (d, J=10.2 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 4.37 (br d, J=5.6 Hz, 2H), 3.49 (tt, J=12.0, 3.4 Hz, 1H), 2 .98 (br t, J=12.2 Hz, 2H), 2.63 (s, 3H), 2.16 (br d, J=12.5 Hz, 2H), 1.93 (qd, J= 12.6, 4.0 Hz, 2H), 1.50 (s, 9H).

Stage I. tert-Butyl 4-[7-(8-cyano-2-methyl-imidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnolin-3yl]piperidine-1-carboxylate (0.060 g, 0.12 mmol) was dissolved in anhydrous 1,4-dioxane (4 ml), and a 4.0 M solution of HCl in 1,4-dioxane (0.15 ml, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, after which the reaction was concentrated on a rotary vacuum evaporator. The crude product was triturated in Et ₂ O (5 ml) then dried under high vacuum to give 6-[5-fluoro-3-(4-piperidyl)cinnolin-7-yl]-2-methyl-imidazo[1,2- b]pyridazine-8-carbonitrile hydrochloride (0.060 g, 100%) in the form of a brownish solid.

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

Using the procedure described above for Example 29, additional compounds described herein were prepared by replacing the appropriate aryl halide in Step H, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 91 MS m/z 363.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.77 (d, J= 2.4 Hz, 1H), 9.54 (d, J= 2.1 Hz, 1H), 8.84 (s, 1H), 8.35 (s, 1H), 8.16 (d, J= 9.2 Hz, 1H), 8.08 (s, 1H), 3.61 3.70 (m, 3H), 3.28 - 3.37 (m, 2H), 2.67 (s, 3H), 2.31 - 2.44 (m, 4H), No protons corresponding to NH and HCl were observed. 92 MS m/z 380.4 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.27 (d, J= 1.2 Hz, 1H), 8.78 (s, 1H), 8.46 (dd, J= 11.0, 1.2 Hz, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.12 (dd, J= 10.4, 1.5 Hz, 1H), 3.59 - 3.69 (m, 3H), 3.27 - 3.37 (m, 2H), 2.66 (d, J= 0.9 Hz, 3H), 2.32 - 2.45 (m, 4H), Protons, the corresponding NH and HCl were not observed. 93 MS m/z 387.5 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.61 (d, J= 1.5 Hz, 1H), 9.01 (d, J= 1.5 Hz, 1H), 8.80 (s, 1H) , 8.31 (s, 1H), 8.21 (d, J= 1.2 Hz, 1H), 8.13 (dd, J= 10.5, 1.7 Hz, 1H), 3.60 - 3.70 (m, 3H), 3.28 - 3.36 (m, 2H), 2.66 (d, J= 0.9 Hz, 3H), 2.31 - 2.45 (m, 4H) ,Protons corresponding to NH and HCl were not observed. 94 MS m/z 363.4 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.47 (s, 1H), 8.75 (s, 1H), 8.44 (br d, J= 9.5 Hz, 1H), 8.29 (s , 1H), 8.15 (dd, J= 10.7, 1.5 Hz, 1H), 7.99 (d, J= 9.5 Hz, 1H), 3.60 - 3.69 (m, 3H), 3.25 - 3.37 (m, 2H), 2.69 (s, 3H), 2.30 - 2.44 (m, 4H), No protons corresponding to NH and HCl were observed. 95 MS m/z 362.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.61 (s, 2H), 8.47 (s, 1H), 8.40 (s, 1H), 8.19 (dd, J= 10.7, 1, 2 Hz, 1H), 8.03 (dd, J= 9.0, 1.7 Hz, 1H), 7.87 (d, J= 9.2 Hz, 1H), 4.36 (s, 3H) , 3.62 - 3.70 (m, 3H), 2.39 - 2.46 (m, 2H), 2.28 - 2.39 (m, 2H), Protons corresponding to NH and HCl were not observed; CHg is overlapped by the solvent peak. 96 MS m/z 380.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.99 (s, 1H), 8.51 (d, J = 17.4 Hz, 2H), 8.32 (d, 7 = 10.7 Hz, 1H), 8.18 (s, 1H), 7.59 (d, J= 12.2 Hz, 1H), 4.25 (s, 3H), 3.72 (t, J= 10.1 Hz, 1H), 3.61 (d, 7= 12.2 Hz, 2H), 3.28-3.32 (m, 2H), 2.22-2.47 (m, 4H), Protons corresponding to NH and HCl, not were observed. 97 MS m/z 380.4 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.06 (s, 1H), 8.84 (s, 1H), 8.60 (s, 1H), 8.41 (br d, 7= 7.0 Hz , 1H), 8.22 (br d, 7= 10.1 Hz, 1H), 7.66 (d, 7= 11.3 Hz, 1H), 4.40 (s, 3H), 3.82 ( t, 7= 10.4 Hz, 1H), 3.68 (d, 7= 12.5 Hz, 2H), 3.35-3.42 (m,

- 106 043655

2H), 2.47 (d, J= 11.9 Hz, 2H), 2.33-2.44 (m, 2H), Protons corresponding to NH and HC1 were not observed. 99 MS m/z 363.4 [M+H] ⁺ ; Ή NMR (methanol-d4) δ: 9.14 (s, 1H), 8.59 (d, J= 9.8 Hz, 1H), 8.47 (d, J= 10.1 Hz, 1H), 8.44 (dd, J= 10.7, 1.5 Hz, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 3.60 - 3.70 (m, 3H) , 3.30 - 3.35 (m, 2H), 2.67 (d, J= 0.9 Hz, ZN), 2.31 - 2.43 (m, 4H), Protons corresponding to NH and HCl, were not observed. 101 MS m/z 376.5 [M+H] ⁺ ; Ή NMR (methanol-d4) δ: 8.84 (d, J= 1.2 Hz, 1H), 8.81 (s, 1H), 8.39 (s, 2H), 8.29 (s, 1H ), 8.21 (dd, J= 10.4, 1.2 Hz, 1H), 3.62 - 3.67 (m, 3H), 3.28 - 3.33 (m, 2H), 3, 04 (s, 3H), 2.55 (s, 3H), 2.30 - 2.43 (m, 4H), No protons corresponding to NH and HCl were observed. 103 MS m/z 376.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.21 (s, 1H), 8.75 (s, 1H), 8.27 8.39 (m, 2H), 8.12 (d, J= 10.6 Hz, 1H), 8.08 (s, 1H), 3.62 - 3.69 (m, 3H), 3.29 - 3.36 (m, 2H), 2.78 (s, 3H), 2 .65 (s, 3H), 2.30 - 2.45 (m, 4H), No protons corresponding to NH and HCl were observed. 104 MS m/z 387.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.67 (d, J= 1.5 Hz, 1H), 8.64 (s, 1H), 8.64 (br s, 1H), 8.63 (br s , 1H), 8.42 (d, J= 1.5 Hz, 1H), 8.25 (br d, J= 10.1 Hz, 1H), 4.36 (s, 3H), 3.69 - 3.75 (m, 1H), 3.66 (d, J= 12.8 Hz, 2H), 2.42 (d, J= 12.5 Hz, 2H), 2.35 (qd, J= 12 ,8, 3.4 Hz, 2H), No protons corresponding to NH and HCl were observed, CH 2 overlapped by the solvent peak. 105 MS m/z 391.2 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.86 (s, 1H), 8.23 (dd, J= 10.8, 1.5 Hz, 1H), 7.92 (s, 1H), 7.81 (d, J= 0.7 Hz, 1H), 7.53 (s, 1H), 3.42 - 3.52 (m, 1H), 3.33 (br d, J= 12.2 Hz, 2H ), 3.20 (q, J= 7.6 Hz, 2H), 2.87 - 2.96 (m, 2H), 2.56 (s, 3H), 2.14 - 2.22 (m, 2H), 1.92 (dq, J= 11.2, 4.2 Hz, 2H), 1.51 (t, J= 7.6 Hz, ZH), The proton corresponding to NH was not observed. 106 MS m/z 393.1 [M+H] ⁺ ; Ή NMR (DMSO^b) δ: 9.18 (s, 1H), 8.39 (dd, J= 11, 1.5 Hz, 1H), 8.16 (s, 1H), 8.09 (d , J= 0.7 Hz, 1H), 7.56 (s, 1H), 4.22 (s, 3H), 3.47-3.56 (m, 3H), 3.01 - 3.09 ( m, 2H), 2.39 (s, 3H), 2.07 - 2.24 (m, 4H), No proton corresponding to NH was observed. 107 MS m/z 393.1 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 8.93 (s, 1H), 8.32 (d, J= 11 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 5.77 (br s, 1H), 4.99 (s, 2H), 3.12 - 3.20 (m, 3H), 2.71 - 2.80 (m , 2H), 2.43 (s, 3H), 1.96 - 2.03 (m, 2H), 1.82 - 1.96 (m, 2H), No proton corresponding to NH was observed. 109 MS m/z 380.4 [M+H] ⁺ ; Ή NMR (methanol^) δ: 9.22 (s, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.31 (d, J= 10.4 Hz, 1H) , 7.82 (t, J= 8.2 Hz, 1H), 7.68 (d, J= 8.9 Hz, 1H), 4.37 (s, 3H), 3.85 (t, J= 11.3 Hz, 1H), 3.68 (d, J= 12.2 Hz, 2H), 3.34 - 3.42 (m, 2H), 2.48 (d, J= 12.8 Hz, 2H), 2.39 (q, J= 11.8 Hz, 2H), Protons corresponding to NH and HCl were not observed. 112 MS m/z 403.1 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.78 (s, 1H), 8.22 (d, J= 12Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7 .10 (s, 1H), 3.33 - 3.49 (m, 1H), 3.31 (d, J= 12.4 Hz,

- 107 043655

2H), 2.90 (t, J= 12.2 Hz, 2H), 2.70 - 2.74 (m, 1H), 2.56 (s, 3H), 2.17 (d, J= 12 ,4 Hz, 2H), 1.85 - 1.92 (m, 2H), 1.25 - 1.38 (m, 2H), 1.22 - 1.25 (m, 2H), Proton corresponding to NH , was not observed. 118 MS m/z 393.1 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.59 (s, 1H), 8.03 (d, J= 1.2 Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J= 10.4, 1.2 Hz, 1H), 7.63 (s, 1H), 3.43 - 3.50 (m, 3H), 3.01 (t, J= 12 Hz, 2H), 2.90 (s, 3H), 2.83 (s, 3H), 2.25 (d, J = 13.2 Hz, 2H), 2.03 2.06 (m, 2H), Proton corresponding to NH , was not observed. 126 MS m/z 377.2 [M+H] ⁺ ; Ή NMR (DMSO-7 ₆ ) δ: 9.13 (s, 1H), 8.41 (d, J= 10.5 Hz, 1H), 8.11 (s, 1H), 7.33 (s, 1H), 3.43 (s, 2H), 3.24 (s, 1H), 3.16 (d, J= 12.0 Hz, 2H), 2.78 (s, 3H), 2.55 ( s, 3H), 2.05 - 1.82 (m, 4H), No protons corresponding to NH were observed. 133 MS m/z 394.1 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.03 (s, 1H), 8.47 (dd, J= 11.2, 1.6 Hz, 1H), 8.24 (s, 1H), 8.22 ( s, 1H), 3.59 - 3.63 (m, 3H), 3.24 - 3.28 (m, 2H), 2.92 (s, 3H), 2.85 (s, 3H), 2 .29 - 2.37 (m, 4H), a proton corresponding to NH was observed 137 MS m/z 378.0 [M+H] ⁺ ; ^X H NMR (DMSO-7b) δ: 9.00 (s, 1H), 8.29 (d, J= 9.8 Hz, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 3.22 - 3.31 (m, 1H), 3.14 (d, J= 11.9 Hz, 2H), 2.76 (s, 3H), 2.71 (d, J= 11 .0 Hz, 2H), 2.60 (s, 3H), 1.97 - 2.00 (m, 2H), 1.82 - 1.93 (m, 2H). 148 MS m/z 378.1 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.91 (s, 1H), 8.54 (dd, J= 11, 1.6 Hz, 1H), 7.89 (s, 2H), 3.42 - 3.48 (m, 1H), 3.33 (br d, J= 12 Hz, 2H), 2.89 - 2.95 (m, 2H), 2.73 (s, 6H), 2.16 - 2.19 (m, 2H), 1.92 - 1.96 (m, 2H), No proton corresponding to NH was observed. 148 MS m/z 394.1 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.89 (s, 1H), 8.33 (dd, J= 10, 1.2 Hz, 1H), 7.91 (s, 1H), 7.59 ( s, 1H), 3.44 - 3.50 (m, 1H), 3.33 (d, J= 12.4 Hz, 2H), 3.04 (s, 3H), 2.89 - 2.95 (m, 2H), 2.68 (s, 3H), 2.18 (d, J = 12.4 Hz, 2H), 1.90 - 1.94 (m, 2H), Proton corresponding to NH, not observed. 162 MS m/z 377.1 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.89 (s, 1H), 8.38 (dd, J= 9.6, 1.2 Hz, 1H), 8.24 (s, 1H), 7, 91 (s, 1H), 7.79 (s, 1H), 4.32 (s, 3H), 3.38 - 3.51 (m, 3H), 2.94 - 3.00 (m, 2H) , 2.78 (s, 3H), 2.21 - 2.24 (m, 2H), 1.97 - 2.07 (m, 2H), No proton corresponding to NH was observed. 163 MS m/z 393.1 [M+H] ⁺ ; Ή NMR (chloroform-t/) δ: 8.88 (s, 1H), 8.42 (dd, J= 10.8, 1.2 Hz, 1H), 8.20 (s, 1H), 7, 97 (s, 1H), 7.31 (s, 1H), 4.29 (s, 3H), 4.23 (s, 3H), 3.57 3.62 (m, 3H), 3.05 - 3.15 (m, 4H), 2.31 - 2.36 (m, 2H), No proton corresponding to NH was observed. 172 MS m/z 391.2 [M+H] ⁺ ; Ή NMR (DMSO-7 ₆ ) δ: 9.06 (s, 1H), 8.74 (s, 1H), 8.44 - 8.57 (m, 1H), 8.08 (d, J= 12 .9 Hz, 2H), 4.26 (s, 3H), 3.03 - 3.20 (m, 4H), 2.95 (d, J= 7.9 Hz, 1H), 2.71 (t , 7= 11.6 Hz, 2H), 1.97 (d, 7= 11.9 Hz, 2H), 1.85 (qd, 7= 12.3, 3.9 Hz, 2H), 1.44 (t, 7= 7.6 Hz, 3H).

- 108 043655

187 MS m/z 402.2 [M+H] ⁺ ; Ή NMR (chloroform-d) δ: 8.94 (s, 1H), 8.62 (br s, 1H); 8.23 (dd, J= 10.4, 1.2 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 4.32 (s, 2H), 3.56 3.60 (m, 3H), 3.11 (br s, 2H), 2.56 (s, 3H), 2.26 - 2.35 (m, 4H). 194 MS m/z 429.1 [M+H] ⁺ ; Ή NMR (methanol-d^δ: 9.29 (s, 1H), 9.15 (s, 1H) 8.55 (br s, 2H), 8.27 - 8.28 (m, 2H), 8 .19 (s, 1H), 7.33 (s, 1H), 3.60 - 3.64 (m, 3H), 3.25 - 3.29 (m, 2H), 2.58 (s, 3H ), 2.30 - 2.41 (m, 4H), The proton corresponding to NH was not observed. 195 MS m/z 455.2 [M+H] ⁺ ; Ή NMR (methanol-d^δ: 8.59 (s, 1H), 8.25 (dd, J= 10.8, 1.2 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.61 - 7.65 (m, 2H), 7.42 - 7.49 (m, 3H), 6.96 (s, 1H), 3.59 - 3.63 (m , 3H), 3.25 - 3.28 (m, 2H), 2.55 (s, 3H), 2.27 - 2.38 (m, 4H), No proton corresponding to NH was observed. 196 MS m/z 394.0 [M+H] ⁺ ; Ή NMR (DMSO-de) δ: 9.00 (s, 1H), 8.30 - 8.48 (m, 2H), 8.17 (s, 1H), 7.80 (s, 1H), 3 .44 - 3.51 (m, 1H), 3.33 (d, J= 10.2 Hz, 2H), 2.89 - 3.00 (m, 2H), 2.75 (s, 3H), 2.60 (s, 3H), 2.00 - 2.17 (m, 4H). 204 MS m/z 405.2 [M+H] ⁺ ; Ή NMR (methanol-d^δ: 8.93 (s, 1H), 8.33 (dd, J= 10.9, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J= 0.6 Hz, 1H), 7.86 (s, 1H), 3.43 - 3.50 (m, 2H), 3.26 - 3.31 (m, 1H), 3, 09 (t, J= 8 Hz, 2H), 2.91 - 2.98 (m, 2H), 2.53 (s, 3H), 2.17 (d, J= 12.2 Hz, 2H), 1.90 - 2.08 (m, 4H), 1.12 (t, J= 7.4 Hz, ZH), The proton corresponding to NH was not observed. 207 MS m/z 407.2 [M+H] ⁺ ; Ή NMR (methanol-d^δ: 9.05 (s, 1H), 8.42 (dd, J= 10.8, 1.2 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 4.10 (t, J= 6 Hz, 2H), 3.63 - 3.66 (br s, 3H), 3.35 - 3.36 (m, 2H), 3.28 - 3.32 (m, 2H), 2.58 (s, 3H), 2.32 - 2.42 (m, 4H), NH and OH protons were not observed. 211 MS m/z 405.2 [M+H] ⁺ ; Ή NMR (methanol-d^δ: 8.94 (s, 1H), 8.33 (dd, J= 10.9, 1.3 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J= 0.7 Hz, 1H), 7.82 (s, 1H), 3.74 - 3.67 (m, 1H), 3.48 - 3.44 (m, 1H), 3, 36 (s, 2H), 2.97 (td, J= 12.5, 2.6 Hz, 2H), 2.53 (s, 3H), 2.19 (d, J= 12.7 Hz, 2H ), 3.01 - 2.94 (m, 2H), 1.53 (d, J= 6.9 Hz, 6H) The proton corresponding to NH was not observed.

