CN115335057A

CN115335057A - Method for inhibiting casein kinase

Info

Publication number: CN115335057A
Application number: CN202180021029.6A
Authority: CN
Inventors: 周恩兴; 刘源; 王汉平; 王京; 邵宁; 武广龙
Original assignee: Beijing Yuanji Huayi Biotechnology Co ltd
Current assignee: Beijing Yuanji Huayi Biotechnology Co ltd
Priority date: 2020-03-27
Filing date: 2021-03-26
Publication date: 2022-11-11
Also published as: WO2021190616A1

Abstract

The present disclosure provides methods of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formulae (I) through (IV), or a pharmaceutically acceptable salt thereof.

Description

Methods of inhibiting casein kinase

Background

Biological clocks link our daily sleep and activity cycles to the external environment. Biological clock disorders are associated with a number of human diseases, including depression, seasonal affective disorder, and metabolic disorders. For example, biological clocks regulate a variety of downstream rhythms such as sleep and wake, body temperature, and hormone secretion rhythms (Ko and Takahashi, hum Mol Gen 15, R271-R277). In addition, diseases such as depression, seasonal affective disorder and metabolic disorders may be associated with circadian rhythms (Barnard and Nolan, PLoS genet.2008. Month 5; 4 (5): e 1000040.).

Phosphorylation of biological clock proteins is an important factor in controlling the periodic rhythm of the biological clock. Casein kinase I δ (CK 1 δ) or CK1 ∈ are closely related Ser-Thr protein kinases that act as key biological clock regulators, each of which greatly alter circadian rhythms as evidenced by mammalian mutations. Thus, inhibitors of CK1 δ/ε are useful in the treatment of circadian rhythm disorders and other related diseases.

Disclosure of Invention

Methods of inhibiting CK1 δ and/or CK1 epsilon and methods and compositions for treating related diseases and/or disorders are provided.

In one aspect, the present application provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula I:

wherein Ar is ¹ Is optionally substituted with one or more (e.g., 1 to 2 or more than 2) R ₁ Aryl substituted with a substituent, and R ₁ Each independently selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethyl, perfluoroalkoxy, hydroxyl, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxide, wherein the substituent on the sulfur atom is alkyl, sulfonamide,

<xnotran> (hydrido) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , N- N, N- , </xnotran>

Wherein the substituents on the amino hydrocarbyl nitrogen atom are selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen forms, with the two substituents attached thereto, a 5-to 8-membered heterocyclyl or heteroaryl ring group,

amino and N-monosubstituted or N, N-disubstituted amino,

wherein the substituents on the amino nitrogen are selected from the group consisting of: hydride ions, alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, hydrocarbonyl, arylsulphonyl, and alkylsulfonyl, or wherein the amino nitrogen forms a 5-to 8-membered heterocyclyl or heteroaryl ring with the two substituents attached thereto;

wherein X ₁ 、X ₂ And X ₃ Each independently is C or N;

R ₇ is absent or is-CN;

a is absent and is

Or a ring A, or a ring B,

wherein R is ₂ is-NH ₂ -CN or Z, in the presence of a catalyst,

wherein Z is independently selected from the group consisting of: hydride ions, hydrocarbyl groups, halogens, carboxyl groups, cyano groups, azido groups, hydrocarbyl sulfonyl groups, carbonyloxyhydrocarbyl groups, carbonylamido groups, and-X-Y,

wherein-X is-O, -S or-NQ,

y is a hydride ion, a hydrocarbyl or a hydrocarbyl aryl,

q is a hydride ion, hydrocarbyl, hydroxyhydrocarbyl, 2-, 3-, or 4-pyridylalkyl or arylalkyl,

wherein R is ₃ Is a halogen or a-CN group,

wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group in which up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and optionally said ring A is substituted by R ₄ Is substituted by a substituent, and R ₄ Is = O;

b is absent and is

Or a ring (B) of a cyclic structure,

wherein R is ₅ Independently selected from the group consisting of: -COO-C ₁ -C ₆ Alkyl, -CO-R ₁₀ And R ₅₂ ，

Wherein R is ₁₀ Is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said R ₁₀ Optionally via R ₈ Substituent group(s), said R ₈ The substituent being C ₁ -C ₆ An alkyl group, a carboxyl group,

wherein R is ₅₂ Independently selected from the group consisting of: azido, hydride ions, alkyl, amide, haloalkyl, perhaloalkyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl substituted with one or more substituents selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , - , , - , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , - , , </xnotran>Sulfonylamino, heterocycloalkylsulfonylamino and N-monosubstituted or N, N-disubstituted aminoalkyl,

wherein the substituents on the amino hydrocarbyl nitrogen are selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen forms, with the two substituents attached thereto, a 5-to 8-membered heterocyclyl or heteroaryl ring group,

wherein R is ₆ Is C ₁ -C ₆ Alkyl or R ₆₁ ，

Wherein R is ₆₁ Independently selected from the group consisting of: an azido group, a hydride ion, a hydrocarbyl group, an amido group, a hydrocarbylamino group, a halohydrocarbyl group, a perhalohydrocarbyl group, and an aryl substituent optionally substituted with one or more substituents selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , </xnotran>Amino, heterocycloalkylsulfonylamino and N-monosubstituted or N, N-disubstituted aminoalkyl,

wherein the substituents on the amino hydrocarbyl nitrogen atom are selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl and hydrocarbonacyl radicals, or wherein the aminoalkyl nitrogen forms, with the two substituents attached thereto, a 5-to 8-membered heterocyclyl or heteroaryl ring radical,

wherein ring B is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring B is optionally substituted by R ₉ Is substituted by a substituent, and the R ₉ Is PMB.

In some embodiments, in the compounds of formula I, R ₁ Is F.

In some embodiments, the compound of formula I comprises said one R ₁ And (4) a substituent.

In some embodiments, in the compounds of formula I, R ₃ Is F or-CN.

In some embodiments, in the compounds of formula I, a is one of the following:

in some embodiments, in the compounds of formula I, R ₅ is-COO-CH ₂ CH ₃ or-CO-R ₁₀ 。

In some embodiments, in the compounds of formula I, R ₁₀ Is composed of

In some embodiments, in the compounds of formula I, R ₈ is-CH ₃ 。

In some embodiments, in the compounds of formula I, R ₆ is-CH ₃ 。

In some embodiments, in the compound of formula I, B is one of the following:

in some embodiments, the compound of formula I is selected from the group consisting of:

in some embodiments, in the compounds of formula I, X ₁ Is C, X ₂ Is C, X ₃ Is N, R ₇ Is absent, A is

And B is

Wherein R is ₂ Is Z, Z is-NR ₂₃ R ₂₄ ，

R ₂₃ Is hydride ion or C ₁ -C ₆ A hydrocarbon group, R ₂₄ Independently selected from the group consisting of: hydride ion, lower alkyl, aryl lower alkyl, hydroxy lower alkyl and2-pyridyl lower alkyl group, 3-pyridyl lower alkyl group and 4-pyridyl lower alkyl group,

Ar ¹ is aryl substituted by halogen or halogeno, lower alkyl or alkoxy,

R ₆ is R ₆₁ ，R ₆₁ Is hydride ion or C ₁ -C ₆ A hydrocarbon group, and

R ₅ is R ₅₂ ，R ₅₂ Is a hydride ion or a lower alkyl group.

In some embodiments, in the compound of formula I, X ₁ Is C, X ₂ Is C, X ₃ Is N, R ₇ Is absent, A is

And B is

Wherein R is ₂ Is Z, Z is-OR ₂₅ ，

R ₂₅ Is a hydride ion, C ₁ -C ₆ An alkyl or aryl lower alkyl group,

Ar ¹ aryl independently substituted with halogen, lower alkyl or alkoxy,

R ₆ is R ₆₁ ，R ₆₁ Is C ₁ -C ₆ A hydrocarbon group,

R ₅ is R ₅₂ ，R ₅₂ Is a hydride ion.

And B is

Wherein R is ₂ Is a group of-CN which is,

Ar ¹ aryl substituted by halogen, lower alkyl or alkoxy,

R ₆ is R ₆₁ ，R ₆₁ Is a lower alkyl group, and

R ₅ is R ₅₂ ，R ₅₂ Is a hydride ion or a lower alkyl group.

In another aspect, the present application provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula II:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

X ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₅ and X ₆ Each independently being C or N, and,

R ₂ is absent or is = O,

R ₃ is absent or is a-CN group,

a is absent and is

Or a ring (A) of the cyclic structure,

wherein R is ₄ Is a halogen, and the halogen is a halogen,

wherein R is ₅ Selected from the group consisting of: -NH ₂ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-OH and C ₁ -C ₆ alkyl-O-CO-C ₁ -C ₆ An alkyl group, a carboxyl group,

wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group in which up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and optionally said ring A is substituted by R ₆ Substituent(s) substituted, R ₆ Is set as the ratio of (n = O),

b is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said B is optionally substituted by one or more R ₇ Is substituted by a substituent group, and

wherein R is ₇ Each independently selected from the group consisting of: CO-C ₁ -C ₆ Alkyl, bn, = O, C ₁ -C ₆ Alkyl, CO-NH-C ₁ -C ₆ Alkyl, CO-C ₁ -C ₆ alkyl-CN, R ₈ 、R ₈ -C ₁ -C ₆ Alkyl and CO-R ₈ -C ₁ -C ₆ Alkyl radical, wherein R ₈ Is a 4 to 7 membered cycloalkyl or heterocycloalkyl or 5 to 6 membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-.

In some embodiments, in the compound of formula II, R ₁ Is F.

In some embodiments, in the compound of formula II, n is 1.

In some embodiments, in the compound of formula II, n is 2.

In some embodiments, in the compound of formula II, R ₄ Is F.

In some embodiments, in the compound of formula II, R ₅ Selected from the group consisting of: -NH ₂ 、-CH ₃ 、-CH ₂ -NH-CH ₃ 、-CH ₂ -OH and-CH ₂ -O-CO-CH ₃ 。

In some embodiments, in the compound of formula II, a is selected from the group consisting of:

in some embodiments, in the compound of formula II, R ₇ Selected from the group consisting of: -Bn, = O, -CH ₃ 、-CO-CH ₃ 、-CO-CH ₂ -CH ₃ 、-CO-CH-(CH ₃ ) ₂ 、-CO-NH-CH ₃ 、-CO-CH ₂ -CN、R ₈ 、R ₈ -CH ₃ and-CO-R ₈ -CH ₃ Wherein R is ₈ Is composed of

In some embodiments, in the compound of formula II, R ₇ The number of (2) is 1 or 2.

In some embodiments, in the compound of formula II, B is selected from the group consisting of:

in some embodiments, the compound of formula II is selected from the group consisting of:

in another aspect, the present application also provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula III:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

X ₁ and X ₂ Each independently being C or N, and,

a is absent and is

Or a ring A, or a ring B,

wherein R is ₂ Is C ₁ -C ₆ An alkyl group, which is a radical of an alkyl group,

ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring C is optionally substituted by R ₃ Substituent group, R ₃ Is the range of = O,

c is

Or a ring C, or a ring of the formula,

wherein R is ₄ is-CN, -COO-C ₁ -C ₆ An alkyl group or an amide group,

R ₅ is C ₁ -C ₆ Alkyl radical, and

ring C is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring C is optionally substituted by R ₆ Substituent group, R ₆ Is = O.

In some embodiments, in the compound of formula III, R ₁ Is F.

In some embodiments, in the compound of formula III, n is 1.

In some embodiments, in the compound of formula III, R ₂ is-CH ₃ 。

In some embodiments, in the compound of formula III, a is

In some embodiments, in the compound of formula III, R ₄ is-CN, -CO-NH ₂ or-COO-CH ₃ 。

In some embodiments, in the compound of formula III, R ₅ is-CH ₃ 。

In some embodiments, in the compound of formula III, C is selected from the group consisting of:

in some embodiments, the compound of formula III is selected from the group consisting of:

in another aspect, the present application provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula IV:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

R ₂ is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said R ₂ Is optionally via R ₃ Substituent group(s), and R ₃ Is = O.

In some embodiments, in the compound of formula IV, R ₁ Is F.

In some embodiments, in the compound of formula IV, n is 1.

In some embodiments, in the compound of formula IV, R ₂ Is composed of

In some embodiments, the compound of formula IV is selected from the group consisting of:

in some embodiments, the method is an in vitro method, an ex vivo method, or an in vivo method.

In another aspect, the present application also provides a method of treating a neurological and/or psychiatric disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of formulae I to IV, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or condition is a mood disorder, a sleep disorder, or a circadian rhythm disorder.

In some embodiments, the mood disorder is selected from the group consisting of: depression and bipolar disorder.

In some embodiments, in the methods of the present application, a compound selected from the group consisting of:

4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-2H-indazol-3-yl) pyrimidin-2-amine,

4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3,4-b ] pyridin-5 (7H) -one,

4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3,4-b ] pyridin-7 (5H) -one,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydro-2H-indazole,

4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -2,4,5, 6-tetrahydrocyclopenta [ c ] pyrazole,

2- (4-fluorophenyl) -5- (4-methoxybenzyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridine,

3-fluoro-4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridinecarbonitrile,

4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine-2, 3-dicarbonitrile,

4- (1- (4-fluorophenyl) -1H-1,2, 3-triazol-5-yl) pyridine,

1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester,

(1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-1,2, 3-triazol-4-yl) (4-methylpiperazin-1-yl) methanone,

1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile,

4- (2- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-3-yl) pyrimidin-2-amine,

4- (2- (4-fluorophenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyrimidin-2-amine,

4- (2- (4-fluorophenyl) -7- (1-methylpiperidin-4-yl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyrimidin-2-amine,

1- (3- (2-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-7-yl) ethan-1-one,

2- (4-fluorophenyl) -3- (pyridin-4-yl) imidazo [1,2-a ] pyrazine,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine,

1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) ethan-1-one,

4- (2- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-3-yl) furo [3,4-b ] pyridin-5 (7H) -one,

4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyrimidin-2-amine,

4- (2- (4-fluorophenyl) -5- (1-methylpiperidin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyrimidin-2-amine,

1- (3- (2-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

5-benzyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine,

1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-amine,

2- (4-fluorophenyl) -1- (pyridin-4-yl) -4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole,

1- (2- (4-fluorophenyl) -3- (2- ((methylamino) methyl) pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-5-yl) ethan-1-one,

1- (2- (4-fluorophenyl) -3- (2- (hydroxymethyl) pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-5-yl) ethan-1-one,

(4- (2- (4-fluorophenyl) -5- (piperazin-1-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) methanol,

1- (2- (4-fluorophenyl) -3- (pyrimidin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-5-yl) ethan-1-one,

1- (2- (4-fluorophenyl) -3- (pyridazin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

1- (2- (3, 4-difluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

(R) -1- (2- (4-fluorophenyl) -7-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazin-5-one,

2- (4-fluorophenyl) -5-methyl-3- (pyridin-4-yl) -4, 5-dihydropyrazolo [1,5-a ] pyrazin-6 (7H) -one,

2-acetyl-7- (4-fluorophenyl) -8- (pyridin-4-yl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrazine-6-carbonitrile,

1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) propan-1-one,

1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) -2-methylpropan-1-one,

1- (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines,

4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methylpyridine-1-oxide,

(4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) acetic acid methyl ester,

(2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone,

2- (4-fluorophenyl) -N-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxamide,

3- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) -3-oxopropanenitrile,

1- (2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one,

3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile,

3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide,

8- (4-fluorophenyl) -7- (pyridin-4-yl) -3, 4-dihydropyrrolo [1,2-a ] pyrazin-1 (2H) -one,

3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid methyl ester,

3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid methyl ester,

2- (4-fluorophenyl) -4-methyl-1- (5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-4-yl) -1H-pyrrole-3-carbonitrile,

3- (4-fluorophenyl) -1-methyl-4- (5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-4-yl) -1H-pyrrole-2-carbonitrile,

2- (4-fluorophenyl) -4-methyl-1- (pyridin-4-yl) -1H-pyrrole-3-carbonitrile,

2- (4-fluorophenyl) -4-methyl-1- (2-methylpyridin-4-yl) -1H-pyrrole-3-carboxamide,

3- (4-fluorophenyl) -2- (2-methylpyridin-4-yl) -2,5,6, 7-tetrahydro-4H-pyrrolo [3,4-c ] pyridin-4-one,

(R) -5- (3- (4-fluorophenyl) -4- (pyridin-4-yl) isoxazol-5-yl) dihydrofuran-2 (3H) -one, and

(R) -4- (3- (4-fluorophenyl) -4- (pyridin-4-yl) isoxazol-5-yl) dihydrofuran-2 (3H) -one.

Other aspects and advantages of the present application will be readily apparent to those skilled in the art from the following detailed description. Only illustrative embodiments of the present application have been shown and described in the following detailed description. As will be realized, the application is capable of other and different embodiments and its several details are capable of modifications in various obvious respects, all without departing from the application. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present application will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "figures"), of which:

FIG. 1 illustrates the synthetic scheme for compound 2-1.

FIG. 2 illustrates the synthetic scheme for compounds 3-8.

FIG. 3 illustrates the synthetic schemes for compounds 2-5, 2-6, 2-7 and 2-8.

FIG. 4 illustrates the synthetic scheme for compounds 1-2.

FIG. 5 illustrates the synthetic scheme for compounds 2-12, 2-13 and 2-14.

FIG. 6 illustrates the synthetic scheme for compounds 1-4.

FIG. 7 illustrates the synthetic scheme for compounds 2-16.

FIG. 8 illustrates the synthetic scheme for compounds 3-4, 3-5, 3-2 and 3-1.

FIG. 9 illustrates the synthetic scheme for compounds 1-10.

FIG. 10 illustrates the synthetic scheme for compounds 3-7.

FIG. 11 illustrates the synthetic scheme for compounds 2-27.

FIG. 12 illustrates the synthetic scheme for compounds 2-28.

FIG. 13 illustrates the synthetic scheme for compounds 2-29 and 2-31.

FIG. 14 illustrates the synthetic scheme for compounds 2-30.

FIG. 15 illustrates the synthetic scheme for compounds 2-33.

FIG. 16 illustrates the synthetic scheme for compounds 2-34.

FIG. 17 illustrates the synthetic scheme for compounds 2-32.

FIG. 18 illustrates the synthetic scheme for compounds 2-36.

FIG. 19 illustrates the synthetic scheme for compounds 1-5.

FIG. 20 illustrates a synthetic scheme for compounds 1-13.

FIGS. 21-24 illustrate synthetic schemes for compounds 2-37 through 2-40.

FIG. 25 illustrates the synthetic scheme for compounds 3-11.

FIG. 26 illustrates the synthetic scheme for compounds 2-41.

FIG. 27 illustrates the synthetic scheme for compounds 3-12.

FIGS. 28-29 illustrate synthetic schemes for compounds 2-42 through 2-43.

FIG. 30 illustrates the synthetic scheme for compounds 3-13.

FIGS. 31-36 illustrate synthetic schemes for compounds 2-44 through 2-49.

FIG. 37 illustrates the synthetic scheme for compounds 3-14.

FIGS. 38-49 illustrate synthetic schemes for compounds 2-50 through 2-61.

Detailed Description

While various embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

Definition of

As used herein, the term "alkyl" generally refers to a straight or branched chain saturated hydrocarbon substituent containing from 1 to 20 carbon atoms (i.e., a substituent resulting from the removal of hydrogen from a hydrocarbon); for example, containing 1 to 12 carbon atoms; in another example, from 1 to 10 carbon atoms; in another embodiment, from 1 to 6 carbon atoms; and in another embodiment, from 1 to 4 carbon atoms (such as, 1,2,3, or more than 3 carbon atoms). Examples of such substituents include, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, iso-propyl)Butyl, sec-butyl, and tert-butyl), pentyl, isopentyl, hexyl, and the like. In some instances, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) is prefixed by the "C _a -C _b "means where a is the minimum number of carbon atoms in the substituent and b is the maximum number. Thus, for example, "C ₁ -C ₆ Alkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms. For example, alkyl groups may be optionally further substituted.

