KR20060063872A - Pyrazoloisoquinoline derivatives as kinase inhibitors - Google Patents

Abstract

Novel pyrazoloisoquinoline derivatives as kinase inhibitors are disclosed which are suitable for producing pharmaceuticals for the prophylaxis and therapy of diseases whose course involves an increased activity of NIK.

Description

Pyrazoloisoquinoline derivatives as kinase inhibitors}

The present invention relates to novel pyrazoloisoquinoline derivatives, processes for their preparation, their pharmaceutical uses, in particular those for use in inhibiting kinases. More specifically, it is used to inhibit NFκB-induced kinase (NIK). Thus, pyrazoloisoquinoline derivatives can be used to treat various diseases, particularly multiple sclerosis (MS), involving inflammatory components due to increased NIK activity.

NFκB is a heterodimeric transcription factor that is capable of activating a number of genes, particularly pro-inflammatory cytokines such as IL-1, IL-2, TNFα or IL-6. NFκB is present in the cytoplasm of cells and complexes with IκB, a naturally occurring inhibitor in the cytoplasm. For example, when cells are stimulated by cytokines, IκB is phosphorylated and protein is subsequently degraded. This proteolysis leads to the activation of NFκB and then transferred to the nucleus of the cell, which then activates a number of pre-inflammatory genes in the nucleus.

In diseases such as rheumatoid arthritis (inflammatory related), osteoarthritis or asthma, NFκB is activated above normal levels. Drugs such as glucocorticoids, salicylates or gold salts used to treat rheumatoids have been demonstrated to inhibit NFκB-activated signal chains or directly interfere with the transcription of these genes at various sites.

IκB kinase (IKK) plays a major role in the NFκB signal transduction pathway because it mediates phosphorylation of IκB. IKK is likewise activated by phosphorylation. NFκB-induced kinase (NIK) is a Ser / Thr kinase that participates in IKK activation. By overexpressing NIK in cell culture, it was possible to augment the expression of NFκB-induced adsorption molecule ICAM1 or NFκB-activated reporter genes in a stimulation-independent manner. NIK interacts with and phosphorylates the IKKα subunit of IKK to modulate this effect. In contrast, by overexpressing dominant negative NIK mutations in cell culture, it was possible to inhibit the expression of the NFκB-activated reporter gene and also inhibit the IL1-induced expression of the adsorption molecule ICAM1. By overexpressing the NIK C-terminal domain responsible for interacting with IKK, it was also possible to inhibit TNFα-induced expression of NFκB-activated reporter genes in cell culture. Pyrazoloisoquinoline derivatives with direct inhibitory activity against NIK similarly not only inhibit TNFα release in peripheral blood lymphocytes of LPS-stimulated and IL1β-stimulated humans, but also IL1β in LPS-stimulated whole human blood. May also inhibit TNFα and IL6 release. The pyrazoloisoquinoline compounds have anti-inflammatory activity, as already described in the publication of GB 2 185 255 A.

In an effort to obtain effective compounds for treating diseases associated with increased activity of NFκB-induced kinases, the pyrazoloisoquinoline derivatives according to the present invention are very specific for NIK and are potent inhibitors, even in water. It was found to have good solubility.

Accordingly, the present invention relates to the following compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts thereof.

In the above formula,

A is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, and unsubstituted or -OR ¹ , -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , Each independently is substituted one or more times with -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ or -CN, wherein R ¹ is hydrogen,-(C ₁ -C ₆ ) -alkyl, -(C ₆ -C ₁₄ ) aryl or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 6 and x is An integer from 0 to 12, y is an integer from 1 to 13, and the sum of x and y is 2n + 1;

-OR ¹ ,

-SR ¹ ,

-S (O) -R ¹ ,

-S (O) ₂ -R ¹ ,

-C (O) -OR ¹ ,

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1],

-C (O) -NR ¹ R ¹ ,

-C (O) -NR ¹ -SO ₂ R ¹ ,

-NR ¹ R ¹ ,

-CN,

5 to 14 reduced heteroaryl [wherein the heteroaryl is substituted one or more times independently by a ring or R ² beach, where, R ² is - (C ₁ -C ₄₎ - alkyl, -OH, -O - (C _1- C ₄₎ - alkyl, ^{halogen, -N (R 3) -R 4} ( wherein, R ³ and R ⁴ are each independently a hydrogen atom or - (C ₁ -C ₄₎ - alkyl), Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, and y is 1 to Is an integer of 9 and the sum of x and y is 2n + 1), -CN-, SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ^1, or -C (O) -NR ¹ R ¹ ],

-(C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted each independently one or more times by R ² , and R ² is as defined above, or

5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), and

, -O(CH₂)_a-(이때, a는 1 내지 4의 정수이다), O, S, NR², -C(O)-, -NR²-C(O)-, -C(O)-NR²-, -NR²-SO₂-, -SO₂-NR²-, -NR²-C(O)-NR²- 또는 -(C₁-C₄)-알킬렌이며, 이때, 알킬렌은 직쇄 또는 측쇄이며, 비치환되거나 R¹에 의해 각각 독립적으로 1회 이상 치환되고, R¹ 및 R²는 상기 정의된 것과 같고, B is a covalent bond, -C = CR ^1- ,

_{, -O (CH 2) a -} ( wherein, a is an integer of 1 to 4), O, S, NR 2, -C (O) -, -NR 2 -C (O) -, -C (O ) -NR ^2- , -NR ² -SO _2- , -SO ₂ -NR ^2- , -NR ² -C (O) -NR ² -or-(C ₁ -C ₄ ) -alkylene, wherein alkylene is a straight-chain or branched, each unsubstituted or independently substituted one or more times by R ^1, R ¹ and R ² have the same meanings as defined above,

D is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, unsubstituted or substituted each independently one or more times by R ¹ , and R ¹ is as defined above,

5 to 14 heteroaryl group of reduction (where the heteroaryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above),

5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above),

- (C ₆ -C ₁₄₎ - aryl (wherein aryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), or

- or cycloalkyl (wherein cycloalkyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined _{above), - (C 3 -C 6} )

B to D are hydrogen, halogen, fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, and x is 0 to Is an integer of 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1], or-(CH ₂ ) _a -YR ³ , wherein a is an integer of 1 to 4, and Y Is O, S, NR ² , and R ³ is-(C ₁ -C ₆ ) -alkyl,-(C ₆ -C ₁₄ ) -aryl or-(C ₃ -C ₆ ) -cycloalkyl],

R is hydrogen,-(C ₁ -C ₆ ) -alkyl or-(C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein aryl is unsubstituted or is independently of each other by R ² ; Substituted one or more times, wherein R ² is as defined above;

X and Z are the same or different and each independently

Hydrogen atom,

- (C ₁ -C ₄₎ - alkyl,

-OH,

-O- (C ₁ -C ₄ - alkyl),

halogen,

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1],

-C (O) -OR ¹ ,

-C (O) -NR ¹ R ¹ ,

-C (O) -NR ¹ -SO ₂ R ¹ ,

-NR ¹ R ¹ ,

-NR ¹ -C (O) -NR ¹ R ¹ ,

-NR ¹ -C (O) -R ¹ ,

-NR ¹ -C (O) -OR ¹ ,

-OC (O) -NR ¹ R ¹ ,

-CN,

-SR ¹ ,

-S (O) -R ¹ ,

-S (O) ₂ -R ¹ ,

-S (O) ₂ -NR ¹ R ¹ ,

-NR ¹ -SO ₂ -R ¹ ,

5 to 12 reducing heterocycles, wherein the heterocycles are unsubstituted or substituted each independently one or more times with R ² ; or

- (C ₃ -C ₆₎ - cycloalkyl is selected from: [In this case, the cycloalkyl is unsubstituted or substituted by R are each independently substituted one or more times with a ^2], wherein, R ¹ and R ² are the same as defined above, And

Provided that if A is (C ₁ -C ₆ ) -alkyl, -OR ¹ , -C (O) -OR ¹ , or heteroaryl, then one of the following applies:

B is not a covalent bond or is not-(C ₁ -C ₄ ) -alkylene,

D is not heteroaryl, heterocycle,-(C ₆ -C ₁₄ ) -aryl,-(C ₃ -C ₆ ) -cycloalkyl, or

X and Z are not both-(C ₁ -C ₄ ) -alkyl, -OH, -O- (C ₁ -C ₄ ) -alkyl, or halogen.

The present invention,

A is-(C ₁ -C ₃ ) -alkyl, wherein alkyl is straight or branched, and -OR ¹ or -C (O) -OR ¹ , wherein R ¹ is hydrogen,-(C ₁ -C ₃ ) -Alkyl or -CF ₃ ), fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 3, x is 0 Is an integer of 6 to 6, y is an integer of 1 to 7, the sum of x and y is 2n + 1),

B is a covalent bond

D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently with one, and a substituted 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ^4, wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl],

Pyridyl; wherein pyridyl is unsubstituted or substituted by R ² are each independently 1, 2, or 3 times, wherein R ² is as defined above, or

- (C ₄ -C ₆₎ - cycloalkyl; wherein cycloalkyl is unsubstituted or substituted by R ² are each independently 1, 2, or 3 times, wherein R ² is as defined above, and

R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl,

X and Z are the same or different and are each independently hydrogen, -C (O) -O (C 1 -C 3) _{alkyl, -OCH 3, -N (CH 3} ) 2 or halogen, to a compound of formula I It is about.

The present invention,

A is-(C ₁ -C ₃ ) -alkyl wherein alkyl is straight or branched, unsubstituted or substituted independently or once each by -OR ¹ or -C (O) -OR ¹ Where R ¹ is hydrogen, — (C ₁ -C ₃ ) -alkyl or —CF ₃ ],

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 3, x is an integer of 0 to 6, and y is 1 to Is an integer of 7 and the sum of x and y is 2n + 1;

B is a covalent bond

D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently 1, 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ⁴ , wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl],

Heteroaryl selected from the group consisting of pyridyl, furanyl, pyrrolyl, isoxazolyl, benzofuranoyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl and thiophenyl, wherein the heteroaryl is Unsubstituted or substituted each independently one or more times by R ² , wherein R ² is — (C ₁ -C ₂ ) -alkyl, —OH, —O— (C ₁ -C ₂ ) -alkyl, fluorine, chlorine Or bromine, -N (CH ₃ ) ₂ or -CF ₃ ], or

- (C ₄ -C ₆₎ - cycloalkyl, or [wherein cycloalkyl is unsubstituted or substituted by R ² independently represent one, two or three times each Beach, wherein R ² is as defined above,

B to D are ((CH ₂ ) _a -YR ³ , wherein a is an integer from 1 to 2, Y is O, and R ³ is-(C ₁ -C ₃ ) -alkyl;

R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl,

Each independently are X and Z are the same or different, a hydrogen, -C (O) -O (C 1 -C 3) _{alkyl, -OCH 3, -N (CH 3} ) 2 or halogen, the compounds of formula (I) It is about.

The present invention,

5-pyridin-2-yl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline,

5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline,

1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline,

1,3-dimethyl-5- (2,6-difluorophenyl) -1H-pyrazolo [4,3-c] -isoquinoline,

1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline,

1-benzyl-5-naphthyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline,

5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline,

7-methoxycarbonyl-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline,

7-methoxycarbonyl-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline,

7-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

7-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline,

6-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline,

6-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline,

8-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline,

8-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline,

1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline,

3-methyl-5-phenyl-9-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5-pyridin-2-yl-9-trifluoromethyl-1H-pyrazolo [4,3-c] -isoquinoline, and

Regarding the compound of formula I, selected from the group consisting of 3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] -isoquinoline will be.

In another aspect of the present invention, the present invention also provides

5-benzo [b] thiophen-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline,

7-bromo-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

7-bromo-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

5- (3-chloro-benzo [b] thiophen-2-yl) -3-methyl-1H-pyrazolo [4,3-c] -isoquinoline,

5- (2-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline,

5- (6-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline,

3-ethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

3-ethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-ethyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline,

5-furan-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline,

7-methoxy-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (3-methyl-benzofuran-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline,

3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

6-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

6-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

8-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

8-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

9-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

9-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

3,9-dimethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (3-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (4-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (3-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (4-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (3,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2,6-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (4-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2,4-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (2,6-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline,

6-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

6-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

8-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

8-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

9-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

9-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3,9-dimethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5- (1-methyl-1H-pyrrole-2-yl) -1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5-quinolin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5-quinolin-3-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5-quinoxalin-2-yl-1H-pyrazolo [4,3-c] isoquinoline,

3-methyl-5-thiophen-2-yl-1H-pyrazolo [4,3-c] isoquinoline, and

A compound of formula (I) selected from the group consisting of 3-methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline.

The term “(C ₁ -C ₆ ) -alkyl” is a hydrocarbon radical, the carbon chain being straight or branched, having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 3 Tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutane or neohexyl. Examples of (C ₃ -C ₆ ) -cycloalkyl radicals are 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "aryl" means an aromatic hydrocarbon radical having 6 to 14 carbon atoms in the ring. Examples of (C ₆ -C ₁₄ ) -aryl radicals are phenyl, naphthyl such as 1-naphthyl and 2-naphthyl, biphenyl such as 2-biphenyl, 3-biphenyl, and 4 -Biphenyl, anthryl and fluorenyl. Biphenyl radicals, naphthyl radicals, and especially phenyl radicals are preferred aryl radicals. The aryl radicals, in particular the phenyl radicals, may be substituted one or more times, preferably once, twice or three times, by the same or different radicals, preferably the radicals are a series of (C ₁ -C ₈ )- Alkyl, in particular (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₈ ) -alkoxy, especially (C ₁ -C ₄ ) -alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy (C ₁ -C ₄ ) -alkyl, for example hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl , Aminocarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl. In a corresponding manner, radicals such as arylalkyl or arylcarbonyl can also be applied. Arylalkyl radicals are in particular benzyl and 1-naphthylmethyl, 2-naphthylmethyl, 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl, and 9-fluoroenyl methyl. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals, which are one or more (C ₁ -C ₈ ) -alkyl radicals in the aryl moiety, in particular (C ₁ -C ₄ ) -alkyl radicals, for example , 2-methylbenzyl, 3-methylbenzyl and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3 4-, 5-, 6-, 7-, and 8-methyl-1-naphthylmethyl, and 1-, 3-, 4-, 5-, 6-, 7-, and 8-methyl-2 -Naphthylmethyl, benzyl radicals and naphthylmethylradicals, at least one (C ₁ -C ₈ ) -alkoxy radical, in particular a (C ₁ -C ₄ ) -alkoxy radical, for example 4 -Methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals such as 2- , 3-, 4-nitrobenzyl, halobenzyl radicals, such as 2-, 3-, 4-chlorobenzyl, 2-, 3-, 4-fluorobenzyl, 3,4-dichloro Benzyl, pentamethylene, for methyl benzyl radical, such as a fluoro-benzyl, and trifluoromethyl, and is substituted by a 3-, and 4-tri (trifluoromethyl) methyl benzyl and 3,5-bis-fluorobenzyl.

In mono substituted phenylradicals, the substituents may be at positions 2, 3, or 4. Double substituted phenyl may be substituted at 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5. In triple substituted phenyl radicals the substituents are in 2,3,4 position, 2,3,5 position, 2,4,5 position, 2,4,6 position, 2,3,6 position or 3,4,5 position There may be.

The clues provided for the aryl radicals can be applied to the divalent arylene radicals, for example phenylene radicals, in a corresponding manner, and examples of phenylene radicals can be represented as 1,4-phenylene or 1,3-phenylene. . Phenylene - (C ₁ -C ₆₎ - alkyl, in particular phenylene-methyl- _{(-C 6 H 4 -CH 2 -} ), phenylene-ethyl, (C ₁ -C ₆₎ - alkylene-phenyl, especially from Methylenephenyl (-CH ₂ -C ₆ H _4- ). Phenylene- (C ₂ -C ₆ ) -alkenyl is in particular phenyleneethenyl and phenylenepropenyl.

The term “5-14 reduced heteroaryl” refers to a 5-14 reduced monocyclic or polycyclic radical comprising 1, 2, 3, 4, 5 heteroatoms as reduction. For example, heteroatoms may be N, O, or S. If there are several heteroatoms they may be the same or different. Heteroaryl radicals may be substituted once or several times, preferably once, twice or three times, by the same or different radicals, wherein the radicals to be substituted are a series of-(C ₁ -C ₈ ) -alkyl, in particular- (C ₁ -C ₄ ) -alkyl,-(C ₁ -C ₈ ) -alkoxy, in particular-(C ₁ -C ₄ ) -alkoxy, halogen, nitro, —N (R ¹⁰ ) ₂ , trifluoromethyl, Hydroxyl, hydroxy- (C ₁ -C ₄ ) -alkyl, for example hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxy Carbonyl, aminocarbonyl,-(C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl and the like. 5 to 14 reduced heteroaryls are suitably monocyclic or bicyclic aromatic radicals, comprising 1, 2, 3, 4 identical or different heteroatoms of N, O, S, the number suitably 1, 2, 3 and may be substituted by 1, 2, 3, 4, particularly 1 to 3 identical or different substituents, wherein the substituents are a series of-(C ₁ -C ₆ ) _{-alkyl, - (C 1 -C 6)} - alkoxy, fluorine, chlorine, nitro, -N (R ¹⁰⁾ _2, trifluoromethyl, hydroxyl, hydroxy - (C ₁ -C ₄₎ -alkyl, -(C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy, benzyl. Particularly suitably, heteroaryl is a 5 to 10 reduced monocyclic or bicyclic aromatic radical, in particular a 5- to 6-membered monocyclic aromatic radical, 1, 2, 3, in particular 1 Or a series of-(C ₁ -C ₄ ) -alkyl, halogen, hydroxyl, -N (R ¹⁰ ) ₂ ,-(C ₁ substituted with two or more of the same or different heteroatoms of N, O, and S -C ₄ ) -alkoxy, phenyl, phenoxy, benzyloxy, benzyl may be substituted by the same or different substituents.