Halides for use in step H were prepared according to the following procedures.

Example 29-1.

8-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloro-2-methylimidazo[1,2-b]pyridazine.

Step A. LiAlH ₄ (2.42 g, 64 mmol) was slowly added to ethyl 3-amino-6-chloropyridazine-4-carboxylate (4.0 g, 19.9 mmol) in dry THF (1 ml) at 0° WITH. The mixture was stirred at 0°C for 30 minutes. The excess reagent was carefully quenched with water (1 ml), then a 15% aqueous NaOH solution (1 ml) was added. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give (3-amino-6-chloropyridazin-4yl)methanol (1.0 g, 32%). MS m/z 160.1, 162.1 [M+H] ⁺ .

Step B: (3-Amino-6-chloropyridazin-4-yl)methanol (1.0 g, 6.3 mmol) was combined with DIEA (2.44 g, 18.8 mmol) and 1-bromopropan-2-one (860 mg, 6.3 mmol) in isopropyl alcohol (10 ml). The reaction vessel was degassed, and then purged with nitrogen three times. The mixture was stirred at 80°C for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-50% EtOAc in petroleum ether to give (6-chloro-2-methylimidazo[1,2b]pyridazin-8-yl)methanol (0.9 g, 73%). MS m/z 198.2, 200.2 [M+H] ⁺ .

Step C: (6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)methanol (900 mg, 4.5 mmol) was combined with TBS-C1 (1.72 g, 9.1 mmol) and imidazole (1.24 g, 14.6 mmol) in CH ₂ C1 ₂ (15 ml). The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in petroleum ether to give 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-2-methylimidazo[1,2-b]pyridazine (500 mg , 35.2% yield). MS m/z 312.1, 314.1 [M+H] ⁺ .

Example 29-2.

6-Chloro-8-ethyl-2-methylimidazo[1,2-b]pyridazine.

Step A: 6-Chloropyridazine-3-amine (50 g, 388 mmol) and NaHCO ₃ (65 g, 775 mmol) were combined in MeOH (500 ml). Br ₂ (30 ml, 580 mmol) was added dropwise to the mixture at 0°C. The mixture was stirred at room temperature for 16 hours. Half of the solvent volume was removed under reduced pressure. The rest was poured into water. The resulting solid was collected and dried to give 4-bromo-6-chloropyridazin-3-amine (80 g, 99%). MS m/z 207.9 [M+H] ⁺ .

Step B: 4-Bromo-6-chloropyridazin-3-amine (20 g, 97 mmol), Na ₂ CO ₃ (10.2 g, 97 mmol) and 1 bromopropan-2-one (9.7 ml, 116 mmol) added to isopropyl alcohol (200 ml). The reaction vessel was degassed, and then purged with nitrogen three times. The mixture was stirred at 90°C for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over

- 109043655

Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in petroleum ether to give 8-bromo-6-chloro-2-methylimidazo[1,2b]pyridazine (8.1 g, 34%). MS m/z 245.9, 247.9 [M+H]+.

Step C: 8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (200 mg, 0.82 mmol) was combined with triethylborane (1 M in THF, 2 mL, 2 mmol), K2CO3 (283 mg, 2.05 mmol) and Pd(PPh ₃ ) ₄ (92 mg, 0.08 mmol) in DMF (3 ml). The reaction vessel was degassed, and then purged with nitrogen three times. The mixture was stirred at 100°C for 5 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 6-chloro-8-ethyl-2-methylimidazo[1,2-b]pyridazine (80 mg, 50%). MS m/z 196.0, 198.0 [M+H] ⁺ .

Example 29-3.

6-Chloro-8-cyclopropyl-2-methylimidazo[1,2-b]pyridazine.

Mixture of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1.2 g, 4.9 mmol), cyclopropylboric acid (843 mg, 9.8 mmol), Pd(dppf)Cl ₂ (359 mg, 0.49 mmol) and Na ₂ CO ₃ (1.56 g, 14.7 mmol) in 1,4dioxane (12 ml) and water (3 ml) were stirred at 90°C under N2 atmosphere for 48 h. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 035% EtOAc in petroleum ether to give 6-chloro-8-cyclopropyl-2-methylimidazo[1,2-b]pyridazine (405 mg, 40%). MS m/z 208.0, 210.0 [M+H] ⁺ .

Example 29-4.

6-Chloro-2-methylimidazo[1,2-b]pyridazine-8-carbonitrile.

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1.2 g, 4.9 mmol) was combined with Zn(CN) ₂ (850 mg, 7.3 mmol) and Pd(PPh ₃ ) ₄ (570 mg, 0.49 mmol) in DMF (20 ml). The reaction vessel was degassed, and then purged with nitrogen three times. The mixture was stirred at 100°C for 1 hour under microwave irradiation. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 6-chloro-2-methylimidazo[1,2b]pyridazine-8-carbonitrile (0.5 g, 53%). MS m/z 193.0, 195.0 [M+H] ⁺ .

Example 29-5.

6-bromo-2,4-dimethylbenzo[d]thiazole.

Step A: 2,4-dibromo-6-methylaniline (3.8 g, 14.5 mmol) was combined with KOAc (1.56 g, 15.9 mmol) and acetic anhydride (5.5 mL, 58 mmol) to toluene (40 ml). The mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give N-(2,4-dibromo-6methylphenyl)acetamide (3.9 g, 82%). MS m/z 305.9, 308.0 [M+H] ⁺ .

Step B: N-(2,4-Dibromo-6-methylphenyl)acetamide (4.0 g, 13 mmol) was combined with Lawesson's reagent (10.6 g, 26 mmol) in toluene (40 ml). The mixture was stirred at 110°C for 16 hours. The solvent was removed under vacuum. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give N-(2,4-dibromo-6-methylphenyl)ethanethioamide (3.9 g, 93%). MS m/z 322.9, 324.9 [M+H] ⁺ .

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

Example 29-6.

5-Chloro-2,7-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine

Step A: 6-Chloro-4-methyl-3-nitropyridin-2-amine (187 mg, 1 mmol), iron powder (56 mg, 10 mmol) in AcOH (3 ml) stirred at 100°C for 16 h The mixture was concentrated. An aqueous solution of NaOH (2N) was added to the residue at pH>9. The mixture was filtered through celite. The filtrate was extracted with EtOAc (50 ml 3 times). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine, which was used without further purification (154 mg crude, 85 % crude substance). MS m/z 182.0, 184.0 [M+H] ⁺ .

Step B: 5-Chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.1 g, 6.07 mmol) was dissolved in THF (30 ml). NaH (310 mg, 7.9 mmol) was added portionwise to the mixture at 0°C. After stirring the mixture at 0°C for 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 6.69 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. MeOH (10 ml) was added to the solution, after which the volatile material was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 25% EtOAc in petroleum ether to give a mixture of N-110 043655 alkylated products, which were used without separation (900 mg, 76%). MS m/z 312.0, 314.0

[M+N]+.

Example 29-7.

5-Chloro-2,7-dimethyloxazolo[5,4-b]pyridine.

Step A: A solution of 2,6-dichloro-4-methylnicotinonitrile (3 g, 16 mmol) in H ₂ SO ₄ (15 ml) was stirred at 80°C for 4 hours. The mixture was cooled to room temperature, and then poured into ice water (100 ml). The suspension was filtered. The filter cake was washed with water to obtain 2,6-dichloro-4methylnicotinamide (3.2 g, 91%) as a yellow solid. MS m/z 204.9, 206.9 [M+H] ⁺ .

Step B: To a solution of NaOH (3.7 g, 93 mmol) in H2O (100 ml), Br ₂ (4.7 g, 29.4 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour before adding 2,6-dichloro-4methylnicotinamide (5 g, 24.5 mmol). The mixture was allowed to gradually warm to room temperature over 1 hour. The mixture was then heated to 75°C for 1 hour. The resulting suspension was cooled to room temperature with stirring overnight. The suspension was filtered. The collected solid material was washed with water to obtain 2,6-dichloro-4-methylpyridin-3-amine (3.3 g, 76%). MS m/z 176.9, 178.9 [M+H] ⁺ .

Step C: To a solution of 2,6-dichloro-4-methylpyridin-3-amine (3 g, 17 mmol) in toluene (50 ml) was added KOAc (2 g, 20.4 mmol) and Ac ₂ O (6.9 g, 68 mmol). The mixture was stirred at 70°C for 48 hours. The mixture was cooled to room temperature, and then poured into ice water (100 ml). Water was extracted with EtOAc (60 ml x 3). The combined organic phases were concentrated under reduced pressure. The residue was chromatographed on silica gel, eluted with 25% EtOAc in petroleum ether to give N-(2,6-dichloro-4-methylpyridin-3-yl) acetamide (842 mg, 22%) as a yellow solid. MS m/z 219.0, 221.0 [M+H] ⁺ .

Step D: NaH (128 mg, 3.2 mmol) was added portionwise to a solution of N-(2,6-dichloro-4-methylpyridin-3-yl)acetamide (700 mg, 3.2 mmol) in NMP (10 mL) at room temperature. The reaction vessel was degassed, and then purged with nitrogen three times. The mixture was stirred at 120°C for 2 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-25% EtOAc in petroleum ether to give 5-chloro-2,7-dimethyloxazolo[5,4-b]pyridine (400 mg, 68%). MS m/z 183.1, 185.1 [M+H] ⁺ .

Example 29-8.

-Chloro-2,7-dim ethylthiazolo[5,4-b]pyridine.

N-(2,6-dichloro-4-methylpyridin-3-yl)acetamide (1.6 g, 7.3 mmol) was combined with Lawesson's reagent (5.93 g, 14.7 mmol) in toluene (20 ml) . The mixture was stirred at 110°C for 16 hours. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 5-chloro-2,7-dimethylthiazolo[5,4-b]pyridine (500 mg, 34.4% yield). MS m/z 199.0, 201.0 [M+H] ⁺ .

Example 29-9.

2-Bromo-4,6-dimethyloxazolo[4,5-c]pyridine.

Step A: 2,6-Dimethylpyridin-4-ol (3 g, 24.3 mmol) was added portionwise to conc. HNO3 (11 ml). Conc was then slowly added. H ₂ SO ₄ (16 ml) while maintaining the temperature below 20°C. The mixture was stirred at room temperature for 3 hours. The mixture was then slowly poured onto ice and neutralized with K2CO3. The mixture was extracted with CH ₂ Cl ₂ . The organic phases were concentrated under reduced pressure. The residue was chromatographed on silica gel, eluted with 10-20% MeOH in CH ₂ Cl ₂ to give 2,6-dimethyl-3-nitropyridin-4-ol as a white solid (3.69 g, 90%). MS m/z 169.1 [M+H] ⁺ .

Step B: A mixture of 2,6-dimethyl-3-nitropyridin-4-ol (1.68 g, 10 mmol) and 10% Pd/C (106 mg, 0.1 mmol) in MeOH (16 ml) was stirred under atmosphere H2 for 16 hours. The mixture was filtered through celite to obtain 3-amino-2,6-dimethylpyridin-4-ol as a white solid (1.3 g, 95%). MS m/z 139.0 [M+H] ⁺ .

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

Step D. To a mixture of 4,6-dimethyloxazolo[4,5-c]pyridin-2-amine (600 mg, 3.7 mmol) and CuBr ₂ (2.5 g, 11.1 mmol) in CH3CN (6 ml ) t-butyl nitrite (1.3 mL, 11.1 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 minutes, and then stirred at 55°C for 2 hours. The reaction mixture was made basic with saturated NaHCO ₃ and then extracted with EtOAc (200 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting with 10-20% EtOAc in petroleum ether to give 2bromo-4,6-dimethyloxazolo[4,5-c]pyridine as a white solid (416 mg, 50% yield). MS m/z 227.0, 229.0 [M+H] ⁺ .

- 111 043655

Example 29-10.

2-Bromo-4,6-dimethylthiazolo[4,5-c]pyridine.

Step A: 4-Chloro-2,6-dimethyl-3-nitropyridine (4.7 g, 25 mmol) was combined with Fe powder (4.24 mg, 75 mmol) in AcOH (40 ml). The mixture was stirred at 70°C for 2 hours. Volatile material was removed under reduced pressure. The residue was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-80% EtOAc in petroleum ether to give 4-chloro-2,6dimethylpyridin-3-amine (4.0 g, 99%). MS m/z 157.2, 159.2 [M+H]+.

Step B: 4-Chloro-2,6-dimethylpyridin-3-amine (3.8 g, 24 mmol) was combined with benzoyl isothiocyanate (4.77 g, 29 mmol) in acetone (40 ml) and the mixture was stirred at 56 °C for 2 hours. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-50% EtOAc in petroleum ether to give N-(4,6-dimethylthiazolo[4,5-c]pyridin-2yl)benzamide (6.5 g, 95%). MS m/z 284.2 [M+H] ⁺ .

Step C: N-(4,6-Dimethylthiazolo[4,5-c]pyridin-2-yl)benzamide (4.5 g, 16 mmol) was combined with NaOH (1.27 g, 32 mmol) in H2O (10 ml) and MeOH (30 ml). The mixture was stirred at 100°C for 1 hour under microwave irradiation. Volatile material was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-60% EtOAc in petroleum ether to give 4,6-dimethylthiazolo[4,5-c]pyridin-2-amine (2.7 g, 95%). MS m/z 180.0 [M+H] ⁺ .

Step D: 4,6-Dimethylthiazolo[4,5-c]pyridin-2-amine (2.7 g, 15 mmol) was combined with isobutyl nitrite (4.67 g, 45 mmol) and CuBr ₂ (16.8 g , 75 mmol) in CH3CN (30 ml). The mixture was stirred at 50°C for 0.5 hours. Volatile material was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 0-50% EtOAc in petroleum ether to give 2-bromo-4,6dimethylthiazolo[4,5-c]pyridine (1.0 g, 27%). MS m/z 242.9, 245 [M+H] ⁺ .

Example 29-11.

5-Chloro-2,7-dimethyl-2H-pyrazolo[4,3-b]pyridine.

Step A: 6-Chloro-2-methylpyridin-3-amine (40 g, 282 mmol) was combined with AcOH (32 ml) in MeOH (400 ml). Br ₂ (26 ml, 507 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 16 hours. Volatile material was removed under reduced pressure. The residual reagent was quenched by adding an aqueous solution of NaHSO ₃ . The aqueous solution was neutralized with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in petroleum ether to give 4-bromo-6-chloro-2methylpyridin-3-amine (60 g, 97%). MS m/z 220.9, 222.9 [M+H] ⁺ .

Step B: 4-Bromo-6-chloro-2-methylpyridin-3-amine (13 g, 59 mmol) was combined with isobutyl nitrite (9.13 g, 89 mmol), KOAc (13.3 g, 136 mmol) and AcOH (34 ml, 590 mmol) in toluene (130 ml). The mixture was stirred at 60°C for 10 hours. Volatile material was removed under reduced pressure. The residue was treated with a saturated aqueous NaHCO ₃ solution. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in petroleum ether to give 7-bromo-5-chloro-2H-pyrazolo[4,3-b]pyridine (3.7 g, 27%). MS m/z 232.0, 234.0 [M+H] ⁺ .

Step C: 7-Bromo-5-chloro-2H-pyrazolo[4,3-b]pyridine (3.7 g, 16 mmol) was combined with K2CO3 (4.4 g, 32 mmol) and iodomethane (2.7 g , 19 mmol) in DMF (40 ml). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-20% EtOAc in petroleum ether to give 7-bromo-5-chloro-2methyl-2H-pyrazolo[4,3-b]pyridine (1.5 g, 38%). MS m/z 245.9, 247.9 [M+H] ⁺ .

Step D: 7-Bromo-5-chloro-2-methyl-2H-pyrazolo[4,3-b]pyridine (3.0 g, 12 mmol) was combined with 2,4,6trimethyl-1,3,5,2 ,4,6-trioxatriborinane (5.2 ml, 18 mmol), K2CO3 (6.7 g, 49 mmol) and Pd(PPh ₃ ) ₄ (707 mg, 0.6 mmol) in DMF (30 ml). The reaction mixture was degassed and then purged with nitrogen three times. The mixture was stirred at 100°C for 5 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 5-chloro-2,7-dimethyl-2H-pyrazolo[4,3-b]pyridine (1.2 g, 54%). MS m/z 182.0, 184.0 [M+H] ⁺ .

Example 29-12.

5-Chloro-7-methoxy-2-methyl-2H-pyrazolo[4,3-b]pyridine.

7-Bromo-5-chloro-2-methyl-2H-pyrazolo[4,3-b]pyridine (250 mg, 1.0 mmol) was combined with MeOH (0.2 mL, 5 mmol) and K2CO3 (296.7 mg, 2.15 mmol) in CH3CN (5 ml). The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-25% EtOAc in petroleum ether to give (190 mg, 80%). MS m/z 198.0, 200.0 [M+H] ⁺ .

- 112 043655

Example 29-13.

5-Chloro-7-ethyl-2-methyl-2H-pyrazolo[4,3-b]pyridine.

7-Bromo-5-chloro-2-methyl-2H-pyrazolo[4,3-b]pyridine (200 mg, 0.8 mmol) was combined with triethylborane (1 M in THF, 1.95 mL, 1.95 mmol ), K ₂ CO ₃ (441.6 g, 3.2 mmol) and Pd(PPh ₃ ) ₄ (30 mg, 0.04 mmol) in DMF (3 ml). The reaction mixture was degassed and then purged with nitrogen three times. The mixture was stirred at 100°C for 5 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 5-chloro-7-ethyl-2methyl-2H-pyrazolo[4,3-b]pyridine (72 mg, 45%). MS m/z 196.0, 198.0 [M+H]+.