As used herein, the term "cycloalkyl" generally refers to a carbocyclic substituent having from 3 to 14 carbon atoms resulting from the removal of a hydrogen from a saturated carbocyclic ring molecule. In one embodiment, the cycloalkyl substituent has 3 to 10 carbon atoms. Cycloalkyl groups may be monocyclic, typically containing from 4 to 7 ring atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, cycloalkyl groups may be 2 or 3 rings fused together, such as bicyclo [4.2.0] octane and decahydronaphthyl, and may also be referred to as "bicycloalkyl". For example, cycloalkyl groups may be optionally further substituted.

The term "cycloalkyl" as used herein also includes alkyl groups with C ₆ -C ₁₀ An aromatic ring or a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bonded to a carbon atom of the cycloalkyl group. When such fused cycloalkyl is substituted with one or more substituents, each of the one or more substituents is bonded to a carbon atom of the cycloalkyl unless otherwise specified. Condensed C ₆ -C ₁₀ The aryl or 5-to 10-membered heteroaryl ring may optionally be further substituted. For example, cycloalkyl groups may be optionally further substituted.

As used herein, the term "halogen" generally refers to fluorine (which may be represented by-F), chlorine (which may be represented by-Cl), bromine (which may be represented by-Br), or iodine (which may be represented by-I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.

As used herein, the term "heterocycloalkyl" generally refers to a substituent resulting from the removal of a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms, at least one of which is a heteroatom (e.g., a non-C atom), such as oxygen, nitrogen, or sulfur. For example, as used herein, the term "4-to 7-membered heterocycloalkyl" refers to a substituent that is a monocyclic ring having a total of 4 to 7 members. Alternatively, the heterocycloalkyl group can comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In a group having a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent to which the group is bound can be the at least one heteroatom, or can be a ring carbon atom, where the ring carbon atom can be in the same ring as the at least one heteroatom or where the ring carbon atom can be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, that group or substituent may be bound to the at least one heteroatom, or may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. For example, heterocycloalkyl can be optionally further substituted.

As used herein, the term "heterocycloalkyl" also includes alkyl groups with C _6-10 An aromatic ring or a 5-to 10-membered heteroaromatic ring fused substituent, wherein a group having such a fused heterocycloalkyl group as a substituent is bonded to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one or more substituents, each of the one or more substituents is bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group, unless otherwise specified. Condensed C ₆ -C ₁₀ The aromatic ring or 5-to 10-membered heteroaromatic ring may optionally be further substituted. For example, heterocycloalkyl can be optionally further substituted.

As used herein, the term "heteroaryl" generally refers to an aromatic ring structure containing 5 to 14 ring atoms, wherein at least one ring atom is a heteroatom (e.g., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of: carbon, oxygen, nitrogen and sulfur. Heteroaryl groups can be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include (but are not limited to): 6-membered ring substituents such as pyridyl, pyrazolyl, pyrimidinyl and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuryl, benzisoxazolyl, benzoxazolyl, purinyl and anthranoylyl; and 6/6-membered fused ring substituents such as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl and 1, 4-benzoxazinyl. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent bound to the group can be the at least one heteroatom or can be a ring carbon atom, where the ring carbon atom can be in the same ring as the at least one heteroatom or where the ring carbon atom can be in a different ring from the at least one heteroatom. Similarly, if a heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. For example, heteroaryl groups may be optionally further substituted.

The term "heteroaryl" as used herein also includes a heteroaryl group linked to a linker such as C ₅ Or C ₆ Carbocyclic ring of C _4-10 A substituent fused to a carbocyclic ring or fused to a 4-to 10-membered heterocyclic ring, such as pyridyl and quinolyl, wherein a group having the fused heteroaryl group as a substituent is bonded to a hetero atom of an aromatic carbon or a heteroaryl group of the heteroaryl group. When such a fused heteroaryl group is substituted with one or more substituents, each of the one or more substituents is bound to an aromatic carbon of the heteroaryl group or a heteroatom of the heteroaryl group, unless otherwise specified. Condensed C _4-10 The carbocycle or 4-to 10-membered heterocycle may optionally be further substituted. For example, heteroaryl groups may be optionally further substituted.

As used herein, the term "aryl" generally refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have 6 to 18 carbon atoms. For example, an aryl substituent mayHaving 6 to 14 carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl, and anthracenyl. The term "aryl" may also include aryl radicals such as C ₅ Or C ₆ Carbocyclic ring of C _4-10 A substituent fused to a carbocyclic ring or fused to a 4-to 10-membered heterocyclic ring, such as phenyl, naphthyl and anthracenyl, wherein a group having the fused aryl group as a substituent is bonded to the aromatic carbon of the aryl group. When such a fused aryl group is substituted with one or more substituents, each of the one or more substituents is bonded to an aromatic carbon of the fused aryl group, unless otherwise specified. Condensed C _4-10 The carbocycle or 4-to 10-membered heterocycle may optionally be further substituted. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl (also known as "1,2,3, 4-tetrahydronaphthyl"), indenyl, isoindolyl, indanyl, anthracyl, phenanthryl, benzonaphthylmethylene (also known as "sulfophenyl"), and fluorenyl, respectively. For example, aryl groups may be optionally further substituted.

In some cases, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is represented by the prefix "X to Y membered," where X is the minimum number of atoms forming the cyclic portion of the substituent and Y is the maximum number. Thus, for example, a 5-to 8-membered heterocycloalkyl group refers to a heterocycloalkyl group containing from 5 to 8 atoms (including one or more heteroatoms) in the cyclic moiety of the heterocycloalkyl group.

As used herein, the term "hydrogen" generally refers to a hydrogen substituent, and may be represented as — H.

As used herein, the term "hydroxy" generally refers to — OH. When used in combination with another term, the prefix "hydroxy" generally refers to the substituent to which the prefix is attached being substituted with one or more hydroxy substituents. Compounds with carbons attached to one or more hydroxyl substituents include, for example, alcohols, enols, and phenols. For example, the hydroxyl group may be optionally further substituted.

As used herein, the term "cyano" (also referred to as "nitrile") generally refers to — CN.

A substituent is "substitutable" or "substitutable" if it comprises at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano are not within this definition.

If a substituent is described as "substituted," a non-hydrogen substituent replaces a hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl substituent. To illustrate, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. It will be appreciated that if there is more than one substitution on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).

As used herein, the terms "substituent", "group" and "group" are used interchangeably.

If a substituent is described as "optionally substituted," that substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of a series of substituents, then one or more hydrogens on that carbon may be replaced (as much as possible) individually and/or together with an independently selected optional substituent. If a substituent nitrogen is described as optionally substituted with one or more of a range of substituents, then one or more hydrogens on that nitrogen may each be replaced (as far as possible) with an independently selected optional substituent. One exemplary substituent may be described as-NR 'R ", wherein R' and R", together with the nitrogen atom to which they are attached, may form a heterocyclic ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the heterocycloalkyl moiety may be optionally substituted. The heterocyclic ring formed by R' and R ", together with the nitrogen atom to which they are attached, may be partially or fully saturated, or aromatic. In one embodiment, the heterocyclic ring consists of 4 to 10 atoms.

If a substituent is described as "independently selected from" a group, the choice of each substituent is independent of the other substituent(s). Thus, each substituent may be the same or different from another (other) substituent.

As used herein, the term "formula I" (or formula II, formula III, or formula IV) may be referred to hereinafter as "a compound of the invention. These terms are also defined to include all forms of the compounds of formula I (or formula II, formula III, or formula IV), including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomers, polymorphs, and metabolites thereof. For example, a compound of formula I or a pharmaceutically acceptable salt thereof may exist in unsolvated as well as solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, independent of humidity. However, when the solvent or water binding is weak, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on the humidity and drying conditions. Under these circumstances, the nonstoichiometry will become normal.

The compounds of "formula I" (or formula II, formula III or formula IV) may have asymmetric carbon atoms. The carbon-carbon bond of the compounds of formula I may be represented herein by a solid, solid or dashed wedge. The use of a solid line to indicate a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers (e.g., specifically enantiomers, racemic mixtures, etc.) of that carbon atom are included. The use of solid or dashed wedges to indicate bonds to asymmetric carbon atoms is meant to indicate that only the indicated stereoisomers are intended to be included. The compounds of the present application may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to indicate a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers are intended to be included. For example, unless otherwise specified, it is intended that the compounds of formula I (or formula II, formula III or formula IV) may exist in the form of their enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to indicate a bond to one or more asymmetric carbon atoms in a compound of formula I (or formula II, formula III or formula IV) and the use of a solid wedge or dashed wedge to indicate a bond to other asymmetric carbon atoms in the same compound means that a mixture of diastereomers is present.

The compounds of the present application (e.g., compounds of formula I, formula II, formula III, formula IV, formula V, or formula VI) can be present in the form of clathrates or other complexes. Included within the scope of the invention are complexes, such as inclusion complexes, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the aforementioned solvates. Also included are composites of formula I (or formula II, formula III or formula IV) containing two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of these complexes, reference is made to j.pharm.sci.,64 (8), pp 1269-1288 (1975, 8) of Haleblian.

Stereoisomers of formula I (or formula II, formula III or formula IV) include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers and tautomers of compounds of formula I (or formula II, formula III or formula IV), including compounds that exhibit more than one isomeric type; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition salts and base addition salts in which the counterion is optically active, for example D-lactate or L-lysine, or racemic, for example DL-tartrate or DL-arginine.

When any racemate crystallizes, two different types of crystals may form. The first type is the racemic compound mentioned above (true racemate), in which a crystal containing equimolar amounts of the two enantiomers in a homogeneous form is produced. The second type is a racemic mixture or aggregate, in which equimolar amounts of the two forms of the crystal, each containing a single enantiomer, are produced.

Compounds of formula I (or formula II, formula III or formula IV) may exhibit tautomerism and structural isomerism. For example, the compounds of formula I may exist in several tautomeric forms, including enol and imine forms, ketone and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of formula I (or formula II, formula III or formula IV). Tautomers exist as mixtures of tautomeric sets in solution. In solid form, usually one tautomer predominates. Although one tautomer may be described, this application includes all tautomers of compounds of formula I (or formula II, formula III, or formula IV).

The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I (or formula II, formula III, or formula IV) above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of formula I (or formula II, formula III or formula IV) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Certain isotopically-labeled compounds of formula I (or formula II, formula III or formula IV), for example, are incorporated into ³ H and ¹⁴ c, and the like, suitable for drug and/or substrate tissue distribution determination. Tritiated (i.e. by tritiation) ³ H) And carbon-14 (i.e. ¹⁴ C) Isotopes are used for their ease of preparation and detectability. In addition, via heavier isotopes (e.g. deuterium, i.e. deuterium) ² H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be useful in certain situations. Isotopically labeled compounds of formula I (or formula II, formula III, or formula IV) can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced drug stability at different temperatures and humidities, or advantageous solubility in water or oil. In some cases, salts of compounds are also used as aids in the isolation, purification and/or resolution of compounds.

The term "treating" as used herein generally means, unless otherwise indicated, reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition. The term "treatment" as used herein generally refers to the therapeutic action of "treating" as defined above, unless otherwise indicated. The term "treatment" may also include both adjuvant and neoadjuvant treatment of a subject.

Where the salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro environment), the salt may be pharmaceutically acceptable. The term "pharmaceutically acceptable salt" generally refers to a salt prepared by combining a compound of the present application (e.g., a compound of any of formulas I through IV) with an acid or a base, the anion of which is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly suitable as products of the methods of the present application due to their greater aqueous solubility relative to the parent compound. For medical use, salts of the compounds of the present application are non-toxic "pharmaceutically acceptable salts". Salts encompassed within the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present application that are typically prepared by reacting the free base with a suitable organic or inorganic acid.

The compounds of the present application are typically administered in an amount effective to treat the conditions described herein. The compounds of the invention are administered by any suitable route, in the form of pharmaceutical compositions adapted to that route, and in dosages that are effective for the intended treatment. The therapeutically effective dose of the compound required to treat the progression of a medical condition can be readily determined by one of ordinary skill in the art using preclinical and clinical methods well known in the medical arts. The term "therapeutically effective amount" as used herein generally refers to an amount of a compound administered that is capable of relieving, to some extent, one or more symptoms of the disorder being treated.

Use and method

The present application provides a method of inhibiting CK1 δ or CK1 ∈ activity. The method may comprise administering an effective amount of a compound of formula I:

wherein Ar is ¹ Can optionally be optionally substituted with one or more (e.g., 1 to 2 or more than 2) R ₁ Aryl substituted with a substituent, and R ₁ May each be independently selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoralkyl, trifluoromethyl alkyl, perfluoralkoxy, hydroxyl, sulfydryl, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxide, wherein the substituent on the sulfur atom can be alkyl, sulfonamide,

Wherein the substituent on the amino hydrocarbyl nitrogen atom may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl and hydrocarbonacyl radicals, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring radical,

amino and N-monosubstituted or N, N-disubstituted amino,

wherein the substituents on the amino nitrogen may be selected from the group consisting of: hydride ions, alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl, hydrocarboyl, arylsulfonyl and alkylsulfonyl groups, or wherein the amino nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring group;

wherein X ₁ 、X ₂ And X ₃ May each independently be C or N;

R ₇ may be absent or-CN;

a may be absent, is

Or a ring A, or a ring B,

wherein R is ₂ Can be-NH ₂ -CN or Z, in the presence of a catalyst,

wherein Z may be independently selected from the group consisting of: hydride ions, hydrocarbyl groups, halogens, carboxyl groups, cyano groups, azido groups, hydrocarbyl sulfonyl groups, carbonyloxyhydrocarbyl groups, carbonylamido groups, and-X-Y,

wherein-X can be-O, -S or-NQ,

y can be a hydride ion, a hydrocarbyl or a hydrocarbyl aryl,

Q can be a hydride ion, hydrocarbyl, hydroxyhydrocarbyl, 2-, 3-, or 4-pyridylalkyl or arylalkyl,

wherein R is ₃ Can be a halogen or a-CN group,

wherein ring A may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said ring A may optionally be substituted by R ₄ Substituent group(s), and R ₄ May be = O;

b may be absent and is

Or a ring B,

wherein R is ₅ May be independently selected from the group consisting of: -COO-C ₁ -C ₆ Alkyl, -CO-R ₁₀ And R ₅₂ ，

Wherein R is ₁₀ Can be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms can be replaced by a heteroatom selected from = N-and-O-, and said R ₁₀ Optionally via R ₈ Substituent group(s), said R ₈ The substituent may be C ₁ -C ₆ An alkyl group, a carboxyl group,

wherein R is ₅₂ May be independently selected from the group consisting of: azido, hydride ion, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl that may be substituted with one or more substituents selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , - , , - , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , - , , , N- N, N- </xnotran>A substituted amino hydrocarbon group,

wherein the substituent on the amino hydrocarbyl nitrogen may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring group,

wherein R is ₆ Can be C ₁ -C ₆ Alkyl or R ₆₁ ，

Wherein R is ₆₁ May be independently selected from the group consisting of: (ii) an azido group, a hydride ion, a hydrocarbyl group, an amido group, a hydrocarbylamino group, a halohydrocarbyl group, a perhalohydrocarbyl group, and an aryl substituent which may be optionally substituted with one or more substituents selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , N- N, </xnotran>An N-disubstituted amino hydrocarbon group, wherein,

wherein the substituent on the nitrogen atom of the amino hydrocarbyl group may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl and hydrocarbonacyl radicals, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring radical,

wherein ring B may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and optionally said ring B may be substituted by R ₉ Is substituted by a substituent, and the R ₉ May be a PMB.

In some cases, the compound of formula I may comprise a compound of formula Ia:

wherein R is ₁ May each be independently selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethyl, perfluoroalkoxy, hydroxyl, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxy, wherein the substituents on the sulfur atom may be alkyl, sulfonamide,

Wherein the substituent on the nitrogen atom of the amino hydrocarbyl group may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring group,

amino and N-monosubstituted or N, N-disubstituted amino,

wherein X ₁ 、X ₂ And X ₃ May each independently be C or N;

R ₇ may be absent or-CN;

a may be absent and is

Or a ring (A) of the cyclic structure,

wherein R is ₂ Can be-NH ₂ -CN or Z, in the presence of a catalyst,

wherein-X can be-O, -S or-NQ,

y can be a hydride ion, a hydrocarbyl or a hydrocarbyl aryl,

wherein R is ₃ Can be a halogen or a-CN group,

wherein ring A can be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms can be replaced by a heteroatom selected from = N-and-O-, and said ring A can optionally be substituted with R ₄ Is substituted by a substituent, and R ₄ May be = O;

b may be absent and is

Or a ring (B) of a cyclic structure,

Wherein R is ₁₀ May be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said R ₁₀ Optionally via R ₈ Substituted by a substituent, said R ₈ The substituent may be C ₁ -C ₆ An alkyl group, a carboxyl group,

wherein R is ₅₂ May be independently selected from the group consisting of: azido, hydride ions, alkyl, amide, haloalkyl, perhaloalkyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl that may be substituted with one or more substituents selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino arylalkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyl, alkoxycarbonyl-alkyl, heterocyclooxy, hydroxycarbonyl-alkyl heterocyclylthio, heterocyclylamino, cyclohydrocarbyloxy, cycloalkylthio, cycloalkylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylalkyloxy, arylhydrocarbylthio, arylalkylamino, heterocyclyl, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbonyl, arylcarbonylArylhydrocarbylacyl, hydrocarbylacyloxy, arylhydrocarbylacyloxy, hydroxyalkyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxythio, hydrocarbyloxycarbonyl, hydroxycarbonyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylalkylthio, hydrocarbyloxycarbonylhydrocarbyloxyoxy, hydrocarbyloxycarbonylhydroylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, heterocycloalkoxy, alkylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, heteroaryl-sulphonylamino, heteroarylalkylsulphonylamino, cycloalkylsulphonylamino and N-mono-or N, N-disubstituted aminoalkyl,

wherein the substituent on the amino hydrocarbyl nitrogen may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl and hydrocarbonacyl radicals, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring radical,

wherein R is ₆ Can be C ₁ -C ₆ Alkyl or R ₆₁ ，

Wherein R is ₆₁ May be independently selected from the group consisting of: (ii) an azido group, a hydride ion, a hydrocarbyl group, an amido group, a hydrocarbylamino group, a halohydrocarbyl group, a perhalohydrocarbyl group, and an aryl substituent which may be optionally substituted with one or more substituents selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino arylalkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyl, alkoxycarbonylalkyl, heterocyclooxy, hydroxycarbonylalkyl heterocyclylthio, heterocyclylamino, cyclohydrocarbyloxy, cycloalkylthio, cycloalkylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylalkyloxy, arylhydrocarbylthio, arylalkylamino, heterocyclyl, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbonyl, arylcarbonylAlkylcarbonyl, arylhydrocarbylacyl, hydrocarbylacyloxy, arylhydrocarbylacyloxy, hydroxyalkyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyalkylylthio, hydrocarbyloxycarbonyl, hydroxycarbonyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylalkylthio, hydrocarbyloxycarbonylhydroyloxy, hydrocarbyloxycarbonylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbyloxy, heterocycloalkoxy, alkylsulphonylamino, arylsulfonylamino, arylalkylsulphonylamino, heteroarylsulphonylamino, heteroarylalkylsulphonylamino, cycloalkylsulphonylamino, heterocycloalkylsulphonylamino and N-monosubstituted or N, N-disubstituted aminoalkyl,

wherein the substituent on the amino hydrocarbyl nitrogen atom may be selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen and the two substituents attached thereto may form a 5-to 8-membered heterocyclyl or heteroaryl ring group,

wherein ring B can be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms can be replaced by a heteroatom selected from = N-and-O-, and said ring B can optionally be substituted with R ₉ Is substituted by a substituent, and the R ₉ May be a PMB.