The term "5-12 reduced heterocycle" refers to a partially or fully saturated monocyclic or bicyclic 5- to 12-membered heterocyclic ring. Examples of hetero atoms are N, O, and S. The heterocycle may be unsubstituted or substituted by the same or different substituents on one or more carbon atoms or one or more heteroatoms. These substituents are as defined above in relation to the heteroaryl radicals.

Examples of the terms “5-14 reduced heteroaryl” and “5-12 reduced heterocycle” include acridinyl, azaspirodecanyl, azefinyl, azetidinyl, aziridinyl, benzimidazol, benzo Furanyl, benzothiofuranyl, benzothiophenyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl , Carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxoranyl, 1,3 -Dioxorenyl, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imide Dazolyl, 1H-indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromenyl, isodazolyl, isoindolinyl, Indolyl, isoquinolinyl, isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxalininyl, ketopiperazinyl, morpholinyl , Naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadia Zolyl, 1,2-oxathipanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolinyl , Oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenooxathinyl, phenooxazinyl, phthalazinyl, piperazinyl, piperidinyl , Pterridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazorinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl, pyrimididi Neil, Pyridinyl, Pyridino , Pyrrolinyl, 2H-pyrroyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolininyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroqui Nolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl , 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thientanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiethananyl, thiomorpholinyl, thiophenyl , Thiophenolyl, thiopyranyl, 1,2,3-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5 -Triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred radicals are benzodioxolane, benzofuran, benzothiazole, benzothiophene, benzoxazole, β-carboline, quinazoline, quinoline, quinoxaline, cynoline, cyclohepta [b] -5-pyrrole, 4, 5-dihydro-1,3-oxazole, dihydropyridine, 4,5-dihydro-1,3-triazole, 1,3-dioxolane, furan, 3-hydroxypyro-2,4-dione , Imidazole, 2-imidazoline, imidazolidine, indazole, indole, indoline, isoquinoline, isoindole, isoindolin, isoxazolone, isothiazole, isoxazole, morpholine, oxadiazole Dindione, oxadiazole, 1,2,3,5-oxathiadiazole 2-oxide, oxazole, 1,3-oxazolidine, 5-oxa-1,2,4-thiadiazole, fur Hydroazepine, perhydro-1,4-dioxane, phthalazine, piperazine, piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, tetrahydrofuran, 1, 2,3,4-tetrahydroisoquinoline, tetrahydropyripy That can be derived from 1,2,3,4-tetrahydroquinoline, tetrahydrothiophene, tetrazole, 1,3-thiazole, thiazolidine, thiomorpholine, thiophene, triazole and triazolone to be.

The present invention also provides a process for preparing a compound of formula (I) and / or a stereoisomer of a compound of formula (I), and / or a physiologically acceptable salt of a compound of formula (I), the process consisting of:

a) reacting a compound of formula IV with a compound of formula Va or Vb to obtain a compound of formula VI;

The compound of formula VI is reacted in the presence of phosphorus pentoxide and phosphorus oxychloride to afford the protected compound of formula I, finally removing the protecting group.

b) Compounds of formula (I) prepared according to the method of (a) and present as enantiomers due to their chemical structure are separated into pure enantiomers by means of salting means with enantiomerically pure acids or bases, and chromatographed on chiral stationary phases. Or inductively react with chiral enantiomerically pure compounds such as amino acids, isolate the resulting diastereoisomers, remove chiral subgroups, or

c) The compound of formula (I) prepared according to the method of (a) or (b) is isolated in free form or, if an acid or base group is present, is converted to its physiologically acceptable salt.

Starting compounds of the formulas (IV), (Va), (Vb) and the reagents used may be prepared using known methods or purchased commercially.

For example, the reaction can be performed by reacting 3,5-substituted 1H-pyrazol-4-ylamine (compound of formula IV) with an acid (compound of formula Va) according to the carbodiimide method or by acid chloride And a corresponding amide (Formula VI) as summarized in Scheme I. Such amide forming reactions to form compounds of Formula VI can be carried out using any method known in the art. In general, it has been found that the use of acid chlorides of formula Vb provides the desired amides. The reaction can generally be carried out in the presence of a suitable organic base such as an amine solvent at room temperature reaction conditions. Amine solvents include, for example, pyridine, triethylamine and the like. In certain cases, additional organic solvents may be used as cosolvents. Cosolvents include halogenated solvents such as chloroform, methylene chloride and the like. Co-solvent combinations of pyridine / methylene chloride or triethylamine / methylene chloride are suitable.

The starting compound of formula IV can be prepared by the steps shown in Scheme II. In step A of process II, the 1,3 diketo compound of formula II is treated with a suitable reagent to make an oxime of formula IIIa. Such conversion can be carried out using any known reaction in which modifications can be made. For example, such reactions can be carried out using nitrites such as sodium nitrite in the presence of an acid such as acetic acid (see J. Fluor. Chem., (1997), 84 , p 107).

In step B of Scheme II, the oxime of formula IIIa is further reacted with hydrazine to form a nitrozo compound of formula IIIb, wherein R is hydrogen (see J. Fluor. Chem., (1997), 84 ). , p 107). The nitrozo compound of formula IIIb is hydrotreated to give the starting compound of formula IV. Any known hydrogenation reaction is used to reduce the nitrozo group to an amino group. In general, it has been found that catalytic hydrogenation on palladium / carbon provides the compound of formula IV.

Advantageously it has been found that in some cases the use of excess hydrazine in Step B of Scheme II directly leads to an amino starting compound of Formula IV as seen in Scheme II. This is particularly advantageous and economical since there is no hydrogenation step of step c in Scheme II.

All protected compounds of formula (I) can be prepared from compounds of formula (VI) in the presence of phosphorus pentoxide and phosphorus oxychloride in boiling xylene. In some cases the reaction may be carried out without any solvent in the presence of phosphorus pentoxide and boiling phosphorus oxychloride. This ring closure step can be carried out in two stages, first of which a compound of formula VI and phosphorus oxychloride are reacted in boiling nitrobenzene, followed by successively reacting tin chloride and these mixtures. This reaction step can also be carried out using other suitable Lewis acids. Protected compounds of formula (I) are also used as starting compounds for the deprotection of functional groups and for the addition of additional functional groups.

When occurring in diastereomeric or enantiomeric form and with these mixtures in the selected synthesis, the compounds of formula (I) are separated into pure stereoisomers by chromatography on an optional chiral support in step b), or In the case where the semi-compound can form a salt, the diastereomeric salt can be fractionated and separated using an optically active base or acid as an auxiliary material. Suitable chiral stationary phases for thin layers or column-chromatographic separations of enantiomers include modified silica gel supports (also called Pirkle phases) and high molecular weight carbohydrates such as triacetyl cellulose. For analysis purposes, it is also possible to use gas-chromatographic methods in chiral stationary phases after appropriate derivatization reactions known to those skilled in the art. In order to separate racemic carboxylic acids into enantiomers, commercially obtainable methods such as optically active bases such as (-)-nicotine, (+)-and (-)-phenylethylamine, quinine Differently dissolved diastereomeric salts are prepared using base, L-lysine or L- / D-arginine, then the differently soluble components are separated into solids, and the immediately soluble diastereomers are separated from the mother liquor, Pure enantiomers are separated from diastereomeric salts obtained in this way. In principle the same way, optically active acids such as (+)-10-camphorsulfonic acid, D- and L-tartaric acid, D- and L-lactic acid, (+)-and (-)- It is also possible to use mandelic acid to convert racemic compounds of the formula (I) comprising basic groups such as amino groups into pure enantiomers. A chiral compound comprising an alcohol or an amine functional group is converted to the corresponding ester or to an amide using pure amino acids as appropriately activated or optionally N-protected enantiomers, and conversely to pure carboxy-protected enantiomers. It is also possible to convert chiral carboxylic acids to amides using amino acids and also to the corresponding chiral esters using pure hydroxycarboxylic acids which are enantiomers such as lactic acid. To separate existing diastereomers using the chirality of amino acids or alcohol radicals introduced in pure form into the enantiomers, and to remove the chiral molecular residues incorporated subsequently using crystallization or chromatography with appropriate stationary phases. Using suitable methods, isomers can be separated.

The acid or basic product of the compound of formula I may exist in salt form, in free form. Pharmacologically acceptable salts are suitable, for example alkali or alkaline earth metals or hydrochlorides, hydrobromide, sulfates, hemisulfates, all possible phosphates, and in the form of amino acid salts, natural base salts or carboxylic acids.

Physiologically acceptable salts may be prepared by known methods according to step c), which may be prepared from compounds of formula (I) including compounds capable of forming salts, including diastereomeric forms. Compounds of formula (I) are stable alkali metal salts, alkaline earth metal salts or optionally base reagents such as hydroxides, carbonates, hydrogen carbonates, alkoxides, ammonia or organic bases such as trimethylamine or triethylamine, ethanolamine or triethanolamine, Or an ammonium salt optionally substituted with a basic amino acid such as lysine, ornithine, or arginine. Strong acids may also be used to make stable acid addition salts when the compounds of formula (I) contain basic groups. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid, acetic acid, oxalic acid, tartaric acid All inorganic and organic acids such as succinic acid and trifluoroacetic acid are suitable for this purpose.

The present invention provides a pharmaceutically suitable, physiologically acceptable carrier and an effective amount of at least one compound of formula (I) and / or physiologically acceptable salts of compounds of formula (I) and / or selective diastereomers of compounds of formula (I) It relates to a medicament consisting of substances, additives and / or other active compounds, and auxiliary substances.

The present invention relates to at least one compound of formula I (all possible isomeric forms), and mixtures thereof in any proportion, and / or physiologically acceptable salts thereof, pharmaceutically suitable and physiologically acceptable excipients and, where appropriate, It relates to a pharmaceutical composition composed of other suitable active compounds, additives or auxiliaries.

Because of their pharmacological properties, the compounds according to the invention are suitable for the preparation of medicaments for the selective prevention and treatment of all diseases associated with increased NIK activity.

The present invention comprises administering a therapeutically effective amount of a compound of Formula (I), or an isoform thereof, or a pharmaceutically acceptable salt thereof, to a patient suffering from a disease associated with increased activity of NIK. A method for treating a disease associated with increased activity of

Formula I

In the above formula,

A, B, D, X, Z and R are as defined above.

The invention also relates to a method for treating a disease as described above using a compound of one of the embodiments as described below. In general, the compounds of the present invention are suitable for treating diseases of the cause due to inflammatory components.

Such diseases include degenerative joint diseases, including osteoarthritis and rheumatoid arthritis. The compounds of formula (I) are suitable for treating transplantation such as asthma and rejection in parts of the body for transplanted organs and rejection of transplanted organs for bodies with transplanted organs. Compounds of formula (II) are suitable for treating inflammatory bowel disease, Alzheimer's disease, stroke, diabetes, atherosclerosis, multiple sclerosis.

In another aspect of the invention, treating a disease associated with inflammation, comprising administering a therapeutically effective amount of a compound of Formula (I), or an isomeric form thereof, or a pharmaceutically acceptable salt thereof, to a patient suffering from the disease associated with inflammation It's about how to:

Formula I

In the above formula,

A is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, and unsubstituted or -OR ¹ , -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , Each independently is substituted one or more times with -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ or -CN, wherein R ¹ is hydrogen,-(C ₁ -C ₆ ) -alkyl, -(C ₆ -C ₁₄ ) aryl or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 6 and x is An integer from 0 to 12, y is an integer from 1 to 13, and the sum of x and y is 2n + 1;

-OR ¹ ,

-SR ¹ ,

-S (O) -R ¹ ,

-S (O) ₂ -R ¹ ,

-C (O) -OR ¹ ,

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1],

-C (O) -NR ¹ R ¹ ,

-C (O) -NR ¹ -SO ₂ R ¹ ,

-NR ¹ R ¹ ,

-CN,

5 to 14 reduced heteroaryl [wherein the heteroaryl is substituted one or more times independently by a ring or R ² beach, where, R ² is - (C ₁ -C ₄₎ - alkyl, -OH, -O - (C _1- C ₄₎ - alkyl, ^{halogen, -N (R 3) -R 4} ( wherein, R ³ and R ⁴ are each independently a hydrogen atom or - (C ₁ -C ₄₎ - alkyl), Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, and y is 1 to Is an integer of 9 and the sum of x and y is 2n + 1), -CN-, SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ^1, or -C (O) -NR ¹ R ¹ ],

-(C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted each independently one or more times by R ² , and R ² is as defined above, or

5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), and

, -O(CH₂)_a-(이때, a는 1 내지 4의 정수이다), O, S, NR², -C(O)-, -NR²-C(O)-, -C(O)-NR²-, -NR²-SO₂-, -SO₂-NR²-, -NR²-C(O)-NR²- 또는 -(C₁-C₄)-알킬렌이며, 이때, 알킬렌은 직쇄 또는 측쇄이며, 비치환되거나 R¹에 의해 각각 독립적으로 1회 이상 치환되고, R¹ 및 R²는 상기 정의된 것과 같고, B is a covalent bond, -C = CR ^1- ,

_{, -O (CH 2) a -} ( wherein, a is an integer of 1 to 4), O, S, NR 2, -C (O) -, -NR 2 -C (O) -, -C (O ) -NR ^2- , -NR ² -SO _2- , -SO ₂ -NR ^2- , -NR ² -C (O) -NR ² -or-(C ₁ -C ₄ ) -alkylene, wherein alkylene is a straight-chain or branched, each unsubstituted or independently substituted one or more times by R ^1, R ¹ and R ² have the same meanings as defined above,

D is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, unsubstituted or substituted each independently one or more times by R ¹ , and R ¹ is as defined above,

5 to 14 heteroaryl group of reduction (where the heteroaryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above),

5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above),

- (C ₆ -C ₁₄₎ - aryl (wherein aryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), or

- or cycloalkyl (wherein cycloalkyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined _{above), - (C 3 -C 6} )

B to D are hydrogen, halogen, fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, and x is 0 to Is an integer of 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1], or-(CH ₂ ) _a -YR ³ , wherein a is an integer of 1 to 4, and Y Is O, S, NR ² , and R ³ is-(C ₁ -C ₆ ) -alkyl,-(C ₆ -C ₁₄ ) -aryl or-(C ₃ -C ₆ ) -cycloalkyl],

R is hydrogen,-(C ₁ -C ₆ ) -alkyl or-(C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein aryl is unsubstituted or each independently by R ² Substituted one or more times, wherein R ² is as defined above;

X and Z are the same or different and each independently

Hydrogen atom,

- (C ₁ -C ₄₎ - alkyl,

-OH,

-O- (C ₁ -C ₄ - alkyl),

halogen,

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1],

-C (O) -OR ¹ ,

-C (O) -NR ¹ R ¹ ,

-C (O) -NR ¹ -SO ₂ R ¹ ,

-NR ¹ R ¹ ,

-NR ¹ -C (O) -NR ¹ R ¹ ,

-NR ¹ -C (O) -R ¹ ,

-NR ¹ -C (O) -OR ¹ ,

-OC (O) -NR ¹ R ¹ ,

-CN,

-SR ¹ ,

-S (O) -R ¹ ,

-S (O) ₂ -R ¹ ,

-S (O) ₂ -NR ¹ R ¹ ,

-NR ¹ -SO ₂ -R ¹ ,

5 to 12 reducing heterocycles, wherein the heterocycles are unsubstituted or substituted each independently one or more times with R ² ; or

- the same as the cycloalkyl is selected from: [wherein, cycloalkyl beach is unsubstituted or substituted by R ² each independently one or more times], wherein, R ¹ and R ² are defined above - (C ₃ -C ₆₎ .

In a further aspect of the invention, the compound is

A is-(C ₁ -C ₃ ) -alkyl wherein alkyl is straight or branched, unsubstituted or substituted independently or once each by -OR ¹ or -C (O) -OR ¹ Where R ¹ is hydrogen, — (C ₁ -C ₃ ) -alkyl or —CF ₃ ],

Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 3, x is an integer of 0 to 6, and y is 1 to Is an integer of 7 and the sum of x and y is 2n + 1],

B is a covalent bond

D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently 1, 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ⁴ , wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl],

Heteroaryl selected from the group consisting of pyridyl, furanyl, pyrrolyl, isoxazolyl, benzofuranoyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl and thiophenyl, wherein the heteroaryl is Unsubstituted or substituted independently by R ² one or two times, wherein R ² is — (C ₁ -C ₂ ) -alkyl, —OH, —O— (C ₁ -C ₂ ) -alkyl, fluorine, Chlorine or bromine, -N (CH ₃ ) ₂ or -CF ₃ ], or

- (C ₄ -C ₆₎ - cycloalkyl, or [wherein cycloalkyl is unsubstituted or substituted by R ² independently represent one, two or three times each Beach, wherein R ² is as defined above,

B to D are ((CH ₂ ) _a -YR ³ , wherein a is an integer from 1 to 2, Y is O, and R ³ is-(C ₁ -C ₃ ) -alkyl;

R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl,

X and Z are the same or different and are each independently hydrogen, —C (O) —O (C ₁ -C ₃ ) alkyl, —OCH ₃ , —N (CH ₃ ) ₂ or halogen.

In carrying out the process of the invention, all of the specific compounds mentioned above can be used.

The various diseases mentioned above can be treated using this method of the invention. More particularly, diseases that can be treated without any limitation may be multiple sclerosis, atherosclerosis, inflammatory bowel disease, Alzheimer's disease, stroke and diabetes.