Example 29-14.

2-Bromo-4,6-dimethylthiazolo[5,4-c]pyridine.

Step A: A mixture of 2,6-dimethylpyridin-4-amine (0.5 g, 4.07 mmol) and bromine (0.21 ml, 4.07 mmol) in acetic acid (1 ml) was stirred at room temperature for 2 hours. The mixture was treated with an aqueous solution of 20% sodium hydroxide (10 ml) and extracted with 30 ml of CH ₂ Cl ₂ . The combined organic parts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was suspended in hot heptane. The solid material was collected and dried to give 3-bromo2,6-dimethylpyridin-4-amine (0.43 g, 52%). MS m/z 201.1, 203.1 [M+H] ⁺ .

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

Step C. Mixture of N-((3-bromo-2,6-dimethylpyridin-4-yl)carbamothioyl)benzamide (181 mg, 0.5 mmol), Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol) and Cs ₂ CO ₃ (326 mg, 1 mmol) in DME (5 ml) were stirred at 100°C under N2 for 3 hours. Once complete, the reaction mixture was cooled to room temperature and partitioned between EtOAc (50 ml) and water ( 50 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel, eluting with 30-100% EtOAc in petroleum ether to give N-(4,6-dimethylthiazolo[5,4c]pyridin-2-yl)benzamide as a light yellow solid (92 mg, 65%). MS m/z 284.1 [M+H] ⁺ .

Step D: Mixture of N-(4,6-dimethylthiazolo[5,4-c]pyridin-2-yl)benzamide (2 g, 7.1 mmol) and NaOH (1.42 g, 36 mmol in MeOH (45 ml) ) and water (15 ml) were stirred in a sealed tube at 85°C for 24 hours. The mixture was extracted with EtOAc (150 ml 2 times).

The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting with 50-100% EtOAc in CH ₂ Cl ₂ to give 4,6-dimethylthiazolo[5,4-c]pyridin-2-amine as a light yellow solid (0.88 g, 70 %). MS m/z 180.1 [M+H] ⁺ .

Step E: To a mixture of 4,6-dimethylthiazolo[5,4-c]pyridin-2-amine (880 mg, 4.9 mmol) and CuBr ₂ (3.25 g, 14.7 mmol) in MeCN (10 ml ) tert-butyl nitrite (1.74 mL, 14.7 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours, and then 55°C for 1 hour. A saturated aqueous solution of NaHCO ₃ was added to the reaction mixture. The mixture was extracted with EtOAc (200 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel, eluting with 20% EtOAc in petroleum ether to give 2-bromo-4,6dimethylthiazolo[5,4-c]pyridine as a white solid (595 mg, 50%). MS m/z 242.9, 245.0 [M+H] ⁺ .

Example 29-15.

2-(6-Chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)ethan-1-ol.

Step A: Anhydrous THF (20 ml) was charged into a dry three-neck round bottom flask at -78°C under an inert atmosphere. A solution of n-butyllithium (2.5 M in hexane, 26.1 mL, 65.3 mmol) was added dropwise, followed by the addition of anhydrous acetonitrile (4 mL, 65.3 mmol). The internal temperature was maintained below -70°C during the entire addition process. After stirring for 30 minutes at -78°C, a solution of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (2.0 g, 8.2 mmol, prepared according to Example 43) was added dropwise. in anhydrous THF (20 ml). The mixture was stirred for 2 hours at -78°C. The excess reagent was carefully quenched with a saturated aqueous solution of NH ₄ Cl. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 2-(6-chloro-2-methylimidazo[1,2-b]pyridazin-8yl)acetonitrile (1.2 g, 71%). MS m/z 207.1, 209.1 [M+H] ⁺ .

Step B: 2-(6-Chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)acetonitrile (500 mg, 2.4 mmol) was combined with MeOH (0.97 mL, 24 mmol) to conc. . H ₂ SO ₄ (2 ml). The mixture was stirred at 60°C for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in petroleum ether to give methyl 2-(6-chloro-2-methylimidazo[1,2b]pyridazin-8-yl)acetate (500 mg, 86 %). MS m/z 240.1, 242.1 [M+H]+.

Step C. To methyl 2-(6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)acetate (500 mg, 2.1 mmol) in dry THF (5 ml) small parts at 0° C LiAlH4 (183 mg, 5.2 mmol) was added. The mixture was stirred at 0°C for 20 minutes. The reaction mixture was carefully quenched with water (1 ml), then with an aqueous solution of 15% NaOH (1 ml). The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-35% EtOAc in petroleum ether to give 2-(6-chloro-2methylimidazo[1,2-b]pyridazin-8-yl)ethan-1-ol (144 mg, 33% ). MS m/z 212.1, 214.1 [M+H]+.

Example 29-16.

6-Chloro-8-(1H-imidazol-1-yl)-2-methylimidazo[1,2-b]pyridazine.

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (500 mg, 2.0 mmol), prepared according to example 43) was combined with K2CO3 (550 mg, 4.0 mmol) and 1H-imidazole (250 mg, 0.36 mmol) in NMP (5 ml). The mixture was stirred at 120°C for 16 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in petroleum ether to give 6-chloro-8-(1H-imidazol-1-yl)-2-methylimidazo[1,2-b]pyridazine (228 mg, 48 %). MS m/z 234.0, 236.0 [M+H]+.

Example 29-17.

6-Chloro-2-methyl-8-phenoxyimidazo[1,2-b]pyridazine.

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1.0 g, 4.0 mmol) was combined with K2CO3 (1.1 g, 8 mmol) and phenol (0.6 g, 6.0 mmol) in NMP (10 ml). The mixture was stirred at 60°C for 16 hours. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-30% EtOAc in petroleum ether to give 6-chloro-2-methyl-8-phenoxyimidazo[1,2b]pyridazine (560 mg, 53%). MS m/z 260.0, 262.0 [M+H]+.

Example 29-18.

6-Chloro-8-isopropyl-2-methylimidazo[1,2-b]pyridazine.

Step A: 8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (500 mg, 2.05 mmol, prepared according to Example 43) was combined with vinylborinic acid pinacol ester (0.43 ml, 2 .3 mmol), Pd(dppf)Cl ₂ (150 mg, 0.21 mmol) and K2CO3 (850 mg, 6.15 mmol) in 1,4-dioxane (10 ml) and H2O (2 ml). The mixture was stirred at 90°C for 2 hours under N2 atmosphere. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-20% EtOAc in petroleum ether to give 6-chloro-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine (300 mg, 77%). MS m/z 208.0, 210.0 [M+H]+.

Step B: 6-Chloro-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine (250 mg, 1.21 mmol) was combined with PtO ₂ (30 mg, 0.13 mmol) in EtOAc (10 ml). The mixture was stirred at room temperature for 3 hours under an H ₂ atmosphere. The mixture was filtered through celite and the filtrate was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 20-35% EtOAc in petroleum ether to give 6-chloro-8-isopropyl-2-methylimidazo[1,2-b]pyridazine (200 mg, 80%). MS m/z 210.0, 212.0 [M+H]+.

Example 29-19.

6-Chloro-2-methyl-8-propylimidazo[1,2-b]pyridazine.

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1 g, 4.1 mmol, prepared according to Example 43) was combined with propylmagnesium bromide (660 mg, 4.5 mmol) and 2,4 -iron(I)-pentanedione (140 mg, 0.4 mmol) in dry THF (30 ml). The mixture was stirred at 50°C for 1 hour under N ₂ atmosphere. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 20-30% EtOAc in petroleum ether to give 6-chloro-2-methyl-8-propylimidazo[1,2-b]pyridazine (230 mg, 27%). MS m/z 210.0, 212.0 [M+H]+.

Example 30.

Receiving connection 78

CS2CO3

DMF, 60 °C, 4h

7-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4-piperidyl)cinnoline dihydrochloride (55 mg, 0.13 mmol, obtained in Example 7) was combined with Cs ₂ CO ₃ (85 mg, 0.26 mmol), 2-iodopropane

- 114 043655 (26 µl, 0.26 mmol) and DMF (1 ml). The mixture was stirred at 60°C for 4 hours. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel and eluted with 0-10%

MeOH (2N NH3) in CH ₂ Cl ₂ to give 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1isopropyl-4-piperidyl)cinnoline ( 6 mg, 11%).

MS m/z 419.4 [M+H]+; ^1H NMR (methanol^) δ: 8.92 (s, 1H), 8.32 (dd, J=11.0, 1.5 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.91-4.02 (m, 2H), 3.61-3.68 (m, 1H), 3.24-3.33 (m , 2H), 2.73 (s, 3H), 2.56-2.62 (m, 1H), 2.52 (s, 3H), 2.20-2.26 (m, 2H), 2, 06-2.16 (m, 2H), 1.21 (d, J=7.2 Hz, 6H).

Using the procedure described above for Example 30, additional compounds described herein were prepared by substitution of a suitable aryl halide, suitable reagents and reaction conditions to produce compounds such as those selected from:

Conn. Data 83 MS m/z 423.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.17 (s, 1H), 8.60 (d, J= 1.3 Hz, 1H), 8.43 - 8.47 (m, 2H), 8.35 (s, 1H), 4.98 (ddd, J= 47, 5.1, 3.7 Hz, 2H), 3.89 - 3.95 (m, 2H), 3.63 - 3.73 (m , 3H), 3.40 - 3.48 (m, 2H), 2.88 (d, J= 0.9 Hz, 3H), 2.71 (d, J = 0.9 Hz, 3H), 2 .46 - 2.53 (m, 4H), No protons corresponding to HCl were observed. 98 MS m/z 441.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.15 (s, 1H), 8.54 (d, J= 1.2 Hz, 1H), 8.44 (dd, J= 10.7, 1.5 Hz , 1H), 8.41 (d, J = 0.9 Hz, 1H), 8.34 (s, 1H), 6.53 (tt, J = 53.7, 3.5 Hz, 1H), 3 .82 - 3.96 (m, 4H), 3.64 - 3.71 (m, 1H), 3.49 - 3.59 (m, 2H), 2.87 (d, J= 1.2 Hz , 3H), 2.69 (d, J= 0.9 Hz, 3H), 2.46 - 2.57 (m, 4H), No protons corresponding to HCl were observed. 168 MS m/z 433.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.92 (s, 1H), 8.32 (d, J= 11 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 3.60 (m, 1H), 3.30 (br s, 4H), 2.73 (s, 3H), 2.52 (s, 3H), 2.26 - 2.32 (m, 2H), 2.01 (m, 2H), 1.41 (d, J= 6 Hz, 6H), 1.21 (m, 3H). 170 MS m/z 451.6 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.90 (s, 1H), 8.30 (d, J= 10.5 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H ), 7.87 (s, 1H), 4.64 (dd, J= 50, 5.0 Hz, 2H), 3.51 (m, 1H), 3.15-3.32 (m, 2H) , 3.07 (br s, 2H), 2.73 (s, 3H), 2.52 (s, 3H), 2.13 (d, J= 12.5 Hz, 2H), 1.85 (q , J= 12 Hz, 2H), 1.32 (d, J= 6 Hz, 6H). 199 MS m/z 437.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.90 (s, 1H), 8.29 (d, J= 10 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 4.64 (dd, J= 50, 5.0 Hz, 2H), 3.60 (m, 1H), 3.13 - 3.19 (m, 1H), 2 .95 - 3.08 (m, 5H), 2.72 (s, 3H), 2.52 (s, 3H), 2.00 - 2.30 (m, 5H), 1.90 - 2.00 (m, 1H).

Example 31.

Receiving connection 158

Step A: A solution of oxalyl chloride (105 µl, 1.2 mmol) in CH2C12 (1.4 ml) was cooled to -78°C. DMSO (150 µl, 2.1 mmol) in CH2C12 (0.5 ml) was added to the solution. The solution was stirred at -78°C for 30 minutes. 3-(dimethylamino)propan-1-ol (55 mg, 0.53 mmol) in CH2C12 (1 ml) was added to the solution. The solution was stirred for 30 minutes at -78°C. Triethylamine (42 μL, 0.30 mmol) was added to the solution. The mixture was allowed to slowly warm to 0°C over ~30 min. The excess reagent was quenched by adding a saturated aqueous solution of NaHCO ₃ . The organic layer was removed and dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was used directly in the next step without further purification.

Step B: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(4-piperidyl)cinnoline dihydrochloride (45 mg, 0.10 mmol, prepared in Example 7) combined with CH2C12 (2 ml), triethylamine (42 µl, 0.30 mmol), and EtOH (0.2 ml). 3-(dimethylamino)propanal (53 mg, 0.52 mmol, from step A) in CH2Cl2 (0.5 ml) was added to the mixture. The mixture was stirred at room temperature until homogeneous, and then sodium triacetoxyborohydride (64, 0.30 mmol) was added. After stirring for 20 minutes at room temperature, the mixture was concentrated. The residue was dissolved in TFA and CH2C12 and dried on celite. The dry material was chromatographed on a C18 reverse phase column, eluted with 5-60% CH ₃ CN (0.1% TFA) in H ₂ O (0.1% TFA). The collected fractions were concentrated. The residue was separated in CH2C12 and an aqueous solution of 1 M K2CO3. The organic layers were loaded onto silica gel, eluted with 0-10% MeOH (2N NH3) in CH2C12 to give 3-[4-[7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5- fluoro-cinnolin-3-yl]-1-piperidyl]-N,N-dimethyl-propan-1-amine (7 mg, 15%).

- 115 043655

MS m/z 462.5 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 8.96 (s, 1H), 8.36 (dd, J=11.0, 1.5 Hz, 1H), 8.25 (s, 1H),

8.02 (s, 1H), 7.90 (d, J=0.9 Hz, 1H), 3.54-3.60 (m, 2H), 3.46-3.53 (m, 1H) , 3.20-3.26 (m, 2H), 2.99-3.08 (m,

2H), 2.92 (s, 6H), 2.81-2.90 (m, 2H), 2.74 (d, J=0.9 Hz, 3H), 2.53 (s, 3H), 2.26-2.37 (m, 4H), 2.14 (quin, J=7.2

Hz, 2H).

Using the procedure described above for Example 31, additional compounds described herein were prepared by substituting the appropriate alcohol in Step A, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 145 MS m/z 535.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.91 (s, 1H), 8.31 (dd, J= 10.8, 1.4 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.71 (d, J= 7.9 Hz, 1H), 7.67 (d, J= 7, 9 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.31 (t, J= 7.7 Hz, 1H), 4.45 (t, J= 6.6 Hz , 2H), 3.23 -3.31 (m, 1H), 3.12 (br d, J= 11.3 Hz, 2H), 2.73 (s, 3H), 2.52 (s, 3H ), 2.47 (t, J= 6.6 Hz, 2H), 2.16 - 2.28 (m, 4H), 2.01-2.15 (m, 4H), Protons corresponding to HCl, not were observed. 159 MS m/z 521.2 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.94 (s, 1H), 8.34 (dd, J= 10.7, 1.3 Hz, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.90 (d, J= 0.9 Hz, 1H), 7.71 (d, J= 7.9 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.31 (d, J= 8.2 Hz, 1H), 4.51 (t , J= 6.4 Hz, 2H), 3.24 - 3.31 (m, 1H), 3.18 (br d, J= 11.3 Hz, 2H), 2.94 (t, J= 6 .4 Hz, 2H), 2.75 (s, 3H), 2.53 (s, 3H), 2.39 - 2.46 (m, 2H), 2.02 - 2.20 (m, 4H) . 160 MS m/z 485.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.89 (s, 1H), 8.29 (dd, J= 11.0, 1.2 Hz, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.85 (d, J= 1.2 Hz, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.53 (d, J= 1.8 Hz , 1H), 6.32 (t, J= 2.1 Hz, 1H), 4.29 (m, 2H), 3.26 - 3.31 (m, 1H), 3.20 (br d, J = 11.6 Hz, 2H), 2.72 (d, J= 0.9 Hz, ZN), 2.51 (s, ZN), 2.46 - 2.50 (m, 2H), 2.28 - 2.36 (m, 2H), 2.07 - 2.21 (m, 6H).

Example 32.

Receiving connection 127

Step A. 2-[4-[7-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnolin-3-yl]-1piperidyl]ethanol dihydrochloride (200 mg, 0.41 mmol obtained in example 19) was combined with CH ₂ Cl ₂ (4 ml) and triethylamine (0.22 ml, 1.6 mmol). Methanesulfonyl chloride (137 μL, 0.81 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was washed with an aqueous solution of 1 M K2CO3. The organic layers were loaded onto silica gel, eluted with 0-10% MeOH (2N NH3) in CH ₂ Cl ₂ to give 2-[4-[7-(2,8-Dimethylimidazo[1,2b]pyridazin-6-yl) -5-fluoro-cinnolin-3-ul]-1-piperidyl]ethyl methanesulfonate. MS m/z 499.4 [M+H] ⁺ .

Step B. 2-[4-[7-(2,8-Dimethylimidazo[1,2-b]pyridazin-6-ul)-5-fluoro-cinnolin-3-yl]-1piperidyl]ethyl methanesulfonate (30 mg, 0.06 mmol) was combined with N,N-dusopronulethylamine (105 µl, 0.60 mmol), DMF (1 ml) and dimethylamine hydrochloride (55 mg, 0.60 mmol). The mixture was heated at 40°C for 18 hours. Volatile material was removed. The residue was dissolved in TFA and CH ₂ Cl ₂ and dried on celite. The dry material was chromatographed on a C18 reverse phase column, eluted with 5-65% CH3CN (0.1% TFA) in H ₂ O (0.1% TFA). The collected material was concentrated. The residue was dissolved in 1.25 M HCl in MeOH. Volatiles were removed. The residue was suspended in CH3CN, sonicated, collected by filtration and dried to give 2-[4-[7-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-cinnolin-3-yl ]-1-piperidyl]-N,N-dimethyl-ethanamine trihydrochloride (13 mg, 39%).