In some cases, the compound of formula I may comprise a compound of formula Ia:

wherein R is ₁ May each independently be a halogen, and may,

n can be 0, 1 or 2,

X ₁ 、X ₂ and X ₃ May each independently be C or N;

R ₇ may be absent or be-CN,

a may be absent and is

Or a ring (A) of the cyclic structure,

R ₂ can be-NH ₂ Or a group of-CN groups,

R ₃ can be a halogen or a-CN group,

ring a may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said ring a may optionally be substituted by R ₄ Is substituted by a substituent, and R ₄ Is = O;

b may be absent and is

Or a ring (B) of a cyclic structure,

R ₅ may be independently selected from the group consisting of: -COO-C ₁ -C ₆ Alkyl and-CO-R ₁₀ ，

Wherein R is ₁₀ Can be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms can be replaced by a heteroatom selected from = N-and-O-, and said R ₁₀ Optionally via R ₈ Substituent group(s), said R ₈ The substituent may be C ₁ -C ₆ An alkyl group, which is a radical of an alkyl group,

wherein R is ₆ Can be C ₁ -C ₆ An alkyl group, a carboxyl group,

In some cases, in the compound of formula I or formula Ia, R ₁ May be F.

In some cases, in the compound of formula Ia, n may be 1.

In some cases, in the compound of formula I or formula Ia, R ₃ May be F or-CN.

In some cases, in the compound of formula I or formula Ia, a may be one of:

in some cases, in the compound of formula I or formula Ia, R ₅ Can be-COO-CH ₂ CH ₃ or-CO-R ₁₀ 。

In some cases, in the compound of formula I or formula Ia, R ₁₀ (may be)

In some cases, in the compound of formula I or formula Ia, R ₈ Can be-CH ₃ 。

In some cases, in the compound of formula I or formula Ia, R ₆ Can be-CH ₃ 。

In some cases, in the compound of formula I or formula Ia, B may be one of:

in some cases, the compound of formula I or formula Ia may be a compound in table 1.

TABLE 1 Compounds of formula I or formula Ia

In some cases, in the compounds of formula I, X ₁ Can be C, X ₂ Can be C, X ₃ Can be N, R ₇ May be absent, A may be

And B may be

Wherein R is ₂ Can be Z, Z can be-NR ₂₃ R ₂₄ ，

R ₂₃ Can be hydride ion or C ₁ -C ₆ A hydrocarbon group, R ₂₄ May be independently selected from the group consisting of: hydride ions, lower alkyl, aryl lower alkyl, hydroxy lower alkyl and 2-pyridyl lower alkyl, 3-pyridyl lower alkyl and 4-pyridyl lower alkyl;

Ar ¹ may be aryl which may be substituted by halogen or halo, lower alkyl or alkoxy;

R ₆ can be R ₆₁ ，R ₆₁ Can be hydride ion or C ₁ -C ₆ A hydrocarbyl group; and is

R ₅ Can be R ₅₂ ，R ₅₂ May be hydride ions or lower alkyl groups.

In some cases, in the compound of formula I, X ₁ Can be C, X ₂ Can be C, X ₃ Can be N, R ₇ May be absent, A may be

And B may be

Wherein R is ₂ Can be Z, Z can be-OR ₂₅ ，

R ₂₅ Can be hydride ion, C ₁ -C ₆ Alkyl or aryl lower alkyl;

Ar ¹ may be aryl which may be independently substituted with halogen, lower alkyl or alkoxy;

R ₆ can be R ₆₁ ，R ₆₁ Can be C ₁ -C ₆ A hydrocarbyl group; and is

R ₅ Can be R ₅₂ ，R ₅₂ May be a hydride ion.

And B can be

Wherein R is ₂ Can be-CN;

Ar ¹ may be aryl which may be substituted by halogen, lower alkyl or alkoxy;

R ₆ can be R ₆₁ ，R ₆₁ May be a lower alkyl group; and is

R ₅ Can be R ₅₂ ，R ₅₂ It may be a hydride ion or a lower alkyl group.

The compounds of formula I may also include any of the compounds described in WO 99/58523, which is incorporated herein by reference in its entirety.

The present application also provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula II:

wherein R is ₁ May be a halogen;

n can be 0, 1 or 2;

X ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₅ and X ₆ May each independently be C or N;

R ₂ may be absent or = O;

R ₃ may be absent or-CN;

a may be absent and is

Or a ring A, or a ring B,

wherein R is ₄ It may be a halogen, and it may be,

wherein R is ₅ May be selected from the group consisting of: -NH ₂ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-OH and C ₁ -C ₆ alkyl-O-CO-C ₁ -C ₆ An alkyl group, which is a radical of an alkyl group,

wherein ring A may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said ring A may optionally be substituted by R ₆ Substituent(s) substituted, R ₆ May be = O;

b may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said B may optionally be substituted by one or more R ₇ The substituent group is used for substitution,

wherein R is ₇ The substituents may each be independently selected from the group consisting of: CO-C ₁ -C ₆ Alkyl, bn, = O, C ₁ -C ₆ Alkyl, CO-NH-C ₁ -C ₆ Alkyl, CO-C ₁ -C ₆ alkyl-CN, R ₈ 、R ₈ -C ₁ -C ₆ Alkyl and CO-R ₈ -C ₁ -C ₆ Alkyl radical, wherein R ₈ Can be a 4 to 7 membered cycloalkyl or heterocycloalkyl or a 5 to 6 membered heteroaryl, wherein up to 2 carbon atoms can be replaced by a heteroatom selected from = N-and-O-.

In some cases, in the compound of formula II, R ₁ May be F.

In some cases, in the compound of formula II, n may be 1.

In some cases, in the compound of formula II, n may be 2.

In some cases, in the compound of formula II, R ₄ May be F.

In some cases, in the compound of formula II, R ₅ May be selected from the group consisting of: -NH ₂ 、-CH ₃ 、-CH ₂ -NH-CH ₃ 、-CH ₂ -OH and-CH ₂ -O-CO-CH ₃ 。

In some cases, in the compound of formula II, a may be selected from the group consisting of:

in some cases, in the compound of formula II, R ₇ May each be independently selected from the group consisting of: -Bn, = O, -CH ₃ 、-CO-CH ₃ 、-CO-CH ₂ -CH ₃ 、-CO-CH-(CH ₃ ) ₂ 、-CO-NH-CH ₃ 、-CO-CH ₂ -CN、R ₈ 、R ₈ -CH ₃ and-CO-R ₈ -CH ₃ Wherein R is ₈ (may be)

In some cases, in the compound of formula II, R ₇ The number of (c) may be 1 or 2.

In some cases, in the compound of formula II, B may be selected from the group consisting of:

in some cases, wherein the A may be

In some cases, wherein the A may be

In some cases, where X ₁ May be C.

In some cases, where X ₆ May be N.

In some cases, wherein the compound may have the structure:

in some cases, where R is ₁ Can be F, n can be 1,X ₁ And X ₃ Can be C, X ₂ And X ₆ Can be N, R ₂ And R ₃ May be absent, R _n1 And R _n2 May independently be optionally substituted, B may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said B may be optionally substituted.

In some cases, wherein R ₁ Can be F, n can be 1,X ₁ And X ₃ Can be C, X ₂ And X ₆ Can be N, R ₂ And R ₃ B may be absent, may be a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein up to 2 carbon atoms may be replaced by heteroatoms selected from = N-and-O-, and said B may be optionally substituted.

In some cases, wherein R ₁ Can be F, n can be 1,X ₁ And X ₃ Can be C, X ₂ And X ₆ Can be N, R ₂ And R ₃ May be absent, B may be selected from the group consisting of:

and said B may be optionally substituted.

In some cases, where R is ₁ Can be F, n can be 1,X ₁ And X ₃ Can be C, X ₂ And X ₆ Can be N, R ₂ And R ₃ May be absent, B may be

And said B may optionally be via C ₁ -C ₆ Alkyl or CO-C ₁ -C ₆ Alkyl substitution.

In some cases, the compound of formula II may be one of the compounds in tables 2-1 to 2-2.

TABLE 2-1 Compounds of formula II

TABLE 2-2 Compounds of formula II

The present application also provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula III:

wherein R is ₁ May be a halogen;

n can be 0, 1 or 2;

X ₁ and X ₂ May each independently be C or N;

a may be absent, is

Or ring A;

wherein R is ₂ Can be C ₁ -C ₆ An alkyl group, a carboxyl group,

ring a may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said ring C may optionally be substituted by R ₃ Substituent(s) substituted, R ₃ May be = O;

c can be

Or ring C;

wherein R is ₄ Can be-CN, -COO-C ₁ -C ₆ An alkyl group or an amide group,

R ₅ can be C ₁ -C ₆ Alkyl radical, and

ring C may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced by a heteroatom selected from = N-and-O-, and said ring C may optionally be replaced by R ₆ Substituent(s) substituted, R ₆ May be = O.

In some cases, in the compound of formula III, R ₁ May be F.

In some cases, in the compound of formula III, n may be 1.

In some cases, in the compound of formula III, R ₂ Can be-CH ₃ 。

In some cases, in the compound of formula III, wherein ring a may be a 5-membered heteroaryl.

In some cases, in the compound of formula III, wherein 2 carbon atoms of said a may be replaced with a heteroatom selected from = N-and-O-.

In some cases, in the compound of formula III, wherein the ring a may be

In some cases, the compound may have the structure:

wherein R is ₁ May be halogen, n may be 0, 1 or 2 _A1 、R _A2 And R _A3 May be independently selected from C and N.

In some cases, wherein R _A1 May be N.

In some cases, in the compound of formula III, a may be

In some cases, in the compound of formula III, R ₄ Can be-CN, -CO-NH ₂ or-COO-CH ₃ 。

In some cases, in the compound of formula III, R ₅ Can be-CH ₃ 。

In some cases, in the compound of formula III, C may be selected from the group consisting of:

in some cases, the compound of formula III may be one of the compounds in table 3.

TABLE 3 Compounds of formula III

The present application also provides a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula IV:

wherein R is ₁ May be a halogen;

n can be 0, 1 or 2;

R ₂ can be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said R ₂ Optionally via R ₃ Substituent(s) substituted, R ₃ May be = O.

In some cases, in the compound of formula IV, R ₁ May be F.

In some cases, in the compound of formula IV, n may be 1.

In some cases, in the compound of formula IV, R ₂ (may be)

In some cases, the compound of formula IV may be one of the compounds in table 4.

TABLE 4 Compounds of formula IV

In some cases, the method may be an in vitro method, an ex vivo method, or an in vivo method. For example, a compound of the present application (e.g., a compound of formula I through formula IV) can be administered to one or more cells (or cell lines) in vitro to control the growth or activity of these cells. In another example, a compound of the present application (e.g., a compound of formula I through formula IV) can be administered to a patient (e.g., a mammal, such as a human patient) in need thereof.

The present application also provides a method of treating a neurological and/or psychiatric disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of formulae I to IV, or a pharmaceutically acceptable salt thereof.

In some cases, the disease or condition is a mood disorder, a sleep disorder, or a circadian rhythm disorder.

In some cases, the mood disorder is selected from the group consisting of: depression and bipolar disorder.

The methods of the present application may further comprise administering to a subject in need thereof a pharmaceutical composition comprising one or more compounds of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

The compounds of the present application may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which means the compound enters the blood stream directly from the mouth.

In another embodiment, the compounds of the present application may also be administered directly into the bloodstream, muscle, or internal organ. Suitable parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless injectors, and infusion techniques.

In another embodiment, the compounds of the present application may also be administered topically to the skin or mucosa, i.e., transdermally or transdermally. In another embodiment, the compounds of the present application may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.

The dosage regimen of the compound and/or the composition containing the compound is based on a variety of factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; as well as the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels on the order of about 0.01mg to about 100mg per kilogram of body weight per day are suitable for treating the above conditions. In one embodiment, the total daily dose (single administration or divided administration) of the compounds of the invention is typically from about 0.01 to about 100mg/kg, such as from about 0.1 to about 50mg/kg, from about 0.5 to about 30mg/kg (i.e., mg of the compound of the invention per kg of body weight). In one embodiment, the dose is 0.01 to 10mg/kg per day. In another embodiment, the dose is 0.1 to 1.0mg/kg per day. Dosage unit compositions may contain such amounts or factors thereof to make up the daily dose. In many cases, compound administration can be repeated multiple times (usually no more than 4 times) a day. Multiple administrations per day can generally be used to increase the total daily dose, if desired.

For oral administration, the compositions may be provided in the form of lozenges comprising 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500mg of the active ingredient to adjust the dosage to the patient according to the symptoms. The medicament typically contains from about 0.01mg to about 500mg of the active ingredient, or in another embodiment, from about 1mg to about 100mg of the active ingredient. The intravenous dose may be in the range of about 0.1 to about 10mg/kg per minute during a constant rate infusion.

Suitable subjects according to the present application include mammalian subjects. Mammals according to the present invention include, but are not limited to, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, etc., and encompass mammals in utero. In one embodiment, the human is a suitable subject. The human subject may be of either sex and at any stage of development.

In another embodiment, the present application includes the use of one or more compounds of the present application for the manufacture of a medicament for the treatment of the conditions recited herein.

To treat the conditions mentioned above, the compounds of the present application may be administered as the compound itself. Alternatively, pharmaceutically acceptable salts are suitable for medical applications due to their greater aqueous solubility relative to the parent compound.

In another embodiment, the present application includes a pharmaceutical composition. The pharmaceutical compositions comprise a compound of the present application in the presence of a pharmaceutically acceptable carrier. The carrier can be solid, liquid, or both, and can be formulated with the compound as a unit dosage composition, e.g., a lozenge, that can contain from 0.05% to 95% by weight of the active compound. The compounds of the present application can be coupled to suitable polymers as targeted drug carriers. Other pharmacologically active substances may also be present.

The compounds of the present application may be administered by any suitable route, in the form of a pharmaceutical composition suitable for that route, and in a dose effective for the intended treatment. The active compounds and compositions can be administered, for example, orally, rectally, parenterally or topically.

The compounds of the present application may be used to treat various conditions or disease states, either alone or in combination with other therapeutic agents. The compound of the present application and the other therapeutic agent may be administered simultaneously (in the same dosage form or separate dosage forms) or sequentially.

By "administering two or more compounds in combination" is meant that the two compounds are administered close enough in time that the presence of one compound alters the biological effect of the other compound. Two or more compounds may be administered simultaneously, together or sequentially. Alternatively, simultaneous administration may be carried out by mixing the compounds prior to administration or administering the compounds at the same point in time but at different anatomical sites or using different routes of administration.

The phrases "co-administration," "simultaneous administration," and "performing simultaneous administration" mean that the compounds are administered in combination.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present application, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, such as bp, base pair; kb, kilobases; pl, picoliter; s or sec, seconds; min, min; h or hr, hours; aa, an amino acid; nt, nucleotide; i.m., intramuscular; i.p., intraperitoneally; s.c., subcutaneous; and so on.

EXAMPLE 1 preparation of Compound 2-1

FIG. 1 illustrates the synthetic scheme for compound 2-1. As shown in fig. 1, the specific synthesis steps are as follows:

step 1: 2-bromo-3- (4-fluorophenyl) -3-oxopropanoic acid methyl ester

NBS (9.98g, 56.1mmol) and AIBN (0.73g, 5.1mmol) were added to methyl 3- (4-fluorophenyl) -3-oxopropanoate (10g, 51mmol) in 130mL CHCl ₃ In the solution of (1). The mixture was stirred at 62 ℃ for 15 hours. The reaction mixture was concentrated under pressure. The crude material was then loaded onto a silica gel column and eluted with PE/EA (20. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₀ H ₈ BrFO ₃ :275.07, experimental values: 274.7.

step 2:2- (4-fluorophenyl) imidazo [1,2-a ] pyrazine-3-carboxylic acid methyl ester

Methyl 2-bromo-3- (4-fluorophenyl) -3-oxopropanoate (14g, 50.9mmol) and pyrazin-2-amine (9.68g, 101.8mmol) were dissolved in 100mL EtOH. The mixture was heated to reflux for 18h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography and eluted with DCM/MeOH (50. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₀ FN ₃ O ₂ :271.25, experimental values: 271.8.

and 3, step 3:2- (4-fluorophenyl) imidazo [1,2-a ] pyrazine-3-carboxylic acid

Reacting 2- (4-fluorophenyl) imidazo [1, 2-a)]Pyrazine-3-carboxylic acid methyl ester (0.7g, 2.6 mmol) was dissolved in MeOH (40 mL). LiOH (0.31g, 13mmol) dissolved in 10mL of water was added. The reaction mixture was stirred at room temperature for 15h. The reaction mixture was adjusted to pH =5-6 with HCl (1 mol/L) and then concentrated under reduced pressure, and the crude product was dissolved in ethyl acetate and washed with water. The solvent was concentrated and the crude material was loaded onto a silica gel column and eluted with DCM/MeOH (20. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₈ FN ₃ O ₂ :257.22, experimental value: 257.8.

and 4, step 4:2- (4-fluorophenyl) -N-methoxy-N-methylimidazo [1,2-a ] pyrazine-3-carboxamide

2- (4-fluorophenyl) imidazo [1, 2-a)]Pyrazine-3-carboxylic acid (0.7g, 2.7mmol) and SOCl ₂ (0.026mL, 3.5 mmol) was heated to reflux in dry DCE (30 mL) for 1h, after which the mixture was evaporated and distilled. The resulting acid chloride was dissolved in toluene and added dropwise over a period of 20min at 0 ℃ to N, O-dimethylhydroxylamine (0.17g, 2.7 mmol) and K ₂ CO ₃ (0.82g, 5.8mmol) in H ₂ O-toluene mixture (1, 100 mL). After stirring for 2H, the organic phase is treated with dilute aqueous NaOH and H ₂ And (4) washing. The solvent was evaporated under vacuum. The crude material was loaded onto a silica gel column and eluted with PE/EA (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₅ H ₁₃ FN ₄ O ₂ :300.29, experimental value: 300.8.

and 5:1- (2- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-3-yl) ethan-1-one

Reacting CH at-78 ℃ ₃ A3M solution of MgBr in Tetrahydrofuran (THF) (0.26g, 2.2 mmol) was added 2- (4-fluorophenyl) -N-methoxy-N-methylimidazo [1,2-a ]]Pyrazine-3-carboxamide (0.5g, 1.7 mmol) in a stirred solution in THF (20 mL). The mixture was allowed to stand at room temperature and then stirred for 16h. A saturated solution of ammonium chloride was added and the mixture was extracted with EtOAc. The solvent was evaporated under vacuum and the crude material was loaded onto a silica gel column and eluted with PE/EA (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₀ FN ₃ O:255.25, experimental values: 255.8.

and 6:4- (2- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-3-yl) pyrimidin-2-amine

1, 1-dimethoxy-N, N-dimethylmethylamine (0.31g, 2.5mmol) was added continuously to 1- (2- (4-fluorophenyl) imidazo [1,2-a ]]Pyrazin-3-yl) ethan-1-one (100mg, 0.4 mmol) in n-propanol (20 mL). The reaction mixture was heated at 92 ℃ for 3h. Guanidine (0.12g, 1.9mmol) and K were then added ₂ CO ₃ (0.25g, 1.8mmol). The reaction mixture was stirred at 92 ℃ for 16h. Sodium hydroxide solution (5N, 50mg) was added. The reaction mixture was stirred at 92 ℃ for 8h. The solvent is then removed under vacuum and the residue is removedThe material was dissolved in EtOAc and washed with water. The residue was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₆ H ₁₁ FN ₆ :306.3, experimental values: 306.9. ¹ H NMR(400MHz,CDCl ₃ )δ9.35(dd,J＝4.7Hz,1.4Hz,1H),9.22(s,1H),8.22(d,J＝5.2Hz,1H),8.05(d,J＝4.7Hz,1H),7.71-7.67(m,2H),7.18(t,J＝8.7Hz,2H),6.60(d,J＝5.3Hz,1H)。