Drugs according to the invention can be administered by oral, inhalation, rectal, transdermal or subcutaneous, arterial, intraperitoneal, or intravenous injection. Oral administration is appropriate.

The present invention comprises the preparation of a pharmacologically suitable, physiologically acceptable excipient, where appropriate, other suitable active compound, excipient, or auxiliary component together with at least one compound of formula (II) in a form suitable for administration It relates to the process of manufacturing a drug.

Suitable solid or herbal preparations can be granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops, injectable solutions, and common auxiliary substances such as carrier materials Sustained release active compounds may also be prepared using disintegrants, binders, coatings, swelling agents, glidants, lubricants, flavors, sweeteners, and solubilizing agents. Auxiliary materials commonly used among those mentioned above are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, cellulose and derivatives thereof, cod liver oil, sunflower oil, peanut oil, or sesame Oils, animal and vegetable oils such as polyethylene glycol, solvents such as sterile water, and monohydric or polyhydric alcohols such as glycerol.

Pharmaceutical preparations are preferably prepared and administered in unit doses, each unit containing as a active ingredient a specific dose of a compound of formula II according to the invention. For solid unit doses such as tablets, capsules, dragees or suppositories, the dose will be about 1000 mg, suitably about 50 mg to 300 mg, and for ampoule injection solutions up to about 300 mg, suitably about 10 mg to A dose of 100 mg is included.

Depending on the activity of the compound of formula II, the daily dose of the active compound is about 20 mg to 1000 mg, suitably about 100 mg to 500 mg, which is suitable for treating an adult body weight of about 70 kg. However, it is also possible to use higher or lower doses. The daily dose may be administered once in a single dose form, or in multiple doses divided into several smaller units or at predetermined time intervals.

In general, the major peaks can be obtained in each case using mass-spectrometry methods (FAB-MS, ESI-MS) to determine the final product. Temperature is expressed in degrees Celsius, and RT refers to room temperature (22 ° C to 26 ° C). Abbreviations used herein are those with narrated descriptions or commonly used.

The present invention will be described in more detail with reference to the following examples.

Manufacturing Example

In general, the compounds of the present invention prepared below are characterized using high pressure liquid chromatography (HPLC) using one of three methods.

Method A: HPLC was performed on Synergi 2U Hydro-RP 20 × 4.0MM COL, water (0.1% trifluoroacetic acid / acetonitrile (0.1% trifluoroacetic acid) = 10/90 → 90/10).

Method B: Agilent 1100 Series LC / MSD YMC Pro C ₁₈ S5 120A 4.6X30MM Col, Waterf (0.1% trifluoroacetic acid / acetonitrile (0.1% trifluoroacetic acid) = 95/5 → 5/95), run time 5 minutes.

The mass spectrum is performed as follows:

Method A: Micromass LCT-TOF MS, Scan M / Z 100-1000.

Method B: Micromass LCZ-TOF MS, Scan M / Z 100-800.

Example 1

3,5-diphenyl-1H-pyrazolo [4,3-c] isoquinoline (1)

a) N- (3,5-diphenyl-1H-pyrazol-4-yl) benzylamine (2)

574 mg hydroxybenzotriazole and 822 μl diisopropylcarbodiimide were added to a 10 ml methylene chloride solution of 260 mg benzoic acid and a 500 ml 2 ml acetonitrile solution of 3,5-diphenyl-1H-pyrazol-4-ylamine Is added dropwise at 0 ° C .; The mixture was then stirred for 12 hours at room temperature (RT), then water was added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue contained the title compound and was used for the next reaction without further purification.

b) 3,5-diphenyl-1H-pyrazolo [4,3-c] isoquinoline (1)

201 mg phosphorus pentoxide was added to 10 ml xylene solution of 240 mg N- (3,5-diphenyl-1H-pyrazol-4-yl) benzylamine (2), followed by dropwise addition of 195 [mu] L phosphorus oxychloride at 150 [deg.] C. The reaction solution was stirred at 150 ° C. for 4 hours, stirred at room temperature for 12 hours, saturated sodium hydrogen carbonate solution was added, and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, then HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80 / 20 → 10/90). The following materials were obtained:

1. C ₂₂ H ₁₅ N ₃ (321.38); MS (ESI) 322 (M + H)

Example 2

5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (3)

a) 3-methoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (4)

311 mg hydroxybenzotriazole and 445 μl diisopropylcarbodiimide were added to a 10 ml dimethylformamide solution of 160 mg 3-methoxybenzoic acid and 200 mg 3-methyl-5-phenyl-1H-pyrazol-4-ylamine Add; The mixture was then stirred for 12 h at RT, water was added and the whole material was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, then HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80 / 20 → 10/90). The following materials were obtained:

4 C ₁₇ H ₁₅ N ₃ O ₂ (293.33); MS (ESI) 294 (M + H).

b) 5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (3)

128 mg 3-methoxy-N- (3-methyl-5-phenyl-1 H-parazol-4-yl) benzamide (4) was suspended in 5 ml xylene and the suspension was heated at 160 ° C .; 119 mg phosphorus pentoxide was added and the mixture was stirred at 160 ° C. for 15 minutes. 27 μl phosphorus oxychloride was added dropwise to the suspension, and then stirred at 160 ° C. for 12 hours; Saturated sodium hydrogen carbonate solution was then added and the whole material was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, then HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80 / 20 → 10/90). The following materials were obtained:

3. C ₁₈ H ₁₅ N ₃ O (298.34); MS (ESI 290 (M + H)

Example 3

3- (3-methyl-1H-pyrazolo [4,3-c] isoquinolin-5-yl) phenol (5)

Methyl chloride solution of 380 μL 1M boron tribromide was mixed with 55 mg 5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (3) at -78 ° C. It was added dropwise to the solution. The reaction solution was stirred at RT for 12 h, concentrated under reduced pressure, HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid)) 80/20 → 10/90). The following materials were obtained:

5. C ₁₇ H ₁₃ N ₃ O (275.31); MS (ESI 276 (M + H)

Example 4

5- (2-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (6)

a) 2-methoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (7)

Prepared in a similar manner to Example 2a), using 175 mg 2-methoxybenzoic acid as starting material. The following materials were obtained:

7. C ₁₈ H ₁₇ N ₃ O ₂ (307.36); MS (ESI) 308 (M + H)

b) 5- (2-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (6)

90 mg 2-methoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (7) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

6. C ₁₈ H ₁₅ N ₃ O ₂ (289.34); MS (ESI) 290 (M + H)

Example 5

5- (2,3-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (8)

a) 2,3-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (9)

Prepared in a similar manner to Example 2a) using 210 mg 2,3-dimethoxybenzoic acid as starting material. The following materials were obtained:

9. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI 338) (M + H)

b) 5- (2,3-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (8)

40 mg 2,3-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (9) was prepared in a similar manner to Example 1b) using starting material . The following materials were obtained:

8. C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI) 320 (M + H)

Example 6

5- (2,4-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (10)

a) 2,4-dimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (11)

Prepared in a similar manner to Example 2a) using 210 mg 2,4-dimethoxybenzoic acid as starting material. The following materials were obtained:

11. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI) 338 (M + H)

b) 5- (2,4-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (10)

87 mg 2,4-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (11) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

10. C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI) 320 (M + H)

Example 7

5- (2,6-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (12)

a) 2,6-dimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (13)

Prepared in a similar manner to Example 2a) using 210 mg 2,6-dimethoxybenzoic acid as starting material. The following materials were obtained:

13. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI) 338 (M + H)

b) 5- (2,6-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (12)

100 mg 2,6-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (13) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

12. C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI 320) (M + H)

Example 8

5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (14)

a) 3,4-dimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (15)

Prepared in a similar manner to Example 2a) using 210 mg 3,4-dimethoxybenzoic acid as starting material. The following materials were obtained:

15. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI) 338 (M + H)

b) 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (14)

100 mg 3,4-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (15) was prepared in a similar manner to Example 1b) using starting material . The following materials were obtained:

14. C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI) 320 (M + H)

Example 9

5- (3,5-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (16)

a) 3,5-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (17)

210 mg 3,5-dimethoxybenzoic acid was prepared in a similar manner to Example 2a) using starting material. The following materials were obtained:

17. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI) 338 (M + H)

b) 5- (3,5-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (16)

60 mg 3,5-dimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (17) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

16. C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI) 320 (M + H)

Example 10

5- (2,3,4-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (18)

a) 2,3,4-trimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (19)

244 mg 2,3,4-trimethoxybenzoic acid was prepared in a similar manner to Example 2a) using starting material. The following materials were obtained:

19. C ₂₀ H ₂₁ N ₃ O ₄ (367.41); MS (ESI) 368 (M + H)

b) 5- (2,3,4-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (18)

73 mg 2,3,4-trimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (19) as a starting material in a similar manner to Example 1b) Prepared. The following materials were obtained:

18.C ₂₀ H ₁₉ N ₃ O ₃ (349.39) MS (ESI) 350 (M + H)

Example 11

5- (2,4,6-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (20)

a) 2,4,6-trimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (21)

244 mg 2,4,6-trimethoxybenzoic acid was prepared in a similar manner to Example 2a) using starting material. The following materials were obtained:

21. C ₂₀ H ₂₁ N ₃ O ₄ (367.41); MS (ESI) 368 (M + H)

b) 5- (2,4,6-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (18)

63 mg 2,4,6-trimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (21) as a starting material in a similar manner to Example 1b) Prepared. The following materials were obtained:

20. C ₂₀ H ₁₉ N ₃ O ₃ (349.39); MS (ESI) 350 (M + H)

Example 12

5- (3,4,5-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (22)

a) 3,4,5-trimethoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (23)

244 mg 3,4,5-trimethoxybenzoic acid was prepared in a similar manner to Example 2a) using starting material. The following materials were obtained:

23. C ₂₀ H ₂₁ N ₃ O ₄ (367.41); MS (ESI) 368 (M + H)

b) 5- (3,4,5-trimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (22)

65 mg 3,4,5-trimethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (23) as starting material, analogous to Example 2b) It was prepared by. The following materials were obtained:

22. C ₂₀ H ₁₉ N ₃ O ₃ (349.39); MS (ESI) 350 (M + H)

Example 13

5- (2-ethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (24)

a) 2-ethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (25)

Prepared in a similar manner to Example 2a) using 191 mg 2-ethoxybenzoic acid as starting material. The following materials were obtained:

25. C ₁₉ H ₁₉ N ₃ O ₂ (321.389); MS (ESI) 322 (M + H)

b) 5- (2-ethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (24)

60 mg 2-ethoxy-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (25) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

24. C ₁₉ H ₁₇ N ₃ O (303.37); MS (ESI) 304 (M + H)

Example 14

5- (4-diethylaminophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (26)

a) 4-diethylamino-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) benzamide (27)

222 mg 4-diethylaminobenzoic acid was prepared in a similar manner to Example 2a) using starting material. The following materials were obtained:

27. C ₂₁ H ₂₄ N ₄ O (348.45); MS (ESI) 349 (M + H)

b) 5- (4-diethylaminophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (26)

Prepared in a similar manner to Example 1b) using 130 mg 4-diethylamino-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (27). The following materials were obtained:

26. C ₂₁ H ₂₂ N ₄ (330.44); MS (ESI) 331 (M + H)

Example 15

3-methyl-5-pyridin-4-yl-1H-pyrazolo [4,3-c] isoquinoline (28)

a) N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) isonicotiamide (29)

205 mg isocorticoylyl * HCl is added to a 2 ml pyridine solution of 200 mg 3-methyl-5-phenyl-1 H-pyrazol-4-ylamine and the mixture is stirred at RT for 12; Then the whole material was extracted with methylene chloride by adding water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, then HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80 / 20 → 10/90). The following materials were obtained:

27. C ₁₆ H ₁₄ N ₄ O (278.32); MS (ESI) 279 (M + H)

b) 3-methyl-5-pyridin-4-yl-1H-pyrazolo [4,3-c] isoquinoline (28)

110 mg N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) isonicotinamide (29) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

28. C ₁₆ H ₁₂ N ₄ (260.30); MS (ESI) 261 (M + H)

Example 16

3-methyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline (30)

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) nicotinamide (31)

205 mg nicotinoyl chloride * HCl was prepared in a similar manner to Example 15a) using starting material. The following materials were obtained:

31. C ₁₆ H ₁₄ N ₄ O (278.32); MS (ESI) 279 (M + H)

b) 3-methyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline (30)

140 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) nicotinamide (31) was prepared in a similar manner to Example 1b) using starting material 31. The following materials were obtained:

30. C ₁₆ H ₁₂ N ₄ (260.30); MS (ESI) 261 (M + H)

Example 16A

3-methyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline (30)

The title compound was prepared using a modification procedure as described herein.

a) Pyridine-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (C1).

Using 1.207 g picolinoyl chloride hydrochloride as starting material, it was prepared in a similar manner to Example 33 (B1), except that the product was purified using MPLC (12 g SiO ₂ , 45% ethyl acetate: heptane). To give the title material as a light brown amorphous solid.

HPLC R _T = 2.33 min

C ₁₆ H ₁₄ N ₄ O (278.32) MS (ESI, method A) 279 (M + H).

b) 3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline (C).

1.349 g pyridine-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide was prepared in a similar manner to Example 33 (B) using starting material. The title compound was obtained as a brown solid.

HPLC R _T = 2.05 min.

C ₁₆ H ₁₂ N ₄ (260.30) MS (ESI, method A) 261 (M + H).

Example 17

3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline (32)

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -pyridine-2-carboxamide (33)

205 mg pyridine-2-carbonyl chloride * HCl as starting material was prepared in a similar manner as in Example 15a). The following materials were obtained:

33. C ₁₆ H ₁₄ N ₄ O (278.32); MS (ESI) 279 (M + H)

b) 3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline (32)

110 mg N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -pyridine-2-carboxamide (33) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

32. C ₁₆ H ₁₂ N ₄ (260.30); MS (ESI) 261 (M + H)

Example 18

5-benzyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (34)

a) N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -2-phenylacetamide (35)

152 μl phenylacetylchloride was prepared as a starting material in a similar manner to Example 15a). The following materials were obtained:

35. C ₁₈ H ₁₇ N ₃ O (291.36); MS (ESI) 292 (M + H)

b) 5-benzyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (34)

50 mg N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -2-phenylacetamide was prepared in a similar manner to Example 1b) using 35 as a starting material (35). The following materials were obtained:

34. C ₁₈ H ₁₅ N ₃ (273.34); MS (ESI) 274 (M + H)

Example 19

3-methyl-5-phenethyl-1H-pyrazolo [4,3-c] isoquinoline (36)

a) N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -3-phenylpropionamide (37)

172 μl 3-phenylpropionyl chloride was used as starting material and prepared in a similar manner as in Example 15a). The following materials were obtained:

37. C ₁₉ H ₁₉ N ₃ O (305.38); MS (ESI) 306 (M + H)

b) 3-methyl-5-phenethyl-1H-pyrazolo [4,3-c] isoquinoline (36)

110 mg N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -3-phenylpropionamide (37) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

36. C ₁₈ H ₁₅ N ₃ (287.37); MS (ESI) 288 (M + H)

Example 20

3-methyl-5- (1-methylpiperidin-4-yl) -1H-pyrazolo [4,3-c] isoquinoline (38)

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -1-methylpiperidine-4-carboxamide (39)

207 mg 1-methylpiperidine-4-carboxylic acid * HCl and 197 μl diisopropylethylamine were prepared in a similar manner to Example 2a) using starting materials. The following materials were obtained:

39. C ₁₇ H ₂₂ N ₄ O (298.39); MS (ESI) 299 (M + H)

b) 3-methyl-5- (1-methylpiperidin-4-yl) -1H-pyrazolo [4,3-c] isoquinoline (38)

220 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -1-methylpiperidine-4-carboxamide (39) as a starting material in a similar manner to Example 1b) Prepared. The following materials were obtained:

38. C ₁₇ H ₂₀ N ₄ (280.38); MS (ESI) 281 (M + H)

Example 21

7,8-dimethoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (40)

a) 1- (3,4-dimethoxyphenyl) butane-1,3-dione (41)

3.9 g sodium hydride was first placed in 150 ml cyclohexane and 16.3 ml ethylacetate solution of 15 g 1- (3,4-dimethoxy phenyl) ethanone was added. The reaction solution was heated at 80 ° C. for 1 hour, then acetic acid was added and the whole was extracted with MTB-ether. The MTB-ether phase was dried over magnesium sulfate and rotary evaporated. The residue was chromatographed through silica gel (ethyl acetate / heptane 1/6). The following was obtained:

41. C ₁₂ H ₁₄ O ₄ (222.24); MS (ESI) 223 (M + H)

b) 1- (3,4-dimethoxyphenyl) butane-1,2,3-trione 2-oxime (42)

5 g 1- (3,4-dimethoxyphenyl) butane-1,3-dione (41) was first added to 25 ml acetic acid, and 5 ml water in which 1.71 g sodium nitrite was dissolved was added dropwise at 15 ° C. The reaction solution is stirred at RT for 1 hour and left for 2 hours. 50 g ice is added to the solution and the whole solution is left at 0 ° C. for 12 hours to precipitate the product. The product is filtered continuously through suction and dried at 50 ° C. in a drying oven. The following product was obtained:

42. C ₁₂ H ₁₃ NO ₅ (251.24); MS (ESI) 252 (M + H)

c) 5- (3,4-dimethoxyphenyl) -3-methyl-4-nitro-1H-pyrazole (43)