MS m/z 448.5 [M+H] ⁺ ; 1H NMR (methanol-d ₄ ) δ: 9.15 (s, 1H), 8.56 (m, 1H), 8.43 (d, J=9.5 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 3.93 (br s, 2H), 3.68-3.83 (m, 5H), 3.46 (br d, J=10.4 Hz, 2H ), 3.07 (s, 6H), 2.87 (s, 3H), 2.70 (s, 3H), 2.48-2.63 (m, 4H), No protons corresponding to HCl were observed.

- 116 043655

Example 33.

Getting connection 141 ci

1) B ₂ pin ₂ , KOAc SPhos Pd G ₂ 1,4-dioxane

2) SPhos Pd G ₂ K ₂ CO ₃ , H ₂ O Ar-CI (Step A)

Step A: 8-Bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine (124 mg, 0.50 mmol) was combined with 3-(1Hpyrazol-1-yl)propan-1-ol ( 252 mg, 2.0 mmol) and cesium carbonate (650 mg, 2.0 mmol) in CH ₃ CN (4 ml). The mixture was stirred at 40°C for 16 hours. EtOAc (10 ml) was added to the mixture. The mixture was filtered through celite. The filtrate was concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH in EtOAc to give 6-chloro-2-methyl-8-(3-pyrazol-1ylpropoxy)imidazo[1,2-b]pyridazine (70 mg, 48%) . MS m/z 292.3 [M+H]+.

Step B: tert-Butyl 4-(7-chloro-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (73 mg, 0.20 mmol, prepared in Example 29) was combined with bis(pinacolato)diborone ( 64 mg, 0.25 mmol), KOAc (59 mg, 0.60 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1 '-biphenyl-2yl)palladium(P) (14 mg, 0.02 mmol) and 1,4-dioxane (3 ml). The mixture was stirred at 90°C for 1 hour. An aqueous solution of 1 M K2CO3 (1 ml) was added to the mixture, then another part of chloro(2dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'- amino-1,1'-biphenyl-2-yl)palladium(P) (14 mg, 0.02 mmol) and 6-chloro-2-methyl-8-(3-nirazol-1-ylpropoxy)imidazo[1, 2-b]pyridazine (70 mg, 0.24 mmol) (in 1 ml 1,4-dioxane). The mixture was stirred at 80°C for 1 hour. The mixture was partitioned between EtOAc and H2O. The organic layer was concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH in EtOAc to give tert-butyl 4-[5-fluoro-7-[2-methyl-8-(3-pyrazol-1ylpropoxy)imidazo[1,2-b ]pyridazin-6-yl]cinnolin-3-yl]piperidine-1-carboxylate (110 mg, 94%). MS m/z 587.3 [M+H] ⁺ .

Step C. tert-Butyl 4-[5-fluoro-7-[2-methyl-8-(3-pyrazol-1-ylpropoxy)imidazo[1,2-b]niridazin-6yl]cinnolin-3-yl]piperidine -1-carboxylate (110 mg, 0.18 mmol) was dissolved in trifluoroacetic acid (1 ml) and 1 ml CH ₂ Cl ₂ . The solution was dried on celite. The dry material was chromatographed on a C18 reverse phase column, eluted with 5-65% CH3CN (0.1% TFA) in H ₂ O (0.1% TFA). The required fractions were concentrated. The residue was dissolved in 1.25 M HCl in MeOH. Volatiles were removed. The residue was suspended in CH ₃ CN, sonicated, filtered and dried to give 5fluoro-7-[2-methyl-8-(3-pyrazol-1-ylpropoxy)imidazo[1,2-b]pyridazin-6-yl]- 3-(4-piperidyl)cinnoline dihydrochloride (66 mg, 63%) as a pale yellow solid.

MS m/z 487.4 [M+H] ⁺ ; 1H NMR (methanol^) δ: 9.18 (s, 1H), 8.44 (d, J=10.7 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H), 8 .33 (s, 1H), 8.08 (s, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 6 .41 (t, J=2.3 Hz, 1H), 4.67 (t, J=6.7 Hz, 2H), 4.58 (t, J=6.7 Hz, 2H), 3.63 -3.70 (m, 3H), 3.29-3.35 (m, 2H), 2.70 (s, 3H), 2.59 (quin, J=6.3 Hz, 2H), 2, 33-2.45 (m, 4H), No protons corresponding to NH and HCl were observed.

Using the procedure described above for Example 33, additional compounds described herein were prepared by substituting the appropriate alcohol in Step A, suitable reagents, and reaction conditions to produce compounds such as those selected from:

- 117 043655

Conn. Data 138 MS m/z 450.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.20 (s, 1H), 8.46 (dd, J= 10.7, 1.2 Hz, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 5.06 (t, J= 5.0 Hz, 2H), 3.90 (t, J= 5.0 Hz, 2H), 3.63 - 3.71 (m, 3H), 3.29 - 3.37 (m, 2H), 3.12 (s, 6H), 2.69 (s, 3H), 2.32 2.46 (m, 4H), Protons corresponding to NH and HO were not observed. 139 MS m/z 464.5 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.19 (s, 1H), 8.45 (dd, J= 10.5, 1.4 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 4.82 (t, J= 6.1 Hz, 2H), 3.63 - 3.70 (m, 3H), 3.55 - 3, 60 (m, 2H), 3.28 - 3.37 (m, 2H), 3.03 (s, 6H), 2.70 (s, 3H), 2.49 2.56 (m, 2H), 2.31 - 2.45 (m, 4H), No protons corresponding to NH and HO were observed. 140 MS m/z 473.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.16 (s, 1H), 8.42 (d, J = 10.4 Hz, 1H), 8.38 (s, 1H), 8.35 (s, 1H ), 8.04 (s, 1H), 7.92 (d, J= 1.8 Hz, 1H), 7.63 (s, 1H), 6.40 (t, J= 2.1 Hz, 1H ), 5.01 - 5.06 (m, 2H), 4.85 - 4.90 (m, 2H), 3.63 - 3.71 (m, 3H), 3.29 - 3.37 (m , 2H), 2.69 (s, 3H), 2.32 - 2.46 (m, 4H), No protons corresponding to NH and HC1 were observed. 142 MS m/z 487.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.19 (s, 2H), 8.45 (dd, J= 10.5, 1.4 Hz, 1H), 8.41 (d, J= 0.9 Hz , 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.84 (t, J= 1.7 Hz, 1H), 7.67 (t, J= 1.7 Hz , 1H), 4.77 (t, J= 5.8 Hz, 2H), 4.71 (t, J= 7.3 Hz, 2H), 3.62 - 3.71 (m, 3H), 3 .29 - 3.37 (m, 2H), 2.71 (s, 3H), 2.65 - 2.70 (m, 2H), 2.32 - 2.45 (m, 4H), Protons corresponding NH and HC1 were not observed. 150 MS m/z 537.4 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 9.72 (s, 1H), 9.16 (s, 1H), 8.44 (d, J = 10.6 Hz, 1H), 8.40 (s, 1H ), 8.32 (s, 1H), 8.11-8.16 (m, 1H), 8.08 (s, 1H), 7.89 - 7.95 (m, 1H), 7.68 - 7.77 (m, 2H), 5.00 (t, J= x Hz, 2H), 4.83 (t, J= x Hz, 2H), 3.63 - 3.70 (m, 3H), 3.28 - 3.37 (m, 2H), 2.80 (dt, J= 13.4, 6.4 Hz, 2H), 2.72 (d, J= 0.9 Hz, 3H), 2 ,31 - 2.45 (m, 4H), The proton corresponding to NH was not observed.

Example 34.

Receiving connection 223

aq. CH ₂ O, NaBH(OAc) ₃ , MgSO ₄ , DCM, rt, 5 d Me ₂ N

Step A. A screw cap test tube was loaded with 3-chloro-7-(2,8-dimethylimidazo[1,2b]pyridazin-6-yl)-5-fluoro-cinnoline (0.037 g, 0.11 mmol), tert. butyl N-[(1S*,5R*)-3azabicyclo[3.1.0]hexan-6-yl]carbamate (0.034 g, 0.17 mmol), granular cesium carbonate (0.110 g, 0.338 mmol), and RuPhos precatalyst Pd G4 (0.0011 g, 0.0013 mmol). Anhydrous 1,4dioxane (5 ml) was added last and the mixture was purged with argon for 10 min. The test tube was tightly closed with a screw cap, placed in a preheated aluminum thermostat and vigorously stirred at 100°C for 2 hours. Then the reaction mixture was cooled to room temperature. The brown heterogeneous reaction mixture was diluted with saturated aqueous Na ₂ CO ₃ (20 ml) and extracted with CH ₂ Cl ₂ (2 times 30 ml). The combined CH ₂ Cl ₂ extracts were diluted with additional CH ₂ Cl ₂ (30 ml) and washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The brown crude product was purified by silica gel column chromatography (CH ₂ Cl ₂ /ammonia in methanol (1.0 M) gradient elution) to give the desired tert-butyl N-[(1S*,5R*)-3-[7-(2 ,8dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-cinnolin-3-yl]-3-azabicyclo[3.1.0]hexan-6yl]carbamate (0.048 g, 87%) as yellow solid matter.

MS m/z 490.3 [M+H]+; ¹ H NMR (chloroform-d) δ: 8.54 (s, 1H), 7.97 (dd, J=11.3, 1.2 Hz, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.47 (s, 1H), 6.76 (s, 1H), 4.83 (br s, 1H), 4.07 (br d, J=9.6 Hz, 2H), 3.72 (br d, J=9.9 Hz, 2H), 2.76 (s, 3H), 2.55 (s, 3H), 2.46 (br s, 1H), 2.00 (br s, 2H), 1.47 (m, 9H).

Step B. tert-Butyl N-[(1S*,5R*)-3-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl] -3-azabicyclo[3.1.0]hexan-6-yl]carbamate (0.048 g, 0.098 mmol) was dissolved in CH ₂ Cl ₂ (5 ml), and trifluoroacetic acid (0.10 ml, 1 .3 mmol), which led to an immediate change in color to wine red. The reaction mixture was closed and left at room temperature for 17 hours. The wine-red solution was then concentrated on a rotary vacuum evaporator. The red crude oil was purified by C18 column chromatography with

- 118 043655 reverse phase (H2O:MeCN (0.1% TFA) gradient elution) to give (1S*,5R*)-3-[7-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl )-5-fluoro-cinnolin-3-yl]-3-azabicyclo[3.1.0]hexane-6-amine tetra(trifluoroacetic acid) (0.054 g, 65%) in the form of a dark red oil. MS m/z 390.3 [M+H]+.

Step C. (1S*,5R*)-3-[7-(2,8-dimethylimidazo[1,2-6]pyridazin-6-yl)-5-fluoro-cinnolin-3-yl]-3azabicyclo[3.1 .0]hexane-6-amine tetra(trifluoroacetic acid) (0.050 g, 0.059 mmol) was dissolved in CH ₂ Cl ₂ (3 ml) in a screw cap test tube. 37% aqueous formaldehyde (0.018 mL, 0.24 mmol) was added, followed by anhydrous MgSO ₄ (0.021 g, 0.17 mmol), triethylamine (0.025 mL, 0.18 mmol), and NaBH(OAc) ₃ (0.031 g , 0.15 mmol). The flask was capped and the reaction mixture was vigorously stirred at room temperature for 5 days. The reaction mixture was then diluted with CH2Cl2 (30 ml), washed with saturated aqueous Rochelle salt (20 ml) and brine (20 ml), then dried over anhydrous Na2SO4, decanted, and concentrated on a rotary vacuum evaporator to give dark yellow solid/oil mixture. H (CH ₂ Cl ₂ /ammonia in methanol (1.0 M) gradient) to obtain the required (1S*,5R*)-3-[7-(2,8-dimethylimidazo[1,2-b]pyridazine-6 -yl)-5-fluoro-cinnolin-3-yl]-N,N-dimethyl-3azabicyclo[3.1.0]hexan-6-amine (0.021 g, 85%) as a yellow solid.

MS m/z 418.3 [M+H] ⁺ ; ^1H NMR (chloroform-d) δ: 8.54 (s, 1H), 7.98 (dd, J=11.3, 1.3 Hz, 1H), 7.76 (s, 1H), 7. 45 (s, 1H), 6.76 (s, 1H), 3.83 (ABq, J=126.7, 9.6 Hz, 4H), 2.74 (s, 3H), 2.54 (s , 3H), 2.40 (s, 6H), 1.93 (s, 2H), 1.57 (s, 1H).

Using the procedure described above for Example 34, additional compounds described herein were prepared by substituting the appropriate amine in Step A, suitable reagents, and reaction conditions to produce compounds such as those selected from:

Conn. Data 80 MS m/z 378.4 [M+H] ⁺ ; Ή NMR (DMSO-D ₆ ) δ: 9.29 (br s, 2H), 8.94 (s, 1H), 8.44 (br s, 1H), 8.39 (br s, 1H), 8 .19 (dd, J = 11.3, 1.3 Hz, 1H), 7.60 (s, 1H), 4.06 - 4.20 (m, 4H), 3.26 - 3.35 (m , 4H), 2.73 (s, 3H), 2.54 (s, 3H). 81 MS m/z 406.4 [M+H] ⁺ ; Ή NMR (DMSO-Db) δ: 9.53 (br s, 1H), 9.11 (br s, 1H), 8.93 (s, 1H), 8.45 (br s, 1H), 8. 39 (br s, 1H), 8.19 (d, J= 11.3 Hz, 1H), 7.67 (s, 1H), 4.87 (br d, J= 12.0 Hz, 2H), 3.45 (br s, 2H), 3.12 (dd, J= 14.2, 11.7 Hz, 2H), 2.73 (s, 3H), 2.54 (m, 3H), 1, 39 (d, J = 6.3 Hz, 6H). 86 MS m/z 406.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.44 (s, 1H), 7.84 - 7.94 (m, 2H), 7.66 (s, 1H), 6.90 (s, 1H), 3 .92 - 4.00 (m, 1H), 3.83 - 3.90 (m, 1H), 3.54 - 3.62 (m, 1H), 3.35 - 3.46 (m, 2H) , 2.99 - 3.08 (m, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.42 (s, 6H), 1.99-2.09 (m , 1H).

- 119 043655

88 MS m/z 420.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.50 (s, 1H), 7.96 (dd, J= 11.4, 1.4 Hz, 1H), 7.88 (s, 1H), 7, 69 (s, 1H), 7.29 (s, 1H), 4.64 - 4.73 (m, 2H), 3.02 - 3.13 (m, 2H), 2.67 (s, 3H) , 2.57 (tt, J = 11.3, 3.8 Hz, 1H), 2.48 (s, 3H), 2.37 (s, 6H), 2.10 (br d, J = 12, 2 Hz, 2H), 1.60 (qd, J= 12.2, 4.0 Hz, 2H). 89 MS m/z 406.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.49 (s, 1H), 7.95 (dd, J = 11.6, 1.5 Hz, 1H), 7.89 (d, J = 0.6 Hz, 1H), 7.70 (d, J= 0.9 Hz, 1H), 6.94 (s, 1H), 3.95 - 4.02 (m, 1H), 3.85 - 3.92 (m, 1H), 3.60 (td, J= 10.1, 7.0 Hz, 1H), 3.40 - 3.47 (m, 1H), 2.99 - 3.07 (m, 1H ), 2.68 (d, J = 0.9 Hz, ZN), 2.48 (s, ZN), 2.38 - 2.45 (m, 7H), 1.99 - 2.08 (m, 1H). 209 MS m/z 404.3 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 8.55 (s, 1H), 7.99 (dd, J= 11.3, 1.4 Hz, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 5.13 (bs, 1H), 3.74 (d, J = 9.3 Hz, 1H), 3.69 (s, 1H), 3 .57 (dd, J = 9.7, 1.7 Hz, 1H), 3.09 (dd, J = 9.9, 1.4 Hz, 1H), 2.80 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 2.48 (s, 3H), 2.15 (d, J= 9.6 Hz, 1H), 1, 99 (d, J= 9.7 Hz, 1H). 215 MS m/z 404.3 [M+H] ⁺ ; Ή NMR (chloroform-7) δ: 8.55 (s, 1H), 7.99 (dd, J= 11.3, 1.3 Hz, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 5.13 (bs, 1H), 3.73 (bs, 1H), 3.68 (bs, 1H), 3.57 (d, J= 9.0 Hz, 1H), 3.09 (d, J = 9.3 Hz, 1H), 2.80 (bs, 1H), 2.75 (s, 3H), 2.54 (s, 3H) , 2.48 (s, 3H), 2.15 (d, J= 9.5 Hz, 1H), 2.00 (d, J= 9.5 Hz, 1H). 217 MS m/z 404.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.77 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.22 (d, J= 10.7 Hz, 1H), 7.58 (s, 1H), 4.48 (ABq, J = 36.1, 9.0 Hz, 4H), 3.68 (s, 2H), 3.47 (dd, J = 7 .4 Hz, 2H), 2.84 (s, 3H), 2.68 (s, 3H), 2.50 (dd, J = 7.3 Hz, 2H), No protons corresponding to NH and HCl were observed . 218 MS m/z 418.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.82 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.18 (d, J= 10.8 Hz, 1H), 7.28 (s, 1H), 4.21 (ABq, J= 59.7, 8.7 Hz, 4H), 3.53 (s, 2H), 3.23 - 3.18 (m , 2H), 2.83 (s, 3H), 2.68 (s, 3H), 2.14 - 2.06 (m, 2H), 1.97 - 1.90 (m, 2H), Protons, the corresponding NH and HCl were not observed. 219 MS m/z 418.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 8.43 (s, 1H), 7.90 (dd, J= 11.5, 1.3 Hz, 1H), 7.83 (s, 1H), 7, 63 (s, 1H), 7.25 (s, 1H), 3.98 (s, 4H), 3.81 (ddd, J= 7.5, 3.7, 1.9 Hz, 4H), 2 .61 (s, 3H), 2.45 (s, 3H), 2.04 (ddd, J= 7.4, 3.7, 1.9 Hz, 4H), Protons corresponding to NH and TFA were not observed . 220 MS m/z 404.3 [M+H] ⁺ ; ^X H NMR (chloroform-tT) δ: 8.63 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.00 (dd, J= 11.2, 1 ,0 Hz, 1H), 6.99 (s, 1H), 4.23 (ABq, J= 51.2, 11.5 Hz, 4H), 4.00 (s, 2H), 3.74 (dd , J= 6.9 Hz, 2H), 2.74 (s, 3H), 2.59 (s, 3H), 2.51 (dd, J= Ίβ Hz, 2H), Protons corresponding to NH and TFA, were not observed. 221 MS m/z 418.3 [M+H] ⁺ ; Ή NMR (methanol-^) δ: 8.73 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.08 (d, J= 11.2 Hz, 1H ), 7.04 (s, 1H), 4.13 (s, 4H), 3.28 (dd, J= 7.3, 5.7 Hz, 4H), 2.77 (s, 3H), 2 .62 (s, 3H), 2.18 (dd, J= 7.3, 5.6 Hz, 4H), No protons corresponding to NH and TFA were observed. 224 MS m/z 434.3 [M+H] ⁺ ; Ή NMR (chloroform-i/) δ: 8.56 (s, 1H), 7.98 (dd, J= 11.3, 1.3 Hz, 1H), 7.77 (s, 1H), 7, 46 (s, 1H), 7.09 (s, 1H), 3.92 - 3.79 (m, 4H), 2.74 (s, 3H), 2.54 (s, 3H), 2.29 (s, 6H), 2.00 (dd, J= 13.7, 5.9 Hz, 2H), 1.67 (dt, J= 12.9, 5.9 Hz, 2H), 1.03 ( s, 3H).