EXAMPLE 2 preparation of Compounds 3-8

FIG. 2 illustrates the synthetic scheme for compounds 3-8. As shown in fig. 2, the specific synthesis steps are as follows:

step 1: (Z) -3- ((allyloxy) imino) -3- (4-fluorophenyl) propionitrile

O-allylhydroxylammonium chloride (1.35g, 12.3 mmol) and KOAc (1.2g, 12.3 mmol) were de-centered in MeOH (5 mL). The mixture was stirred at 25 ℃ for 30min. Simultaneously, 3- (4-fluorophenyl) -3-oxopropanenitrile (2g, 12.3mmol) dissolved in MeOH (15 mL) was added dropwise over a period of 5 minutes. The reaction mixture was then stirred at 60 ℃ for 16h. The solvent was then concentrated under vacuum. The crude material was loaded onto a silica gel column and eluted with PE/EA (20. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ O:218.23, experimental values: 218.9.

and 2, step: 2- (4-fluorophenyl) -4-methyl-1H-pyrrole-3-carbonitrile

Reacting [ (cod) IrCl] ₂ (0.31g, 0.4mmol), agOTf (0.24g, 0.9mmol) and NaBH ₄ (35mg, 0.9 mmol) was de-centered in THF (10 mL). The mixture was then stirred under nitrogen at 25 ℃ for 20min. (Z) -3- ((allyloxy) imino) -3- (4-fluorophenyl) propionitrile (2g, 9.2mmol) dissolved in THF (20 mL) was added. The reaction mixture was then stirred at 25 ℃ for 18h and subsequently heated to 50 ℃ for 24h. The solvent was then concentrated under vacuum. The crude material was loaded onto a silica gel column and eluted with PE/EA (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₉ FN ₂ :200.22, experimental value: 200.9.

and step 3:2- (4-fluorophenyl) -4-methyl-1- (pyridin-4-yl) -1H-pyrrole-3-carbonitrile

2- (4-fluorophenyl)) -4-methyl-1H-pyrrole-3-carbonitrile (100mg, 0.49mmol), 4-iodopyridine (204mg, 1.00mmol), K ₂ CO ₃ A mixture of (207mg, 1.50mmol) and CuI (9.5mg, 0.05mmol) was mixed with NMP (4 mL). The system was evacuated and replaced with an argon atmosphere. The mixture was then stirred on a microwave for 2.5h at 200 ℃. The mixture was extracted with EtOAc, the solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₂ FN ₃ :277.30, experimental value: 277.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.60(s,2H),7.28–7.20(m,2H),7.12–7.05(m,2H),7.02(d,J＝5.5Hz,2H),6.79(d,J＝1.0Hz,1H),2.30(d,J＝0.9Hz,3H)。

EXAMPLE 3 preparation of Compounds 2-5, 2-6, 2-7 and 2-8

FIG. 3 illustrates the synthetic schemes for compounds 2-5, 2-6, 2-7 and 2-8. As shown in fig. 3, the specific synthetic steps are as follows:

step 1:2- (4-fluorophenyl) imidazo [1,2-a ] pyrazine

2-bromo-1- (4-fluorophenyl) ethanone (10g, 46.1mmol) and NaHCO were added ₃ (11.6 g,138.3 mmol) was added to a stirred solution of pyrazin-2-amine (4.38g, 46.1 mmol) in 300mL EtOH. The mixture was heated to reflux for 4h. The solvent was then concentrated under vacuum. The crude material was loaded onto a silica gel column and eluted with DCM/MeOH (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₈ FN ₃ :213.22, experimental value: 213.9.

and 2, step: 3-bromo-2- (4-fluorophenyl) imidazo [1,2-a ] pyrazines

NBS (1g, 4.7 mmol) was dissolved in CH ₃ CN (30 mL), the solution was stirred at 0 ℃. Then 2- (4-fluorophenyl) imidazo [1,2-a ] is added]Pyrazine (1g, 5.6 mmol). The mixture was stirred at 0 ℃ for 2h. The solvent was concentrated and dissolved in EA, washed with water and the solvent was concentrated under vacuum. The crude material was loaded onto a silica gel column and eluted with PE/EA (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₇ BrFN ₃ :292.11, experimental value: 291.7.

and step 3:2- (4-fluorophenyl) -3- (pyridin-4-yl) imidazo [1,2-a ] pyrazine

Pyridin-4-ylboronic acid (63mg, 0.51mmol) and Pd (PPh) ₃ ) ₄ (79mg, 0.068 mmol) 3-bromo-2- (4-fluorophenyl) imidazo [1, 2-a) was added]Pyrazine (100mg, 0.34mmol) was dissolved in EtOH (3 mL). Toluene (1 mL) and sodium carbonate solution (2N, 0.5 mL) were added. The mixture was then degassed by purging with nitrogen. The mixture was stirred at 100 ℃ for 3h on a microwave. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₁ FN ₄ :290.30, experimental value: 290.8. ¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝1.2Hz,1H),8.85(d,J＝5.9Hz,2H),8.05(dd,J＝4.7,1.4Hz,1H),7.97(d,J＝4.7Hz,1H),7.70–7.58(m,2H),7.44(dd,J＝4.5,1.5Hz,2H),7.09(t,J＝8.7Hz,2H)。

and 4, step 4:2- (4-fluorophenyl) -3- (pyridin-4-yl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine

Reacting NaBH ₄ (26mg, 0.69mmol) 4- [2- (4-fluorophenyl) imidazo [1,2-a ] was added]Pyrazin-3-yl radicals]Pyridine (100mg, 0.35mmol) in EtOH (5 mL). The mixture was stirred at 80 ℃ for 16h. The solvent was then concentrated and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₅ FN ₄ :294.33, experimental values: 294.9. ¹ H NMR(400MHz,CDCl ₃ )δ8.68(dd,J＝4.5,1.5Hz,2H),7.50–7.34(m,2H),7.26(dd,J＝4.5,1.6Hz,2H),6.97(dd,J＝9.7,7.8Hz,2H),4.28(s,2H),3.86(t,J＝5.4Hz,2H),3.29(t,J＝5.4Hz,2H)。

and 5:1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) ethan-1-one

To 4- [2- (4-fluorophenyl) -5H,6H,7H, 8H-imidazo [1,2-a ]]Pyrazin-3-yl]To a solution of pyridine (20 mg) in THF (5 mL) was added acetic anhydride (14 mg). The reaction mixture was stirred at 25 ℃ for 6h. The solvent was then concentrated and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₇ FN ₄ O:336.37, experimental value: 336.9. ¹ H NMR(400MHz,CDCl ₃ )δ8.70(d,J＝5.7Hz,2H),7.49–7.33(m,2H),7.28–7.18(m,2H),6.98(dd,J＝12.0,5.5Hz,2H),4.91(s,2H),4.06(t,J＝5.3Hz,2H),3.90(t,J＝5.3Hz,2H),2.26(s,3H)。

step 6:2- (4-fluorophenyl) -3- (tributylstannyl) imidazo [1,2-a ] pyrazine

Stirring of 3-bromo-2- (4-fluorophenyl) imidazo [1,2-a ] at-78 ℃ under nitrogen atmosphere]Pyrazine (100mg, 0.34mmol) and N-BuLi (39mg, 0.34mmol) in THF (5 mL) were then added 2.4N TMEDA (0.43 mL). The reaction mixture was stirred at-78 ℃ for 1h. Tributylchlorostannane (166mg, 0.51mmol) was then added. The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with saturated ammonium chloride solution and washed several times with diethyl ether, then the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₄ H ₃₄ FN ₃ Sn:502.27, experimental value: 503.7.

and 7:4- (2- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-3-yl) furo [3,4-b ] pyridin-5 (7H) -one

Reacting 4-bromofuro [3,4-b ]]Pyridin-5 (7H) -one (8.5mg, 0.04mmol) and Pd (PPh) ₃ ) ₄ (9mg, 0.008mmol) 2- (4-fluorophenyl) -3- (tributylstannyl) imidazo [1, 2-a)]Pyrazine (20mg, 0.04mmol) in 1, 4-dioxane (5 mL). The reaction mixture was stirred at 80 ℃ under nitrogen for 16h. The mixture was extracted with EtOAc, the solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₁ FN ₄ O ₂ :346.32, experimental value: 346.8. ¹ H NMR(400MHz,CDCl ₃ )δ9.15(d,J＝5.0Hz,1H),7.93(dd,J＝8.8,5.4Hz,2H),7.81–7.69(m,2H),7.66(s,1H),7.55(dd,J＝5.7,3.3Hz,1H),7.15(t,J＝8.7Hz,2H),5.52(s,2H)。

EXAMPLE 4 preparation of Compounds 1-2

FIG. 4 illustrates the synthetic scheme for compounds 1-2. As shown in fig. 4, the specific synthesis steps are as follows:

step 1:4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3,4-b ] pyridin-5 (7H) -one

Reacting 4-bromo-7H-furo [3,4-b ]]Pyridin-5-one (169.5007mg, 0.792mmol)、Na ₂ CO ₃ (139.9200mg, 1.32mmol) and Pd (dppf) Cl ₂ (48.2460mg, 0.066 mmol) 1- (4-fluorophenyl) -3-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (200mg, 0.66mmol) in MePh/H ₂ O (11 mL). The reaction mixture was stirred at 100 ℃ for 16h. The reaction mixture was filtered and concentrated to provide a crude product. The residue was purified by combi-flash (PE/EA = 1) to provide 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b) as a white solid product]Pyridin-5 (7H) -one (170mg, 79.1% yield), determined by LCMS, MS (ESI): calculated mass value C ₁₇ H ₁₂ FN ₃ O ₂ 309.1, m/z experimental value 310.0[ m ] +H] ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.87(d,J＝5.1Hz,1H),7.35(d,J＝5.1Hz,1H),7.25-7.14(m,4H),6.68(s,1H),5.38(s,2H),2.33(s,3H)。

EXAMPLE 5 preparation of Compounds 2-12, 2-13 and 2-14

FIG. 5 illustrates the synthetic scheme for compounds 2-12, 2-13 and 2-14. As shown in fig. 5, the specific synthesis steps are as follows:

step 1:3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester

2-ethoxy-2-oxoethane diazonium salt (19.2g, 0.167mmol) was added to a solution of intermediate 1 (20.0 g, 0.167mol) in toluene (200 mL) at room temperature and the resulting mixture was stirred at 130 ℃ for 3h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (3. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ O ₂ :235.08, experimental value: 234.9.

step 2:1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester

1, 2-dibromoethane (15 g) was added to a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (15.6 g) and potassium carbonate (18.4 g) in acetonitrile (200 mL) at room temperature. The resulting mixture was stirred at 90 ℃ for 4h. The reaction mixture was cooled to room temperature and concentrated under pressure and diluted with water (200 mL). The reaction mixture was extracted with DCM (50ml × 3), filtered and washed with waterConcentrating under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (10, 1) to afford 13.5g (59.5%) of the product as a white solid. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₄ BrFN ₂ O ₂ :341.02, experimental values: 340.7.

and 3, step 3: 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

Phenylmethylamine (4.7 g) and NaHCO were added at room temperature ₃ (3.7 g) to a solution of ethyl 2- (2-bromoethyl) -5- (4-fluorophenyl) pyrazole-3-carboxylate (13.5 g) and potassium iodide (13 g) in acetonitrile (200 mL) was added. The resulting mixture was stirred at 90 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure and diluted with water (100 mL). The reaction mixture was extracted with DCM (30ml × 3), filtered and concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (3. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₆ FN ₃ O:322.13, experimental values: 321.8.

and 4, step 4: 5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

LAH (2.1 g) was added to 2- (4-fluorophenyl) -5- (1-methylphenyl) -6H, 7H-pyrazolo [1,5-a ] at 0 deg.C]Pyrazin-4-one (8.9 g) in THF (100 mL). The resulting mixture was stirred at 25 ℃ overnight. The reaction mixture was quenched with ice-cold water and diluted with water (100 mL). The reaction mixture was extracted with DCM (30ml × 3), filtered and concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (4.3%) to provide 4.3g (50.3%) of the product as a white solid. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₈ FN ₃ :308.15, experimental values: 307.8.

and 5: 5-benzyl-3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

NBS (1270mg, 7.14mmol) was added to 2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ] under ice-cooling]Pyrazine (2000 mg, 6.49mmol) was in a stirred solution in acetonitrile (50 mL). The mixture was stirred for 1h and diluted with water (100 mL). The reaction mixture was extracted with EA (50ml. X.3), filtered and put under pressureAnd (5) concentrating. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (4.1) to afford 1.3g (51.7%) of the product as a white solid. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₇ BrFN ₃ :386.06, experimental value: 385.7.

step 6: 5-benzyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Pd (dppf) Cl ₂ (377 mg), pyridin-4-ylboranediol (476 mg), K ₃ PO ₄ (1.6 g) 3-bromo-2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1, 5-a) was added]Pyrazine (1 g) in DMF (30 mL) and the mixture was taken up in N ₂ The reaction was carried out at 80 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with MeOH/DCM (20.1) to afford 0.55g (55.3%) of the product as a white solid. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₂₄ H ₂₁ FN ₄ :385.18, experimental values: 384.8.

and 7:2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Ammonium formate (454 mg), pd/C (140 mg) was added to 4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]Pyridine (140 mg) in MeOH (20 mL) and the mixture was heated to 50 deg.C for 3h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was charged to a silica gel column and eluted with MeOH/DCM (20.6%) to provide 60mg (56.6%) of the product as a white solid. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₇ H ₁₅ FN ₄ :295.13, experimental value: 294.9.

and step 8:1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Acetyl acetate was added to 4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl]Pyridine in THF, and the mixture was stirred at room temperature for 1h. The reaction mixture was concentrated under pressure. The crude material was charged to a silica gel column and eluted with MeOH/DCM (20. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows:C ₁₉ H ₁₇ FN ₄ o:337.14, experimental value: 336.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.60(dd,J＝15.4,5.2Hz,2H),7.42–7.36(m,2H),7.14(dd,J＝12.9,5.4Hz,2H),7.04(t,J＝8.7Hz,1H),4.91(s,1H),4.77(s,1H),4.35(dt,J＝28.1,5.5Hz,2H),4.19(t,J＝5.5Hz,1H),4.04(t,J＝5.5Hz,1H),2.28(s,3H)。

EXAMPLE 6 preparation of Compounds 1-4

FIG. 6 illustrates the synthetic scheme for compounds 1-4. As shown in fig. 6, the specific synthesis steps are as follows:

step 1:2- (4-fluorophenyl) -2,3a,4,5,6,7-hexahydro-3H-indazol-3-one

Ethyl 2-oxocyclohexane-1-carboxylate (10.3911g, 0.0610mol) and DIEA (14.319g, 0.111mol) were added to a solution of (4-fluorophenyl) hydrazine (7g, 0.0555mol) in EtOH (100 mL). The reaction mixture was stirred at 100 ℃ for 16h. The reaction was complete and checked by LCMS. The mixture was concentrated to provide the crude product. Subjecting the mixture to hydrogenation with H ₂ O (50 mL) was quenched, filtered and concentrated to provide the product 2- (4-fluorophenyl) -2,3a,4,5,6, 7-hexahydro-3H-indazol-3-one (9.5g, 62.7% yield) as a yellow solid, which was determined by LCMS, MS (ESI): mass calculated value C ₁₃ H ₁₃ FN ₂ O232.1, m/z experiment value 233.1[ M ] +H] ⁺ 。

Step 2: 3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-2H-indazole

POBr is added ₃ (11.0682g, 0.0387mol) was added to a solution of 2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-3 aH-indazol-3-one (3 g,0.0129 mol) in ACN (30 mL). The reaction mixture was stirred at 90 ℃ for 16h. The reaction was complete and checked by LCMS. Using Na ₂ CO ₃ The pH of the mixture (60% SMA and 30% product) was adjusted to 7-8. The mixture was extracted with EA (30ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash (PE/EA =5 1) to provide the product 3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-2H-indazole (0.6 g,13.2% yield) as a yellow oil, which was determined by LCMS, MS (ESI): calculated mass value C ₁₃ H ₁₂ BrFN ₂ 294.0, m/z trueTest value 294.9[ m ] +H] ⁺ 。

And step 3:2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydro-2H-indazole

Pyridine-4-yl borane diol (62.6882mg, 0.51mmol), K ₃ PO ₄ (216.2400mg, 1.02mmol) and Pd (dppf) Cl ₂ (24.8540mg, 0.034 mmol) was added to a solution of 3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydroindazole (100mg, 0.34mmol) in DMF (11 mL). The reaction mixture was stirred at 100 ℃ for 5h. The reaction was complete and checked by LCMS. By H ₂ The reaction was quenched with O (30 mL). The mixture was concentrated. The mixture was then extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash (PE/EA = 1) to provide the product 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydro-2H-indazole (24mg, 24.1% yield) as a white solid, which was determined by LCMS, MS (ESI): calculated mass value C ₁₈ H ₁₆ FN ₃ 293.1, m/z experimental value 293.9[ deg. ] M + H] ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.56(dd,J＝4.4、1.6Hz,2H),7.29-7.21(m,2H),7.15(dd,J＝4.4、1.6Hz,1H),2.68(t,J＝6.0Hz,1H),2.59(t,J＝6.0Hz,1H),1.82(d,J＝5.6Hz,1H),1.74(d,J＝5.6Hz,1H)。

EXAMPLE 7 preparation of Compounds 2-16

FIG. 7 illustrates the synthetic scheme for compounds 2-16. As shown in fig. 7, the specific synthesis steps are as follows:

step 1:2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole

Cyclohexane-1, 2-dione (2.7079g, 0.02415mol) and NH ₄ OAc (6.1985g, 0.0805mol) was added to a solution of 4-fluorobenzaldehyde (2g, 0.0161mol) in EtOH (30 mL). The reaction mixture was stirred at 80 ℃ for 2h. The reaction was complete and checked by LCMS. The mixture was concentrated to provide the crude product. The residue was purified by combi-flash (PE/EA =0 1) to provide the brown solid product 2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-1H-benzo [ d]Imidazole (3.4 g,92.6% yield), determined by LCMS, MS (ESI): mass calculated value C ₁₃ H ₁₃ FN ₂ 216.1, m/z experimental value 217.1[ 2 ], [ M + H ]] ⁺ 。

Step 2:2- (4-fluorophenyl) -1- (pyridin-4-yl) -4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole

4-iodopyridine (568.783mg, 2.7746mmol) and K are added under microwave ₂ CO ₃ (574.342mg, 4.1619mmol) and CuI (26.3587mg, 0.13873mmol) were added to a solution of 2- (4-fluorophenyl) -4,5,6, 7-tetrahydro-1H-1, 3-benzobisoxazole (300mg, 1.3873mmol) in NMP (4 mL). The reaction mixture was stirred at 220 ℃ for 2.5 hours. The reaction was complete and checked by LCMS. The reaction was quenched slowly with water (20 mL) and the mixture was extracted with EA (30ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash (PE/EA = 1) to provide the white solid product 2- (4-fluorophenyl) -1- (pyridin-4-yl) -4,5,6,7-tetrahydro-1H-benzo [ d]Imidazole (5mg, 1.20% yield), determined by LCMS, MS (ESI): calculated mass value C ₁₈ H ₁₆ FN ₃ Experimental value 293.1, m/z, 293.9[ 2 ], [ M + H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ8.71(dd,J＝4.5,1.6Hz,2H),7.37-7.32(m,2H),7.11(dd,J＝4.5,1.6Hz,2H),7.01-6.95(m,2H),2.76(t,J＝5.8Hz,2H),2.48(t,J＝5.8Hz,2H),1.93-1.85(m,4H)。