6.77 g 1- (3,4-dimethoxyphenyl) butane-1,2,3-trione 2-oxime (42) is dissolved in 54 ml acetic acid, 0.96 g hydrazine is added dropwise at room temperature and the mixture is stirred for 2 hours. Stir continuously at 60 ° C. Ice was added to the reaction solution to neutralize with sodium carbonate and extracted with MTB-ether. The organic phase was dried over magnesium sulfate and rotary evaporated. The following materials were obtained:

43. C ₁₂ H ₁₃ N ₃ O ₃ (247.26); MS (ESI) 248 (M + H)

d) 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl amine (44)

4.84 g 5- (3,4-dimethoxyphenyl) -3-methyl-4-nitro-1H-pyrazole (43) was dissolved in 80 ml ethanol and 0.5 g Pd / C was added to this solution. The solution was shaken under hydrogen for 2 hours, filtered through magnesium sulfate and rotary evaporated. The residue was chromatographed through silica gel (ethyl acetate / heptane 3/1). The following product was obtained:

44. C ₁₂ H ₁₅ N ₃ O ₂ (233.27); MS (ESI) 234 (M + H)

e) N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide (45)

500 mg 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (44) and 280 μl benzoyl chloride were prepared in a similar manner as in Example 15a). The following materials were obtained:

45. C ₁₉ H ₁₉ N ₃ O ₃ (337.38); MS (ESI) 338 (M + H)

f) 7,8-dimethoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (40)

187 mg N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide (45) was prepared in a similar manner to Example 1b) as a starting material. The following materials were obtained:

40 C ₁₉ H ₁₇ N ₃ O ₂ (319.37); MS (ESI) 320 (M + H)

Example 22

7-methoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (46)

a) 1- (4-methoxyphenyl) butane-1,3-dione (47)

15 g 1- (4-methoxyphenyl) ethanone was prepared in a similar manner to Example 21a) as a starting material. The following materials were obtained:

47. C ₁₁ H ₁₂ O ₃ (192.22); MS (ESI) 193 (M + H)

b) 1- (4-methoxyphenyl) butane-1,2,3-trione 2-oxime (48)

5 g 1- (4-methoxyphenyl) butane-1,3-dione (47) was prepared in a similar manner to Example 21b) using starting material. The following materials were obtained:

48.C ₁₁ H ₁₁ NO ₄ (221.21) MS (ESI) 222 (M + H)

c) 5- (4-methoxyphenyl) -3-methyl-4-nitrozo-1H-pyrazole (49)

4.19 g 1- (4-methoxyphenyl) butane-1,2,3-trione 2-oxime (48) was prepared in a similar manner to Example 21c) as a starting material. The following materials were obtained:

49.C ₁₁ H ₁₁ N ₃ O ₂ (217.23) MS (ESI) 218 (M + H)

d) 5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (50)

3.17 g 5- (4-methoxyphenyl) -3-methyl-4-nitro-1H-pyrazole (49) was prepared in a similar manner to Example 21d) as a starting material. The following materials were obtained:

50.C ₁₁ H ₁₃ N ₃ O (203.25) MS (ESI) 204 (M + H)

e) N- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide (51)

500 mg 5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (50) and 315 μl benzoyl chloride were prepared in a similar manner to Example 15a). The following materials were obtained:

51. C ₁₈ H ₁₇ N ₃ O ₂ (307.36); MS (ESI) 308 (M + H)

f) 7-methoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (46)

230 mg N- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide (51) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

46. C ₁₈ H ₁₅ N ₃ O (289.34); MS (ESI) 290 (M + H)

Example 22A

7-methoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (46)

The title compound was also prepared through the modification process described herein using the procedure described below.

a) 5- (4-methoxy-phenyl) -3-methyl-1H-pyrazol-4-ylamine (A2) (Example 22 (d))

6.80 g sodium dithionite was added to a 50 ml water mixture with 1.23 g 5- (4-methoxy-phenyl) -3-methyl-4-nitro-1H-pyrazole (Example 22 (c)) at 70 ° C. The reaction mixture was stirred for 15 minutes. 5 ml ethanol was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Admixture with ether gave the title compound as a beige solid:

Melting Point 120-122 ° C, C ₁₁ H ₁₃ N ₃ O (203.24), MS (ESI, method B) 204 (M + H).

b) N- [5- (4-methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -benzamide (A1) (Example 22 (e))

110 μl pyridine is added to a 10 ml dichloromethane solution of 230 mg 5- (4-methoxy-phenyl) -3-methyl-1H-pyrazol-4-ylamine, followed immediately by 174 mg benzoyl chloride. The reaction mixture was stirred at rt for 2 h and concentrated. The residue was purified by MPLC, eluting with 80/20 ethyl acetate / heptane to afford the title compound as a white solid,

Melting point 230-232 ° C., C ₁₈ H ₁₇ N ₃ O ₂ (307.36), MS (ESI, Method B) 308 (M + H).

c) 7-methoxy-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (A) (Example 22 (f))

740 mg phosphorus pentoxide is added to a 1.7 mL phosphorus oxychloride solution of 108 mg N- [5- (4-methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -benzamide and the reaction solution is 4.5 Stir under reflux for hours. After cooling ice was carefully added and saturated sodium bicarbonate solution was added. The whole was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified using MPLC, eluting with 50/50 heptane / ethylacetate. This gave the title compound as an off-white solid,

C ₁₈ H ₁₅ N ₃ O (289.34), MS (ESI, method A) 290 (M + H), HPLC R _T 2.87 min.

Example 23

7,8-dimethoxy-5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo- [4,3-c] isoquinoline (52)

a) N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] -3-methoxybenzamide (53)

300 mg 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (44) and 242 mg 3-methoxybenzoyl chloride as starting materials in a similar manner to Example 15a) Prepared. The following materials were obtained:

53.C ₂₀ H ₂₁ N ₃ O ₄ (367.41) MS (ESI) 368 (M + H)

7,8-dimethoxy-5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (52)

Similar to Example 1b) using 291 mg N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] -3-methoxybenzamide (53) as starting material It was prepared by the method. The following materials were obtained:

52.C ₂₀ H ₁₉ N ₃ O ₃ (349.39) MS (ESI) 350 (M + H)

Example 24

7,8-dimethoxy-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline (54)

a) N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide (55)

Example 15a) using 200 mg 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg pyridine-2-carbonylchloride * HCl as starting materials. Prepared in a similar way. The following materials were obtained:

55. C ₁₈ H ₁₈ N ₄ O ₃ (338.37); MS (ESI) 339 (M + H)

b) 7,8-dimethoxy-3-methyl-5-pyridin-2-yl-1H-pyrazolo- [4,3-c] isoquinoline (54)

Similar to Example 1b) using 160 mg N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide (55) as starting material It was prepared by the method. The following materials were obtained:

54.C ₂₀ H ₁₉ N ₃ O ₃ (320.35) MS (ESI) 321 (M + H)

Example 25

7,8-dimethoxy-3-methyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline (56)

a) N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] nicotinamide (57)

Prepared in a similar manner to Example 15a) using 200 mg 5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg nicotinyl chloride * HCl as starting materials It was. The following materials were obtained:

57.C ₁₈ H ₁₈ N ₄ O ₃ (338.37) MS (ESI) 339 (M + H)

7,8-dimethoxy-3-methyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline (56)

126 mg N- [5- (3,4-dimethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] nicotinamide (57) was prepared in a similar manner to Example 1b) using starting material. The following materials were obtained:

56.C ₂₀ H ₁₉ N ₃ O ₃ (320.35) MS (ESI) 321 (M + H)

Example 26

7-methoxy-5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo- [4,3-c] isoquinoline (58)

a) 3-methoxy-N- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide (59)

Prepared in a similar manner to Example 15a) using 300 mg 5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-ylamine (50) and 277 mg 3-methoxybenzoyl chloride as starting materials. . The following materials were obtained:

59.C ₁₉ H ₁₉ N ₃ O ₃ (337.38) MS (ESI) 338 (M + H)

b) 7-methoxy-5- (3-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (58)

Similar to Example 1b) using 263 mg 3-methoxy-N- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] benzamide- (59) as starting material It was prepared by the method. The following materials were obtained:

58.C ₁₉ H ₁₇ N ₃ O ₂ (319.37) MS (ESI) 320 (M + H)

Example 27

5-phenyl-1H-pyrazolo [4,3-c] isoquinoline-3-carboxylic acid (60)

A 36 ml aqueous solution of 2.1 g potassium permanganate was added to a 36 ml pyridine solution of 600 mg 5-phenyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline. The mixture was stirred at 40 ° C. for 12 h. The resulting suspension was filtered through suction through silica gel and the filtrate was concentrated under reduced pressure and the residue was purified by HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1). % Trifluoroacetic acid) = 80/20-> 10/90). The following materials were obtained:

60.C ₁₇ H ₁₁ N ₃ O ₂ (289.30) MS (ESI) 290 (M + H)

Example 28

Methyl 5-phenyl-1H-pyrazolo [4,3-c] isoquinoline-3-carboxylic acid salt (61)

18 μl thionyl chloride was added to 0.5 ml methanol and the mixture was stirred for 30 minutes. 0.5 ml methanol solution of 19 mg 5-phenyl-1H-pyrazolo [4,3-c] isoquinoline-3-carboxylic acid (60) was added dropwise. After the mixture was stirred at RT for 12 hours, saturated sodium hydrocarbon solution was added, and the whole was extracted once with ethyl acetate and methylene chloride. After combining the organic phases, drying over magnesium sulfate and concentrating under reduced pressure, the residue was purified by HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid). ) = 80/20 → 10/90). The following materials were obtained:

61.C ₁₈ H ₁₃ N ₃ O ₂ (303.32) MS (ESI) 304 (M + H)

Example 29

(5-phenyl-1H-pyrazolo [4,3-c] isoquinolin-3-yl) methanol (62)

7.5 mg lithium aluminum hydride was added to 1.5 ml tetrahydrofuran and the mixture was stirred for 10 minutes. 1.5 ml tetrahydrofuran of 6 mg methyl 5-phenyl-1H-pyrazolo [4,3-c] isoquinoline-3-carboxylate (61) was added dropwise. The mixture was stirred at 80 ° C. for 3 hours before water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure, and the residue was purified by HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) 80/20 → 10/90). The following materials were obtained:

62.C ₁₇ H ₁₃ N ₃ O ₁ (275.31) MS (ESI) 276 (M + H)

Example 30

2- (3-methyl-1H-pyrazolo [4,3-c] isoquinolin-5-yl) phenol (63)

Prepared in a similar manner to Example 3 using 210 mg 5- (2-methoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (6). The following materials were obtained:

63.C ₁₇ H ₁₃ N ₃ O (275.31) MS (ESI) 276 (M + H)

Example 31

4- (3-methyl-1H-pyrazolo [4,3-c] isoquinolin-5-yl) benzene-2,4-diol (64)

9 mg 5- (3,5-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (16) was prepared in a similar manner to Example 3 as a starting material. The following materials were obtained:

64. C ₁₇ H ₁₃ N ₃ O ₂ (291.31); MS (ESI) 292 (M + H)

Example 32

4- (3-methyl-1H-pyrazolo [4,3-c] isoquinolin-5-yl) benzene-1,2-diol (65)

40 mg 5- (2,3-dimethoxyphenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (8) was prepared in a similar manner to Example 3 as a starting material. The following materials were obtained:

65. C ₁₇ H ₁₃ N ₃ O ₂ (291.31); MS (ESI) 292 (M + H)

Example 33

3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (B).

a) N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide (B1).

370 μl benzoyl chloride was added to a 8.5 mL pyridine rt solution of 550 mg 3-methyl-5-phenyl-1H-pyrazol-4-ylamine (UK 2 185 255, prepared by the procedure described in Example 2A). . The reaction was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in chloroform, washed with 0.5N hydrochloric acid and then with saturated aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC (12 g SiO ₂ , 40% ethyl acetate: heptane) to afford the title compound as a colorless solid.

HPLC R _T = 2.35 min.

C ₁₇ H ₁₅ N ₃ O (277.33) MS, (ESI, method A) 278 (M + H).

b) 3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (B).

565 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide was added to 5 mL nitrobenzene followed by 270 μl POCl ₃ and the resulting mixture was heated to 185 ° C. After 1 h, 0.4 mL SnCl ₄ solution (1.0 M heptane solution) was added and the mixture was heated for an additional 2 h, then concentrated under reduced pressure and using MPLC (12 g SiO ₂ , 35% ethyl acetate: heptane) Purification gave the title compound as a brown solid.

HPLC R _T = 2.85 min.

C ₁₇ H ₁₃ N ₃ (259.31) MS, (ESI, method A) 260 (M + H).

Example 34

3-methyl-5-thiophen-2-yl-1H-pyrazolo [4,3-c] isoquinoline (D).

a) Thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (D1).

Obtained in a similar manner to Example 33 (B1) using 120 μl 2-thiophencarbonylchloride as starting material, except that the product was purified using MPLC (12 g SiO ₂ , 30% ethyl acetate: heptane) to give an amorphous orange color. The title compound was obtained as a solid.

HPLC R _T = 2.28 min.

C ₁₅ H ₁₃ N ₃ OS (283.36) MS (ESI, method A) 284 (M + H).

b) 3-methyl-5-thiophen-2-yl-1H-pyrazolo [4,3-c] isoquinoline (D).

To a 11.0 mL phosphorus oxychloride suspension of 682.4 mg thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide, 5.00 g phosphorus pentoxide was added and the resulting suspension was 120 ^o heated at C for 5 h. The reaction mixture was cooled to room temperature, cooled by addition of water and ice and neutralized with sodium carbonate solid. The aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue is purified using MPLC (4 g SiO ₂ , 30% ethyl acetate: dichloromethane) to afford the title compound as a brown solid.

HPLC R _T = 3.19 min.

C ₁₅ H ₁₁ N ₃ S (265.34) MS (ESI, method A) 266 (M + H).

Example 35

5-furan-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) furan-2-carboxylic acid (3-methyl-5-phenyl-1H-pyrazol-4-yl) -amide (E1).

To a rt solution of 4 mL methylene chloride of 337.3 mg 3-methyl-5-phenyl-1 H-pyrazol-4-ylamine was added 407 μl triethylamine and 201 μl 2-chlorofuroyl. After 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with saturated sodium carbonate solution and brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as an amorphous yellow solid and could be used without further purification.

HPLC R _T = 2.08 min.

C ₁₅ H ₁₃ N ₃ O ₂ (267.30) MS (ESI, method A) 268 (M + H).

b) 5-furan-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (E).

419.1 mg E1 is prepared as a starting material in a similar manner to Example C, except that the residue is purified using MPLC (12 g SiO ₂ , 20% ethyl acetate: dichloromethane) to obtain the title compound as a pale yellow solid.

HPLC R _T = 2.73 min.

C ₁₅ H ₁₁ N ₃ O (249.29) MS (ESI, method A) 250 (M + H).

Example 36

5- (3-chloro-benzo [b] thiophen-2-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 3-Chloro-benzo [b] thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (F1).

627 mg 3-chlorobenzo [b] thiophene-2-carbonylchloride was prepared as a starting material using a method similar to Example 35 (E1). The title compound is obtained, which is an off-white solid.

HPLC R _T = 3.08 min.

C ₁₉ H ₁₄ ClN ₃ OS (367.86) MS (ESI, method A) 368 (M + H).

b) 5- (3-chloro-benzo [b] thiophen-2-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (F).

Using a method similar to Example 34 (D), start 484 mg 3-chloro-benzo [b] thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide Prepared as a material. Obtain the title compound as a light brown solid.

HPLC R _T = 3.63 min.

C ₁₉ H ₁₂ ClN ₃ S (349.85) MS (ESI, method A) 350 (M + H).

Example 37

5- (6-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 6-chloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -nicotinamide (G1).

426 mg 6-chloronicotinoyl chloride was prepared as a starting material using a method similar to Example 35 (E1). Obtain the title compound as a colorless solid.

HPLC R _T = 2.27 min.

C ₁₆ H ₁₃ ClN ₄ O (312.76) MS (ESI, method A) 313 (M + H).

b) 5- (6-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (G).

Using a method similar to Example 34 (D), using 400 mg 6-chloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -nicotinamide as starting material, The reaction time is 48 hours. Obtain the title compound as a light brown solid.

HPLC R _T = 2.70 min.

C ₁₆ H ₁₁ ClN ₄ (294.07) MS (ESI, method A) 295 (M + H).

Example 38

5- (2-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 2-Chloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -nicotinamide (H1).

404 mg 2-chloronicotinoyl chloride was prepared as starting material using a method similar to Example 35 (E1). The title compound is obtained, which is an amorphous brown solid.

HPLC R _T = 2.03 min.

C ₁₆ H ₁₃ ClN ₄ O (312.76) MS (ESI, method A) 313 (M + H).

b) 5- (2-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (H).

511.5 mg 2-chloro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -nicotinamide as a starting material was prepared using a method similar to Example 34 (D), except that The reaction time is 36 h and the residue is purified by MPLC (4 g SiO ₂ , 40% ethyl acetate: dichloromethane) to afford the title compound as a light brown solid.

HPLC R _T = 2.42 min.

C ₁₆ H ₁₁ ClN ₄ (294.76) MS, Method A (ESI) 295 (M + H).

Example 39

5-benzo [b] thiophen-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) Benzo [b] thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (I1).

4.6 mL pyridine solution of 380 mg 3-methyl-5-phenyl-1 H-pyrazol-4-ylamine and 454 mg benzo [b] thiophene-2-carbonylchloride chloride using a method similar to Example 33 (B1) Was prepared as a starting material. After operation the residue contained the title compound as a yellow solid and was used without further purification.

HPLC R _T = 2.77 min.

C ₁₉ H ₁₅ N ₃ OS (333.41) MS (ESI, method A) 334 (M + H).

b) 5-benzo [b] thiophen-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (I).