Example 35.

Receiving connection 203

Step A. Tert-butyl 4-[3-(2,7-dimethylindazol-5-yl)-5-fluorocinnolin-7-yl]-3,6-dihydro-2H-pyridin-1- was loaded into a flat-bottomed test tube. carboxylate (20 mg, 0.0422 mmol), potassium osmate(VI) dihydrate (2.00 mg, 0.00543 mmol), 4-methylmorpholine N-oxide (11.0 mg, 0.0911 mmol), acetone (0 .2 ml) and water (0.053 ml, 2.9 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding dropwise saturated aqueous NaHSO ₃ solution with stirring for 5 minutes. The resulting black suspension was extracted with EtOAc. The combined organic extracts were washed with water, dried and concentrated to give tert-butyl 4[3-(2,7-dimethylindazol-5-yl)-5-fluoro-cinnolin-7-yl]-3,4-dihydroxy-piperidin-1 -carboxylate (cisdiol, racemate) (14.0 mg, 0.0276 mmol, 65.3% yield) as a yellow solid. MS m/z 508.2 [M+H]+.

Step B. Tert-butyl 4-[3-(2,7-dimethylindazol-5-yl)-5-fluoro-cinnolin-7-yl]3,4-dihydroxy-piperidine-1-carboxylate (7, 00 mg, 0.0138 mmol), trifluoroacetic acid (0.22 ml, 2.9 mmol) and dichloromethane (0.5 ml). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. 1.25 N was added to the mixture. HCl in methanol (1 ml). The mixture was concentrated (this step was repeated three times). The solid was washed with ethyl acetate, ether and hexane in a funnel

- 120 043655 with a filter layer, and then lyophilized to obtain 4-(3-(2,7-dimethyl-2H-indazol-5-yl)-5fluorocinnolin-7-yl)piperidin-3,4-diol hydrochloride (cis- diol, racemate) (7.3 mg, 0.018 mmol, 100% yield).

MS m/z 408.3 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 8.69 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.85 (d, J=11 Hz, 1H), 4.35 (dd, J=5, 1.5 Hz, 1H), 4.30 (s, 3H), 3.40 (m, 6H), 2.70 (s, 3H). NH and OH protons were not observed.

Example 36.

Receiving connection 146

Step A: 2,6-Dimethylpyridin-3-ol (996 mg, 8.1 mmol) was dissolved in aqueous sodium hydroxide (2.0 M, 4.1 ml) with stirring at room temperature. Iodine (2.65 g, 10.4 mmol) was added to this stirred solution. The mixture was heated to 50°C and stirred for 3 hours. The mixture was neutralized with an aqueous solution of hydrochloric acid (6 M), then quenched with a saturated aqueous solution of sodium thiosulfate. MeOH (5 ml) was added to the mixture, and then the reaction mixture was concentrated. CH ₂ Cl ₂ (90 ml) and MeOH (10 ml) were added and the reaction mixture was stirred for 10 minutes, then filtered. The filtrate was concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give 4-iodo-2,6-dimethylpyridin-3-ol (564.6 mg, 28%).

MS m/z 250.1 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 7.61 (s, 1H), 2.47 (s, 3H), 2.39 (s, 3H), No proton corresponding to OH was observed.

Step B. tert-Butyl 4-(7-chloro-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (500 mg, 1.37 mmol), sodium tert-butoxide (198 mg, 2.06 mmol ), and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'biphenyl)[2-2'-amino-1,1'-biphenyl)]palladium(II) (103 mg, 0.14 mmol), 1,4-dioxane (10 ml), and diphenylmethanimine (260 μl, 1.55 mmol) were combined, degassed with argon and heated to 100°C for 16 h. After the reaction mixture had cooled to room temperature, hydroxylamine hydrochloride ( 445 mg, 6.4 mmol), potassium acetate (815 mg, 8.3 mmol) and methanol (30 ml). The reaction mixture was stirred at room temperature for 7 hours. The mixture was concentrated and the residue was partitioned between EtOAc and H ₂ O. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-10% MeOH in CH2Cl2 to give tert-butyl 4(7-amino-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (337 mg, 71%).

MS m/z 347.3 [M+H]+; ^1H NMR (methanol- _d4 ) δ: 7.87 (s, 1H), 7.14 (s, 1H), 7.06 (dd, J=11.6, 1.8 Hz, 1H), 4 ,30 (d, J=13.7 Hz, 2H), 3.29 (tt, J=12.2, 3.7 Hz, 1H), 2.92-3.11 (m, 2H), 2, 04 (d, J=12.2 Hz, 2H), 1.87 (qd, J=12.6, 4.3 Hz, 2H), 1.51 (s, 9H), NH ₂ protons were not observed.

Step C. tert-Butyl 4-(7-amino-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (187 mg, 0.54 mmol) was dissolved in trifluoroacetic acid (4.0 ml) and stirred at room temperature for 5 minutes. Sodium nitrite (43 mg, 0.63 mmol) was added to the mixture, which was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (4.0 ml) and water (1.0 ml). To this stirred solution at room temp.

- 121 043655 Potassium iodide (394 mg, 2.37 mmol) was added to the mixture in portions. The mixture was stirred for 20 minutes at room temperature. Diisopropylethylamine (1.4 mL, 8.0 mmol) and di-tert-butyl dicarbonate (800 μL, 3.35 mmol) were added to the mixture. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexane to give tert-butyl 4-(5-fluoro-7-iodocinnolin-3-yl)piperidine -1carboxylate (119 mg, 48%).

MS m/z 402.3 [M+H-tBu] ⁺ ; ¹ H NMR (CDCl ₃ ) δ: 8.82 (s, 1H), 7.84 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 4.36 (br s, 2H), 3.45 (tt, J=12.2, 3.7 Hz, 1H), 2.97 (t, J=11.0 Hz, 2H), 2.15 (br d, J=13, 1 Hz, 2H), 1.91 (qd, J=12.5, 4.3 Hz, 2H), 1.50-1.54 (m, 9H).

Step D. tert-butyl 4-(5-fluoro-7-iodocinnolin-3-yl)piperidine-1-carboxylate, copper iodide (1.0 mg, 0.0053 mmol) and bis(triphenylphosphine)palladium(P) dichloride (6.2 mg, 0.0088 mmol) were combined under nitrogen followed by the addition of CH3CN (2.0 mL). The solution was degassed with argon for 30 s, after which trimethylamine (40 μL, 0.29 mmol) was added. The solution was degassed with argon for 3 min, after which trimethylsilylacetylene (20 μl, 0.14 mmol) was added. This mixture was stirred at room temperature under nitrogen for 16 hours. The mixture was concentrated and the residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexane to give tert-butyl 4-(5-fluoro-7-((trimethylsilyl)ethynyl )cinnolin-3-yl)piperidin-1-carboxylate (24.5 mg, 72%). MS m/z 372.5 [M+H-t-Bu] ⁺ .

Step E: tert-Butyl 4-(5-fluoro-7-((trimethylsilyl)ethynyl)cinnolin-3-yl)piperidin-1-carboxylate (25 mg, 0.057 mmol) was dissolved in MeOH (2.0 mL). The stirred solution was cooled to 0°C. Potassium carbonate (17.9 mg, 0.130 mmol) was added and the reaction mixture continued to stir at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (8.0 ml). The mixture was partitioned between CH ₂ Cl ₂ and H2O. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 4-(7-ethynyl5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate as a crude mixture, which was used without purification. MS m/z 300.0 [M+Ht-Bu]+. tert-Butyl 4-(7-ethynyl-5-fluoro-cinnolin-3-yl)piperidine-1carboxylate (20 mg, 0.057 mmol), copper iodide (0.3 mg, 0.002 mmol), bis(triphenylphosphine) palladium(P ) dichloride (4.4 mg, 0.0063 mmol) and 4-iodo-2,6-dimethyl-pyridin-3-ol (15.8 mg, 0.063 mmol) were combined under nitrogen followed by the addition of N,N-dimethylformamide (1.0 ml). The solution was degassed with argon for 30 s followed by the addition of trimethylamine (50.0 μL, 0.36 mmol). This solution was degassed with argon for 5 minutes, then stirred at 45°C under argon for 20 hours. The mixture was concentrated and the residue was chromatographed on silica gel, eluted with 0-30% MeOH in CH ₂ Cl ₂ to give tert-butyl 4-[7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluorocinnolin-3-yl]piperidine-1-carboxylate (10.3 mg, 38%). MS m/z 477.5 [M+H] ⁺ .

Step F. tert-Butyl 4-[7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluoro-cinnolin-3-yl]piperidine-1carboxylate (10.3 mg, 0.022 mmol) was dissolved in trifluoroacetic acid (2 ml). After 15 minutes, the volatile material was removed. The residue was chromatographed on a C18 reverse phase column, eluted with 0-100% CH3CN in H2O (added 0.1% v/v TFA). The collected fractions were concentrated. The residue was dissolved in 1.25 M HCl in MeOH. The volatile material was removed to give 2-[5-fluoro-3-(4piperidyl)cinnolin-7-yl]-5,7-dimethylfuro[2,3-c]pyridine hydrochloride (8.3 mg, 93%).

MS m/z 377.5 [M+H]+; ¹ H NMR (methanol-d ₄ ) δ: 9.11 (s, 1H), 8.48 (s, 1H), 8.40 (br d, J=10.1 Hz, 1H), 8.04 ( s, 1H), 7.99 (s, 1H), 3.69-3.77 (m, 1H), 3.66 (br d, J=12.8 Hz, 2H), 3.34-3, 39 (m, 2H), 3.12 (s, 3H), 2.84 (s, 3H), 2.27-2.50 (m, 4H), No protons corresponding to NH and HCl were observed.

- 122 043655

Example 37.

Receiving connection 191

Step A: Combine 4-chloro-2,6-dimethyl-3-nitro-pyridine (1.1054 g, 5.9239 mmol, acetonitrile (4.0 ml), and aqueous hydrochloric acid (concentrated, 57%, 4 .0 ml) and heated to 70°C for 20 hours. The mixture was partitioned between CH ₂ Cl ₂ , saturated aqueous Na ₂ CO ₃ and aqueous NaOH (1 M). The aqueous layer was extracted with CH ₂ Cl _2. Combined organics phases were dried over Na ₂ SO ₄ , filtered and concentrated.The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexane to give 4-iodo-2,6-dimethyl-3-nitropyridine (1.48 g, 90% MS m/z 279.1 [M+H]+.

Step B: 4-Iodo-2,6-dimethyl-3-nitropyridine (1.004 g, 3.611 mmol), tin chloride dihydrate (3.32 g, 14.7 mmol) and EtOAc (5.0 mL) were combined and heated to 60°C for 10 min. The mixture was partitioned between EtOAc, saturated aqueous Na ₂ CO ₃ and aqueous NaOH (1 M). The aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give 4-iodo-2,6-dimethylpyridin-3-amine (723.7 mg, 81%). MS m/z 249.1 [M+H]+.

Step C. 4-Iodo-2,6-dimethyl-pyridin-3-amine (724 mg, 2.92 mmol), di-tert-butyl dicarbonate (2.2 ml, 9.2 mmol), 4-dimethylaminopyridine ( 42 mg, 0.34 mmol) and CH ₂ Cl ₂ (5.0 ml) were combined and stirred at 40°C for 17 hours. The mixture was concentrated and the residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tert-butyl N-tert-butoxycarbonyl-N(4-iodo-2,6-dimethyl-3-pyridyl)carbamate (489 mg, 37%). MS m/z 449.4 [M+H] ⁺ .

Step D. tert-Butyl N-tert-butoxycarbonyl-N-(4-iodo-2,6-dimethyl-3-pyridyl)carbamate (489 mg, 1.1 mmol), aqueous NaOH (1 M, 4.0 ml) and MeOH (4.0 ml) were combined and stirred at 70°C for 7 hours. The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted twice with MeOH/CH ₂ Cl ₂ (1:9) and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tert-butyl N-(4-iodo-2,6-dimethyl-3-pyridyl)carbamate (278 mg, 73%). MS m/z 349.1 [M+H]+; ^1H NMR (CDCl3) δ: 7.54 (s, 1H), 6.00 (br d, J=2.7 Hz, 1H), 2.57 (s, 3H), 2.48 (s, 3H ), 1.53 (s, 9H).

Step E. tert-Butyl 4-(5-fluoro-7-((trimethylsilyl)ethynyl)cinnolin-3-yl)piperidin-1-carboxylate (from Example 38, 104 mg, 0.24 mmol) was dissolved in methanol (2 ,0 ml). The stirred solution was cooled to 0°C. Potassium carbonate (50.6 mg, 0.366 mmol) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (8.0 ml). The mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 4-(7-ethynyl-5-fluorocinnolin-3-yl)piperidin-1-carboxylate as a crude mixture, which was used without purification. MS m/z 300.0 [M+H-tBu] ⁺ . tert-Butyl 4-(7-ethynyl-5-fluoro-cinnolin-3-yl)piperidin-1-carboxylate (86 mg, 0.24 mmol) was dissolved in DMF (1.0 ml). The vessel was purged with argon. Triethylamine (135 μL, 0.97 mmol) was added. The vessel was again purged with argon. This solution was added to a mixture of copper iodide (1.4 mg, 0.0073 mmol), bis(triphenylphosphine)palladium(II) dichloride (10.2 mg, 0.0146 mmol) and tert-butyl N-(4-iodo-2, 6-dimethyl-3-pyridyl)carbamate (93 mg, 0.27 mmol) under argon. The solution was stirred at 50°C for 17 hours. The mixture was concentrated and the residue was partitioned between CH2C12 and brine. The aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated to give tert-butyl 4-[7-[2-[3-(tert-butoxycarbonylamino)-2,6-dimethyl-4-pyridyl]ethynyl]-5-fluoro-cinnoline-3 -yl]piperidine-1-carboxylate as the crude mixture, which was used without purification. MS m/z 576.5 [M+H]+.

Step F. tert-Butyl 4-[7-[2-[3-(tert-butoxycarbonylamino)-2,6-dimethyl-4-pyridyl]ethynyl]-5fluoro-cinnolin-3-yl]piperidine-1-carboxylate ( 140 mg, 0.24 mmol), tetrahydrofuran (4.0 mL) and tetrabutylammonium fluoride (1.0 M in THF, 730 μL, 0.73 mmol) were combined and stirred at 65°C for 2 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel, eluted with 0-30% MeOH in CH ₂ Cl ₂ to give tert-butyl 4-[7-(5,7-dimethyl-1H-pyrrolo[2,3c]pyridin-2-yl )-5-fluoro-cinnolin-3-yl]piperidine-1-carboxylate (34.2 mg, 30%). MS m/z 476.5 [M+H]+.

Step G. tert-Butyl 4-[7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-fluoro-cinnolin-3yl]piperidine-1-carboxylate (34 .2 mg, 0.0719 mmol) was dissolved in trifluoroacetic acid (1 ml). After 1 min, the volatile material was removed. The residue was chromatographed on a reverse phase C18 column, eluted with 0-100% CH ₃ CN in H2O (with 0.1% v/v TFA), and subsequently chromatographed on silica gel, eluted with 0-100% MeOH (with by adding 2.5% v/v NH ₄ OH) in CH ₂ Cl ₂ to give 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-5- fluoro-3-(piperidin4-yl)cinnoline hydrochloride.

MS m/z 376.3 [M+H]+; 1H NMR (methanol- _d4 ) δ: 8.95 (s, 1H), 8.23 (s, 1H), 8.22 (dd, J=10.7, 1.2 Hz, 1H), 7, 67 (s, 1H), 7.41 (s, 1H), 3.50-3.61 (m, 3H), 3.17-3.26 (m, 2H), 2.99 (s, 3H) , 2.64 (s, 3H), 2.18-2.34 (m, 4H), No protons corresponding to NH and HCl were observed.

Example 38.