EXAMPLE 8 preparation of Compounds 3-1, 3-2, 3-4 and 3-5

FIG. 8 illustrates the synthetic scheme for compounds 3-1, 3-2, 3-4 and 3-5. As shown in fig. 8, the specific synthetic steps are as follows:

step 1: (E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) acrylonitrile

4-fluorobenzaldehyde (3.1462g, 0.0253mol) and K were added ₂ CO ₃ (1.3993g, 0.0101mol) to a solution of 2- (pyridin-4-yl) acetonitrile (2g, 0.0169mol) in MeOH (30 mL) was added. The reaction mixture was stirred at 80 ℃ for 4h. The reaction was complete and checked by LCMS. The mixture was concentrated to provide the crude product. Water was then added, the reaction mixture was filtered and the filter cake was concentrated to provide the product (E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) acrylonitrile (1.8g, 40.2% yield) as a brown solid, which was determined by LCMS, MS (ESI): calculated mass value C ₁₄ H ₉ FN ₂ 224.1, m/z experimental value 225.0[ m ] +H] ⁺ 。

Step 2:3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid methyl ester

DBU (1322.4000mg, 8.7mmol) was added to a mixture of (2E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) propan-2-enenitrile (1300mg, 5.80mmol) and methyl 2-isocyanoacetate (574.7140mg, 5.8mmol) in THF (210 mL) at room temperature. The mixture was stirred at 75 ℃ for 16h. The reaction mixture was completed and checked by LCMS, then the mixture was concentrated. The reaction was quenched with water (20 mL). The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash (PE/EA =0 1) to provide the brown solid product methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (0.35g, 0.02% yield), which was determined by LCMS, MS (ESI): calculated mass value C ₁₇ H ₁₃ FN ₂ O ₂ 296.1, m/z experimental value 296.9[ deg. ], M + H] ⁺ 。

And 3, step 3:3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid methyl ester

DABCO (11.3120mg, 0.101mmol) and DMF (0.5 mL) was added to a solution of methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (300mg, 1.01mol) in DMC (10 mL). The resulting mixture was heated to 90 ℃ and stirred at this temperature for 16h. LCMS (ENB 190609-146-R1) shows the reaction is complete. The reaction was slowly quenched with water (20 mL) and the mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford the brown solid product methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (120mg, 36.8% yield), which was determined by LCMS, MS (ESI): calculated mass value C ₁₈ H ₁₅ FN ₂ O ₂ Experimental value of 310.1, m/z 311.0[ 2 ], [ M + H ]] ⁺ 。

And 4, step 4:3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid

KOH (53.7600mg, 0.96mmol) was added to a solution of methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxylate (100mg, 0.32mmol) in MeOH/H2O =1 (6 mL) at 25 ℃. Will be provided withThe mixture was stirred at 80 ℃ for 15 hours. LCMS showed reaction completion. The pH of the mixture was adjusted to 7-8 using 4N HCl. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford the brown solid product 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid (60mg, 60.1% yield), which was determined by LCMS, MS (ESI): calculated mass value C ₁₇ H ₁₃ FN ₂ O ₂ Experimental value of 296.1, m/z 297.0[ m ] +H] ⁺ 。

And 5:3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide

Reacting NH at 25 ℃ ₄ Cl (31.8mg, 0.6mmol), DIEA (77.4mg, 0.6mmol) and HATU (91.2mg, 0.24mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxylic acid (60mg, 0.2mmol) in DMF (10 mL). The mixture was stirred at 25 ℃ for 2 hours. LCMS showed reaction completion. The reaction was quenched with water (20 mL) and the mixture was extracted with EA (50ml. X.3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to provide the product 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide as a brown solid (70mg, 118.5% yield), which was determined by LCMS, MS (ESI): calculated mass value C ₁₇ H ₁₄ FN ₃ O295.1, m/z experimental value 296.0[ m ] +H] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ8.44(s,2H),7.32(dd,J＝8.7,5.4Hz,2H),7.17(t,J＝8.6Hz,2H),7.12(s,1H),7.00(d,J＝11.8Hz,2H),5.17(s,2H),4.06(s,3H)。

And 6:3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile

Reacting POCl at 25 DEG C ₃ (93.2688mg, 0.6096mmol) and TEA (61.5696mg, 0.6096mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxamide (60mg, 0.02mmol) in THF (10 mL). The mixture was stirred at 25 ℃ for 2 hours. LCMS showed reaction completion. The reaction was quenched with water (20 mL) and the mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash (PE/EA = 0)To afford the product 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile as a brown solid (7 mg,11.9% yield), which was determined by LCMS, MS (ESI): calculated mass value C ₁₇ H ₁₂ FN ₃ 277.1, m/z experimental value 278.0[ m ] +H] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ8.49(d,J＝5.3Hz,2H),7.32-7.29(m,2H),7.13-7.08(m,3H),7.07-7.05(m,2H),3.91(s,3H)。

EXAMPLE 9 preparation of Compounds 1-10

FIG. 9 illustrates the synthetic scheme for compounds 1-10. As shown in fig. 9, the specific synthetic steps are as follows:

step 1: 1-azido-4-fluorobenzene

4-fluoroaniline (5g, 45mmol) was dissolved in 3M aqueous HCl (50 mL) at 0 ℃. Slow addition of NaNO ₂ (3.72g, 54mmol) and the resulting solution was stirred at the same temperature for 0.5h. NaN dissolved in water (20 mL) was then added in portions ₃ (4.38g, 67.5 mmol) and the mixture was stirred at room temperature for 0.5h. The reaction mixture was extracted with MTBE (50ml _ 2) and the combined organic layers were purified over Na ₂ SO ₄ Dried, filtered off and the solvent evaporated under vacuum to afford the crude product.

And 2, step: 4- ((trimethylsilyl) ethynyl) pyridine

TEA (9.9mg, 98mmol) and PPh ₃ (77mg, 0.2mmol) and PdCl ₂ (PPh ₃ ) ₂ (344mg, 0.4mmol) was added to a solution of 4-iodopyridine (2g, 9.8mmol) in THF (30 mL). The mixture was evacuated and treated with N ₂ Backfilling several times to remove oxygen from the solution. The reaction mixture was stirred at 25 ℃ for 1h. CuI (56mg, 0.2mmol) and ethynyltrimethylsilane (1.44g, 14.7 mmol) were added. The reaction mixture was stirred at 25 ℃ for 15h. Water (50 mL) was added. The residue was extracted with EA (30ml × 3). The reaction mixture was concentrated to provide a crude product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₀ H ₁₄ NSi, molecular weight: 176.31, experimental value: 176.0. ¹ H NMR(400MHz,CDCl ₃ )δ8.57(d,J＝5.6Hz,2H),7.31(dd,J＝4.5,1.6Hz,2H),0.27(s,9H)。

and step 3:4- (1- (4-fluorophenyl) -1H-1,2, 3-triazol-5-yl) pyridine

4- ((trimethylsilyl) ethynyl) pyridine (639mg, 3.65mmol) and t-BuOK (409mg, 3.65mmol) were added to a solution of 1-azido-4-fluorobenzene (500mg, 3.65mmol) in DMF (20 mL). The reaction mixture was stirred at 25 ℃ for 15h. Water (20 mL) was added. The residue was extracted with EA (2 × 20ml). The crude material was dried over sodium sulfate and dried under a stream of nitrogen in a Radleys discharge apparatus to provide the crude product. The reaction mixture was concentrated under pressure. The crude product was added to a silica gel column and CH was used ₂ Cl ₂ MeOH (15. The residue was purified by general preparative HPLC to give the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₀ FN ₄ Molecular weight: 240.24, experimental value: 240.9. ¹ H NMR(400MHz,MeOD)δ8.58(dd,J＝4.7,1.4Hz,2H),8.23(s,1H),7.57-7.45(m,2H),7.42-7.26(m,4H)。

EXAMPLE 10 preparation of Compounds 3-7

FIG. 10 illustrates the synthetic scheme for compounds 3-7. As shown in fig. 10, the specific synthesis steps are as follows:

step 1:3- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester

Methyl 2-isocyanoacetate (6.18g, 62.4mmol) and Ag ₂ CO ₃ (1.15g, 4.2mmol) was added to a solution of 1-ethynyl-4-fluorobenzene (5g, 42mmol) in NMP (20 mL). The mixture was stirred at 80 ℃ for 1h under nitrogen atmosphere. The mixture was extracted with EtOAc. The solvent was evaporated under vacuum and the crude material was loaded onto a silica gel column and eluted with PE/EA (20. The chemical formula is as follows: calculated value (M + H +) C ₁₂ H ₁₀ FNO ₂ :219.22, experimental value: 219.9.

step 2:3- (4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxylic acid methyl ester

A solution of NaH (0.66g, 27.4 mmol) in DMF (5 mL) was cooled to 0 ℃ in a dry ice water bath. A solution of methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3g, 13.7 mmol) in DMF (10 mL) was added. The mixture was stirred at 0 ℃ for 1h, then ICH was added ₃ (2.9g, 20.5mmol). The reaction mixture was stirred at 25 ℃ for 1h. 5mL of water was added, and the mixture was extracted with EtOAc. Evaporating the solvent under vacuum and adding the crude material to siliconGel column and elute with PE/EA (20. The chemical formula is as follows: calculated value (M + H +) C ₁₃ H ₁₂ FNO ₂ :233.24, experimental value: 233.9.

and 3, step 3:3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester

The mixture of ICl (8.4 g, 5.1mmol) and CCl was added ₄ To the solution was added methyl 3- (4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxylate (1g, 4.3mmol) to CCl ₄ (5 mL). The mixture was stirred at 0 ℃ for 15min. The solvent was evaporated under vacuum and the crude material was loaded onto a silica gel column and eluted with PE/EA (20. The chemical formula is as follows: calculated value (M + H +) C ₁₃ H ₁₁ FINO ₂ :359.14, experimental values: 359.6.

and 4, step 4:3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid

NaOH (0.22g, 5.5 mmol) was added to methyl 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylate (0.4 g,1.1 mmol) in MeOH/H ₂ Solution in O (6 mL). The mixture was stirred at 60 ℃ for 5h. The reaction was adjusted to pH 5-6 with HCl (6 mol/L) and extracted with EtOAc. The solvent was evaporated under vacuum to afford the crude product. The chemical formula is as follows: calculated value (M + H +) C ₁₂ H ₉ FINO ₂ :345.11, experimental value: 345.7.

and 5:3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxamide

HATU (502mg, 1.32mmol), DIEA (506mg, 3.3mmol) and NH were added ₄ Cl (177mg, 3.3mmol) was added to a solution of 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid (380mg, 1.1 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 1h. 5mL of water was added, and the mixture was extracted with EtOAc. The solvent was evaporated under vacuum to afford the crude product. The chemical formula is as follows: calculated value (M + H +) C ₁₂ H ₁₀ FIN ₂ O:344.13, experimental values: 344.7.

step 6:3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carbonitrile

Adding POCl ₃ (468mg, 3.05mmol) and Et ₃ N (309mg, 3.05mmol) was added to a solution of 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxamide (350mg, 1.02mmol) in THF (5 mL). The mixture was stirred at room temperatureAnd (4) 1h. The solvent was evaporated under vacuum and the crude material was loaded onto a silica gel column and eluted with PE/EA (20. The chemical formula is as follows: calculated value (M + H +) C ₁₂ H ₈ FIN ₂ :326.11, experimental value: 326.6.

and 7:3- (4-fluorophenyl) -1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile

A solution of 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carbonitrile (50mg, 0.15mmol) in THF (3 mL) was stirred at-78 deg.C under a nitrogen atmosphere, then 2.4M n-BuLi (0.19 mL) was added. The reaction mixture was stirred at-78 ℃ for 1h. Then, 2-isopropoxy-4, 5-tetramethyl-1, 3, 2-dioxaborane (86mg, 0.46mmol) was added thereto. The reaction mixture was stirred at room temperature for 1h. The reaction was quenched with saturated ammonium chloride solution and washed several times with diethyl ether. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H +) C ₁₈ H ₂₀ BFN ₂ O ₂ :326.18, experimental values: 326.8.

and 8:3- (4-fluorophenyl) -1-methyl-4- (5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-4-yl) -1H-pyrrole-2-carbonitrile

Reacting 4-bromofuro [3,4-b ]]Pyridin-5 (7H) -one (38mg, 0.18mmol), na ₂ CO ₃ (38mg, 0.36mmol) and Pd (dppf) Cl ₂ (13mg, 0.018mmol) 3- (4-fluorophenyl) -1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (60mg, 0.018mmol) in toluene/H ₂ O (5.5 mL). The mixture was stirred under nitrogen at 100 ℃ for 16h. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H +) C ₁₉ H ₁₂ FN ₃ O ₂ :333.32, experimental value: 333.7. ¹ H NMR(400MHz,CDCl ₃ )δ8.50(d,J＝5.3Hz,1H),7.69(s,1H),7.35–7.22(m,2H),7.10(t,J＝8.6Hz,2H),6.88(d,J＝5.3Hz,1H),5.33(s,2H),3.93(s,3H)。

EXAMPLE 11 preparation of Compounds 2-27

FIG. 11 illustrates the synthetic scheme for compounds 2-27. As shown in fig. 11, the specific synthesis steps are as follows:

step 1:1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) propan-1-one

Adding Et ₃ N addition of 4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]-2-methylpyridine in DCM. Propionyl chloride was then added and the mixture was stirred at room temperature for 2h. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₀ H ₁₉ FN ₄ O:350.40, experimental value: 350.9. ¹ H NMR(400MHz,CDCl ₃ )δ8.59(d,J＝10.7Hz,2H),7.46-7.35(m,2H),7.11(s,2H),7.07-6.96(m,2H),4.90(s,1H),4.76(s,1H),4.37(s,1H),4.26(d,J＝43.4Hz,2H),4.04(s,1H),2.65-2.20(m,2H),1.36-1.06(m,3H)。

EXAMPLE 12 preparation of Compounds 2-28

FIG. 12 illustrates the synthetic scheme for compounds 2-28. As shown in fig. 12, the specific synthesis steps are as follows:

step 1:1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) -2-methylpropan-1-one

Et is added ₃ Adding 4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ] into N]Pyrazin-3-yl]-2-methylpyridine in DCM. 2-methylpropanoyl chloride was then added and the mixture was stirred at room temperature for 2h. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₁ H ₂₂ FN ₄ O:364.42, experimental value: 364.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.58(s,2H),7.42-7.38(m,2H),7.12(d,J＝3.7Hz,2H),7.08-7.00(m,2H),4.85(d,J＝37.0Hz,2H),4.24(dd,J＝80.9,32.3Hz,2H),1.96(s,1H),1.39-1.04(m,2H)。

EXAMPLE 13 preparation of Compounds 2-29 and 2-31

FIG. 13 illustrates the synthetic scheme for compounds 2-29 and 2-31. As shown in fig. 13, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester

2-ethoxy-2-oxoethane diazonium salt was added to a solution of 1-ethynyl-4-fluorobenzene in toluene (300 mL) at room temperatureTo the solution, and the resulting mixture was stirred at 130 ℃ for 3h. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to flash chromatography and eluted with PE/EA (3. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ O ₂ :234.23, experimental value: 234.9.

1, 2-dibromoethane was added to a solution of ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate and potassium carbonate in acetonitrile (200 mL) at room temperature, and the resulting mixture was stirred at 90 ℃ for 4H. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to flash chromatography and eluted with PE/EA (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₄ BrFN ₂ O ₂ :341.18, experimental values: 342.02.

Phenylmethylamine and NaHCO at room temperature ₃ To a solution of 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester and potassium iodide in acetonitrile (200 mL) was added and the resulting mixture was stirred at 90 ℃ for 16H. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to flash chromatography and eluted with PE/EA (3. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₆ FN ₃ O:324.36, experimental values: 321.9.

LAH was added to 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] at 0 deg.C]Pyrazine-4 (5H) -one in THF (100 mL) and the resulting mixture was stirred at 25 deg.C overnight. The reaction mixture was quenched with ice-cold water. The mixture was filtered and the filtrate was extracted with DCM. The solvent was evaporated under vacuum and the crude material was added to flash chromatography and eluted with PE/EA (4. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₈ FN ₃ :307.37, experimental value: 307.9.

NBS was added to 5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] under ice-cooling]Pyrazine in a stirred solution in acetonitrile. The mixture was stirred for 2h. The solvent was evaporated under vacuum and the crude material was added to flash chromatography and eluted with PE/EA (4. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₇ BrFN ₃ :386.27, experimental value: 387.7.

step 6: 5-benzyl-2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Adding Pd (dppf) Cl ₂ Pyridine-4-ylboranediol, K ₃ PO ₄ Adding 5-benzyl-3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Dissolving pyrazine in DMF, and adding mixture in N ₂ The reaction was carried out at 80 ℃ for 3h. The mixture was extracted with DCM. The solvent was evaporated under vacuum and the crude material was added to flash chromatography and eluted with PE/EA (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₅ H ₂₃ FN ₄ :398.49, experimental value: 398.9.

and 7:2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Ammonium formate (454 mg), pd/C (140 mg) was added to 5-benzyl-2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (140 mg) in MeOH (20 mL) and the mixture was heated to 50 ℃ for 3h. The solvent was evaporated under vacuum and the crude material was added to flash chromatography and eluted with DCM/MeOH (20. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₈ H ₁₇ FN ₄ :308.36, experimental value: 308.9.

and 8:1- (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Adding Et ₃ N addition of 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine in DCM. Acetyl chloride was then added and the mixture was stirred at room temperature for 1h. Evaporating the solvent under vacuum, adding the crude material to flash chromatography andelute with DCM/MeOH (20. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₀ H ₁₉ FN ₄ O:350.40, experimental value: 350.9. ¹ H NMR(400MHz,CDCl ₃ )δ8.47(dd,J＝20.0,5.2Hz,1H),7.47-7.36(m,2H),7.02(t,J＝8.7Hz,2H),6.93(dd,J＝26.4,6.0Hz,2H),4.87(s,1H),4.74(s,1H),4.37(t,J＝5.4Hz,1H),4.30(t,J＝5.4Hz,1H),4.18(t,J＝5.3Hz,1H),4.02(t,J＝5.4Hz,1H),2.55(s,3H),2.22(d,J＝37.2Hz,3H)。

and step 9:4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methylpyridine-1-oxide

1- [2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4H,6H, 7H-pyrazole was dissolved in DCM and cooled to 0 ℃ C, m-chloroperoxybenzoic acid was added and the reaction mixture was stirred at room temperature for 1h. The mixture was saturated with Na ₂ CO ₃ Washing with aqueous solution over Na ₂ SO ₄ Dried, filtered and concentrated to provide the desired product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₀ H ₁₉ FN ₄ O ₂ :366.40, experimental value: 366.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.28(dd,J＝13.4,6.6Hz,1H),7.47-7.33(m,2H),7.08-6.94(m,4H),4.88(s,1H),4.74(s,1H),4.37(t,J＝5.4Hz,1H),4.30(d,J＝5.8Hz,1H),4.19(d,J＝5.4Hz,1H),4.03(t,J＝5.4Hz,1H),2.54(s,3H),2.24(d,J＝32.6Hz,3H)。

EXAMPLE 14 preparation of Compounds 2-30

FIG. 14 illustrates the synthetic scheme for compounds 2-30. As shown in fig. 14, the specific synthetic steps are as follows:

step 1:1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid methyl ester

1-bromo-2-chloroethane (5.5213g, 0.0385mol) and K were added ₂ CO ₃ (3.1878g, 0.0231mol) to a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (1.8g, 0.0077mol) in acetone (20 mL) was added. The reaction mixture was stirred at 70 ℃ for 4h. The reaction was complete and checked by LCMS. The mixture was concentrated and then H was added ₂ O, filtration and concentration of the filter cake. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₃ ClFN ₂ O ₂ Molecular weight: 283.70, experimental values: 283.0.

step 2: (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol

LAH (0.2160 g,0.0054 mol) was added to a solution of methyl 1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (1.6 g,0.0054 mol) in tetrahydrofuran (30 mL) at 0 ℃. The reaction mixture was stirred at 0-25 ℃ for 2h. The reaction was complete and checked by LCMS. By H ₂ The reaction was quenched with O (50 mL). The mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₃ ClFN ₂ O, molecular weight: 255.69, experimental values: 255.0.

and step 3:2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

NaH (84.72mg, 3.53mmol) was added to a solution of (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol (900mg, 3.53mmol) in DMF (10 mL) at 0 ℃ and the reaction mixture was stirred at 0-25 ℃ for 2H. The reaction was complete and checked by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ O, molecular weight: 219.23, experimental value: 219.0.

and 4, step 4: 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

NBS (284.8mg, 1.6mmol) was added to 2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ]][1,4]Oxazine (350mg, 1.6 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 ℃ for 16h. The reaction was complete and checked by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ BrFN ₂ O, molecular weight: 298.13, experimental value: 298.9.

and 5:2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

Pyridine-4-yl borane diol (184.3770mg, 1.5mmol), K ₃ PO ₄ (106mg, 0.5 mmol), X-phos (47.7000mg, 0.1mmol) and Pd ₂ (dba) ₃ (45.8mg, 0.05mmol) 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]A solution of oxazine (150mg, 0.50mmol) in 1, 4-dioxane (10 mL). The reaction mixture was stirred at 90 ℃ for 16h. The reaction was complete and checked by LCMS, then filtered and concentrated. ¹ H NMR (400mhz, dmso) δ 8.50 (dd, J =4.5,1.6hz, 2h), 7.43-7.36 (m, 2H), 7.25-7.17 (m, 2H), 7.10 (dd, J =4.5,1.6hz, 2h), 4.92 (s, 2H), 4.22 (t, J =5.0hz, 2h), 4.14 (t, J =5.1hz, 2h) formula: calculated value (M + H) ⁺ )C ₁₇ H ₁₅ FN ₃ O, molecular weight: 296.32, experimental value: 296.0.