Prepared using 544 mg benzo [b] thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide as a starting material, using a method similar to Example 34 (D). However, the residue is purified by recrystallization from ethyl acetate to give the title compound as a brown solid.

HPLC R _T = 3.62 min.

C ₁₉ H ₁₃ N ₃ S (315.40) MS (ESI, method A) 316 (M + H).

Example 40

3-methyl-5- (3-methyl-benzofuran-2-yl) -1H-pyrazolo [4,3-c] isoquinoline.

a) 3-Methyl-benzofuran-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (J1).

492 mg 3-methylbenzofuran-2-carbonyl chloride was prepared as starting material using a method similar to Example 39 (I1). This title compound is obtained as an amorphous yellow solid.

HPLC R _T = 2.88 min.

C ₂₀ H ₁₇ N ₃ O ₂ (331.38) MS (ESI, method A) 332 (M + H).

b) 3-methyl-5- (3-methyl-benzofuran-2-yl) -1H-pyrazolo [4,3-c] isoquinoline (J).

735 mg 3-methyl-benzofuran-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide was prepared using a method similar to Example 39 (I) as a starting material. . The title compound is obtained as a brown solid.

HPLC R _T = 3.58 min.

C ₂₀ H ₁₅ N ₃ O (313.37) MS (ESI, method A) 314 (M + H).

Example 41

3-methyl-5-quinoxalin-2-yl-1H-pyrazolo [4,3-c] isoquinoline

a) quinoxaline-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (K1)

Using a method similar to Example 38 (H1), 393.4 mg 2-quinoxaloyl chloride was prepared as starting material. The title compound is obtained as a reddish brown solid.

HPLC R _T = 2.57 min.

C ₁₉ H ₁₅ N ₅ O (329.36) MS (ESI, method A) 330 (M + H).

b) 3-methyl-5-quinoxalin-2-yl-1H-pyrazolo [4,3-c] isoquinoline (K)

Using a method similar to Example 34 (D), 423 mg quinoxaline-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide was prepared as a starting material, except that Water was purified by recrystallization from methanol. The title compound is obtained as a brown solid.

HPLC R _T = 3.34 min

C ₁₉ H ₁₃ N ₅ (311.35) MS (ESI, method A) 312 (M + H).

Example 42

5-isoxazol-5-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) isoxazole-5-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (L1).

315 mg isoxazole-5-carbonyl chloride was prepared as starting material using a method similar to Example 39 (I1). This title compound is obtained as a brown solid.

HPLC R _T = 1.97 min.

C ₁₄ H ₁₂ N ₄ O ₂ (268.28) MS (ESI, method A) 269 (M + H).

b) 5-isoxazol-5-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (L).

Prepared using 274.6 mg isoxazole-5-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide as a starting material using a method similar to Example 34 (D), except the reaction The time is 24 hours and the residue is purified using MPLC (4 g SiO ₂ , 40% ethyl acetate: dichloromethane) to afford the title compound as an off-white solid.

HPLC R _T = 2.45 min.

C ₁₄ H ₁₀ N ₄ O (250.26) MS (ESI, method A) 251 (M + H).

Example 43

3-methyl-5- (1-methyl-1H-pyrrole-2-yl) -1H-pyrazolo [4,3-c] isoquinoline.

a) 1-Methyl-1H-pyrrole-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (M1).

301 mg N-methylpyrrole-2-carbonyl chloride was prepared as a starting material using a method similar to Example 39 (I1). This title compound is obtained as an amorphous brown solid.

HPLC R _T = 2.33 min.

C ₁₆ H ₁₆ N ₄ O (280.34) MS (ESI, method A) 281 (M + H).

b) 3-methyl-5- (1-methyl-1H-pyrrole-2-yl) -1H-pyrazolo [4,3-c] isoquinoline (M).

Prepared using 432 mg 1-methyl-1H-pyrrole-2-carboxylic acid (3-methyl-5-phenyl-1H-pyrazol-4-yl) -amide as a starting material using a method similar to Example 34 (D) However, the residue was purified using MPLC (4 g SiO ₂ , 40% ethyl acetate: dichloromethane) to afford the title compound as a yellow solid.

HPLC R _T = 2.72 min.

C ₁₆ H ₁₄ N ₄ (262.32) MS (ESI, method A) 263 (M + H).

Example 44

3-methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline.

a) 3-Methyl-thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (N1).

414 mg 3-methylthiophene-2-carbonyl chloride was prepared as a starting material using a method similar to Example 39 (I1). This title compound is obtained as a brown solid.

HPLC R _T = 2.45 min.

C ₁₅ H ₁₆ N ₃ OS (297.39) MS (ESI, method A) 298 (M + H).

b) 3-methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline (N).

Prepared using 562 mg 3-methyl-thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide as a starting material using a method similar to Example 34 (D) Provided that the residue was dissolved in methanol and purified by MPLC (4 g SiO ₂ , 10% ethyl acetate: dichloromethane, more polar portions) to give the title compound and the N-methylated compound as a brown solid (cf. Example 45 (O)) is obtained.

HPLC R _T = 2.95 min.

C ₁₆ H ₁₃ N ₃ S (279.08) MS (ESI, method A) 280 (M + H).

Example 45

1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline.

a) 1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline (O).

This compound was combined with 3-methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline (Compound N in Example 44 above) in MPLC (4 g SiO). ₂ , 10% ethyl acetate: dichloromethane, less polar portion) to afford the title compound as a brown solid.

HPLC R _T = 3.25 min.

C ₁₇ H ₁₅ N ₃ S (293.10) MS (ESI, method A) 294 (M + H).

Example 46

5-phenyl-3-ethyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 1-phenylpentane-1,3-dione-2-oxime (P4)

As described herein, the compounds were prepared according to the method of Saloutin et al, J. Flourine Chem, vol 84, pp107-111. A stirred suspension of 25 mL glacial acetic acid of 8.8 g 1-phenylpentane-1,3-dione was treated with a 20 mL aqueous solution of 3.85 g sodium nitrite maintained at 15 ° C. or lower. The reaction mixture was allowed to come to room temperature and stirred for 4 hours. The reaction mixture was diluted with 100 mL water and then extracted with ethyl acetate. The organic portion was washed with water and brine and dried over magnesium sulfate. Concentration gives the title compound as a yellow solid, Melting point 87-88 ° C.

C ₁₁ H ₁₁ NO ₃ (205.23), MS (ESI, method B) 204 (MH).

TLC (3/7 ethyl acetate / heptane) R _f = 0.3.

b) 3-ethyl-4-nitrozo-5-phenyl-1 H-pyrazole (P3)

A 100 mL ethanol solution of 9.45 g 1-phenylpentane-1,3-dione-2-oxime was cooled to 0 ° C. and then treated with 10 mL ethanol of 2.7 mL hydrazine hydrate and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue dissolved in ethyl acetate. The organic portion was washed with water and brine and dried over magnesium sulfate. Concentration gives a green oil, which is solidified when left, which is purified by elution with 3/2 ethyl acetate / heptane using MPLC to give the title compound as a brown semisolid.

C ₁₁ H ₁₁ N ₃ O (201.23), MS (ESI, method B) 200 (MH)

TLC (1/1 ethyl acetate / heptane) R _f = 0.25.

c) 4-amino-3-ethyl-5-phenyl-1 H-pyrazole (P2)

A 220 mL ethanol solution of 6.3 g 3-ethyl-4-nitrozo-5-phenyl-1 H-pyrazole was treated with 2.0 g 10% palladium / carbon catalyst and hydrogenated at RT and 50 psi for 16 hours. The reaction mixture was filtered through celite and washed well with ethanol. The filtrate is concentrated to afford the title compound as a brown oil.

C ₁₁ H ₁₃ N ₃ (187.25), MS (ESI, method B) 188 (M + H).

TLC (1/1 ethyl acetate / heptane) R _f = 0.28.

d) N- (3-ethyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide (P1)

Prepared using 2.0 mL benzoyl chloride in a similar manner as in Example A1 except that the reaction mixture was stirred at RT for 5 hours and then concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine and dried over magnesium sulfate. Using MPLC, eluting with 2/3 ethyl acetate / heptane, concentration and purification gave the title compound as a white solid, melting point 215-216 ° C.

C ₁₈ H ₁₇ N ₃ O (291.14), MS (ESI, method B) 292 (M + H)

HPLC R _T 2.47 min.

e) 5-phenyl-3-ethyl-1H-pyrazolo [4,3-c] isoquinoline (P)

Prepared using 0.87 g N- (3-ethyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide in a similar manner to Example 34 (D), except that the residue was recrystallized from methanol and browned. The title compound is obtained as a solid of crystals, melting point 250-251 ° C.

C ₁₈ H ₁₅ N ₃ (273.13), MS (ESI, method B) 272 (MH).

HPLC R _T = 3.03 min.

Example 47

3-ethyl-5- (pyridin-3-yl) -1H-pyrazolo [4,3-c] isoquinoline.

N- (pyridin-3-yl)-(3-ethyl-5-phenyl-1H-pyrazol-4-yl) amide (Q1)

Prepared by stirring for 16 hours at RT using 420 mg nicotinoyl chloride hydrochloride and 0.383 ml pyridine in a similar manner to Example 22e. The reaction mixture was washed with water and brine and the organic portion was dried over magnesium sulfate and concentrated. The residue is eluted with 3/1 ethyl acetate / heptane by MPLC to afford the title compound as a white solid, melting point 212-213 ° C ..

C ₁₇ H ₁₆ N ₄ O (292.35), MS (ESI, method A) 293 (M + H)

HPLC R _T = 1.85 min.

b) 3-ethyl-5- (pyridin-3-yl) -1H-pyrazolo [4,3-c] isoquinoline (Q)

In a similar manner to Example 34 (D), with reflux 700 mg N- (pyridin-3-yl)-(3-ethyl-5-phenyl-1 H-pyrazol-4-yl) amide for 6 hours It was prepared by. The residue is eluted with 4/1 ethyl acetate / heptane by MPLC to afford the title compound as a white solid, melting point 219-220 ° C.

C ₁₇ H ₁₄ N ₄ (274.23), MS (ESI, method A) 275 (M + H)

HPLC R _T = 2.29 min.

Example 48

5- (2,6-difluoro-phenyl) -3-methyl-1H-pyrazole [4,3-c] isoquinoline, trifluoroacetic acid salt

a) 2,6-difluoro-N- (3-methyl-5-phenyl H-pyrazol-4-yl) -benzamide (R1)

268.5 mg 2,6-difluorobenzoyl chloride was added dropwise to a 4.5 ml pyridine solution of 263.4 mg 3-methyl-5-phenyl-1 H-pyrazol-4-ylamine at room temperature. The reaction mixture was stirred for 24 hours, and the formed precipitate was filtered off and washed with dichloromethane to afford the title compound.

HPLC R _T = 2.37 min.

C ₁₇ H ₁₃ F ₂ N ₃ O (313.31) MS (ESI, method A) 314 (M + H)

b) 5- (2,6-difluoro-phenyl) -3-methyl-1H-pyrazole [4,3-c] isoquinoline, trifluoroacetic acid salt (R)

In a similar manner to Example 33 (B), 188 mg 2,6-difluoro-N- (3-methyl-5-phenyl H-pyrazol-4-yl) -benzamide was prepared as starting material. The residue was purified using MPLC (4 g SiO ₂ , dichloromethane / methanol, gradient 95/5 → 40/60). The title was further purified using preparative HPLC (monochrome 10u C18 100x21.2mm column, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid), gradient 95/5 → 0/100) Obtain the compound.

HPLC R _T 2.77 min.

C ₁₇ H ₁₁ F ₂ N ₃ (295.09), MS (ESI, method A) 296 (M + H)

Example 49

5- (2-chloro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 2-chloro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (S1)

In a similar manner to Example 33 (B1), 266 mg 2-chloro-benzoyl chloride was prepared as starting material, except the reaction mixture was stirred for 24 hours before concentration. The residue is mixed with dichloromethane to afford the title compound as a white precipitate.

HPLC R _T 2.42 min.

C ₁₇ H ₁₄ ClN ₃ O (312.06) MS (ESI, method A) 313 (M + H).

b) 5- (2-chloro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (S)

In a similar manner to Example 33 (B), 401 mg 2-chloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide was prepared as starting material. The reaction mixture was diluted with water and extracted with dichloromethane. The organic portion is concentrated under reduced pressure and purified by MPLC (4 g SiO ₂ , dichloromethane / methanol = 99/1 → 50/50) to afford the title compound.

HPLC R _T 2.94 min.

C ₁₇ H ₁₂ ClN ₃ (293.76) MS (ESI, method A) 294 (M + H)

Example 50

5- (4-fluoro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 4-fluoro-N- (3-methyl-5-phenyl-1H-pyrazol-yl) -benzamide (T1)

In a similar manner to Example 48 (S1), preparation using 241 mg 4-fluorobenzoyl chloride gives the title compound as a white precipitate.

HPLC R _T 2.46 min.

C ₁₇ H ₁₄ FNO ₃ (295.31) MS (ESI, method A) 296 (M + H)

b) 5- (4-fluoro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (T)

Prepared using 236 mg 4-fluoro-N- (3-methyl-5-phenyl-1H-pyrazol-yl) -benzamide in a similar manner to Example 22A, except that the reaction mixture was refluxed for 10 hours. I was. After working the cream solid residue is the title compound.

HPLC (Method A) R _T

C ₁₇ H ₁₂ FN ₃ (297.30) MS (ESI,)

Example 51

3-methyl-5-p-tolyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 4-methyl-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (U1)

In a similar manner to Example 33 (B1), it was prepared using 227 mg p-toluoyl chloride. Concentration of the reaction mixture gives a solid, which is mixed with dichloromethane to afford the title compound.

HPLC R _T 2.55 min.

C ₁₈ H ₁₇ N ₃ 0 (291.36) MS (ESI, method A) 292 (M + H).

b) 3-methyl-5-p-tolyl-1H-pyrazolo [4,3-c] isoquinoline (U)

In a similar manner to Example 33 (B), it is prepared using 192 mg 4-methyl-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide, except that the reaction mixture is Diluted with water and extracted with dichloromethane. The organic portion is concentrated under reduced pressure and purified by MPLC (4 g SiO ₂ , dichloromethane / methanol, gradient = 99/1 → 50/50) to afford the title compound.

HPLC R _T 3.08 min.

C ₁₈ H ₁₅ N ₃ (273.34) MS (ESI, method A) 274 (M + H).

Example 52

3-methyl-5-o-tolyl-1H-pyrazolo [4,3-c] isoquinoline

a) 2-methyl-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) benzamide (V1)

In a similar manner to Example 33 (B1), it was prepared using 301 mg o-toluoyl chloride. Concentration of the reaction mixture gives a solid which is mixed with dichloromethane and recrystallized from ethyl acetate to give the title compound.

HPLC R _T 2.46 min.

C ₁₈ H ₁₇ N ₃ 0 (291.36) MS (ESI, method A) 292 (M + H)

b) 3-methyl-5-o-tolyl-1H-pyrazolo [4,3-c] isoquinoline (V)

In a similar manner to Example 22A, prepared using 303 mg 2-methyl-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl), except the reaction was heated for 4 hours and the residue Silver is miscible in methanol to afford the title compound.

HPLC R _T 2.90 min.

C ₁₈ H ₁₅ N ₃ (273.34) MS (ESI, method A) 274 (M + H)

Example 53

5- (4-chlorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) -chloro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (W1)

In a similar manner to Example 33 (B1), it was prepared using 283 mg 4-chlorobenzoyl chloride. Concentration of the reaction mixture gives a solid which is mixed with dichloromethane to afford the title compound.

HPLC R _T 2.66 min.

C ₁₇ H ₁₄ ClN ₃ 0 (311.77), MS (ESI, method A) 312 (M + H).

b) 5- (4-chlorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (W)

In a similar manner to Example 33 (B), 289 mg 4-chloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide was prepared. The reaction mixture was partitioned between water and dichloromethane. The organic portion was concentrated and blended with hot ethyl acetate. Purification of the brown solid using MPLC (5 g SiO ₂ , dichloromethane / methanol solvent gradient → 100/0 → 0/100) affords the title compound.

HPCL R _T 3.29 min.

C ₁₇ H ₁₂ ClN ₃ (293.07), MS (ESI, method A) 294 (M + H).

Example 54

5- (2-fluorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 2-fluoro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide (X1)

In a similar manner to Example 33 (B1), it was prepared using 249 mg 4-fluorobenzoyl chloride. The residue obtained from concentration was mixed with dichloromethane. The solid obtained is purified by MPLC (5 g SiO 2, methanol / dichloromethane = 0/100 → 10/100) to afford the title compound.

HPLC R _T 2.43 min.

C ₁₇ H ₁₄ FN ₃ 0 (295.32) MS (ESI, method A) 296 (M + H).

b) 5- (2-fluorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (X)

Prepared using 182 mg 2-fluoro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide in a similar manner to Example 34 (D), except 10.7 ml oxy Phosphorus chloride was used and the reaction stirred for 4 hours. Blending the residue with ethyl acetate / dichloromethane (1/1) affords the title compound as a cream solid.

HPLC R _T 2.82 min.

C ₁₇ H ₁₂ FN ₃ (277.10) MS (ESI, method A) 278 (M + H).

Example 55

5- (2,4-difluorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 2,4-difluoro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (Y1)

Prepared using 297 mg 2, 4-difluorobenzoyl chloride in a similar manner to Example 33 (B1). The residue is miscible with dichloromethane to afford the title compound.

HPLC R _T 2.53 min.