Receiving connection 82

Pd ₂ dba ₃ , BINAP NaOtBu, Dioxane

80°C,16h

1) _NaNO2 , TFA, rt

2) CuCI, CuCI ₂

MeCN, 0 °C

2) NH ₂ OH HCl, KOAc, MeOH rt, 72h

Step A. 5-Bromo-3-fluoro-benzene-1,2-diamine (1.07 g, 5.2 mmol), tert-butyl 4-(2bromoacetyl)piperidine-1-carboxylate (1.60 g, 5 .2 mmol) and DMF (80 ml) were combined and stirred at room temperature for 16 hours, 50°C for 24 hours, and 70°C for 24 hours. After cooling to room temperature, potassium carbonate (1.08 g, 7.84 mmol) and di-tert-butyl dicarbonate (1.4 ml, 6.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and brine. The organic layer was washed twice with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tert-butyl 4-(6-bromo-8-fluoroquinoxalin-2-yl)piperidin-1-carboxylate and tert-butyl 4-(7-bromo -5-fluoroquinoxalin-2-yl)piperidine 1-carboxylate in the form of an approximately 1:1 mixture (distinct peaks are designated compounds A and B in 1H NMR; overlapping peaks are designated apparent peaks apt) (1.23 g, 58%).

MS m/z 310.2 [M+H-CO ₂ -t-Bu] ⁺ ; 1H NMR (CDCl ₃ ) δ: 8.84 (s, 1H, A), 8.82 (s, 1H, B), 8.12 (t, J=1.7 Hz, 1H, A), 8. 09 (t, J=1.7 Hz, 1H, B), 7.61 (dd, J=9.2, 2.1 Hz, 1H, A), 7.58 (dd, J=9.0, 2.0 Hz, 1H, B), 4.34 (apt d, J =12.2 Hz, 4H), 3.17 (apt qt, J = 11.9, 3.7 Hz, 2H), 2, 94 (apt br tt, J=13.1, 2.8 Hz, 4H), 1.99-2.06 (m, 4H), 1.93 (apt quint J=11.6, 4.0 Hz, 4H), 1.51 (apt d, J=1.8 Hz, 18H).

- 124 043655

Step B: 1:1 mixture of tert-butyl 4-(6-bromo-8-fluoroquinoxalin-2-yl)piperidine-1-carboxylate and tert-butyl 4-(7-bromo-5-fluoroquinoxalin-2-yl)piperidine -1-carboxylate was combined with sodium tert-butoxide (760 mg, 7.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (74 mg, 0.08 mmol), racemic 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (144 mg, 0.23 g), toluene (13.0 ml) and benzophenone imine (500 μl, 3.6 mmol) under nitrogen atmosphere. The vessel was purged with argon for 6 minutes, then heated to 80°C for 20 hours. Hydroxylamine hydrochloride (1.37 g, 19.6 mmol), potassium acetate (2.47 g, 25.2 mmol) and MeOH (65 ml). The mixture was stirred at room temperature for 24 hours and then concentrated. The residue was partitioned between saturated aqueous Na ₂ CO ₃ solution, saline and CH ₂ Cl ₂ . The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tert-butyl 4-(6-amino-8fluoroquinoxalin-2-yl)piperidine-1-carboxylate (340.0 mg, 38%).

MS m/z 291.3 [M+H-t-Bu] ⁺ ; ¹ H NMR (DMSO-d ₆ ) δ: 8.69 (s, 1H), 7.01 (dd, J=12.5, 2.1 Hz, 1H), 6.77 (d, J=2, 1 Hz, 1H), 6.11 (s, 2H), 4.03-4.21 (m, 2H), 3.06 (tt, J=11.5, 3.4 Hz, 1H), 2, 89 (br s, 2H), 1.86-1.93 (m, 2H), 1.66 (qd, J=12.6, 4.4 Hz, 2H), 1.43 (s, 9H).

Step C: Sodium nitrite (23.9 mg, 0.346 mmol) was added to a stirred solution of tert-butyl 4(6-amino-8-fluoroquinoxalin-2-yl)piperidine-1-carboxylate in trifluoroacetic acid (1.5 ml ). The mixture was stirred at room temperature for 1 minute. The mixture was concentrated and double azeotroped with MeCN. The residue was dissolved in acetonitrile (1.4 ml) and cooled to 0°C. This solution was added dropwise to a solution of copper(T) chloride (47 mg, 0.47 mmol) and copper(P) chloride (95 mg, 0.71 mmol) in acetonitrile (1.2 ml) at 0°C. After stirring for 1 min at 0°C, the reaction mixture was partitioned between EtOAc, saturated aqueous Na ₂ CO ₃ and aqueous NaOH (1 M). The aqueous layer was extracted with EtOAc.

The combined organic phases were dried over Na2SO4, filtered and concentrated to give 6-chloro-8-fluoro-2-(4-piperidyl)quinoxaline (130.0 mg) as a crude mixture which was used without purification. MS m/z 266.3 [M+H] ⁺ . 6-Chloro-8-fluoro-2-(4-piperidyl)quinoxaline (61 mg, 0.23 mmol), CH ₂ Cl ₂ (3.0 ml), N,N-diisopropylethylamine (400 μl, 2.3 mmol ) and di-tert-butyl dicarbonate (230 μl, 0.96 mmol) were combined and stirred at room temperature for 18 hours. The mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-40% EtOAc in hexane to give tert-butyl 4(6-chloro-8-fluoroquinoxalin-2-yl)piperidin-1-carboxylate (52.7 mg, 50%).

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

Step D: Combine 6-Chloro-2,8-dimethyl-imidazole[1,2-b]pyridazine (50.0 mg, 0.275 mmol), 1,1'bis(diphenylphosphino)ferrocene palladium(P) dichloride (15 mg , 0.019 mmol), bis(pinacolato)diborone (96 mg, 0.37 mmol) and potassium acetate (dried at 250°C under vacuum immediately before use, 89 mg, 0.89 mmol) and 1,4-dioxane (1 .5 ml). The mixture was stirred under argon at 95°C for 2 hours. Tert-butyl 4-(6-chloro-8-fluoroquinoxalin-2-yl)piperidine-1-carboxylate (65.8 mg, 0.180 mmol) was added to the mixture ), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'biphenyl-2-yl) palladium(P) (6.6 mg, 0 .0091 mmol) and an aqueous solution of K2CO3 (1 M, 750 µl). The mixture was purged with argon and then stirred at 80°C for 16 hours. The reaction mixture was partitioned between EtOAc and H ₂ O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 0-100% EtOAc in hexane to give tert-butyl 4-[6-(2,8dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroquinoxaline-2 -yl]piperidine-1-carboxylate (44 mg, 52%). MS m/z 477.6 [M+H] ⁺ .

Step E. tert-Butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroquinoxalin-2yl]piperidine-1-carboxylate (45 mg, 0.094 mmol ) was dissolved in CH ₂ Cl ₂ (2 ml) and TFA (2 ml). After 10 minutes, the volatile material was removed. The residue was dissolved in methanolic hydrogen chloride solution (1.25 M) and concentrated to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(4piperidyl)quinoxaline hydrochloride ( 47 mg, quant.).

MS m/z 311.3 [M+H]+; 1H NMR (methanol-d ₄ ) δ: 9.11 (s, 1H), 8.75 (s, 1H), 8.51 (d, J=0.9 Hz, 1H), 8.358.46 (m, 2H), 3.64 (dt, J=12.9, 3.2 Hz, 2H), 3.58 (tt, J=11.0, 3.8 Hz, 1H), 3.24-3.32 (m, 2H), 2.87 (s, 3H), 2.71 (s, 3H), 2.35-2.42 (m, 2H), 2.26-2.34 (m, 2H), No protons corresponding to NH and HCl were observed.

- 125 043655

Example 39.

Receiving connection 116

Step A: tert-Butyl 4-(7-chloro-5-fluorocinnolin-3-yl)piperidin-1-carboxylate (500 mg, 1.4 mmol) was combined with tri-butyl(1-ethoxyvinyl)tin (0.52 ml, 1.54 mmol) and CsF (470 mg, 3.08 mmol) in 1,4dioxane (16 ml). The mixture was stirred at 90°C for 2 hours under N ₂ atmosphere. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel, eluted with 10-20% EtOAc in petroleum ether to give tert-butyl 4-(7-(1-ethoxyvinyl)-5-fluorocinnolin-3yl)piperidine-1-carboxylate (500 mg, 90%) . MS m/z 402.7 [M+H]+.

Step B: tert-Butyl 4-(7-(1-ethoxyvinyl)-5-fluorocinnolin-3-yl)piperidin-1-carboxylate (480 mg, 1.2 mmol) was combined with NBS (235 mg, 1.32 mmol ) in THF (20 ml) and H ₂ O (10 ml). The mixture was stirred at room temperature for 10 minutes. THF was removed under reduced pressure. The solution was filtered. The solid was dried to give tert-butyl 4-(7-(2-bromoacetyl)-5-fluorocinnolin-3yl)piperidine-1-carboxylate (500 mg, 92%). MS m/z 474.0, 476.0 [M+Na]+.

Step C. tert-Butyl 4-(7-(2-bromoacetyl)-5-fluorocinnolin-3-yl)piperidin-1-carboxylate (477 mg, 1.06 mmol) was combined with 3,5-dimethylpyrazin-2-amine (234 mg, 1.9 mmol) in EtOH (20 ml). The mixture was stirred at 90°C for 4 hours. The mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluted with 30-50% EtOAc in CH ₂ Cl ₂ to give tert-butyl 4-(7-(6,8-dimethylimidazo[1,2-a]pyrazin-2yl)-5-fluorocinnolin- 3-yl)piperidine-1-carboxylate (270 mg, 53%). MS m/z 477.2 [M+H]+.

Step D. tert-Butyl 4-(7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluorocinnolin-3yl)piperidine-1-carboxylate (230 mg, 0.48 mmol ) was added to TFA (2 ml). The mixture was stirred at room temperature for 1 hour. Volatile material was removed under reduced pressure. The residue was purified by preparative HPLC to give 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-3(piperidin-4-yl)cinnoline hydrochloride (86 mg, 45% yield) .

MS m/z 377.2 [M+H]+; ^1H NMR (DMSO- _d6 ) δ: 8.93 (s, 1H), 8.83 (s, 1H), 8.29-8.38 (m, 2H), 8.11 (s, 1H) , 3.82 (s, 1H), 3.12 (dd, J=12.5, 9.5 Hz, 4H), 2.82 (d, J=13.2 Hz, 3H), 2.41 ( s, 3H), 2.10-2.28 (m, 4H), The proton corresponding to NH was not observed.

- 126 043655

Example 40.

Receiving connection 226

1) B ₂ Pin ₂ , KOAc, SPhos-Pd G2

1,4-dioxane °C, 15h

Mel _{, K2CO3}

DMF, rt, 2 h

2) Oxone, H ₂ O:acetone

F 0 °C, 15 min

Step A: KOAc (6.6 g, 67 mmol) was dried under argon at 180°C for 30 min. The mixture was cooled to room temperature. 7-Bromo-3-chloro-5-fluorocinnoline (90% purity, 3 g, 10.3 mmol) was added along with bis(pinacolato)diborone (3 g, 11.8 mmol), SPhos Pd G2 (300 mg, 0 .41 mmol) and 1,4-dioxane (40 ml). The mixture was heated at 80°C for 15 hours. The mixture was diluted in EtOAc and filtered through celite. The filtrate was concentrated under vacuum. The residue was chromatographed on silica gel, eluted with 20-50% EtOAc in CH ₂ Cl ₂ to give crude boric acid. This material was suspended in 100 ml of 1:1 acetone:H ₂ O at 0°C. Oxon (20 g, 32.3 mmol) was added. The mixture was stirred at 0°C for 15 minutes. The reaction mixture was diluted in 600 ml H2O, and then filtered. The collected material was dried to give 3-chloro-5-fluorocinnolin-7-ol (1.92 g, 84%) as a dark yellow solid.

1H NMR (DMSO-d ₆ ) δ: 11.34 (s, 1H), 8.39 (s, 1H), 7.49 (s, 1H), 7.40 (dd, J=11.2 Hz, 1H).

Step B: 3-Chloro-5-fluorocinnolin-7-ol (1.9 g, 8.6 mmol, 90% purity) was dissolved in DMF (37 ml). K2CO3 (3.8 g, 27 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. Iodomethane (1.9 mL, 31 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between H2O and EtOAc. The organic layer was washed with H2O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 20% EtOAc in hexane to give 3-chloro-5-fluoro-7-methoxycinnoline (1.04 g, 57%) as a white solid.

¹ H NMR (αcetone-d ₄ ) δ: 8.26 (s, 1H), 7.69 (s, 1H), 7.37 (dd, J=10.5, 2 Hz, 1H), 4.13 (s, 3H).

Step C. 3-Chloro-5-fluoro-7-methoxycinnoline (990 mg, 4.65 mmol), (2R,6S)-1-benzyl-2,6-dimethyl-4(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (purity 80%, 2.14 g, 5.24 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (190 mg, 0.23 mmol), 1,4-dioxane (26 mL) and aqueous K2CO3 (2.0 M, 13 mL, 26 mmol) were heated at 90°C for 4 h. The mixture was partitioned between CH ₂ Cl ₂ and H2O. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 10-20% acetone in CH ₂ Cl ₂ to give 3-((2R,6S)-1-benzyl-2,6dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -5-fluoro-7-methoxycinnoline (1.28 g, 73%) as an off-white solid.

1H NMR (acetone- _d4 ) δ: 8.07 (s, 1H), 7.67 (s, 1H), 7.47-7.51 (m, 2H), 7.30-7.36 (m , 2H), 7.20-7.27 (m,

- 127 043655

2H), 7.00 (s, 1H), 4.11 (s, 3H), 3.97 (d, J=16 Hz, 1H), 3.91 (d, J=16 Hz, 1H), 3 .53-3.60 (m, 1H), 3.10-3.15 (m,

1H), 2.86-2.92 (m, 1H), 2.54-2.62 (m, 1H), 1.32 (d, J=6.5 Hz, 3H), l.21 (d , J=6.5 Hz, 3H).

Step D. 3 -((2R,6S)-1-Benzyl-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-7methoxycinnoline (1.28 g, 3. 39 mmol) was dissolved in 140 ml of 1:1 CH ₂ Cl ₂ : MeOH. 10% Pd/C (300 mg) and 20% Pd(OH) ₂ /C (300 mg) were added. The mixture was stirred under H ₂ (50 psi) for 2 days. The reaction mixture was filtered through celite, washed with CH ₂ Cl ₂ :MeOH. The filtrate was concentrated under vacuum. The residue was partitioned between an aqueous solution of NaOH and CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (20 ml). MnO ₂ (5 g, 57.5 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, washed with CH2Cl2:MeOH. The filtrate was concentrated and the residue was chromatographed on silica gel, eluting with CH ₂ Cl ₂ :MeOH:NH ₄ OH (9:1:0.1) to give 3-((2S,4R,6R)-2,6-dimethylpiperidin- 4-yl)-5-fluoro-7methoxycinnoline (568 mg, 53%) as a yellow solid. This compound is the component with the highest Rf in the product mixture.

1H NMR (methanol- _d4 ) δ: 8.06 (s, 1H), 7.59 (s, 1H), 7.27 (dd, J=10.5, 1.5 Hz, 1H), 4, 06 (s, 3H), 3.43 (tt, J=12.5, 3.5 Hz, 1H), 3.00-3.05 (m, 2H), 2.09 (d, J=12, 5 Hz, 2H), 1.54 (q, J=12.5 Hz, 2H), 1.25 (d, J=6.5 Hz, 6H), The proton corresponding to NH was not observed.

Step E: Solution of 3-((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)-5-fluoro-7-methoxycinnoline (565 mg, 1.95 mmol) in MeOH (2 ml) and CH ₂ Cl ₂ (8 ml) was treated with 37% formaldehyde in water (4 ml, 54 mmol). Sodium triacetoxyborohydride (3.3 g, 16 mmol) was added in three parts after 3 hours. The reaction mixture was partitioned between aqueous NaOH and CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give 5-fluoro-7-methoxy-3-((2S,4r,6R)-1,2,6trimethylpiperidin-4-yl)cinnoline (566 mg, 95% ) in the form of a yellow solid.

1H NMR (methanol- _d4 ) δ: 8.06 (s, 1H), 7.59 (s, 1H), 7.27 (dd, J=10.5, 1.5 Hz, 1H), 4, 06 (s, 3H), 3.43 (m, 1H), 2.50 (m, 2H), 2.41 (s, 3H), 2.08 (d, J=11 Hz, 2H), 1, 82 (q, J=12 Hz, 2H), 1.29 (d, J=6.5 Hz, 6H).

Step F: 5-Fluoro-7-methoxy-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnoline (485 mg, 1.6 mmol) was dissolved in CH ₂ Cl ₂ (4 ml) at 0°C. BBr ₃ (2 mL, 21.2 mmol) was added dropwise. The mixture was difficult to stir after 10 minutes. The mixture was warmed to room temperature. Sticky lumps were broken up with a spatula before the mixture was mixed. The mixture was stirred at room temperature for 16 hours. The mixture was slowly added to ice. NaOH granules were added until the solution became alkaline. Volatile material was removed under vacuum. The crude product was redissolved in 20 ml H ₂ O. Reverse phase chromatography was used to desalt the product. An aqueous solution of HCl was added to the purest fractions. Fractions were concentrated under reduced pressure to give crude 5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7-ol hydrochloride (70% purity, 687 mg, 92 %). This material was found to be a crude 2:1 tautomeric mixture by 1H NMR in CD3OD. MS m/z 290.2 [M+H]+.

Step G. Crude 5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7-ol hydrochloride (70% purity, 685 mg, 1.47 mmol) , N,N-bis(trifluoromethylsulfonyl)aniline (2.7 g, 7.6 mmol), K2CO3 (2.7 g, 20 mmol) and DMF (7 ml) were stirred at room temperature for 15 h. Volatile material was removed under vacuum. The crude product was dissolved in CH2Cl2 and filtered to remove solid impurities. The filtrate was concentrated under vacuum. The residue was chromatographed on silica gel, eluted with 5-20% MeOH in CH ₂ Cl ₂ to give 5-fluoro-3((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7- yl trifluoromethanesulfonate (535 mg, 79% in 2 steps) as a yellow solid.