EXAMPLE 15 preparation of Compounds 2-33

FIG. 15 illustrates the synthetic scheme for compounds 2-33. As shown in fig. 15, the specific synthetic steps are as follows:

step 1: (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone

The solution of 1-methylpiperidine-4-carboxylic acid in oxalyl chloride was heated to 70 ℃ for 1h, after which the solvent was removed in vacuo. Addition of Et ₃ N,4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]Pyridine, and the mixture was stirred at room temperature for 1h. The solvent was evaporated under vacuum and the crude material was purified by PTLC to obtain the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₄ H ₂₆ FN ₅ O:419.21, experimental value: 419.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.57(s,2H),7.47-7.36(m,2H),7.18-6.94(m,4H),4.83(d,J＝43.8Hz,2H),4.37(s,2H),4.13(d,J＝45.8Hz,2H),3.10-2.91(m,2H),2.37(s,2H),1.96(s,2H),1.66(s,4H)。

EXAMPLE 16 preparation of Compounds 2-34

FIG. 16 illustrates the synthetic scheme for compounds 2-34. As shown in fig. 16, the specific synthesis steps are as follows:

step 1: N-methyl-1H-imidazole-1-carboxamides

CDI (500mg, 3.08mmol) and hexamethylenetetramine (95.6 mg, 3.08mmol) were dissolved in DMF (1 mL) and acetonitrile (3 mL). The solution was stirred at room temperature for 2h, then concentrated in a stream of air to a thick oil. Flash chromatography (4% MeOH/CH) ₂ Cl ₂ ) Providing the product.

And 2, step: 2- (4-fluorophenyl) -N-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxamides

N-methyl-1H-imidazole-1-carboxamide (8.7mg, 0.077mol) and TEA (7.78mg, 0.077mol) were added to 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (20mg, 0.07mol) was dissolved in DCM (2 mL). The reaction mixture was stirred at 25 ℃ for 2h. The mixture was concentrated and then purified by preparative TLC and preparative HPLC to provide the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₉ FN ₅ O, molecular weight: 351.39, experimental value: 351.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.57(s,2H),7.40(dd,J＝8.6,5.4Hz,2H),7.22(s,2H),7.05(t,J＝8.7Hz,2H),4.85(s,1H),4.71(s,2H),4.34(t,J＝5.3Hz,2H),4.01(t,J＝5.3Hz,2H),2.88(s,3H)。

EXAMPLE 17 preparation of Compounds 2-32

FIG. 17 illustrates the synthetic scheme for compounds 2-32. As shown in fig. 17, the specific synthetic steps are as follows:

step 1: (4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) acetic acid methyl ester

4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Pyrazin-3-yl) -2-methylpyridine-1-oxide (30 mg) in Ac ₂ The solution in O (2 mL) was stirred at 100 ℃ for 1h. The mixture was concentrated and purified by preparative HPLC to provide the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₂ H ₂₂ FN ₄ O ₃ Molecular weight: 408.43, experimental values: 408.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.59(dd,J＝9.9、5.1Hz,1H),7.40(dd,J＝7.9,5.8Hz,2H),7.15(s,1H),7.06(dd,J＝12.0,5.4Hz,3H),5.22(d,J＝3.5Hz,2H),4.91(s,1H),4.78(s,1H),4.38(t,J＝5.3Hz,1H),4.31(d,J＝5.6Hz,1H),4.20(d,J＝5.5Hz,1H),4.07-4.00(m,1H),2.24(d,J＝32.1Hz,3H),2.10(d,J＝3.5Hz,3H)。

EXAMPLE 18 preparation of Compounds 2-36

FIG. 18 illustrates the synthetic scheme for compounds 2-36. As shown in fig. 18, the specific synthetic steps are as follows:

step 1: 5-benzyl-2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Mixing SM2 (110mg, 0.78mmol) and Cs ₂ CO ₃ (508mg, 1.56mmol) and Pd (dppf) Cl ₂ (38mg, 0.052mmol) 5-benzyl-3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] is added]Pyrazine (200mg, 0.52mmol) in dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 100 ℃ for 3h. The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₂₄ H ₂₁ F ₂ N ₄ Molecular weight: 402.45, experimental value: 402.8.

step 2:2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

Reacting HCOONH ₄ (156mg, 2.48mmol) and Pd/C (10 mg) were added 5-benzyl-2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (100mg, 0.248mmol) in (5 mL) solution. The reaction mixture was stirred at 50 ℃ for 5h. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The product was confirmed by LCMS (in agreement therewith). The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₇ H ₁₅ F ₂ N ₄ Molecular weight: 312.32, experimental value: 312.8.

and step 3:1- (2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Ac is added ₂ O (45.8mg, 0.448mmol) was added to 2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (70mg, 0.224mmol) in THSolution in F (5 mL). The reaction mixture was stirred at 25 ℃ for 15h. The reaction mixture was concentrated under pressure. Adding the crude material to silica gel column and adding CH ₂ Cl ₂ MeOH (10. By preparative TLC (CH) ₂ Cl ₂ MeOH = 6) to provide the product. The residue was purified by chiral preparative HPLC to provide the product. The residue was purified by general preparative HPLC to afford the product. ¹ H NMR (400mhz, meod) δ 8.54 (d, J =68.1hz, 2h), 7.49-7.26 (m, 3H), 7.08 (t, J =8.8hz, 2h), 4.81 (d, J =14.3hz, 2h), 4.34 (dt, J =36.5,5.5hz, 2h), 4.15 (dt, J =11.0,5.5hz, 2h), 2.22 (d, J =35.9hz, 3h). The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₉ H ₁₇ F ₂ N ₄ O, molecular weight: 354.36, experimental value: 354.9.

EXAMPLE 19 preparation of Compounds 1-5

FIG. 19 illustrates the synthetic scheme for compounds 1-5. As shown in fig. 19, the specific synthetic steps are as follows:

step 1:4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine

Pyridine-4-yl borane diol (71.907mg, 0.585mmol) and K ₃ PO ₄ (165.36mg, 0.78mmol) and Pd (dppf) Cl ₂ (28.509mg, 0.039mmol) to a solution of 5-bromo-1- (4-fluorophenyl) -3-methylpyrazole (100mg, 0.39mmol) in DMF (11 mL) was added. The reaction mixture was stirred at 100 ℃ for 5h. The reaction was complete and checked by LCMS. By H ₂ The reaction was quenched with O (30 mL) and the mixture was then concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash (PE/EA = 1) to provide the product 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine (60mg, 509.5% yield) as a white solid, which was determined by LCMS, MS (ESI): mass calculated value C ₁₅ H ₁₂ FN ₃ Experiment value of 253.1, m/z 254.1[ 2 ], [ M + H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.54(dd,J＝4.6,1.4Hz,2H),7.31(t,J＝7.1Hz,4H),7.18(dd,J＝4.6,1.4Hz,2H),6.69(s,1H),2.29(s,3H)。

EXAMPLE 20 preparation of Compounds 1-13

FIG. 20 illustrates a synthetic scheme for compounds 1-13. As shown in fig. 20, the specific synthetic steps are as follows:

step 1:1- (4-fluorophenyl) pyrrole-2-carbonitrile

At 0 deg.C reacting [ (chlorosulfonyl) imino group]Methanone (2897mg, 20.47mmol) was slowly added to a solution of 1- (4-fluorophenyl) pyrrole (3000mg, 18.6mmol) in CAN (30 mL). The reaction mixture was stirred at 0 ℃ for 1h. DMF (3 mL) was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for 1h. Water (20 mL) was added. The residue was extracted with MTBE (30ml × 3). The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (10. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₁ H ₈ FN ₂ Molecular weight: 186.19, experimental value: 187.0.

and 2, step: 5-bromo-1- (4-fluorophenyl) pyrrole-2-carbonitrile

NBS (48mg, 0.27mmol) was added to a solution of 1- (4-fluorophenyl) pyrrole-2-carbonitrile (50mg, 0.27mmol) in THF (3 mL) at 0 deg.C. The reaction mixture was stirred at 25 ℃ for 3h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (PE/EtOAc = 5) to provide the product.

And 3, step 3:1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile

Pyridine-4-yl borane diol (138mg, 1.125mmol), pd (dppf) Cl ₂ (55mg, 0.075mmol) and K ₃ PO ₄ (318mg, 1.5mmol) to a solution of 5-bromo-1- (4-fluorophenyl) pyrrole-2-carbonitrile (200mg, 0.75mmol) in DMF (10 mL) and water (1 mL) was added. The reaction mixture was stirred at 100 ℃ for 15h. The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (3. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₆ H ₁₁ FN ₃ Molecular weight: 263.28, experimental value: 263.9. ¹ H NMR(400MHz,MeOD)δ8.51(dd,J＝4.7,1.6Hz,2H),8.01(d,J＝1.5Hz,1H),7.71(dd,J＝4.9,1.4Hz,2H),7.68–7.62(m,3H),7.37(t,J＝8.6Hz,2H)。

EXAMPLE 21 preparation of Compounds 2-38

As shown in fig. 21, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1- (oxiran-2-ylmethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

To a mixture of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (2.34g, 10mmol) in DMF (30 mL) were added 2- (chloromethyl) oxirane (9.26g, 100mmol), cs ₂ CO ₃ (4.89g, 15mmol). The reaction was stirred at 25 ℃ for 16h. LCMS showed the desired MS was detected as the major peak. With EA (50mL. Multidot.2) and H ₂ The mixture was extracted with O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to yield a white solid (1.96 g, yield: 67.5%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₅ H ₁₅ FN ₂ O ₃ :290.11, experimental value: 291.1. ¹ H NMR(400MHz,DMSO)δ7.94–7.90(m,2H),7.41(s,1H),7.26(t,J＝8.9Hz,2H),4.87(dd,J＝14.5,3.6Hz,1H),4.61(dd,J＝14.5,5.5Hz,1H),4.34(q,J＝7.1Hz,2H),3.42–3.38(m,1H),2.80–2.77(m,1H),2.52-2.51(m,1H),1.34(t,J＝7.1Hz,3H)。

step 2:1- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-2-ol

To a mixture of ethyl 5- (4-fluorophenyl) -2- (oxiran-2-ylmethyl) pyrazole-3-carboxylate (1.45g, 5.0 mmol) in THF (20 mL) was added lithium aluminum hydride (380mg, 10.0 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 4h. LCMS showed the desired MS was detected as the major peak. Quench the reaction with ice, and mix with EA (50mL. Multidot.2) and H ₂ The mixture was extracted with O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a white solid (1.29 g, purity: 90%, yield: 92%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₅ FN ₂ O ₂ :250.11, experimental value: 251.0. ¹ H NMR(400MHz,DMSO)δ7.82-7.77(m,2H),7.21(t,J＝8.9Hz,2H),6.59(s,1H),5.29(t,J＝5.6Hz,1H),5.00(d,J＝4.7Hz,1H),4.56(dd,J＝11.1,6.3Hz,2H),4.07–4.01(m,3H),1.10(d,J＝5.9Hz,3H)。

and step 3:2- (4-fluorophenyl) -6-methyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

To the reaction solution of 1- [3- (4-fluorophenyl) -5- (hydroxymethyl) pyrazol-1-yl]To a mixture of propan-2-ol (1.0 g,4.0 mmol) in toluene (20 mL) was added sulfuric acid (1.96g, 20mmol). The reaction was stirred at 110 ℃ for 4h. Concentrating the mixture to remove organics, and using H ₂ O (20 mL), treated with 1M NaOH to pH7, then EA (50mL. Multidot.2) and H ₂ O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to yield a white solid (305 mg, yield: 32%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₃ FN ₂ O:232.10, experimental value: 233.1. ¹ H NMR(400MHz,DMSO)δ7.82–7.78(m,2H),7.22(t,J＝8.9Hz,2H),6.50(s,1H),4.94(d,J＝15.0Hz,1H),4.75(d,J＝15.1Hz,1H),4.22(dd,J＝12.4,3.1Hz,1H),4.08-4.01(m,1H),3.76(dd,J＝12.1,10.7Hz,1H),1.31(d,J＝6.2Hz,3H)。

and 4, step 4: 3-bromo-2- (4-fluorophenyl) -6-methyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

To 2- (4-fluorophenyl) -6-methyl-4H, 6H, 7H-pyrazolo [3, 2-c)][1,4]A mixture of oxazine (296mg, 1.27mmol) in DCM (5 mL) was added NBS (340mg, 1.905 mmol) and stirred at room temperature for 16h. LCMS showed the desired MS was detected as the major peak. With DCM (50mL. Multidot.2) and H ₂ The mixture was extracted with O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to yield a white solid (340 mg, yield: 86%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₂ BrFN ₂ O:310.01, experimental value: 310.9. ¹ H NMR(400MHz,DMSO)δ7.87–7.81(m,2H),7.34–7.28(m,2H),4.85(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),4.23(dd,J＝12.4,3.0Hz,1H),4.12-4.04(m,1H),3.80(dd,J＝12.2,10.6Hz,1H),1.32(d,J＝6.2Hz,3H)。

and 5:2- (4-fluorophenyl) -6-methyl-3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazines

To 3-bromo-2- (4-fluorophenyl) -6-methyl-4H, 6H, 7H-pyrazolo [3,2-c ]][1,4]Oxazine (155mg, 0.55mmol) in dioxane/H ₂ To a solution of O (20 mL/4 mL) were added pyridin-4-ylboranediol (185mg, 1.5 mmol), and Cs ₂ CO ₃ (2458g, 0.75mmol) and Pd (dppd) Cl ₂ (82mg, 0.1mmol) and the mixture was dried N ₂ Stirring was continued for 4h at 100 ℃. Concentrating the mixture to remove organics, and diluting with H ₂ O (20 mL) dilution followed by EA (50mL. Multidot.2) and H ₂ O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to yield crude product, then passed through SFC (chiralpak-OJ, CO ₂ -MEOH (DEA)) to yield compound 2-38 (crude) and compound 2-39 (27.2mg, hplc: 99.47%). Compounds 2-38 were prepared by HPLC (Gemini-C18X 21.2mm,5um, ACN-H ₂ O0.1% fa, gradient 10% to 40%) to yield compound 2-38 (44.8 mg, hplc 100%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₈ H ₁₆ FN ₃ O:309.13, experimental value: 310.1.

compounds 2-38: ¹ H NMR(400MHz,DMSO)δ8.50(d,J＝5.3Hz,2H),7.41–7.36(m,2H),7.23–7.18(m,2H),7.10(d,J＝6.0Hz,2H),4.93(t,J＝19.5Hz,2H),4.30(dd,J＝12.6,3.1Hz,1H),4.16-4.08(m,1H),3.88–3.81(m,1H),1.34(d,J＝6.2Hz,3H)。

EXAMPLE 22 preparation of Compounds 2-37

As shown in fig. 22, the specific synthetic steps are as follows:

step 1: (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester (2)

PPh in THF (50 mL) ₃ (3360mg, 12.81mmol) and DIAD (5180mg, 25.62mmol) and (R) -1- (Boc-amino) -2-propanol (1795mg, 10.25mmol) were added to a solution of 1- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) ethan-1-one (2000 mg, 8.54mmol). The reaction mixture was stirred at 25 ℃ for 15h. Addition of saturated NH ₄ Aqueous Cl (50 mL). The residue was extracted with EA (30ml × 2). The reaction mixture was concentrated under pressure. Adding the crude material to a silica gel column and applying PE/Ethoac (4.

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₂₀ H ₂₆ FN ₃ O ₄ Molecular weight: 391.44, experimental values: 391.8.

step 2: (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester (3)

TFA (1747mg, 15.32mmol) was added to a solution of ethyl (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (3000mg, 7.66mmol) in DCM (30 mL). The reaction mixture was stirred at 25 ℃ for 15h. The reaction mixture was concentrated under pressure to yield the product.

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₁₅ H ₁₈ FN ₃ O ₂ Molecular weight: 291.33, experimental value: 291.8.

and step 3: (R) -2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (4)

TEA (1390mg, 13.74mmol) was added to a solution of ethyl (R) -1- (1- ((tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (2000mg, 6.87mmol) in MeOH (5 mL). The reaction mixture was stirred at 50 ℃ for 5h. The reaction mixture was concentrated under pressure to yield the product.

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₁₃ H ₁₂ FN ₃ O, molecular weight: 245.26, experimental value: 245.7.

and 4, step 4: (R) -3-bromo-2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (5)

NBS (878mg, 4.935mmol) was added to a solution of (R) -2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (1000mg, 3.29mmol) in THF (20 mL). The reaction mixture was stirred at 50 ℃ for 20h. The reaction mixture was concentrated under pressure to yield the product.

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₁₃ H ₁₁ BrFN ₃ O, molecular weight: 324.15, experimental value: 324.7.

and 5: (R) -2- (4-fluorophenyl) -7-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

To (R) -3-bromo-2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ]]To a solution of pyrazin-4 (5H) -one (1000mg, 3.09mmol) in dimethoxyethane (20 mL) and water (3 mL) was added pyridin-4-ylboronic acid (570mg, 4.63mmol), pd (PPh) ₃ ) ₄ (357mg, 0.309mmol) and Na ₂ CO ₃ (667mg, 6.18mmol). The reaction mixture was stirred at 100 ℃ for 5h. The reaction mixture was concentrated under pressure. Adding the crude material to silica gel column and adding CH ₂ Cl ₂ MeOH (10.

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₁₈ H ₁₅ FN ₄ O, molecular weight: 322.34, experimental values: 322.8.

EXAMPLE 23 preparation of Compounds 2-39

As shown in fig. 23, the specific synthesis procedure was similar to example 21.