C ₁₇ H ₁₃ F ₂ N ₃ 0 (313.31) MS (ESI, method A) 314 (M + H).

b) 5- (2,4-difluorophenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (Y)

Prepared using 233 mg 2,4-difluoro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide using a method similar to Example 33 (B), The reaction mixture is heated for 4 hours after the addition of SnCl ₄ and the addition of water gives a brown precipitate. Mixing this material with hot methanol gives a solid, which is further mixed with dichloromethane and methanol to give the title compound as a white solid.

HPLC R _T 2.93 min.

C ₁₇ H ₁₁ F ₂ N ₃ (295.09) MS (ESI, method A) 296 (M + H).

Example 56

3-methyl-5- (3-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline

a) 3-methyl-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (Z1)

Prepared using 268 mg m-toluoyl chloride in a similar manner to Example 33 (B1). The white precipitate formed in the reaction mixture was collected by filtration, washed with ethyl acetate and dried in vacuo to identify the title compound.

HPLC R _T 2.56 min.

C ₁₈ H ₁₇ N ₃ 0 (291.36) MS (ESI, method A) 292 (M + H).

b) 3-methyl-5- (3-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline (Z)

Prepared using 404 mg 3-methyl-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide in a similar manner to Example 34 (D), except that 10 ml phosphorus oxychloride Was used and the reaction was stirred for 4 hours. Blending the residue with dichloromethane / methanol (95/5) affords the title compound as an off white solid.

HPLC R _T 3.29 min.

C ₁₈ H ₁₅ N ₃ (273.13) MS (ESI, method A) 274 (M + H).

Example 57

5- (2-bromo-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 2-bromo-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (AA1)

Prepared using 380.5 mg 2-bromobenzoyl chloride in a similar manner to Example 33 (B1), except the reaction mixture is stirred for 16 hours. Purification by mixing the residue with dichloromethane in 1% methanol affords the title compound.

HPLC R _T 2.48 min.

C ₁₇ H ₁₄ BrN ₃ 0 (355) MS (ESI, method A) 356 (M + H).

b) 5- (2-bromo-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AA)

Prepared using 196 mg 2-bromo-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide in a similar manner to Example 34 (D), except 6 ml of oxychloride Phosphorus was used and the reaction was stirred for 4 hours. The residue is mixed with dichloromethane to afford the title compound as a white solid.

HPLC R _T 3.17 min.

C ₁₇ H ₁₂ BrN ₃ (337.02) MS (ESI, method A) 338 (M + H).

Example 58

5- (2,4-dichloro-phenyl) -3 -methyl-1H-pyrazoloisoquinoline

a) 2,4-dichloro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (AB1)

Prepared using 363 mg 2,4 dichlorobenzoyl chloride in a similar manner to Example 33 (B1), except the reaction mixture was stirred for 16 hours. The residue is mixed with ethyl acetate / dichloromethane (4/6) to afford the title compound as a cream solid.

HPLC R _T 2.74 min.

C ₁₇ H ₁₅ Cl ₂ N ₃ 0 (345.04) MS (ESI, method A) 346 (M + H).

b) 5- (2,4-dichloro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AB)

Prepared using 115 mg 2,4-dichloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide in a similar manner to Example 34 (D). A cream solid residue was identified with the title compound.

HPLC R _T 3.49 min.

C ₁₇ H ₁₁ Cl ₂ N ₃ (327.03) MS (ESI, method A) 328 (M + H).

Example 59

3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline

a) 2,3,4,5,6-pentafluoro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (AC1)

Prepared using 400 mg 2,3,4,5,6-pentafluoro-benzobenzoyl chloride in a similar manner to Example 33 (B1). Admixture of the residue with methanol / dichloromethane (95/5) affords the title compound.

HPLC R _T 2.72 min.

C ₁₇ H ₁₀ F ₅ N ₃ 0 (367.28) MS (ESI, method A) 368 (M + H).

b) 3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline (AC)

147 mg of 2,3,4,5,6-pentafluoro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide in a similar manner to Example 50 (T) To give the title compound pale creamy.

HPLC (Method A) R _T 3.15 min.

C ₁₇ H ₈ F ₅ N ₃ (349.06) MS (ESI, method A) 350 (M + H).

Example 60

5- (3,4-dichloro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 3,4-dichloro-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -benzamide (AD1)

This compound was carried out using 368 mg benzoyl chloride in the same manner as in Example 33 (B1), except that the reaction mixture was stirred for 70 hours. The cream solid obtained in the work was identified as the title compound.

HPLC (Method A) R _T 2.87 min.

C ₁₇ H ₁₃ Cl ₂ N ₃ O 345.04 MS (ESI, method A) 346.05 (M + H).

b) 5- (3,4-dichloro-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AD)

This compound is carried out using 484 mg 3,4-dichloro-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide in the same manner as in Example 22A. Working to obtain the title compound as a beige solid, no further purification is necessary.

HPLC (method B) R _T 3.61 min.

C ₁₇ H ₁₁ Cl ₂ N ₃ 327 MS (ESI, method B) 328 (M + H).

Example 61

5- (3-Bromo-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 3-bromo-N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -benzamide (AE1)

This compound is obtained in the same manner as in Example 60 (AD), using 385 mg benzoyl chloride to obtain the title compound as a pale yellow solid.

HPLC (Method A) R _T 2.68 min.

C ₁₇ H ₁₄ BrN ₃ O 355.03 MS (ESI, method A) 356.06.

b) 5- (3-bromo-phenyl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AE)

The title compound is obtained in a similar manner as described herein.

Example 62

7-bromo-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline

a) N- [5- (4-bromo-phenyl) -3-methyl-1H-pyrazol-4-yl] -benzamide (AF1)

In a similar manner to Example 22A (A1), 504 mg 4-amino-5- (4-bromo-phenyl) -3-methyl-pyrazole (Lankau et al, Pharmazie (1999), 54 (9), 705-706, with the exception that the reaction mixture is stirred for 16 hours, whereupon it is filtered to give the title compound as a white solid, melting point 273-4 ° C.

HPLC (Method A) R _T 2.12 min.

C ₁₆ H ₁₃ BRN ₄ O 356.03, MS (ESI, method A) 357 (M + H).

b) 7-bromo-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline (AF)

Prepared using 756 mg N- [5- (4-bromo-phenyl) -3-methyl-1H-pyrazol-4-yl] -benzamide in a similar manner to Example 34 (D), except the reaction The mixture was refluxed for 2 hours and the residue was purified using MPLC (4/1 ethyl acetate / heptane) to afford the title compound as a white solid, melting point 299-300 ° C.

HPLC (Method A) R _T 3.65 min.

C ₁₇ H ₁₂ BRN ₃ 337.02, MS (ESI, method A) 338 (M + H).

Example 63

7-bromo-3-methyl-5-pyrid-3-yl-1H-pyrazolo [4,3-c] isoquinoline

a) N- [5- (4-bromo-phenyl) -3-methyl-1H-pyrazol-4-yl] -nicotinamide (AG1)

In a similar manner to Example 22A (A1), it is prepared using 756 mg 4-amino-5- (4-bromo-phenyl) -3-methyl-pyrazole, except the reaction mixture is stirred for 16 hours. The white precipitate in the reaction mixture was filtered, washed with water and dichloromethane and dried to afford the title compound, melting point 262-4 ° C.

HPLC (Method A) R _T 2.12 min.

C ₁₆ H ₁₃ BRN ₄ O 356.02 MS (ESI, method A) 357.04 (M + H).

b) 7-bromo-3-methyl-5-pyrid-3-yl-1H-pyrazolo [4,3-c] isoquinoline (AJ)

The title compound is obtained in a manner analogous to the method described herein.

Example 64

5- (2,5-dimethyl-furan-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 2,5-dimethyl-furan-3-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (AI1)

In a similar manner to Example 35 (E1), it was prepared using 424.5 mg 2,5-dimethyl-3-furoyl chloride. The title compound is obtained as an orange solid.

HPLC (Method A) R _T = 2.80 min.

C ₁₇ H ₁₇ N ₃ O ₂ (295.34) MS (ESI, method A) 296 (M + H).

b) 5- (2,5-dimethyl-furan-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AI)

In a similar manner to Example 34 (D), it was prepared using 562.8 mg 2,5-dimethyl-furan-3-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide, The residue is purified using MPLC (4 g SiO ₂ , 35% ethyl acetate: dichloromethane) to afford the title compound as an orange solid.

HPLC (method B) R _T = 3.22 min.

C ₁₇ H ₁₅ N ₃ O (277.33) MS (ESI, method B) 278 (M + H).

Example 65

3-methyl-5-thiophen-3-yl-1H-pyrazolo [4,3-c] isoquinoline.

a) Thiophene-3-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (AJ1)

In a similar manner to Example 35 (E1), it was prepared using 403.5 mg 3-thiophencarbonyl chloride. This title compound is obtained as a yellow / orange solid.

HPLC (method A) R _T = 2.55 min.

C ₁₅ H ₁₃ N ₃ OS (283.35) MS (ESI, method A) 284 (M + H).

b) 3-methyl-5-thiophen-3-yl-1H-pyrazolo [4,3-c] isoquinoline (AJ)

In a similar manner as in Example 34 (D), 683.3 mg thiophene-3-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide was used, except that the residue Purification by recrystallization from dichloromethane. This title compound is obtained as a brown solid.

HPLC (method B) R _T = 3.14 min.

C ₁₅ H ₁₁ N ₃ S (265.34) MS (ESI, method B) 265 (M + H).

Example 66

6-dimethylamino-5-phenyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) 1- (3-dimethylamino) -phenylbutane-1,3-dione (AK4)

This compound was prepared using 8.15 g (3-dimethylamino) acetophenone by Popic et al., Synthesis, 1991, 195, which took 20 hours to complete the reaction. The residue is purified using copper chelate to afford the title compound as a green solid.

C ₁₂ H ₁₅ NO ₂ 205 MS (ESI, Method B) 206 (M + H)

b) 1- (3-dimethylamino) -phenylbutane-1,2,3-trione 2-oxime (AK3)

Prepared by the same method as Example 22 (b), except that the reaction mixture was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic portion was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow / green solid.

C ₁₂ H ₁₄ N ₂ O ₃ 234 MS (ESI, method B) 235 (M + H)

c) 4-amino-5- (3-dimethylamino-phenyl) -3-methylpyrazole (AK2)

40 ml ethanol solution of 1.25 g 1- (3-dimethylamino) -phenylbutane-1,2,3-trione 2-oxime was treated with 2.8 ml hydrazine hydrate at 5 ° C. and stirred at this temperature for 1 hour. After stirring at room temperature for 20 hours. Concentration of the reaction mixture leaves a brown solid which is mixed with ether to give the title compound as a brown solid.

C ₁₂ H ₁₆ N ₄ 216 MS (ESI, Method B) 217 (M + H).

d) N- [5- (3-dimethylamino-phenyl) -3-methyl-1 H-pyrazol-4-yl] -benzamide (AK1)

In the same manner as in Example 22A, prepared using 460 mg benzoyl chloride and 700 mg 4-amino-5- (3-dimethylamino-phenyl) -3-methylpyrazole, except that the reaction mixture was stirred for 16 hours, The residue is purified using MPLC (using ethyl acetate as eluent) to afford the title compound as a brown solid.

HPLC (method B) R _T 2.55 min.

C ₁₉ H ₂₀ N ₄ O 320 MS (ESI, Method B) 321 (M + H).

e) 6-dimethylamino-5-phenyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AK)

In the same manner as in Example 22A, 660 mg N- [5- (3-dimethylamino-phenyl) -3-methyl-1H-pyrazol-4-yl] -benzamide was prepared. The residue is purified using MPLC (using 4/1 ethyl acetate: heptane as eluent) to give the title compound as a yellow solid, which is the less polar portion of the residue.

HPLC (method B) R _T 3.083 min.

C ₁₉ H ₁₈ N ₄ 302 MS (ESI, Method B) 303 (M + H).

Example 67

8-dimethylamino-5-phenyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline

The more polar component of Example 66 (AK) is the title compound as a yellow solid.

HPLC (method B) R _T 3.076 min.

C ₁₉ H ₁₈ N ₄ 302 MS (ESI, Method B) 303 (M + H).

Example 68

3-methyl-5- (2-methyl sulfanyl-pyridin-3-yl) -1H-pyrazolo [4,3-c] isoquinoline.

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -2-methylsulfanyl-nicotinamide (AL1)

In a similar manner to Example 35 (E1), it was prepared using 489.2 mg 2- (methylthio) nicotinoyl chloride. Obtain the title compound as an off-white solid.

HPLC R _T = 2.54 min.

C ₁₇ H ₁₆ N ₄ OS (324.41) MS (ESI, method A) 325 (M + H).

b) 5- (2,5-dimethyl-furan-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline (AL)

In a similar manner to Example 34 (D), prepared using 263.8 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -2-methylsulfanyl-nicotinamide, provided The residue is purified using MPLC (4 g SiO ₂ , 35% ethyl acetate: dichloromethane) to afford the title compound as a colorless solid.

HPLC (method B) R _T = 3.35 min.

C ₁₇ H ₁₄ N ₄ S (306.39) MS (ESI, method B) 307 (M + H).

Example 69

5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 2-methoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -acetamide (BA1).

To 4.6 mL pyridine room temperature solution of 416 mg 3-methyl-5-phenyl-1 H-pyrazol-4-ylamine was added 242 μl methoxyacetyl chloride. After 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in chloroform and washed with 0.5N hydrochloric acid and saturated aqueous sodium carbonate solution and brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a brown amorphous solid, which was used without further purification.

HPLC R _T = 1.80 min.

C ₁₃ H ₁₅ N ₃ O ₂ (245.29) MS (ESI) 246 (M + H).

b) 5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (BA).

To a 6 mL phosphorus oxychloride suspension of 320 mg 2-methoxy-N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -acetamide was added 2.70 g phosphorus pentoxide and the resulting suspension was 120 ° C. Heated for 5 h. The reaction mixture was cooled to room temperature, cooled by addition of water and ice and neutralized with sodium carbonate solid. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate. The title compound is obtained as a reddish brown solid.

HPLC R _T = 2.42 min.

C ₁₃ H ₁₃ N ₃ O (227.27) MS (ESI) 228 (M + H).

Example 70

1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline.

a) 1-benzyl-3-methyl-5-phenyl-1H-pyrazol-4-ylamine (BB2).

To a 31 mL EtOH 0 ° C. solution of 2.32 g 1-phenyl-butane-1,2,3-trione 2-oxime was added a 2.43 g benzyl hydrazine dihydro chloride / 9 mL EtOH suspension. The reaction mixture was warmed to rt and stirred for 96 h. The reaction mixture was concentrated under reduced pressure and purified by MPLC (120 g SiO ₂ , 45% EtOAc: heptane) to afford 1-benzyl-3-methyl-4-nitrozo-5-phenyl-1H-pyrazole. 2.55 g 1-benzyl-3-methyl-4-nitrozo-5-phenyl-1 H-pyrazole, 34 mL EtOAc, 500 mg 10% Pd / C suspension was reacted under 40 psi H ₂ atmosphere using a Parr apparatus. After 4 hours the suspension was filtered through celite (EtOH eluting), the filtrate was concentrated under reduced pressure and purified using MPLC (120 g SiO ₂ , 60% EtOAc: heptanes) to give the title compound as an orange oil. Get

HPLC R _T = 2.02 min.

C ₁₇ H ₁₇ N ₃ (263.36) MS (ESI) 264 (M + H).

b) cyclohexanecarboxylic acid (1-benzyl-3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (BB1).

To a 3.6 mL pyridine room temperature solution of 445 mg 1-benzyl-3-methyl-5-phenyl-1H-pyrazol-4-ylamine was added 250 μl cyclohexane carbonyl chloride. After 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with 0.5N hydrochloric acid, saturated aqueous sodium carbonate solution, brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as an amorphous light yellow solid. Used without further purification

HPLC R _T = 3.18 min.

C ₂₄ H ₂₇ N ₃ O (373.52) MS (ESI) 374 (M + H).

c) 1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (BB).

462 mg cyclohexanecarboxylic acid (1-benzyl-3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide thiophene-2-carboxylic acid (3-methyl-5-phenyl-1 H-pyrazole-4- To a 5.6 mL phosphorus oxychloride suspension of il) -amide, 2.57 g phosphorus pentoxide was added and the resulting suspension was heated at 120 ° C. for 5 hours. The reaction mixture was cooled to room temperature, cooled by addition of water and ice and neutralized with sodium carbonate solid. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue is purified using MPLC (12 g SiO ₂ , 40% EtOAc: heptanes) to afford the title compound as a brown solid.

HPLC R _T = 4.35 min.

C ₂₄ H ₂₅ N ₃ (355.51) MS (ESI) 356 (M + H).

Example 71

1-benzyl-5-naphth-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline

a) Naphthalene-2-carboxylic acid (1-benzyl-3-methyl-5-phenyl-1 H-pyrazol-4-yl) -amide (BC1).

In a similar manner to Example 70 (BB1), it was prepared using 275.0 mg 2-naphthoyl chloride, except the reaction was stirred for 1 hour, and the product was purified by MPLC (4 g SiO ₂ , 30% EtOAc: heptane). To give the title compound as a light yellow solid.

HPLC R _T = 3.32 min.

C ₂₈ H ₂₃ N ₃ O (417.53) MS (ESI) 418 (M + H).

b) 1-benzyl-5-naphth-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline (BC)

The title compound is obtained in a manner similar to that described herein.