1H NMR (methanol- _d4 ) δ: 8.39 (s, 1H), 8.24 (s, 1H), 7.81 (dd, J=9.5, 2 Hz, 1H), 3.60 ( m, 1H), 2.95 (br s, 2H), 2.63 (br s, 3H), 2.23 (d, J=12.5 Hz, 2H), 2.01 (q, J=12 .5 Hz, 2H), 1.43 (d, J=6.5 Hz, 6H).

Step H: Mixture of 5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7-yl trifluoromethanesulfonate (36 mg, 0.085 mmol), KOAc (30 mg, 0.30 mmol), bis(pinacolato)diborone (26 mg, 0.1 mmol), Pd(dppf)Cl ₂ (7 mg, 0.0084 mmol) and 1,4-dioxane (0.35 ml) were heated at 90°C for 15 hours. The reaction mixture was diluted in EtOAc and filtered through celite. The filtrate was concentrated under vacuum. Crude boric acid was dissolved in Et2O and filtered through celite to remove black insoluble impurities. The filtrate was concentrated with a stream of nitrogen to give 51 mg of crude boric acid in the form of a black oil. 5-Chloro-2,7-dimethyloxazolo[5,4-b]pyridine (11 mg, 0.06 mmol), Pd(dppf)Cl ₂ (7 mg, 0.0084 mmol), 1,4-dioxane (0 .3 ml) and an aqueous solution of K2CO3 (2.0 M, 0.15 ml, 0.3 mmol) was added to the crude boric acid. The mixture was stirred at 90°C for 1 hour. The mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with mixtures of CH ₂ Cl ₂ :MeOH:NH ₄ OH (95:5:0.5) to CH ₂ Cl ₂ :MeOH:NH ₄ OH (90:10:1). Recrystallization was carried out from 1.5 ml of methanol to obtain 5-(5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4-yl)cinnolin-7-yl)2,7-dimethyloxazolo [5,4-b]pyridine (17 mg, 47%) as a white solid.

MS m/z 420.3 [M+H]+; 1H NMR (methanol-d ₄ ) δ: 8.95 (s, 1H), 8.36 (d, J=11 Hz, 1H), 8.16 (s, 1H), 8.10 (s,

- 128 043655

1H), 3.46-3.53 (m, 1H), 2.74 (s, 3H), 2.73 (s, 3H), 2.53 (m, 2H), 2.43 (s, 3H ), 2.13 (d, J=12 Hz, 2H), 1.88 (q,

J=12 Hz, 2H), 1.31 (d, J=6 Hz, 6H).

Using the procedure described above for Example 40, additional compounds described herein were prepared by replacing a suitable heteroaryl halide in step H, suitable reagents and reaction conditions, to obtain compounds such as those selected from:

Conn. Data 227 MS m/z 419.3 [M+H] ⁺ ; Ή NMR (methanol- ₇₄ ) δ: 8.89 (s, 1H), 8.53 (s, 1H), 8.39 (dd, J = 11, 1.5 Hz, 1H), 8.16 ( s, 1H), 7.95 (s, 1H), 4.33 (s, 3H), 3.45 - 3.51 (m, 1H), 2.76 (s, 3H), 2.50 - 2 .55 (m, 2H), 2.43 (s, 3H), 2.13 (d, J= 13.5 Hz, 2H), 1.87 (q, J= 12.5 Hz, 2H), 1 .31 (d, 7= 6.5 Hz, 6H). 228 MS m/z 420.3 [M+H] ⁺ ; Ή NMR (methanol-7 ₄ ) δ: 9.08 (s, 1H), 8.32 (dd, 7 = 10.1 Hz, 1H), 8.20 (s, 1H), 7.55 (s, 1H), 3.48 - 3.55 (m, 1H), 2.84 (s, 3H), 2.68 (s, 3H), 2.50 2.55 (m, 2H), 2.43 ( s, 3H), 2.14 (d, 7= 13.5 Hz, 2H), 1.89 (q, 7= 13 Hz, 2H), 1.31 (d, 7= 6.5 Hz, 6H) .

Biological examples

The following in vitro biological examples demonstrate the utility of the compounds disclosed herein for the treatment of Huntington's disease.

To further describe and assist in understanding the present disclosure, the following non-limiting biological examples are provided to more fully illustrate the scope of the disclosure and should not be construed as limiting its scope in any particular way. Those variations of the present specification which may now be known or later developed, and the determination of which would be within the competence of one skilled in the art, are considered to be within the scope of the present specification and are claimed in the following claims.

Compounds of Formula (I) were tested using the Meso Scale Discovery (MSD) assay proposed in International Application No. PCT/US2016/066042, filed December 11, 2016, claiming priority under U.S. Provisional Patent Application No. U.S. 62/265652, filed December 10, 2015, the entire contents of which are incorporated herein by reference.

The enogeneic huntingtin protein assay used in Example 1 was developed using the Meso Scale Discovery (MSD) ELISA-based electrochemiluminescent assay platform.

Example 1. Analysis for endogenous huntingtin protein.

Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4°C with MW 1 (extended polyglutamine) 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 (100 µl blocking buffer; 5% BSA in PBS) for 4-5 h at room temperature with a vibrating centrifuge, and then three times washed with wash buffer.

Samples (25 μl) were transferred to an antibody-coated MSD plate and incubated overnight at 4°C. After removing the lysates, the plate was washed three times with wash buffer, and 25 μl of #5656S (cell signal; rabbit monoclonal) secondary antibody (diluted to 0.25 μg/ml in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with vibration for 1 hour at room temperature. After incubation with the secondary antibody, the wells were washed with wash buffer, after which 25 μl of SULFO TAG goat anti-rabbit secondary antibody for detection (a necessary aspect of the MSD system) (diluted to 0.25 μg/ml in 0.05% Tween-20 in blocking buffer) and incubated for 1 hour 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 using an SI 6000 image reader (MSD) according to the manufacturer's instructions provided for 96- or 384-well plates. The final IC ₅₀ values (μM) for the studied compounds are shown in table. 1.

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

- 129 043655

Table 1 Conn. 1C ₅₀ Conn. IC _5Q Conn. IC ₅₀ 1 ** 79 ***** 154 ***** 2 ** 80 ***** 155 ***** 3 **** 81 ***** 156 ***** 4 *** 82 ***** 157 ***** 5 ** 83 ***** 158 ***** 6 *** 84 ***** 159 ***** 7 ** 85 **** 160 ***** 9 ** 86 ***** 161 ***** 10 **** 87 ***** 162 ***** eleven ** 88 ***** 163 ***** 12 *** 89 ***** 164 ***** 13 ** 90 ***** 165 ***** 14 * * * * 91 * * 166 ***** 15 ***** 92 ***** 167 ***** 16 **** 93 ***** 168 **** 17 ***** 94 * * * * 169 ***** 18 **** 95 ***** 170 **** 19 ***** 96 ***** 171 ***** 20 ***** 97 *** 172 ***** 23 **** 98 **** 173 ***** 24 **** 99 ***** 174 ***** 25 ***** 100 ***** 175 ***** 26 ***** 101 ***** 176 ***** 27 **** 102 ***** 177 ***** 28 ** 103 ***** 178 ***** 29 ** 104 ***** 179 ***** thirty **** 105 ***** 180 ***** 31 **** 106 ***** 181 ***** 32 ***** 107 ***** 182 ***** 33 ***** 108 ***** 183 ***** 34 ***** 109 * * * 184 ***** 35 ***** 110 ***** 185 ***** 36 ***** 111 ***** 186 ***** 37 ***** 112 ***** 187 ***** 38 ** FROM ***** 188 ***** 39 ** 114 ***** 189 ***** 40 **** 115 ***** 190 ***** 41 **** 116 **** 191 **** 42 **** 117 ***** 192 ***** 43 ***** 118 **** 193 ***** 44 **** 119 *** 194 **** 45 ***** 120 ** 195 ***** 46 ***** 121 ***** 196 ***** 47 122 197 48 ***** 123 ***** 198 **** 49 ***** 124 ***** 199 ***** 50 ***** 125 ***** 200 ***** 51 ***** 126 ***** 201 ***** 52 ***** 127 ***** 202 ***** 53 **** 128 ***** 203 *** 54 **** 129 ***** 204 ***** 55 ***** 130 ***** 205 ****

- 130 -

Claims (20)