Compound 2-39: ¹ H NMR(400MHz,DMSO)δ8.50(dd,J＝4.5,1.6Hz,2H),7.41–7.36(m,2H),7.21(t,J＝8.9Hz,2H),7.10(dd,J＝4.5,1.6Hz,2H),4.95(d,J＝23.8Hz,2H),4.30(dd,J＝12.5,3.1Hz,1H),4.14–4.09(m,1H),3.87–3.82(m,1H),1.35(d,J＝6.2Hz,3H)。

EXAMPLE 24 preparation of Compounds 2-40

As shown in fig. 24, the specific synthetic steps are as follows:

step 1:1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester

To a mixture of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (2.34g, 10mmol) in DMF (20 mL) were added 1-bromo-3-chloropropane (2.37g, 15mmol), and Cs ₂ CO ₃ (4.89g, 15mmol). The reaction was stirred at 25 ℃ for 16h. LCMS showed the desired MS was detected as the major peak. With EA (50mL. Multidot.2) and H ₂ The mixture was extracted with O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to yield a white solid (1.9 g, yield: 58%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₅ H ₁₆ ClFN ₂ O ₂ :310.09, experimental value: 311.1. ¹ H NMR(400MHz,DMSO)δ7.94–7.89(m,2H),7.38(s,1H),7.29-7.23(m,2H),4.67(t,J＝6.9Hz,2H),4.34(q,J＝7.1Hz,2H),3.67(t,J＝6.3Hz,2H),2.32-2.24(m,2H),1.34(t,J＝7.1Hz,3H)。

and 2, step: (1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol and 3- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-1-ol

To a mixture of ethyl 1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (1.24g, 4.0 mmol) in THF (20 mL) was added lithium aluminum hydride (304mg, 8.0 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 4h. LCMS showed the desired MS was detected as the major peak. Quench the reaction with ice, and mix with EA (50mL. Multidot.2) and H ₂ The mixture was extracted with O (50 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give two white solids (compound 3, 730 mg) and (compound 3a, 80mg). Compound 3: the chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₄ ClFN ₂ O:268.08, experimental value: 269.1. ¹ h NMR (400mhz, dmso) δ 7.82-7.78 (m, 2H), 7.24-7.19 (m, 2H), 6.62 (s, 1H), 5.50-5.15 (m, 1H), 4.54 (s, 2H), 4.25 (t, J =6.9hz, 2h), 3.69 (t, J =6.5hz, 2h), 2.27 (p, J =6.6hz, 2h). Compound 3A: the chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₅ FN ₂ O ₂ :250.11, experimental value: 251.1. ¹ H NMR(400MHz,DMSO)δ7.79(dd,J＝8.9,5.6Hz,2H),7.21(t,J＝8.9Hz,2H),6.58(s,1H),5.35(t,J＝5.5Hz,1H),4.61(t,J＝5.1Hz,1H),4.53(d,J＝5.5Hz,2H),4.16(t,J＝7.1Hz,2H),3.45-3.39(m,2H),1.98-1.91(m,2H)。

and step 3:2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5,1-c ] [1,4] oxazepine

To the 3- [3- (4-fluorophenyl) -5- (hydroxymethyl) pyrazol-1-yl group]To a mixture of propan-1-ol (80mg, 0.31mmol) in toluene (10 mL) was added sulfuric acid (157mg, 1.59mmol). The reaction was stirred at 110 ℃ for 4h. Concentrating the mixture to remove organics, and diluting with H ₂ O (20 mL), treated with 1M NaOH to pH about 7, then with EA (30mL. Multidot.2) and H ₂ O (30 mL). The organic layer was washed with brine (50 mL),By anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to yield a white solid (20 mg, yield: 27%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₃ FN ₂ O:232.10, experimental value: 233.1. ¹ H NMR(400MHz,DMSO)δ7.79–7.75(m,2H),7.21(t,J＝8.9Hz,2H),6.63(s,1H),4.63(s,2H),4.46–4.42(m,2H),3.98–3.95(m,2H),1.89–1.84(m,2H)。

and 4, step 4: 3-bromo-2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5,1-c ] [1,4] oxazepine

To 2- (4-fluorophenyl) -4H,6H,7H, 8H-pyrazolo [3,2-c][1,4]To a mixture of oxaazepane (20mg, 0.09mmol) in DCM (5 mL) was added NBS (25mg, 0.135mmol) and stirred at room temperature for 16h. LCMS showed the desired MS was detected as the major peak. With DCM (30mL. Multidot.2) and H ₂ The mixture was extracted with O (30 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to yield a white solid (16 mg, yield: 56%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₂ BrFN ₂ O:310.01, experimental value: 311.0. ¹ H NMR(400MHz,DMSO)δ7.84–7.79(m,2H),7.33–7.27(m,2H),4.68(s,2H),4.53–4.49(m,2H),4.02–3.98(m,2H),1.94-1.87(m,2H)。

and 5:2- (4-fluorophenyl) -3- (pyridin-4-yl) -7, 8-dihydro-4H, 6H-pyrazolo [5,1-c ] [1,4] oxazepine

To 3-bromo-2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5, 1-c)][1,4]Oxazepine (16mg, 0.05mmol) in dioxane/H ₂ To a solution of O (5 mL/1 mL) were added pyridin-4-ylboranediol (19mg, 0.15mmol), and Cs ₂ CO ₃ (25mg, 0.075mmol) and Pd (dppd) Cl ₂ (9mg, 0.01mmol), and the mixture was dried N ₂ Stirring was continued for 4h at 100 ℃. Concentrating the mixture to remove organic solvent, and extracting with H ₂ O (20 mL) diluted then EA (30 mL. Times.2) and H ₂ O (30 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) toThe crude product was produced, which was then purified by HPLC (Gemini-C18X 21.2mm,5um, ACN-H ₂ O0.1% fa, gradient 10% to 40%) to yield a white solid (3.2 mg, yield: 20%, HPLC: 99.72%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₈ H ₁₆ FN ₃ O:309.13, experimental value: 310.1. ¹ H NMR(400MHz,DMSO)δ8.52(s,2H),7.39–7.34(m,2H),7.22(d,J＝4.7Hz,2H),7.08(t,J＝8.8Hz,2H),4.71(s,2H),4.61–4.58(m,2H),4.13–4.10(m,2H),2.08-2.02(m,2H)。

EXAMPLE 25 preparation of Compounds 3-11

As shown in fig. 25, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1-methyl-4- (1H-pyrazolo [3,4-b ] pyridin-4-yl) -1H-pyrrole-2-carbonitrile

Reacting 4-bromo-1H-pyrazolo [3,4-b ]]Pyridine (46mg, 0.23mmol), 2M Na ₂ CO ₃ Aqueous solution (0.5 mL) and Pd (dppf) Cl ₂ (22mg, 0.03mmol) to a solution of 3- (4-fluorophenyl) -1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (50mg, 0.15mmol) in EtOH/toluene =8 (5 mL) was added. The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (PE/EA =1 = 10) to yield the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₈ H ₁₂ FN ₅ :317.33, experimental value: 317.8. ¹ H NMR(400MHz,CDCl ₃ )δ12.43(s,1H),8.49(d,J＝4.9Hz,1H),7.76(s,1H),7.31(dd,J＝6.0,2.8Hz,2H),7.25(s,1H),7.04(t,J＝8.7Hz,2H),6.87(d,J＝4.9Hz,1H),3.97(s,3H)。

EXAMPLE 26 preparation of Compounds 2-41

As shown in fig. 26, the specific synthetic steps are as follows:

step 1:1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester (2)

To a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (1.8g, 0.0077mol) in acetone (20 mL) were added 1-bromo-2-chloroethane (5.5213g, 0.0385mol) and K ₂ CO ₃ (3.1878g, 0.0231mol). The reaction mixture was stirred at 70 deg.CAnd 4h. Completion of the mixture was detected by LCMS. The mixture was concentrated and then H was added ₂ O, filtration and concentration of the filter cake. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₂ ClFN ₂ O ₂ :282.1, experimental value: 283.0.

step 2: (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol (3)

LAH (0.2160 g,0.0054 mol) was added to a solution of ethyl 2- (2-chloroethyl) -5- (4-fluorophenyl) pyrazole-3-carboxylate (1.6 g,0.0054 mol) in tetrahydrofuran (30 mL) at 0 ℃. The reaction mixture was stirred at 0-25 ℃ for 2h. Completion of the reaction was detected by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₂ ClFN ₂ O:254.1, experimental value: 255.0.

and step 3:2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazine (4)

To [2- (2-chloroethyl) -5- (4-fluorophenyl) pyrazol-3-yl at 0 DEG C]Methanol (900mg, 3.53mmol) in DMF (10 mL) was added NaH (84.72mg, 3.53mmol) and the reaction mixture was stirred at 0-25 ℃ for 2h. Completion of the reaction was detected by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ O:218.1, experimental value: 219.0.

and 4, step 4: 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazine (5)

To 2- (4-fluorophenyl) -4H,6H, 7H-pyrazolo [3, 2-c)][1,4]NBS (284.8mg, 1.6 mmol) was added to a solution of oxazine (350mg, 1.6 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 ℃ for 16h. Completion of the reaction was detected by LCMS. By usingH ₂ The reaction was quenched with O (50 mL). The mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was added to a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₀ BrFN ₂ O:290.0, experimental value: 296.9.

To 2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [3, 2-c)][1,4]To a solution of oxazine (50mg, 0.15mmol) in 1, 2-dimethoxyethane (5 mL) were added 4-bromopyridazine (47.70mg, 0.3mmol), na ₂ CO ₃ (47.70mg, 0.4499 mmol) and Pd (dtbpf) Cl ₂ (9.76mg, 0.015mmol). The reaction mixture was stirred at 90 ℃ for 16h. Completion of the reaction was detected by LCMS. The mixture was filtered and concentrated to yield the product. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,DMSO)δ9.24(dd,J＝5.3,1.2Hz,1H),9.05(dd,J＝2.3,1.2Hz,1H),7.56(dd,J＝5.3,2.4Hz,1H),7.46(dd,J＝15.2,8.7Hz,1H),7.39(dd,J＝8.8,5.5Hz,2H),7.23(t,J＝8.9Hz,2H),5.82(d,J＝15.2Hz,1H),5.70(s,1H),5.07(d,J＝8.7Hz,1H),4.53(d,J＝5.5Hz,2H)。

EXAMPLE 27 preparation of Compounds 3-12

As shown in fig. 27, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1-methyl-4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-pyrrole-2-carbonitrile

Reacting 4-bromo-1H-pyrrolo [2,3-b ]]Pyridine (46mg, 0.23mmol), 2M Na ₂ CO ₃ Aqueous solution (0.5 mL) and Pd (dppf) Cl ₂ (22mg, 0.03mmol) to a solution of 3- (4-fluorophenyl) -1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (50mg, 0.15mmol) in EtOH/toluene =8 (5 mL) was added. The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. Subjecting the reaction mixture to pressureConcentrating under force. The residue was purified by preparative TLC (PE/EA =1 = 10) to yield the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₃ FN ₄ :316.34, experimental values: 316.8. ¹ H NMR(400MHz,CDCl ₃ )δ9.66(s,1H),7.32–7.29(m,2H),7.27(d,J＝2.0Hz,2H),7.21(s,1H),7.01(t,J＝8.7Hz,2H),6.81(s,1H),6.31(s,1H),3.95(s,3H)。

EXAMPLE 28 preparation of Compounds 2-42

As shown in fig. 28, the specific synthetic steps are as follows:

step 1:4- (2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-3-yl) pyridin-2-amine

To 3-bromo-2- (4-fluorophenyl) -4H,6H, 7H-pyrazolo [3, 2-c)][1,4]Oxazine (500mg, 1.68mmol) in EtOH/PhMe/H ₂ To a solution in O =8 ₂ CO ₃ (534.24mg, 5.04mmol) and Pd (dppf) Cl ₂ (245.62mg, 0.336mmol). The reaction mixture was stirred at 100 ℃ for 1h. Completion of the reaction was detected by LCMS. The mixture was filtered and concentrated to yield the product. The crude material was loaded onto a silica gel column and eluted with EtOAc. ¹ H NMR(301MHz,DMSO)δ7.81(dd,J＝4.8,1.2Hz,1H),7.45–7.38(m,2H),7.22–7.15(m,2H),6.21–6.17(m,2H),5.87(s,2H),4.81(s,2H),4.17(d,J＝4.8Hz,2H),4.13(d,J＝4.8Hz,2H)。

EXAMPLE 29 preparation of Compounds 2-43

As shown in fig. 29, the specific synthetic steps are as follows:

step 1:4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-amine

4- (3, 4-tetramethylcyclopentyl) pyridin-2-amine (102mg, 0.46mmol), 2M Na ₂ CO ₃ Aqueous solution (0.5 mL) and Pd (dppf) Cl ₂ (45mg, 0.06mmol) 5-benzyl-3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] was added]Pyrazine (120mg, 0.31mmol) in EtOH/toluene =8 (5 mL). The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. The reaction mixture was concentrated under pressure. By preparingType TLC (PE/EA =1 = 4) purified the residue to yield the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₄ H ₂₂ FN ₅ :399.47, experimental values: 399.8.

step 2:4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-amine

Reacting HCOONH ₄ (157mg, 2.5 mmol) and Pd/C (200 mg) were added 4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazin-3-yl) pyridin-2-amine (100mg, 0.25mmol) in MeOH (10 mL). The mixture was stirred at 60 ℃ for 2h. The solution was filtered, the filtrate was collected and the solution was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₆ FN ₅ :309.35, experimental value: 309.8.

and 3, step 3:1- (3- (2-aminopyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

AcOAc (29mg, 0.29mmol) and Et ₃ N (88mg, 0.87mmol) was added 4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazin-3-yl) pyridin-2-amine (90mg, 0.29mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (DCM/MeOH = 20). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₈ FN ₅ O:351.39, experimental value: 351.8. ¹ H NMR(400MHz,CDCl ₃ )δ7.71(d,J＝16.3Hz,1H),7.39(dd,J＝8.4,5.0Hz,2H),7.04(dd,J＝20.6,12.0Hz,2H),6.59(d,J＝10.3Hz,1H),6.39(d,J＝5.6Hz,1H),4.85(d,J＝39.9Hz,2H),4.34(dd,J＝20.7,15.4Hz,2H),4.23–3.95(m,2H),2.37–2.14(m,3H)。

EXAMPLE 30 preparation of Compounds 3-13

As shown in fig. 30, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -4- (3H-imidazo [4,5-b ] pyridin-7-yl) -1-methyl-1H-pyrrole-2-carbonitrile

Reacting 7-bromo-3H-imidazo [4,5-b ]]Pyridine (137mg, 0.69mmol), 2M Na ₂ CO ₃ Aqueous solution (0.5 mL) and Pd (dppf) Cl ₂ (67mg, 0.092mmol) was added3- (4-fluorophenyl) -1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (150mg, 0.46mmol) in a solution of EtOH/toluene =8 (5 mL). The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (PE/EA = 1) to yield the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₈ H ₁₂ FN ₅ :317.33, experimental value: 317.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.19(s,1H),7.93(d,J＝8.4Hz,1H),7.32(td,J＝5.6,2.1Hz,3H),7.04(dd,J＝12.0,5.3Hz,2H),6.98(d,J＝8.4Hz,1H),3.90(s,3H)。

EXAMPLE 31 preparation of Compounds 2-44

As shown in fig. 31, the specific synthetic steps are as follows:

step 1:1- (2- (4-fluorophenyl) -3- (2-methylpyrimidin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Adding Pd (dppf) Cl ₂ (28.5mg, 0.039mmol), 4-bromo-2-methylpyrimidine (101.2mg, 0.585mmol), cs ₂ CO ₃ (381mg, 1.17mmol) 1- (2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydropyrazolo [1,5-a ] was added]Pyrazin-5 (4H) -yl) ethan-1-one (150mg, 0.39mmol) in dioxane/H ₂ O (20. Bringing the mixture to N ₂ The reaction was carried out at 90 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and eluted with MeOH/DCM (25. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₉ H ₁₈ FN ₅ O:351.15, experimental value: 352. ¹ H NMR(400MHz,CDCl3)δ8.37(d,J＝5.4Hz,1H),7.52–7.40(m,2H),7.12(q,J＝8.7Hz,2H),6.77(dd,J＝14.4,5.3Hz,1H),5.17(d,J＝8.5Hz,2H),4.42–4.23(m,2H),4.16(t,J＝5.4Hz,1H),4.01(t,J＝5.4Hz,1H),2.74(d,J＝4.6Hz,3H),2.28(d,J＝11.0Hz,3H)。

EXAMPLE 32 preparation of Compounds 2-45

As shown in fig. 32, the specific synthetic steps are as follows:

step 1:1- (3- (2-ethylpyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Adding Pd (dppf) Cl ₂ (41.7mg, 0.057mmol), 4-bromo-2-ethylpyridine (159mg, 0.855mmol), cs ₂ CO ₃ (557mg, 1.71mmol) 1- [2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ] was added]Pyrazin-5-yl]Ethanone (220mg, 0.57mmol) in dioxane/H ₂ O (20. Bringing the mixture to N ₂ The reaction was carried out at 90 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and eluted with MeOH/DCM (25. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₂₁ H ₂₁ FN ₄ O:364.17, experimental value: 365. ¹ H NMR(400MHz,CDCl ₃ )δ8.50(dd,J＝17.6,4.7Hz,1H),7.39(dd,J＝8.6,5.5Hz,2H),7.01(t,J＝8.7Hz,2H),6.93(s,2H),4.81(d,J＝51.7Hz,2H),4.32(dt,J＝27.2,5.5Hz,2H),4.09(dt,J＝61.0,5.5Hz,2H),2.79(q,J＝7.5Hz,2H),2.21(d,J＝36.5Hz,3H),1.25(t,J＝7.6Hz,3H)。

EXAMPLE 33 preparation of Compounds 2-46

As shown in fig. 33, the specific synthetic steps are as follows:

step 1:1- (3- (6-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

Adding Pd (dppf) Cl ₂ (28.5mg, 0.039mmol), 4-bromo-2-isopropylpyridine (117mg, 0.585mmol), cs ₂ CO ₃ (381mg, 1.17mmol) 1- [2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ] was added]Pyrazin-5-yl]Ethanone (150mg, 0.39mmol) in dioxane/H ₂ O (20. Bringing the mixture to N ₂ The reaction was carried out at 90 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and eluted with MeOH/DCM (25. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₂₂ H ₂₃ FN ₄ O:378.19, experimental value: 379. ¹ H NMR(400MHz,CDCl ₃ )δ8.53(dd,J＝15.1,5.0Hz,1H),7.39(dd,J＝8.2,5.7Hz,2H),7.06–6.91(m,4H),4.82(d,J＝51.0Hz,2H),4.32(dt,J＝27.0,5.5Hz,2H),4.09(dt,J＝60.3,5.5Hz,2H),3.03(dt,J＝13.8,6.9Hz,1H),2.21(d,J＝35.0Hz,3H),1.23(d,J＝6.9Hz,6H)。

EXAMPLE 34 preparation of Compounds 2-47

As shown in fig. 34, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1H-pyrazol-5-ol

To a mixture of methyl 3- (4-fluorophenyl) -3-oxopropanoate (20g, 101.9mmol) in EtOH (250 mL) at 25 ℃ was added hydrodiazoene (6.3g, 203.8mmol). The reaction was stirred at 60 ℃ for 3h. LCMS showed the desired MS was detected as the major peak. The mixture was concentrated and purified by column chromatography (PE/EA = 6/1) to give a purple solid (17.2 g, yield: 98%). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₉ H ₇ FN ₂ 178.05, experimental value: 179.

and 2, step: 6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5,1-b ] oxazole

To a mixture of 3- (4-fluorophenyl) -1H-pyrazol-5-ol (1200mg, 6.74mmol) in ACN (50 mL) at 25 ℃ were added 1, 2-dibromoethane (2500mg, 13.48mmol) and K ₂ CO ₃ (3728mg, 27mmol). The reaction was stirred at 80 ℃ for 3h. LCMS showed the desired MS was detected as the major peak. The reaction mixture was cooled to room temperature and concentrated under pressure, diluted with water (50 mL), extracted with DCM (50ml × 3), filtered and concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₁ H ₉ FN ₂ O:204.07, experimental value: 205.

and step 3: 7-bromo-6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5,1-b ] oxazole

To 6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5,1-b ] under ice-cooling]To a stirred solution of oxazole (3600 mg, 17.63mmol) in acetonitrile (100 mL) was added NBS (1883mg, 10.57mmol). The mixture was stirred at 25 ℃ for 1h. LCMS shows that the required MS is mainly detectedPeak(s). The reaction mixture was concentrated under pressure and diluted with water (50 mL), extracted with EA (50ml × 3), filtered and concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (4. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₁ H ₈ BrFN ₂ O:283.18, experimental values: 284.

and 4, step 4:4- (6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5,1-b ] oxazol-7-yl) pyridin-2-amine