Example 72

3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazole [4,3-c] isoquinoline

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -4-trifluoromethyl-benzamide (BD1)

361 mg 4-trifluoromethylbenzoyl chloride was added dropwise to a 5 ml pyridine solution of 300 mg 3-methyl-5-phenyl-1 H-pyrazol-4-yl amine at room temperature. The reaction mixture was stirred for 16 hours and concentrated. The residue was extracted with dichloromethane and washed with 0.5M chloric acid, at which time the title compound precipitated.

HPLC R _T 2.77 min.

C ₁₈ H ₁₄ F ₃ N ₃ O 345.32 MS (ESI, method A) 346 (M + H).

b) 3-methyl-5- (4-trifluoromethyl-phenyl) -1 H-pyrazole [4,3-c] isoquinoline (BD)

A 15 ml phosphorus oxychloride solution of 393 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -4-trifluoromethyl-benzamide was treated with 2.557 g phosphorus pentoxide and 32 at 120 ° C. Stir for hours. The reaction mixture was concentrated and the residue was carefully placed in ice water. The mixture was neutralized with sodium hydrocarbon and extracted with ethyl acetate. The organic portion was dried over magnesium sulfate, filtered and concentrated to give a solid. Purification using MPLC (5 g SiO ₂ , ethyl acetate / heptane, gradient 10/90 → 100/0) affords the title compound.

HPLC R _T 3.54 min.

C ₁₈ H ₁₂ F ₃ N ₃ (327.31) MS (ESI, method A) 328 (M + H)

Example 73

3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazole [4,3-c] isoquinoline

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -2-trifluoromethyl-benzamide (BE1)

In a similar manner to Example 72 (BD1), it was prepared using 317 mg 2-trifluoromethyl-benzoyl chloride, except that the title compound was separated by direct filtration from the reaction mixture.

HPLC R _T 2.54 min.

C ₁₈ H ₁₄ F ₃ N ₃ O (345.33) MS (ESI, method A) 346 (M + 1).

b) 3-methyl-5- (2-trifluoromethyl-phenyl) -1 H-pyrazole [4,3-c] isoquinoline (BE)

A 2 ml nitrobenzene solution of 174 mg N- (3-methyl-5-phenyl-1 H-pyrazol-4-yl) -2-trifluoromethyl-benzamide and 67 μL phosphorus oxychloride was heated to 185 ° C. After 1 hour, 118 μl SnCl ₄ solution (1.0 M heptane) was added and the reaction heated for an additional 2 hours. The reaction mixture was concentrated and purified using MPLC (4 g SiO ₂ , ethyl acetate / heptane, gradient 50/50 → 100/0, then ethyl acetate / methanol, gradient 95/5 → 80/20) to give the title compound. Get

HPLC R _T 2.92 min.

C ₁₈ H ₁₂ F ₃ N ₃ (327.31) MS (ESI, method A) 328 (M + 1).

Example 74

3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, trifluoro acetic acid salt

a) N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -3-trifluoromethyl-benzamide (BF1)

In a similar manner to Example 72 (BD1), 317 mg 3- (trifluoromethyl) benzoyl chloride was prepared as starting material and stirred for 24 hours before concentration. The residue is mixed with methanol / dichloromethane (5/95) to afford the title compound as a white precipitate.

HPLC R _T 2.75 min.

C ₁₈ H ₁₄ F ₃ N ₃ 0 (345.33) MS (ESI, method A) 346 (M + H).

b) 3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, trifluoroacetic acid salt (BF)

Prepared using 305 mg N- (3-methyl-5-phenyl-1H-pyrazol-4-yl) -3-trifluoromethyl-benzamide in a similar manner to Example 73 (BE), except that Water was purified by HPLC (monochrome 10u C18, 100x21.2mm column, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid), gradient = 95/5 → 0/100), titled above Obtain the compound.

HPLC R _T 3.31 min.

C ₁₈ H ₁₂ F ₃ N ₃ (327.10) MS (ESI, method A) 328 (M + H).

Example 75

5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline

a) 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole (BG2)

6.6 g 4-nitrozo-5-phenyl-3-trifluoromethyl-1H-pyrazole (prepared according to the method described in Saloutin et al, J. Flourine Chem, vol 84, pp107-111)] 200 mL ethanol solution was treated with 2.0 g 10% palladium / carbon catalyst and hydrogenated at room temperature, 50 psi for 7.5 hours. The reaction mixture was filtered through celite and washed well with ethanol. Concentration of the filtrate affords the title compound as a yellow solid.

C ₁₀ H ₈ F ₃ N ₃ (227.20), MS (ESI, method B) 228 (M + H).

TLC (1/1 ethyl acetate / heptane) R _f = 0.35.

b) N- (5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -benzamide (BG1)

A 30 mL dichloromethane solution of 1.0 g 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole was treated with 1.1 mL pyridine followed by 0.57 mL benzoyl chloride. The reaction mixture was stirred at rt for 5 h and then concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was eluted with 2/3 ethyl acetate / heptane using MPLC to afford the title compound as a white solid, melting point 229-230 ° C.

C ₁₇ H ₁₂ F ₃ N ₃ O (331.31), MS (ESI, method B) 330 (MH).

c) 5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline (BG).

A 10 mL nitrobenzene mixture of 1.02 g N- (5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -benzamide was treated with 0.41 mL phosphorus oxychloride and stirred at 185 ° C. for 6 hours. I was. The solvent was distilled off under high vacuum and the residue was partitioned between ethyl acetate and water. The organic portion was washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. Concentration and purification by eluting with 1/3 ethyl acetate / heptane using MPLC afforded the title compound as a white solid, melting point 264-265 ° C.

HPLC R _T 3.32 min.

C ₁₇ H ₁₀ F ₃ N ₃ (313.29), MS (ESI, method B) 314 (M + H).

Example 76

5- (pyridin-2-yl) -3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline

a) N- (pyridin-2-yl)-(5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) amide (BH1)

A 30 mL dichloromethane solution of 1.0 g 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole was treated with 1.1 mL pyridine followed by 0.94 g picolyl chloride. The reaction mixture was stirred at rt for 24 h and concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue is eluted with 3/7 ethyl acetate / heptane using MPLC to give the title compound as a yellow semi-solid.

C ₁₆ H ₁₁ F ₃ N ₄ O (332.31), MS (ESI, method B) 331 (MH).

TLC (1/1 ethyl acetate / heptane) R _f = 0.50.

d) 5- (pyridin-2-yl) -3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline (BH)

As in Example 75 (BG), prepared using 1.02 g N- (pyridin-2-yl)-(5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -amide Provided that the reaction mixture was concentrated, then partitioned between ethyl acetate and water. The organic portion was washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. The residue is eluted with 1 / 1ethyl acetate / heptane using MPLC to afford the title compound as a beige solid.

HPLC R _T 2.77 min.

C ₁₆ H ₉ F ₃ N ₄ (314.29), MS (ESI, method B) 315 (M + H).

Pharmacological Example

Example 77

The pyrazoloisoquinoline derivatives according to the invention were tested for NIK inhibitory activity through various in vitro tests. In this regard, human peripheral blood lymphocytes were pretreated with different concentrations of compounds for 1 hour and stimulated with LPS or IL1β for 24 hours. Next, TNFα release was measured in culture supernatants using a commercial ELISA test kit and the IC50 of a given compound was determined. Cytotoxicity was measured via LDH release using a commercial test kit, and the LD50 of a given compound was determined.

In another test, heparinized whole human blood was pretreated with different concentrations of compound for 1 hour and then stimulated with LPS for 24 hours. A commercial test kit was used to measure IL1β, TNFα, IL6 release in the supernatant 24 hours and to determine the IC50 of a given compound.

The results are shown in the following Tables 1-3.

Example 78

EAE Model

This example describes the effects of the compounds of the present invention on the treatment of multiple sclerosis. As described here, the experimental results are shown using an autoimmune encephalomyelitis (EAE) model. In this model the following procedure was used:

animal:

SJL / J female mice (8 weeks old) were obtained from Jackson Laboratories.

antigen:

Myelin lipids proteosome protein (Myelin Proteolipid Protein) (PLP 139-151 ) (HSLGKWLGHPDKF) (Cat # H-2478) was obtained from BACHEM, Bioscience, Inc (Contact, 3700 Horizon Dr., King of Prussia , PA 19406, 1-610-239-0300 (phone), 1-610-239-0800 (fax)).

Complete Freund's Adjuvant H37 Ra [1 mg / ml Mycobacterium Tuberculosis H37 Ra] was obtained from Difco 1-800-521-0851 (Cat # 3114-60-5, 6 × 10 ml).

Mycobacterium Tuberculosis was also obtained from Difco, 1-800-521-0851 (Cat # 3114-33-8, 6 × 100 mg).

Pertussis toxin

Were obtained from Bordetella spread reutu system (Bordetella Pertussis), (Lyophilized powder containing PBS and lactose) is (. Product # 180, 50ug @ $ 140.00ea) List Biological Laboratories, 1-408-866-6363 .

EAE Induction in Mice

The PLP139-151 peptide was dissolved in a H ₂ O: PBS (1: 1) solution to a concentration of 7.5 mg / 10 ml (75 μg PLP per group) and mycobacterium tuberculosis H37Ra was killed by 40 mg / 10 ml heat treatment. Emulsified with the same amount of CFA supplemented. Mouse abdominal flanks were injected subcutaneously with 0.2 ml peptide solution (0.1 ml each side). On the same day and 72 hours later, mice were injected intravenously with 100 ℓ of saline of 35 ng and 50 ng of pertussis toxin, respectively.

Clinical evaluation

Phase 0: Normal

Step 0.5: partially powerless tail

Step 1: Fully Powered Tail

Stage 2: Damaged Clove Reflections

Step 2.5: Clove reflection delayed (may go to step 3).

Stage 3: partial post-limb limb paralysis

Stage 3.5: One leg is completely paralyzed and the other is partially paralyzed

Stage 4: posterior limb completely paralyzed

Step 4.5: The legs are completely paralyzed and dying

Stage 5: Death from EAE

 Clinical course of EAE

Acute: First clinical event (day 10-18)

Mitigation: clinical improvement following clinical events; At least two days after peaking or recurrence of an acute condition is characterized by a decrease in clinical value (> = 1 rating).

Relapse: Increased clinical value by at least one grade for at least 2 weeks after relapse

In animals treated with the compounds of the present invention, it is generally expected to improve the clinical value.

Example 79

This example demonstrates the effect of the compounds of the invention by inhibiting IL-1β mediated release by NIK from human macrophages activated by Alzheimer's beta amyloid peptide 1-42.

Cell Separation: Monocytes were isolated from peripheral blood mononuclear cells (PBMC) as follows. Whole blood was spread directly onto Histopak 1077-1 column (Sigma Biochemicals) and centrifuged at 800 × g for 15 minutes. PBMC bands of cells were detached into fresh 50 ml culture tubes, diluted 1: 1 with wash buffer (including phosphate buffer, pH 7.4, 2 mM EDTA and 5 mg / ml BSA) and centrifuged at 800 xg for 5 minutes. Cells were then washed with a continuous resuspension of cell pellet in wash buffer and centrifuged at 600 × g for 5 minutes. The washing process is repeated until cleared in the supernatant containing pellets (5 to 6 washes). Then, using a single cell separation kit (Miltenyi Biotec, Inc) containing antibodies against non-monocytes from PBMC, the cells were placed on a magnetic column to remove negatively bound, antibody bound cells, and the fluid was transferred through a single cell volume. By collecting, single cells were purified. Single cells were washed once with wash buffer, inoculated with 10E5 cells per well with 100 μl serum free RPMI 1640 in 96 well plates and incubated for 1 hour in a 37 ° C., 5% CO ₂ /95% humidified tissue culture incubator. After 1 hour, the medium was replaced with 100 μl complete culture medium (RPMI 1640, 10% human serum type AB (heat inactivated), 25 mM HEPES, 2 mM glutamine, 50 U / ml each penicillin and streptomycin) and incubated overnight (16 hours).

Dosage method: The next day, the culture medium was replaced with 100 μl of fresh complete culture medium (with or without human beta amyloid 1-42 peptide (5 μM)), 37 ° C., 5% CO ₂ /95% humidified tissue. The incubator was incubated for 5 hours. The medium was removed and discarded. Each well was washed with Hanks buffered salt (HBSS) containing 1 mM CaCl ₂ and 80 μl HBSS / CaCl ₂ was added. 10 μl HBSS / CaCl ₂ or 10 ml of the NIK inhibitory compound of the invention (10 × stock / HBSS / CaCl ₂ at final concentrations of 23 nM and 206 nM) was then added to the sample, incubated for 15 minutes in a tissue culture incubator, / CaCl ₂ or 10 μl benzoylbenzoyl ATP (BzATP for 300 μM final concentration; 3 mM stock / HBSS / CaCl ₂ ) was added and incubated for an additional 30 minutes in tissue culture incubator. The medium is then transferred to a new 96 well plate at −70 ° C. until the IL-1β content is quantified by ELISA (R & D Systems). Cells are washed once with HBSS / CaCl ₂ and cells are 100 μl ice cooled lysis buffer (100 mM Tris, pH 7.6, 1% Triton X-100, and 1 per 30 ml complete TM protease (Roche Biochemicals, Inc) inhibitors Tablets). Cell lysates are stored at −70 ° C. until IL-1β is quantified by ELISA.

Compounds of the invention are generally expected to reduce BzATP-induced IL-1β secretion.

Claims (18)

A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof. Formula I

In the above formula, A is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, and unsubstituted or -OR ¹ , -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , Each independently is substituted one or more times with -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ or -CN, wherein R ¹ is hydrogen,-(C ₁ -C ₆ ) -alkyl, -(C ₆ -C ₁₄ ) aryl or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 6 and x is An integer from 0 to 12, y is an integer from 1 to 13, and the sum of x and y is 2n + 1; -OR ¹ , -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -C (O) -OR ¹ , Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -CN, 5 to 14 reduced heteroaryl [wherein the heteroaryl is substituted one or more times independently by a ring or R ² beach, where, R ² is - (C ₁ -C ₄₎ - alkyl, -OH, -O - (C _1- C ₄₎ - alkyl, ^{halogen, -N (R 3) -R 4} ( wherein, R ³ and R ⁴ are each independently a hydrogen atom or - (C ₁ -C ₄₎ - alkyl), Or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer from 1 to 4, x is an integer from 0 to 8, and y is 1 To an integer of 9 to 9 and the sum of x and y is 2n + 1), -(C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted each independently one or more times by R ² , and R ² is as defined above, or 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), and B is a covalent bond, -C = CR ^1- ,

_{, -O (CH 2) a -} ( wherein, a is an integer of 1 to 4), O, S, NR 2, -C (O) -, -NR 2 -C (O) -, -C (O ) -NR ^2- , -NR ² -SO _2- , -SO ₂ -NR ^2- , -NR ² -C (O) -NR ² -or-(C ₁ -C ₄ ) -alkylene, wherein alkylene is a straight-chain or branched, each unsubstituted or independently substituted one or more times by R ^1, R ¹ and R ² have the same meanings as defined above, D is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, unsubstituted or substituted each independently one or more times by R ¹ , and R ¹ is as defined above, 5 to 14 heteroaryl group of reduction (where the heteroaryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), - (C ₆ -C ₁₄₎ - aryl (wherein aryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), or - or cycloalkyl (wherein cycloalkyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined _{above), - (C 3 -C 6} ) B to D are hydrogen, halogen, fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, and x is 0 to Is an integer of 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1], or-(CH ₂ ) _a -YR ³ , wherein a is an integer of 1 to 4, and Y Is O, S, NR ² , and R ³ is-(C ₁ -C ₆ ) -alkyl,-(C ₆ -C ₁₄ ) -aryl or-(C ₃ -C ₆ ) -cycloalkyl], R is hydrogen,-(C ₁ -C ₆ ) -alkyl or-(C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein aryl is unsubstituted or is independently of each other by R ² ; Substituted one or more times, wherein R ² is as defined above; X and Z are the same or different and each independently Hydrogen atom, - (C ₁ -C ₄₎ - alkyl, -OH, -O- (C ₁ -C ₄ - alkyl), halogen, Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -NR ¹ -C (O) -NR ¹ R ¹ , -NR ¹ -C (O) -R ¹ , -NR ¹ -C (O) -OR ¹ , -OC (O) -NR ¹ R ¹ , -CN, -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -S (O) ₂ -NR ¹ R ¹ , -NR ¹ -SO ₂ -R ¹ , 5 to 12 reducing heterocycles, wherein the heterocycles are unsubstituted or substituted each independently one or more times with R ² ; or - (C ₃ -C ₆₎ - cycloalkyl is selected from: [In this case, the cycloalkyl is unsubstituted or substituted by R are each independently substituted one or more times with a ^2], wherein, R ¹ and R ² are the same as defined above, And Provided that if A is (C ₁ -C ₆ ) -alkyl, -OR ¹ , -C (O) -OR ¹ , or heteroaryl, then one of the following applies: B is not a covalent bond or is not-(C ₁ -C ₄ ) -alkylene, D is not heteroaryl, heterocycle,-(C ₆ -C ₁₄ ) -aryl,-(C ₃ -C ₆ ) -cycloalkyl, or X and Z are not both-(C ₁ -C ₄ ) -alkyl, -OH, -O- (C ₁ -C ₄ ) -alkyl, or halogen. The method of claim 1, A is-(C ₁ -C ₃ ) -alkyl wherein alkyl is straight or branched, unsubstituted or substituted independently or once each by -OR ¹ or -C (O) -OR ¹ Where R ¹ is hydrogen, — (C ₁ -C ₃ ) -alkyl or —CF ₃ ], Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 3, x is an integer of 0 to 6, and y is 1 to Is an integer of 7 and the sum of x and y is 2n + 1], B is a covalent bond D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently 1, 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ⁴ , wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl], Heteroaryl selected from the group consisting of pyridyl, furanyl, pyrrolyl, isoxazolyl, benzofuranoyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl and thiophenyl, wherein the heteroaryl is Unsubstituted or substituted each independently one or more times by R ² , wherein R ² is — (C ₁ -C ₂ ) -alkyl, —OH, —O— (C ₁ -C ₂ ) -alkyl, fluorine, chlorine Or bromine, -N (CH ₃ ) ₂ or -CF ₃ ], or - (C ₄ -C ₆₎ - cycloalkyl, or [wherein cycloalkyl is unsubstituted or substituted by R ² independently represent one, two or three times each Beach, wherein R ² is as defined above, B to D are ((CH ₂ ) _a -YR ³ , wherein a is an integer from 1 to 2, Y is O, and R ³ is-(C ₁ -C ₃ ) -alkyl; R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl, A compound of formula I, wherein X and Z are the same or different and are each independently hydrogen, —C (O) —O (C ₁ -C ₃ ) alkyl, —OCH ₃ , —N (CH ₃ ) ₂ or halogen. The method of claim 1, 5-pyridin-2-yl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (2,6-difluorophenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-naphthyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 7-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-9-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-pyridin-2-yl-9-trifluoromethyl-1H-pyrazolo [4,3-c] -isoquinoline, and A compound of formula I, selected from the group consisting of 3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] -isoquinoline. 5-benzo [b] thiophen-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 7-bromo-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-bromo-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 5- (3-chloro-benzo [b] thiophen-2-yl) -3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5- (2-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 5- (6-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline, 5-furan-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 7-methoxy-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-methyl-benzofuran-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 6-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 6-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 8-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 8-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 9-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 9-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3,9-dimethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,6-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,4-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,6-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 6-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 6-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 8-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 8-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 9-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 9-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3,9-dimethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (1-methyl-1H-pyrrole-2-yl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinolin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinolin-3-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinoxalin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-thiophen-2-yl-1H-pyrazolo [4,3-c] isoquinoline, and 3-Methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) according to claim 1 together with a pharmaceutically suitable carrier and optionally suitable additives, other active compounds, and auxiliary substances. Use of a compound according to claim 1 for the preparation of a pharmaceutical composition for the selective treatment and prevention of all diseases associated with increased NIK activity. Use of a compound according to claim 2 for the preparation of a pharmaceutical composition for the selective treatment and prevention of all diseases associated with increased NIK activity. The compound of claim 6, wherein the compound is 5-pyridin-2-yl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (2,6-difluorophenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-naphthyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 7-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-9-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-pyridin-2-yl-9-trifluoromethyl-1H-pyrazolo [4,3-c] -isoquinoline, and 3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] -isoquinoline. Use according to claim 6, wherein the disease state is caused by an inflammatory component. 7. The method of claim 6, wherein the disease is osteoarthritis, rheumatoid arthritis, asthma, inflammatory bowel disease, Alzheimer's disease, stroke, diabetes, atherosclerosis, multiple sclerosis, rejection in parts of the body for transplantation organs or parts of organs transplanted to the body Use that is a rejection reaction in. A pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof. Formula I