56 131 206 57 ***** 132 ***** 207 ***** 58 ***** 133 ***** 208 **** 59 ***** 134 ***** 209 **** 60 * *** 135 ***** 210 ***** 61 *** 136 ***** 211 ***** 62 ***** 137 ***** 212 **** 63 ***** 138 **** 213 **** 64 ***** 139 ***** 214 **** 65 **** 140 ***** 215 ***** 66 ***** 141 ***** 216 ***** 67 **** 142 **** 217 ***** 68 ***** 143 ***** 218 ***** 69 ***** 144 ***** 219 ***** 70 ***** 145 ***** 220 **** 71 ***** 146 ***** 221 ***** 72 ***** 147 **** 222 **** 73 ***** 148 ***** 223 ***** 74 ***** 149 ***** 224 ***** 75 ***** 150 ***** 225 ***** 76 ***** 151 ***** 226 ***** 77 ***** 152 ***** 227 ***** 78 ***** 153 ***** 228 **** Regardless of whether a document referenced herein is specifically and separately stated to be incorporated herein by reference, all documents referenced herein are incorporated herein by reference for any and all purposes. to the same extent as if each individual source had been cited in its entirety herein. Having now fully described the subject matter of the claims, it will be appreciated by those skilled in the art that the same may be implemented within a wide range of equivalents without affecting the scope of the subject matter or the specific aspects described herein. The appended claims are intended to be interpreted as including all such equivalents. CLAIM 1. A connection selected from the group consisting of the following: 2-(2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinoline; 6-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)quinoline; 6-(2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinolone; 3-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 4-methyl-6-(2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline; 6-(2-methyl-2H-indazol-5-yl)-2-(1-methylpiperidin-4-yl)quinoline; 2-(2-methyl-2H-indazol-5-yl)-6-(piperazin-1-yl)quinoline; 2-(1-ethylpiperidin-4-yl)-6-(2-methyl-2H-indazol-5-yl)quinoline; 2-(2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinazoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine; N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)quinoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(2,2,6,6-tetramethylpiperidin-4-yl)quinoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline; 7-(2,7-dimethyl-2H-indazol-5-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine; 3-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 6-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(piperidin-4-yl)quinoline; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinazoline; 6-[2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl]-2-(piperidin-4-yl)quinoxaline; 3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 2-methyl-5-[7-(piperidin-4-yl)-1,2,4-benzotriazin-3-yl]-2H-indazol-7-carbonitrile; 3 -(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; - 131 043655 3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 3 -(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)quinoline; 7-(2,7-dimethyl-2H-indazol-5-yl)-3-(piperidin-4-yl)isoquinoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoxaline; 5-fluoro-7-(7-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 6-(2,7-dimethyl-2H-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline; 5-[8-fluoro-2-(piperidin-4-yl)quinazolin-6-yl]-2-methyl-2H-indazole-7-carbonitrile; 8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinazoline; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-2-(piperidin-4-yl)quinazoline; 6-(2,7-dimethyl-2H-indazol-5-yl)-7-fluoro-2-(piperidin-4-yl)quinazoline; 3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(piperidin-4-yl)-1,2,4-benzotriazine; 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-N-methyl-N-(nineridin-4-yl)-1,2,4-benzotriazin-3-amine; 3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4-yl)quinoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperudin-4-yl)-1,2,4-benzotriazine; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(1-methylpiperidin-4-yl)quinoline; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)-8-fluoroquinoline; 8-fluoro-6-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline; 8-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)quinoline; 8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline; 3-(7-methoxy-2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine; 8-fluoro-6-[8-(2-methoxyethoxy)-2-methylimidazo[1,2-b]pyridazin-6-yl]-2-(piperidin-4-yl)quinoline; 6-[8-fluoro-2-(piperidin-4-yl)quinolin-6-yl]-N-(2-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-8amine; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 7-(8-azabicyclo[3.2.1]oct-3-yl)-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,2,4-benzotriazine; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)-1,2,4-benzotriazine; 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(8-ethoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 5-fluoro-7-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-3-(piperidin-4-yl)-1,2,4benzotriazine; 7-(2,4-dimethyl-1,3-benzoxazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,4-dimethyl-1H-benzimidazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine; 5-fluoro-7-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)-1,2,4benzotriazine; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluoro-1,2,4benzotriazine; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]piperidin-1-yl}ethanol; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-propylpiperidin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(propan-2-yl)piperidin-4-yl]cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperazin-1-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5fluorocinnoline; 6-(2,8-dimethylumidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperudin-4-yl)quinoxaline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline; - 132 043655 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)cinnoline; 1-[7-(2,8-dimethylimidazo[1,2-b]iiridazin-6-yl)-5-fluorocinnolin-3-yl]-N,N-dimethyliirrolidin3-amine; 7-(2,8-dimethylimidazo[1,2-b]iiridazin-6-yl)-3-[(2S,6S)-2,6-dimethyliieridin-4-yl]-5fluorocinnoline; 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]-K,K-dimethylpiperidin-4amine; (3R)-1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]-N,Ndimethylpyrrolidin-3-amine; 7-(2,8-dimethylimidazo[1,2-b]iiridazin-6-yl)-3-[(2R,4g,6S)-2,6-dimethyliiridin-4-yl]-5fluorocinnoline; 5-fluoro-7-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline; 6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-a]pyridin-8-carbonitrile; 5-fluoro-7-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-(2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-(7-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-(6-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline; 3-[1-(2,2-difluoroethyl)piperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5fluorocinnoline; 5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline; 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 5-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methyl-2H-indazole-7-carbonitrile; 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline; {6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}methanol; 6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-carbonitrile; 5-fluoro-7-(4-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)-8-fluoroquinoxaline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline; 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; {6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8yl}methanol; 6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8carbonitrile; 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5fluorocinnoline; 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4yl)cinnoline; 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline; 2-{4-[7-(8-ethyl-2-methylimidazo[1,2-b]iridazin-6-yl)-5-fluorocinnolin-3-yl]iieridin-1-yl}ethan1-ol; 7-(2,8-dimethylimidazo[1,2-b]iiridazin-6-yl)-5-fluoro-3-[(2S,6S)-1,2,6-trimethyliieridin-4yl]cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2R,6R)-1-ethyl-2,6-dimethylpiperidin-4-yl]-5fluorocinnoline; 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 2-{4-[7-(2,8-dimethylimidazo[1,2-b]iridazin-6-yl)-5-fluorocinnolin-3-yl]iieridin-1-yl}-N,Ndimethylethan-1-amine ; 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)cinnoline; 3-(azepan-4-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline; 3-[(2S,6S)-2,6-diethyliyeridin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]yridazin-6-yl)-5fluorocinnoline; 3-[(2S,6S)-2,6-diethyl-1-methylpiperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5- 133 043655 fluorocinnoline; 7-(2,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 2-({6-[5-fluoro-3-(piperudin-4-yl)cinnolin-7-ul]-2-methylumidazo[1,2-b]pyridazin-8-yl}oxy)-N,Ndimethylethane- 1-amine; 3-({6-[5-fluoro-3-(piperudin-4-yl)cinnolin-7-ul]-2-methylumidazo[1,2-b]pyridazin-8-yl}oxy)-N,Ndimethylpropan- 1-amine; 5-fluoro-7-{2-methyl-8-[2-(1H-pyrazol-1-yl)ethoxy]imidazo[1,2-b]pyridazin-6-yl}-3-(piperidin-4yl)cinnoline ; 5-fluoro-7-{2-methyl-8-[3-(1H-pyrazol-1-yl)propoxy]imidazo[1,2-b]pyridazin-6-yl}-3-(piperidin4-yl)cinnoline ; 5-fluoro-7-{8-[3-(1H-imidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6-yl}-3(piperidin-4-yl) cinnoline; 7-(2,8-dimetulumidazo[1,2-b]nuridazin-6-ul)-5-fluoro-3-(nurrolidin-3-ul)cinnoline; 7-(1-ethylpiperidin-4-yl)-5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline; 7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridin-2-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-(4,6-dimethyl[1,3]thiazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-{8-[3-(1H-benzimidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6-yl}-5-fluoro-3(piperidin-4-yl)cinnoline ; 5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)cinnoline; 7-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)cinnoline; 7-(1-ethylpiperidin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)cinnoline; 2-{(2S,6S)-4-[7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluorocinnolin-3-yl]-2,6dimethylpiperidin-1 -yl } ethan-1 -ol; 3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 3-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 3-{4-[7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluorocinnolin-3-yl]nineridin-1-yl}-N,Ndimethylpropan-1-amine ; 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-[(2R,6S)-1,2,6-trimethylnineridin-4yl]cinnoline; 7-(2,7-dimethyl-2H-πyrazolo[4,3-b]πpyridin-5-yl)-5-fluoro-3-(πpiperidin-4-yl)cinnoline; 5-fluoro-7-(7-methoxy-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-3-(piperidin-4-yl)cinnoline; 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazoline; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinoline; 3-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydroniridin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2R,6S)-1-ethyl-2,6-dimethylπpiperidin-4-yl]-5fluorocinnoline; 3-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5fluorocinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[(2R,6S)-1-(2-fluoroethyl)-2,6dimethylpiperidin-4-yl ] cinnoline; 5-fluoro-3-(7-fluoro-2-methyl-2H-benzotriazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline; 7-(7-ethyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(7-methoxy-2-methyl-2H-pyrazolo[4,3-b]pyridin-5yl)cinnoline; 7-(7-ethyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 5-[5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-3-yl]-2-methyl-2H-indazole-7-carbonitrile; 6-[5-fluoro-3-(1-methylpiperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8carbonitrile; 3-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline; 6-{5-fluoro-3-[1-(2-hydroxyethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin8-carbonitrile; 6-{5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin-8carbonitrile; - 134 043655 {6-[5-fluoro-3-(1-methylpiperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8yl}methanol; 2-(4-{5-fluoro-7-[8-(hydroxymethyl)-2-methylimidazo[1,2-b]niridazin-6-yl]cinnolin-3yl} piperidin-1-yl)ethan-1-ol ; (6-{5-fluoro-3 -[ 1 -(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin-8yl)methanol; 3-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinoline; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; {6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}acetonitrile; 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-(1-methylazenan-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylazepan-4-yl)-5-fluorocinnoline; 2-{4-[7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluorocinnolin-3-yl]azenan-1-yl}ethan-1-ol; 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinoline; 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinoline; 5-fluoro-7-[8-( 1 H-imidazol-1 -yl)-2-methylimidazo[1,2-b]pyridazin-6-yl]-3 -(piperidin-4yl)cinnoline; 5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline; 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline; 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline; 3-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-7-(2,3,6,7-tetrahydro-1H-azepin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(2-fluoroethyl)azepan-4-yl]cinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6-yl)cinnoline; 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinazoline; 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinazoline; (3S,4S)-4-[3-(2,7-dimethyl-2H-indazol-5-yl)-5-fluorocinnolin-7-yl]piperidin-3,4-diol; 5-fluoro-7-(2-methyl-8-propylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline; {6-[3-(1-ethylnineridin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2-b]niridazin-8yl} acetonitrile; 2-{6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}ethan1-ol; 2-{6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}ethan-1-ol; 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-(2,2,6,6-tetramethyl-1,2,3,6tetrahydropyridin-4-yl )cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2yl)cinnoline; 5-fluoro-7-(2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline; 5-fluoro-7-[2-methyl-8-(propan-2-yl)imidazo[1,2-b]pyridazin-6-yl]-3-(piperidin-4-yl)cinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methyl-8-propylimidazo[1,2-b]pyridazin-6-yl)cinnoline; 2-{4-[7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluorocinnolin-3-yl]piperidin-1-yl}ethane1- ol; 7-(4,6-dimethyl[1,3]oxazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline; 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-[(1S,4S)-5-methyl-2,5diazabicyclo[2.2.1]heptane-2 -yl] cinnoline; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-3-yl)cinnoline; 3-(2,6-diazaspiro[3.4]octan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline; 3-(2,6-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline; 3-(2,7-diazaspiro[3.5]nonan-7-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline; 3-(2,6-diazaspiro[3.4]octan-6-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline; 3-(2,7-diazasniro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluorocinnoline; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-[2-methyl-8-(πpropan-2-yl)imidazo[1,2-b]pyridazin-6yl]cinnoline; (1R,5S,6s)-3-[7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluorocinnolin-3-yl]-N,N-dimethyl-3azabicyclo[ 3.1.0]hexane-6-amine; 1-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]-N,N,4-trimethylpiperidin4-amine; 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-(1,2,3,6-tetrahydroniridin-4-yl)cinnoline; 5-(5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylπpiperidin-4-yl)cinnolin-7-yl)-2,7-dimethyloxazolo[5,4b]pyridine; 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4 - 135 043655 yl)cinnoline and 7-(4,6-dimethyloxazolo[4,5-c]pyridin-2-yl)-5-fluoro-3-((2S,4R,6R)-1,2,6-trimethylpiperidin-4yl)cinnoline; or a form thereof, wherein the form of the compound is selected from the group consisting of a salt and a hydrate form thereof. 2. A salt of the compound according to claim 1 or a form thereof selected from the group consisting of the following: 2-(2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinoline hydrochloride; 6-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)quinoline hydrochloride; 6-(2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride; 3-(2-methyl-2H-undazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride; 4-methyl-6-(2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride; 6-(2-methyl-2H-indazol-5-yl)-2-(1-methylpiperidin-4-yl)quinoline hydrochloride; 2-(1-ethylpiperidin-4-yl)-6-(2-methyl-2H-indazol-5-yl)quinoline hydrochloride; 2-(2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinazoline hydrochloride; 6-[2-methyl-7-(trifluoromethyl)-2H-indazol-5-yl]-2-(piperidin-4-yl)quinoxaline hydrochloride; 3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-1,2,4-benzotriazine dihydrochloride; 6-(2,7-dimethyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoxaline hydrochloride; 6-(2,7-dimethyl-2H-indazol-5-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride; 5-[8-fluoro-2-(piperidin-4-yl)quinazolin-6-yl]-2-methyl-2H-indazole-7-carbonitrile dihydrochloride; 8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinazoline dihydrochloride; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride; 6-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride; 6-(2,7-dimethyl-2H-indazol-5-yl)-7-fluoro-2-(piperidin-4-yl)quinazoline dihydrochloride; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(piperidin-4-yl)quinoline hydrochloride; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(1-methylpiperidin-4-yl)quinoline hydrochloride; 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethylpiperidin-4-yl)-8-fluoroquinoline hydrochloride; 8-fluoro-6-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(piperidin-4-yl)quinoline hydrochloride; 8-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)quinoline hydrochloride; 8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline hydrochloride; 8-fluoro-6-[8-(2-methoxyethoxy)-2-methylimidazo[1,2-b]pyridazin-6-yl]-2-(piperidin-4-yl)quinoline hydrochloride; 6-[8-fluoro-2-(piperidin-4-yl)quinolin-6-yl]-N-(2-methoxyethyl)-2-methylimidazo[1,2-b]pyridazin-8amine hydrochloride; 7-(2,7-dimethyl-2H-undazol-5-yl)-5-fluoro-3-(1,2,3,6-tetrahydronuridin-4-yl)cinnoline hydrochloride; 7-(8-azabicyclo[3.2.1]oct-3-yl)-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-1,2,4-benzotriazine hydrochloride ; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(8-ethoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 5-fluoro-7-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-3-(piperidin-4-yl)-1,2,4benzotriazine hydrochloride; 7-(2,4-dimethyl-1,3-benzoxazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(2,4-dimethyl-1H-benzimidazol-6-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine hydrochloride; 7-(2,7-dimethyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine dihydrochloride; 7-(2,7-dimethyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)-1,2,4-benzotriazine dihydrochloride; 7-(2,8-dimetulymidazo[1,2-b]nuridazin-6-yl)-5-fluoro-3-(1-methylnunerudin-4-yl)-1,2,4- 136 043655 benzotriazine dihydrochloride; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline hydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)isoquinoline hydrochloride; 7-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline hydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperazin-1-yl)cinnoline dihydrochloride; 7-(2,8-gumethylumugazo[1,2-b]yirugazin-6-ul)-3-[(3R,5S)-3,5-gumethylumugazo[1,2-b]yirugazin-6-ul]-5-fluorocinnoline dihydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnoline dihydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 7-(2,8-gumethylumugazo[1,2-b]irugazin-6-ul)-3-[(2S,6S)-2,6-gumethylumugazo[1,2-b]irugazin-6-ul]-5fluorocinnoline hydrochloride; 5-fluoro-7-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-a]pyridin-8-carbonitrile dihydrochloride; 5-fluoro-7-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 5-fluoro-7-(2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride; 5-fluoro-7-(7-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride; 5-fluoro-7-(6-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride; 3-[1-(2,2-difluoroethyl)piperidin-4-yl]-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5fluorocinnoline dihydrochloride; 5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline dihydrochloride; 7-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline dihydrochloride; 7-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride; 5-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methyl-2H-indazole-7-carbonitrile hydrochloride; 5-fluoro-7-(4-fluoro-2-methyl-2H-indazol-5-yl)-3-(piperidin-4-yl)cinnoline hydrochloride; 7-(8-cyclopropyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5fluorocinnoline formate; 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4yl)cinnoline hydrochloride; 7-(2,4-dimethyl-1,3-benzothiazol-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline formate; 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline dihydrochloride; 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline dihydrochloride; 2-{4-[7-(8-ethyl-2-methylgazo[1,2-b]irugazin-6-ul)-5-fluorocinnolin-3-ul]hierugun-1-yl}ethan1-ol dihydrochloride; 2-{4-[7-(2,8-gumethylumugazo[1,2-b]irugazin-6-ul)-5-fluorocinnolin-3-ul]hierugun-1-ul}-N,Ndimethylethan-1-amine trihydrochloride; 5-fluoro-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)cinnoline dihydrochloride; 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline formate; 5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride; 7-(2,7-dimethyl[1,3]thiazolo[5,4-b]pyridin-5-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline formate; 2-({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}oxy)-K,Kdimethylethane- 1-amine trihydrochloride; 3-({6-[5-fluoro-3-(piperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8-yl}oxy)-K,Kdimethylpropan- 1-amine trihydrochloride; 5-fluoro-7-{2-methyl-8-[2-(1H-irazol-1-yl)ethoxu]umugazo[1,2-b]irugazin-6-ul}-3-(iierugun-4-137 043655 yl)cinnoline dihydrochloride; 5-fluoro-7-{2-methyl-8-[3-(III-pyrazol-1-yl)propoxy]imidazo[1,2-b]pyridazin-6-yl}-3-(piperidin4-yl)cinnoline trihydrochloride; 5-fluoro-7-{8-[3-(1H-imidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6-yl}-3(piperidin-4-yl) cinnoline trihydrochloride; 7-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline hydrochloride; 7-{8-[3-(III-benzimidazol-1-yl)propoxy]-2-methylimidazo[1,2-b]pyridazin-6-yl}-5-fluoro-3(piperidin-4-yl)cinnoline trihydrochloride; 5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)cinnoline hydrochloride; 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-3-(7-fluoro-2-methyl-2H-indazol-5-yl)cinnoline hydrochloride; 3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride; 3-(2,7-dimethyl-2N-indazol-5-yl)-5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride; 5-fluoro-7-(7-methoxy-2-methyl-2H-πyrazolo[4,3-b]πpyridin-5-yl)-3-(πpiperidin-4-yl)cinnoline formate; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazoline hydrochloride; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinoline hydrochloride; 3-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-7-(1,2,3,6-tetrahydroniridin-4yl)cinnoline hydrochloride; 5-fluoro-3-(7-fluoro-2-methyl-2H-benzotriαzol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline hydrochloride; 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(7-methoxy-2-methyl-2H-pyrazolo[4,3-b]pyridin-5yl)cinnoline formate; 5-[5-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-3-yl]-2-methyl-2H-indazole-7-carbonitrile hydrochloride; 6-[5-fluoro-3-(1-methylpiperidin-4-yl)cinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8carbonitrile trihydrochloride; 3-(2,7-dimethyl-2H-indazol-5-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline hydrochloride; 6-{5-fluoro-3-[1-(2-hydroxyethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin8-carbonitrile trihydrochloride; 6-{5-fluoro-3-[1-(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin-8carbonitrile trihydrochloride; 2-(4-{5-fluoro-7-[8-(hydroxymethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl]cinnolin-3yl}piperidin-1 -yl)ethan-1-ol trihydrochloride; (6-{5-fluoro-3 -[ 1 -(2-fluoroethyl)piperidin-4-yl]cinnolin-7-yl}-2-methylimidazo[1,2-b]pyridazin-8yl)methanol trihydrochloride; 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinoline hydrochloride; 3-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-7-(piperidin-4-yl)cinnoline hydrochloride; 7-(5,7-dimethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline dihydrochloride; 8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-6-(piperidin-4-yl)quinoline hydrochloride; 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinoline hydrochloride; 5-fluoro-7-[8-( 1 H-imidazol-1 -yl)-2-methylimidazo[1,2-b]pyridazin-6-yl]-3 -(piperidin-4yl)cinnoline formate; 5-fluoro-7-(2-methyl-8-phenoxyimidazo[1,2-b]pyridazin-6-yl)-3-(piperidin-4-yl)cinnoline formate; 7-(4,6-dimethyl[1,3]thiazolo[5,4-c]pyridin-2-yl)-5-fluoro-3-(piperidin-4-yl)cinnoline formate; 6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinazoline hydrochloride; 6-(1-ethylpiperidin-4-yl)-8-fluoro-2-(7-fluoro-2-methyl-2H-indazol-5-yl)quinazoline hydrochloride; {6-[3-(1-ethylpiperidin-4-yl)-5-fluorocinnolin-7-yl]-2-methylimidazo[1,2-b]pyridazin-8yl}acetonitrile formate; 5-fluoro-7-(2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperidin-4-yl)cinnoline dihydrochloride; 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(piperidin-3-yl)cinnoline dihydrochloride; 3-(2,6-diazaspiro[3.4]octan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline trihydrochloride; - 138 043655 3-(2,6-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline trihydrochloride; 3-(2,7-diazaspiro[3.5]nonan-7-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline ditrifluoroacetate; 3-(2,6-diazaspiro[3.4]octan-6-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline ditrifluoroacetate; 3-(2,7-diazaspiro[3.5]nonan-2-yl)-7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnoline ditrifluoroacetate and 7-(2,8-dimethylimidazo[1,2-b]niridazin-6-yl)-5-fluoro-3-(1,2,3,6-tetrahydroniridin-4yl)cinnoline dihydrochloride. 3. Use of a compound according to any one of claims 1, 2 for the treatment or alleviation of Huntington's disease (HD) in a subject in need thereof. 4. Use according to claim 3, wherein the effective amount of the compound is in the range of from about 0.001 to about 500 mg/kg/day. 5. Use of a compound according to any one of claims 1, 2 for the production of a medicament for treating or alleviating Huntington's disease (HD) in a subject in need thereof. 6. Use according to claim 5, wherein the effective amount of the compound in the medicinal product is in the range of from about 0.001 to about 500 mg/kg/day. 7. Use of a compound according to any one of claims 1, 2 for the preparation of a pharmaceutical composition for the treatment or alleviation of Huntington's disease (HD) in a subject in need thereof. 8. Use according to claim 7, wherein the effective amount of the compound in the pharmaceutical composition is in the range of from about 0.001 to about 500 mg/kg/day. 9. A compound according to claim 1 or a form thereof selected from the group consisting of the following: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)-1,2,4benzotriazine, 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluoro-1,2,4-benzotriazine, 2-{4 -[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]piperidin-1-yl}ethanol, 7-(2,8-dimethylimidazo[1 ,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline, 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)- 5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6- yl)cinnoline, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline, 7-(8- ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline, 7-(2,8-dimethylimidazo[1,2-b ]pyridazin-6-yl)-5-fluoro-3-[(2R,6S)-1,2,6-trimethylpiperidin-4yl]cinnoline, and 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2R,6S)-1-ethyl-2,6-dimethylpiperidin-4-yl]-5fluorocinnoline. 10. A compound according to claim 9 or a form thereof selected from the group consisting of the following: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1- methylpiperidin-4-yl)-1,2,4benzotriazine, 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluoro-1,2,4-benzotriazine, 2-{4 -[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin-3-yl]piperidin-1-yl}ethanol, 7-(2,8-dimethylimidazo[1 ,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline and 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)- 5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline. 11. A compound according to claim 9 or a form thereof selected from the group consisting of the following: 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin- 6-yl)cinnoline, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline, 7-( 8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline, 7-(2,8-dimethylimidazo[1,2 -b]pyridazin-6-yl)-5-fluoro-3-[(2R,6S)-1,2,6-trimethylpiperidin-4-yl]cinnoline and 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2R,6S)-1-ethyl-2,6-dimethylpiperidin-4-yl]-5fluorocinnoline. 12. A compound according to claim 9 or a form thereof selected from the group consisting of the following: 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1- methylpiperidin-4-yl)-1,2,4benzotriazine, and 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluoro-1,2,4-benzotriazine. 13. A compound according to claim 9 or a form thereof selected from the group consisting of the following 2-{4-[7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluorocinnolin- 3-yl]piperidin-1-yl}ethanol, 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline, 7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline, 3-(1-ethylpiperidin-4-yl) -5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2 -methylimidazo[1,2-a]pyridin-6-yl)cinnoline, and 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1 -methylpiperidin-4-yl)cinnoline. - 139 043655 14. The connection according to item 9 or its form, selected from the group consisting of the following: 7-(2,8-dim ethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-[(2K,68)-1,2,6-trimethylpyridin-4yl]cinnoline and 7-(2,8-dim ethylimidazo[1,2-b]pyridazin-6-yl)-3-[(2K,68)-1-ethyl-2,6-dim ethylpiperidin-4-yl]-5fluorocinnoline. 15. A salt of the compound or its form according to claim 2, selected from the group consisting of the following: 7-(2,8-dim ethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)-1,2,4benzotriazine dihydrochloride, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline dihydrochloride, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline dihydrochloride and 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline dihydrochloride. 16. A salt of the compound or form thereof according to claim 15, selected from the group consisting of the following: 7-(2,8-dim ethylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)-1,2,4benzotriazine dihydrochloride, and 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline dihydrochloride. 17. A salt of the compound or form thereof according to claim 15, selected from the group consisting of the following: 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline dihydrochloride and 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline dihydrochloride. 18. A salt of the compound or form thereof according to claim 15, selected from the group consisting of the following: 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(2-methylimidazo[1,2-b]pyridazin-6-yl)cinnoline dihydrochloride, 3-(1-ethylpiperidin-4-yl)-5-fluoro-7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)cinnoline dihydrochloride and 7-(8-ethyl-2-methylimidazo[1,2-b]pyridazin-6-yl)-5-fluoro-3-(1-methylpiperidin-4-yl)cinnoline dihydrochloride. 19. A pharmaceutical composition containing a compound according to any one of claims 1, 2 and 9-14, or a form thereof, in mixture with one or more pharmaceutically acceptable excipients. 20. A pharmaceutical composition containing a salt of the compound or its form according to any one of claims 2 and 15-19, mixed with one or more pharmaceutically acceptable excipients. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 140 -