In the above formula, A is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, and unsubstituted or -OR ¹ , -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , Each independently is substituted one or more times with -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ or -CN, wherein R ¹ is hydrogen,-(C ₁ -C ₆ ) -alkyl, -(C ₆ -C ₁₄ ) aryl or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 6 and x is An integer from 0 to 12, y is an integer from 1 to 13, and the sum of x and y is 2n + 1; -OR ¹ , -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -C (O) -OR ¹ , Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -CN, 5 to 14 reduced heteroaryl [wherein the heteroaryl is substituted one or more times independently by a ring or R ² beach, where, R ² is - (C ₁ -C ₄₎ - alkyl, -OH, -O - (C _1- C ₄₎ - alkyl, ^{halogen, -N (R 3) -R 4} ( wherein, R ³ and R ⁴ are each independently a hydrogen atom or - (C ₁ -C ₄₎ - alkyl), Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, and y is 1 to Is an integer of 9 and the sum of x and y is 2n + 1), -CN-, SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ^1, or -C (O) -NR ¹ R ¹ ], -(C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted each independently one or more times by R ² , and R ² is as defined above, or 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), and B is a covalent bond, -C = CR ^1- ,

_{, -O (CH 2) a -} ( wherein, a is an integer of 1 to 4), O, S, NR 2, -C (O) -, -NR 2 -C (O) -, -C (O ) -NR ^2- , -NR ² -SO _2- , -SO ₂ -NR ^2- , -NR ² -C (O) -NR ² -or-(C ₁ -C ₄ ) -alkylene, wherein alkylene is a straight-chain or branched, each unsubstituted or independently substituted one or more times by R ^1, R ¹ and R ² have the same meanings as defined above, D _{is, - (C 1 -C 6)} - alkyl (wherein alkyl is a straight or branched, and substituted one or more by year independently of the unsubstituted R ¹ times 1, R ¹ is the same as defined above), 5 to 14 heteroaryl group of reduction (where the heteroaryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), - (C ₆ -C ₁₄₎ - aryl (wherein aryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), or - or cycloalkyl (wherein cycloalkyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined _{above), - (C 3 -C 6} ) B to D are hydrogen, halogen, fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, and x is 0 to Is an integer of 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1], or-(CH ₂ ) _a -YR ³ , wherein a is an integer of 1 to 4, and Y Is O, S, NR ² , and R ³ is-(C ₁ -C ₆ ) -alkyl,-(C ₆ -C ₁₄ ) -aryl or-(C ₃ -C ₆ ) -cycloalkyl], R is hydrogen,-(C ₁ -C ₆ ) -alkyl or-(C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein aryl is unsubstituted or each independently by R ² Substituted one or more times, wherein R ² is as defined above; X and Z are the same or different and each independently Hydrogen atom, - (C ₁ -C ₄₎ - alkyl, -OH, -O- (C ₁ -C ₄ - alkyl), halogen, Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -NR ¹ -C (O) -NR ¹ R ¹ , -NR ¹ -C (O) -R ¹ , -NR ¹ -C (O) -OR ¹ , -OC (O) -NR ¹ R ¹ , -CN, -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -S (O) ₂ -NR ¹ R ¹ , -NR ¹ -SO ₂ -R ¹ , 5 to 12 reducing heterocycles, wherein the heterocycles are unsubstituted or substituted each independently one or more times with R ² ; or - (C ₃ -C ₆₎ - cycloalkyl is selected from: [In this case, the cycloalkyl is substituted one or more times independently by a ring or R ² Beach], wherein, R ¹ and R ² are as defined above will Equals Provided that if A is (C ₁ -C ₆ ) -alkyl, -OR ¹ , -C (O) -OR ¹ , or heteroaryl, then one of the following applies: B is not a covalent bond or is not-(C ₁ -C ₄ ) -alkylene, D is not heteroaryl, heterocycle,-(C ₆ -C ₁₄ ) -aryl,-(C ₃ -C ₆ ) -cycloalkyl, or X and Z are not both-(C ₁ -C ₄ ) -alkyl, -OH, -O- (C ₁ -C ₄ ) -alkyl, or halogen. The method of claim 11, A is-(C ₁ -C ₃ ) -alkyl wherein alkyl is straight or branched, unsubstituted or substituted independently or once each by -OR ¹ or -C (O) -OR ¹ Where R ¹ is hydrogen, — (C ₁ -C ₃ ) -alkyl or —CF ₃ ], Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 3, x is an integer of 0 to 6, and y is 1 to Is an integer of 7 and the sum of x and y is 2n + 1], B is a covalent bond D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently 1, 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ⁴ , wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl], Heteroaryl selected from the group consisting of pyridyl, furanyl, pyrrolyl, isoxazolyl, benzofuranoyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl and thiophenyl, wherein the heteroaryl is Unsubstituted or substituted each independently one or more times by R ² , wherein R ² is — (C ₁ -C ₂ ) -alkyl, —OH, —O— (C ₁ -C ₂ ) -alkyl, fluorine, chlorine Or bromine, -N (CH ₃ ) ₂ or -CF ₃ ], or - (C ₄ -C ₆₎ - cycloalkyl, or [wherein cycloalkyl is unsubstituted or substituted by R ² independently represent one, two or three times each Beach, wherein R ² is as defined above, B to D are ((CH ₂ ) _a -YR ³ , wherein a is an integer from 1 to 2, Y is O, and R ³ is-(C ₁ -C ₃ ) -alkyl; R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl, X and Z are the same or different and each is independently hydrogen, -C (O) -O (C 1 -C 3) _{alkyl, -OCH 3, -N (CH 3} ) 2 or a halogen composition. The compound of claim 11, wherein the compound of formula I is 5-pyridin-2-yl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (2,6-difluorophenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-naphthyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 7-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 6-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 8-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-9-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-pyridin-2-yl-9-trifluoromethyl-1H-pyrazolo [4,3-c] -isoquinoline, and 3-Methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] -isoquinoline. Use of a compound of formula (I) and / or stereoisomers or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the selective prevention and treatment of all diseases associated with inflammation. Formula I

In the above formula, A is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, and unsubstituted or -OR ¹ , -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , Each independently is substituted one or more times with -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ or -CN, wherein R ¹ is hydrogen,-(C ₁ -C ₆ ) -alkyl, -(C ₆ -C ₁₄ ) aryl or fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , where n is an integer from 1 to 6 and x is An integer from 0 to 12, y is an integer from 1 to 13, and the sum of x and y is 2n + 1; -OR ¹ , -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -C (O) -OR ¹ , Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -CN, 5 to 14 reduced heteroaryl [wherein the heteroaryl is substituted one or more times independently by a ring or R ² beach, where, R ² is - (C ₁ -C ₄₎ - alkyl, -OH, -O - (C _1- C ₄₎ - alkyl, ^{halogen, -N (R 3) -R 4} ( wherein, R ³ and R ⁴ are each independently a hydrogen atom or - (C ₁ -C ₄₎ - alkyl), Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, x is an integer of 0 to 8, and y is 1 to Is an integer of 9 and the sum of x and y is 2n + 1), -CN-, SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ^1, or -C (O) -NR ¹ R ¹ ], -(C ₃ -C ₆ ) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted each independently one or more times by R ² , and R ² is as defined above, or 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), and B is a covalent bond, -C = CR ^1- ,

_{, -O (CH 2) a -} ( wherein, a is an integer of 1 to 4), O, S, NR 2, -C (O) -, -NR 2 -C (O) -, -C (O ) -NR ^2- , -NR ² -SO _2- , -SO ₂ -NR ^2- , -NR ² -C (O) -NR ² -or-(C ₁ -C ₄ ) -alkylene, wherein alkylene is a straight-chain or branched, each unsubstituted or independently substituted one or more times by R ^1, R ¹ and R ² have the same meanings as defined above, D is-(C ₁ -C ₆ ) -alkyl, wherein alkyl is straight or branched, unsubstituted or substituted each independently one or more times by R ¹ , and R ¹ is as defined above, 5 to 14 heteroaryl group of reduction (where the heteroaryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), 5 to 12 heterocycle of reduction (where heterocyclyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), - (C ₆ -C ₁₄₎ - aryl (wherein aryl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined above), or - or cycloalkyl (wherein cycloalkyl is substituted one or more times independently by a ring or R ² Beach, wherein R ² is as defined _{above), - (C 3 -C 6} ) B to D are hydrogen, halogen, fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 4, and x is 0 to Is an integer of 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1], or-(CH ₂ ) _a -YR ³ , wherein a is an integer of 1 to 4, and Y Is O, S, NR ² , and R ³ is-(C ₁ -C ₆ ) -alkyl,-(C ₆ -C ₁₄ ) -aryl or-(C ₃ -C ₆ ) -cycloalkyl], R is hydrogen,-(C ₁ -C ₆ ) -alkyl or-(C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₆ ) -alkyl [wherein aryl is unsubstituted or each independently by R ² Substituted one or more times, wherein R ² is as defined above; X and Z are the same or different and each independently Hydrogen atom, - (C ₁ -C ₄₎ - alkyl, -OH, -O- (C ₁ -C ₄ - alkyl), halogen, Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 6, x is an integer of 0 to 12, and y is 1 to Is an integer of 13 and the sum of x and y is 2n + 1], -C (O) -OR ¹ , -C (O) -NR ¹ R ¹ , -C (O) -NR ¹ -SO ₂ R ¹ , -NR ¹ R ¹ , -NR ¹ -C (O) -NR ¹ R ¹ , -NR ¹ -C (O) -R ¹ , -NR ¹ -C (O) -OR ¹ , -OC (O) -NR ¹ R ¹ , -CN, -SR ¹ , -S (O) -R ¹ , -S (O) ₂ -R ¹ , -S (O) ₂ -NR ¹ R ¹ , -NR ¹ -SO ₂ -R ¹ , 5 to 12 reducing heterocycles, wherein the heterocycles are unsubstituted or substituted each independently one or more times with R ² ; or - the same as the cycloalkyl is selected from: [wherein, cycloalkyl beach is unsubstituted or substituted by R ² each independently one or more times], wherein, R ¹ and R ² are defined above - (C ₃ -C ₆₎ . The method of claim 14, A is-(C ₁ -C ₃ ) -alkyl wherein alkyl is straight or branched, unsubstituted or substituted independently or once each by -OR ¹ or -C (O) -OR ¹ Where R ¹ is hydrogen, — (C ₁ -C ₃ ) -alkyl or —CF ₃ ], Fluoroalkyl of the formula -C _n H _x F _y or fluoroalkoxy of the formula -OC _n H _x F _y , wherein n is an integer of 1 to 3, x is an integer of 0 to 6, and y is 1 to Is an integer of 7 and the sum of x and y is 2n + 1], B is a covalent bond D is phenyl or naphthyl [wherein the phenyl or naphthyl is unsubstituted or substituted each independently 1, 2 or 3 times by R ^2, wherein R ² is hydrogen, fluorine, chlorine or bromine, -CF _3, -(C ₁ -C ₄ ) -alkyl or -N (R ³ ) -R ⁴ , wherein R ³ and R ⁴ are each independently a hydrogen atom or (C ₁ -C ₃ ) -alkyl], Heteroaryl selected from the group consisting of pyridyl, furanyl, pyrrolyl, isoxazolyl, benzofuranoyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl and thiophenyl, wherein the heteroaryl is Unsubstituted or substituted each independently one or more times by R ² , wherein R ² is — (C ₁ -C ₂ ) -alkyl, —OH, —O— (C ₁ -C ₂ ) -alkyl, fluorine, chlorine Or bromine, -N (CH ₃ ) ₂ or -CF ₃ ], or - (C ₄ -C ₆₎ - cycloalkyl, or [wherein cycloalkyl is unsubstituted or substituted by R ² independently represent one, two or three times each Beach, wherein R ² is as defined above, B to D are ((CH ₂ ) _a -YR ³ , wherein a is an integer from 1 to 2, Y is O, and R ³ is-(C ₁ -C ₃ ) -alkyl; R is hydrogen,-(C ₁ -C ₃ ) -alkyl, or -phenyl- (C ₁ -C ₃ ) -alkyl, X and Z are the same or different, and are each independently hydrogen, -C (O) -O (C 1 -C 3) _{alkyl, -OCH 3, -N (CH 3} ) 2 or halogen purposes The compound of claim 14, wherein the compound of formula I is 5-pyridin-2-yl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-trifluoromethyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 5-phenyl-3-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 1,3-dimethyl-5- (3-trifluoromethylphenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (2,6-difluorophenyl) -1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-cyclohexyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 1-benzyl-5-naphthyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5-methoxymethyl-3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] -isoquinoline, 7-methoxycarbonyl-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 7-dimethylamino-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-dimethylamino-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] -isoquinoline, 1,3-dimethyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-9-trifluoromethyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-pyridin-2-yl-9-trifluoromethyl-1H-pyrazolo [4,3-c] -isoquinoline, and 3-methyl-5- (2,3,4,5,6-pentafluoro-phenyl) -1H-pyrazolo [4,3-c] -isoquinoline. The compound of claim 14, wherein the compound of formula I is 5-benzo [b] thiophen-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 7-bromo-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 7-bromo-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 5- (3-chloro-benzo [b] thiophen-2-yl) -3-methyl-1H-pyrazolo [4,3-c] -isoquinoline, 5- (2-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 5- (6-chloro-pyridin-3-yl) -3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-ethyl-5-pyridin-3-yl-1H-pyrazolo [4,3-c] isoquinoline, 5-furan-2-yl-3-methyl-1H-pyrazolo [4,3-c] isoquinoline, 7-methoxy-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-methyl-benzofuran-2-yl) -1H-pyrazolo [4,3-c] -isoquinoline, 3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 6-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 6-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 8-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 8-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 9-chloro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 9-fluoro-3-methyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3,9-dimethyl-5-phenyl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-methyl-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3-bromo-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-chloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (3,4-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,6-dichloro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (4-fluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,4-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (2,6-difluoro-phenyl) -1H-pyrazolo [4,3-c] isoquinoline, 6-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 6-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 8-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 8-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 9-chloro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 9-fluoro-3-methyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3,9-dimethyl-5-pyridin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5- (1-methyl-1H-pyrrole-2-yl) -1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinolin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinolin-3-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-quinoxalin-2-yl-1H-pyrazolo [4,3-c] isoquinoline, 3-methyl-5-thiophen-2-yl-1H-pyrazolo [4,3-c] isoquinoline, and 3-methyl-5- (3-methyl-thiophen-2-yl) -1H-pyrazolo [4,3-c] isoquinoline. Use according to claim 14, wherein the disease is selected from the group consisting of multiple sclerosis, atherosclerosis, inflammatory bowel disease, Alzheimer's disease, stroke and diabetes.