Adding Pd (dppf) Cl ₂ (38.78mg, 0.053 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (134.2mg, 0.61mmol), cs ₂ CO ₃ (518mg, 1.59mmol) 7-bromo-6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b)]Oxazole (150mg, 0.53mmol) in dioxane/H ₂ O (15. Bringing the mixture to N ₂ The reaction was carried out at 90 ℃ for 16h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and eluted with MeOH/DCM (25. The chemical formula is as follows: calculated value (M + H) ⁺ ) The chemical formula is as follows: c ₁₆ H ₁₃ FN ₄ O:296.11, experimental value: 297. ¹ H NMR(400MHz,CDCl ₃ )δ7.70(d,J＝6.0Hz,1H),7.51–7.43(m,2H),7.11(t,J＝8.7Hz,2H),6.58(d,J＝6.0Hz,1H),6.46(s,1H),5.71(s,2H),5.26–5.19(m,2H),4.46–4.40(m,2H)。

EXAMPLE 35 preparation of Compounds 2-48

As shown in fig. 35, the specific synthetic steps are as follows:

step 1: (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone

Methylpiperidine-4-carboxylic acid (41.8mg, 0.29mmol), and T ₃ P (155mg, 0.49mmol) and DIPEA (150.9mg, 1.17mmol) were added to 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (60mg, 0.19mmol) was dissolved in DCM (5 mL). The mixture was stirred at 25 ℃ for 3h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (DCM/MeOH = 5). TransformingThe formula is as follows: calculated value (M + H) ⁺ )C ₂₅ H ₂₈ FN ₅ O:433.53, experimental value: 433.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.48(d,J＝25.6Hz,1H),8.34(s,1H),7.37(s,2H),7.12–6.84(m,3H),4.79(d,J＝43.8Hz,2H),4.33(d,J＝28.8Hz,2H),4.11(d,J＝48.7Hz,2H),3.30(s,2H),3.03(s,2H),2.66(d,J＝20.2Hz,4H),2.54(s,3H),2.40–1.92(m,4H)。

EXAMPLE 36 preparation of Compounds 2-49

As shown in fig. 36, the specific synthetic steps are as follows:

step 1:2- (4-fluorophenyl) -5-methyl-3- (2-methylpyridin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine

To 4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]To a solution of (e) -2-methylpyridine (50mg, 0.16mmol) in HCOOH (3 mL) was added HCHO (24mg, 0.8mmol). The reaction mixture was stirred at 70 ℃ for 2h. Incomplete reaction was detected by LCMS. The reaction mixture was concentrated under pressure. With Na ₂ CO ₃ The mixture was adjusted to pH =8. The organic phase was washed with water (5 mL). The residue was extracted with EA (5 ml _ 3). The solvent was dried over sodium sulfate and dried under a stream of nitrogen in a Radleys discharge apparatus to yield the crude product. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,CDCl ₃ )δ8.42(d,J＝5.2Hz,1H),7.42–7.36(m,2H),7.05–6.97(m,2H),6.94(s,1H),6.90(d,J＝4.8Hz,1H),4.30(t,J＝5.6Hz,2H),3.67(s,2H),3.01–2.94(m,2H),2.54(d,J＝4.0Hz,6H)。

EXAMPLE 37 preparation of Compounds 3-14

As shown in fig. 37, the specific synthetic steps are as follows:

step 1:3- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester

To a solution of 1-ethynyl-4-fluorobenzene (3000 mg, 24.97mmol) in NMP (50 mL) were added methyl 2-isocyanoacetate (3711.3410 mg, 37.455mmol), ag ₂ CO ₃ (2756.6880 mg, 9.988mmol). The reaction mixture was stirred at 80 ℃ for 1h. By LCMS detects the completion of the reaction. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml _ 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₀ FNO ₂ :219.1, experimental value: 220.0.

step 2:3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylic acid methyl ester

Then to methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate [800mg,3.65mmol at 0 deg.C]In CCl ₄ [10mL]Acetyl chloride [592.6030mg,3.65mmol ] was added to the solution in (1)]. The reaction mixture was stirred at 0 ℃ for 15min. Completion of the reaction was detected by LCMS. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₉ FINO ₂ :345.0, experimental value: 345.9.

and step 3:1- (2- ((tert-Butoxycarbonyl) amino) ethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylic acid methyl ester

Then to methyl 3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate [400mg, 1.116mmol]In DMF [10mL]To the solution in (1) was added tert-butyl N- (2-chloroethyl) carbamate [416.776mg,2.32mmol]、K ₂ CO ₃ [480.24mg，3.48mmol]. The reaction mixture was stirred at 100 ℃ for 16h. Completion of the reaction was detected by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the product. The chemical formula is as follows: calculated value (M + Na) ⁺ )C ₁₉ H ₂₂ FIN ₂ O ₄ :488.1, experimental value: 510.9.

and 4, step 4:1- (2-aminoethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylic acid methyl ester

Then to 1- (2- { [ (tert-butoxy) carbonyl]Amino } ethyl) -3- (4-fluorophenyl) -4-iodopyrrole-2-carboxylic acid methyl ester [500mg,1.0240mmol]In DCM [3mL ]]To the solution in (3) was added HCl-dioxane [3mL ]]. Will reactThe mixture was stirred at 25 ℃ for 2h. Completion of the reaction was detected by LCMS. The reaction mixture was concentrated under pressure. With Na ₂ CO ₃ The mixture was adjusted to PH =8. The residue was extracted with EA (. Times.5 mL). The solvent was dried over sodium sulfate and dried in a Radleys discharge apparatus under a stream of nitrogen to yield the crude product. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₄ FIN ₂ O ₂ :388.0, experimental value: 388.9.

and 5:8- (4-fluorophenyl) -7-iodo-3, 4-dihydropyrrolo [1,2-a ] pyrazin-1 (2H) -one

Then to methyl 1- (2-aminoethyl) -3- (4-fluorophenyl) -4-iodopyrrole-2-carboxylate [300mg,0.77mmol]In MeOH [5mL ]]Adding K into the solution ₂ CO ₃ [159.39mg]. The reaction mixture was stirred at 50 ℃ for 2h. Completion of the reaction was detected by LCMS. By H ₂ The reaction was quenched with O (50 mL) and the mixture was concentrated. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the product. Calculated value (M + H) ⁺ )C ₁₃ H ₁₀ FIN ₂ O:356.0, experimental value: 356.8.

and 6:8- (4-fluorophenyl) -7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrrolo [1,2-a ] pyrazin-1 (2H) -one

Then 8- (4-fluorophenyl) -7-iodo-2H, 3H, 4H-pyrrolo [1,2-a ]]Pyrazine-1-one [120mg,0.34mmol]In 1, 4-dioxane [5 mL)]To the solution in (1) was added 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborane [129.5089mg, 0.51mmol%]、KAcO[99.9600mg，1.02mmol]、Pd(dppf)Cl ₂ [49.7080mg]. The reaction mixture was stirred at 100 ℃ for 16h. Completion of the reaction was detected by LCMS. The mixture was extracted with EA (50ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the product. Calculated value (M + H) ⁺ )C ₁₉ H ₂₂ BFN ₂ O ₃ :356.2, experimental values: 357.0.

and 7:4- (8- (4-fluorophenyl) -1-oxo-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrazin-7-yl) furo [3,4-b ] pyridin-5 (7H) -one

Then 8- (4-fluorophenyl) -7- (4, 5-trimethyl-1, 3, 2-dioxaborolan-2-yl) -2H,3H, 4H-pyrrolo [1,2-a ]]Pyrazine-1-one [50mg,0.14mmol]In 1, 4-dioxane [5 mL)]Adding 4-bromo-7H-furo [3,4-b ] to the solution]Pyridin-5-one [44.94mg,0.2100mmol]、Na ₂ CO ₃ [44.52mg，0.42mmol]、Pd(dppf)Cl ₂ [20.47mg，0.0280mmol]. The reaction mixture was stirred at 100 ℃ for 16h. Completion of the reaction was detected by LCMS. Filtering the solution and collecting the filtrate. The reaction mixture was concentrated under pressure. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,CDCl ₃ )δ8.39(d,J＝5.2Hz,1H),8.00(s,1H),7.69(s,1H),7.52(s,1H),7.01(dd,J＝10.0,6.8Hz,2H),6.72(d,J＝5.2Hz,1H),5.82(s,1H),5.28(s,1H),4.37–4.23(m,2H),3.76(s,2H)。

EXAMPLE 38 preparation of Compounds 2-50

As shown in fig. 38, the specific synthetic steps are as follows:

step 1:1- (4-fluorophenyl) -6-hydroxyhexane-1, 3-dione

To a mixture of NaH (60%, 0.56g,14.4 mmol) in dry ether (15 mL) was added ethanol (2 mL) at 0 deg.C under argon, followed by dihydrofuran-2 (3H) -one (0.62g, 7.2mmol). A solution of 1- (4-fluorophenyl) ethan-1-one (1g, 7.2mmol) in diethyl ether (5 mL) was then added slowly at 0 ℃. And the resulting suspension was allowed to warm slowly to room temperature. The reaction mixture was stirred at 25 ℃ for 72h. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₃ FO ₃ :224.23, experimental values: 224.8.

step 2:3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propan-1-ol

To a solution of 1- (4-fluorophenyl) -6-hydroxyhexane-1, 3-dione (500mg, 2.23mmol) in EtOH (20 mL) was added hydrazine hydrate (wt 80%,178mg, 4.46mmol). The mixture was stirred at 25 ℃ for 1h. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₃ FN ₂ O:220.25, experimental value: 220.8.

and 3, step 3:3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propyl methanesulfonate

To a solution of 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propan-1-ol (500mg, 2.27mmol) in DCM (20 mL) at 0 deg.C was added methanesulfonyl chloride (0.264 mL,3.4 mmol) and DIPEA (880mg, 6.8mmol). The mixture was stirred at 25 ℃ for 1h. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₃ H ₁₅ FN ₂ O ₃ S:298.33, experimental values: 298.8.

and 4, step 4:2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole

To a solution of propyl 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanesulfonate (300mg, 1.0 mmol) in DMF (15 mL) at 0 ℃ were added NaI (15.08mg, 0.1mmol) and NaH (29mg, 1.2mmol). The mixture was added at 0 ℃ for 0.5h, then stirred at 25 ℃ for 1h. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₁ FN ₂ :202.23, experimental value: 202.8.

and 5: 3-bromo-2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole

To 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (200mg, 0.99mmol) in CH ₃ NBS (264 mg, 1.48mmol) was added to a solution of CN (15 mL). The mixture was stirred at 25 ℃ for 2h. The reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₂ H ₁₀ BrFN ₂ :281.13, experimental value: 280.8.

and 6:4- (2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-amine

To 3-bromo-2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ]]To a solution of pyrazole (250mg, 0.89mmol) in EtOH/toluene =8 (15 mL) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (294mg, 1.3mmol), 2M Na ₂ CO ₃ Aqueous solution (1.5 mL) and Pd (dppf) Cl ₂ (130mg, 0.18mmol). The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. Will be provided withThe reaction mixture was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₅ FN ₄ :294.33, experimental values: 294.8. ¹ H NMR(400MHz,CDCl ₃ )δ8.45(s,2H),7.65–7.50(m,1H),7.48–7.35(m,2H),7.07(ddd,J＝8.7,5.3,1.9Hz,2H),6.61–6.36(m,2H),4.25(t,J＝7.1Hz,2H),3.09(t,J＝7.1Hz,2H),2.80–2.64(m,2H)。

EXAMPLE 39 preparation of Compounds 2-51

As shown in fig. 39, the specific synthetic steps are as follows:

4- (3, 4-tetramethylcyclopentyl) pyridin-2-amine (102mg, 0.46mmol), 2M Na ₂ CO ₃ Aqueous solution (0.5 mL) and Pd (dppf) Cl ₂ (45mg, 0.06mmol) 5-benzyl-3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] was added]Pyrazine (120mg, 0.31mmol) in EtOH/toluene =8 (5 mL). The mixture was stirred under nitrogen atmosphere on a microwave at 100 ℃ for 1h. The reaction mixture was concentrated under pressure. The residue was purified by preparative TLC (PE/EA = 1). The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₄ H ₂₂ FN ₅ :399.47, experimental values: 399.8.

and 2, step: 4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-amine

Reacting HCOONH ₄ (157mg, 2.5 mmol) and Pd/C (200 mg) were added 4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazin-3-yl) pyridin-2-amine (100mg, 0.25mmol) in MeOH (10 mL). The mixture was stirred at 60 ℃ for 2h. The solution was filtered, the filtrate was collected and the solution was concentrated under pressure. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₇ H ₁₆ FN ₅ :309.35, experimental values: 309.8.

EXAMPLE 40 preparation of Compounds 2-52

As shown in fig. 40, the specific synthetic steps are as follows:

step 1: (4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) carbamic acid tert-butyl ester

To 4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]Pyridine-2-amine (2000mg, 4.99mmol) to a solution in DCM (20 mL) was added (Boc) ₂ O (1631.7300mg, 7.485mmol), DIPEA (1287.4200mg, 9.98mmol), DMAP (121.7560mg, 0.9980mmol). The reaction mixture was stirred at 25 ℃ for 2h. Completion of the reaction was detected by LCMS. The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₉ H ₃₀ FN ₅ O ₂ 499.2, experimental values: 500.1.

and 2, step: (4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) carbamic acid tert-butyl ester

To (4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Pyrazin-3-yl) pyridin-2-yl) carbamic acid tert-butyl ester (1200mg, 2.39mmol) to a solution in EA (10 mL) were added Pd/C (800 mg) and AcOH (0.5 mL). The reaction mixture is reacted in H ₂ Stirring was continued for 2h at 25 ℃. Completion of the reaction was detected by LCMS. Filtering the solution and collecting the filtrate. The reaction mixture was concentrated under pressure. The organic phase was washed with 2M sodium carbonate solution (5 mL). The residue was extracted with EA (10ml × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₂ H ₂₄ FN ₅ O ₂ 409.2, experimental values: 410.1.

and step 3: (4- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) carbamic acid tert-butyl ester

To a solution of tert-butyl (4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) carbamate (230mg, 0.5603mmol) in THF (5 mL) was added formaldehyde (84.05mg, 2.8015mmol). The reaction mixture was stirred at 70 ℃ for 16h. Sodium triacetoxyborohydride (142.54mg, 0.6723mmol) was added.

The reaction mixture was stirred at 25 ℃ for 2h. Completion of the reaction was detected by LCMS. Subjecting the reaction mixture to pressureAnd (5) concentrating. The organic phase was washed with water (5 mL). The residue was extracted with EA (5 ml × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the product. The crude material was loaded onto a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₃ H ₂₆ FN ₅ O ₂ 423.2, experimental value: 424.0.

and 4, step 4:4- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-amine

To a solution of tert-butyl (4- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) carbamate (200mg, 0.47mmol) in DCM (4 mL) was then added HCl-dioxane (4 mL). The reaction mixture was stirred at 25 ℃ for 2h. Completion of the reaction was detected by LCMS. The reaction mixture was concentrated under pressure. The organic phase was washed with 2M sodium carbonate solution (5 mL). The residue was extracted with EA (5 ml _ 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the product. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,DMSO)δ7.83(d,J＝5.2Hz,1H),7.46–7.37(m,2H),7.21–7.14(m,2H),6.21(dd,J＝7.4,2.0Hz,2H),5.90(s,2H),4.16(t,J＝5.4Hz,2H),3.57(s,2H),2.90(t,J＝5.5Hz,2H),2.41(s,3H)。

EXAMPLE 41 preparation of Compounds 2-53

As shown in fig. 41, the specific synthetic steps are as follows:

step 1:1- (2- (4-fluorophenyl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

To 1- [2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-5-yl]Ethanone (1000mg, 2.5958mmol) in 1, 4-dioxane/H ₂ To a solution in O =10]Pyridine (767.18mg, 3.8937mmol) and Na ₂ CO ₃ (825.46mg，7.7874mmol)、Pd(dppf)Cl ₂ (379.51mg, 0.5191mmol). The reaction mixture was stirred at 100 ℃ for 16h. Reaction completion was detected by LCMS. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with DCM/MeOH (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₁ H ₁₈ FN ₅ O:375.1, experimental values: 376.0.

and 2, step: 4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -3, 3-dibromo-1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one

To 1- (2- (4-fluorophenyl) -3- (1H-pyrrolo [2, 3-b) over 6H at room temperature]Pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a]Pyrazin-5 (4H) -yl) ethan-1-one (500mg, 1.3319 mmol) in t-BuOH (10 mL) was added in small portions to Py-HBr ₃ (1704.83mg, 5.3276mmol). The reaction mixture was concentrated under pressure. The organic phase was washed with water (5 mL). The residue was extracted with EA (5 ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₁ H ₁₆ Br ₂ FN ₅ O ₂ :547.0, experimental values: 547.5.

and step 3:4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one

To 4- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazin-3-yl) -3, 3-dibromo-1, 3-dihydro-2H-pyrrolo [2,3-b]To a solution of pyridin-2-one (220mg, 0.4006mmol) in EA (5 mL) was added Pd/C (100 mg). Reaction mixture is reacted in H ₂ Stirring was continued for 5h at 25 ℃. Completion of the reaction was detected by LCMS. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,MeOD)δ8.09(dd,J＝50.2,26.5Hz,2H),7.45–7.34(m,2H),7.09(t,J＝8.8Hz,2H),7.02(dd,J＝14.8,5.2Hz,1H),4.78(d,J＝12.4Hz,2H),4.31(dt,J＝36.0,5.6Hz,2H),4.12(dt,J＝11.0,5.6Hz,2H),2.86(s,2H),2.19(d,J＝39.6Hz,3H)。

EXAMPLE 42 preparation of Compounds 2-54

As shown in fig. 42, the specific synthetic steps are as follows:

step 1: (4-Bromopyridin-2-yl) acetic acid

To a solution of 4-bromo-2-methylpyridine (4.0 g, 0.0233mol) in THF (30 mL) was added dimethyl carbonate (2.52g, 0.0279mol) and LDA (13.8 mL) at-78 deg.C. The mixture was stirred at-78 ℃ for 1h and at room temperature for 5h. LCMS showed reaction completion. Reacting with saturated NH ₄ Quenched with aqueous Cl and washed with water, extracted with EA, and Na ₂ SO ₄ And (5) drying. The crude product was purified by silica gel column (PE: etOAc = 4). The chemical formula is as follows: c ₈ H ₈ BrNO ₂ . Calculated value (M + H) ⁺ ) _: 230.06, experimental value: 231.1.

and 2, step: 2- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ] pyrazin-3-yl ] pyridin-2-yl } acetic acid methyl ester

To a solution of methyl 2- (4-bromopyridin-2-yl) acetate (150mg, 0.652mmol) in DMF (5 mL) at room temperature was added 2- (4-fluorophenyl) -5- (1-methylphenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazine (566.37mg, 1.304mmol), pd (dppf) Cl ₂ (53.2mg, 0.0652mmol) and K ₂ CO ₃ (180.23mg, 1.304mmol). Mixing the mixture in N ₂ Stirring was continued for 3h at 90 ℃. LCMS showed reaction completion. The solution was washed with brine and extracted with EA, over Na ₂ SO ₄ And (5) drying. The crude product was purified by silica gel column (PE: etOAc = 10) to yield the product. The chemical formula is as follows: c ₂₇ H ₂₅ FN ₄ O _2. Calculated value (M + H) ⁺ ): 456.52, experimental value: 457.1.

and 3, step 3:2- (4- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) acetic acid methyl ester

To 2- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ] at room temperature]Pyrazin-3-yl radicals]To a solution of methyl pyridin-2-yl } acetate (300mg, 0.6557mmol) in MeOH (10 mL) was added Pd/C (150 mg). The mixture was stirred for 6h. The reaction was filtered and the filtrate was concentrated under vacuum. The residue was purified by general preparative HPLC to give the product. The chemical formula is as follows: c ₂₁ H ₂₁ FN ₄ O _2. Calculated value (M + H) ⁺ ): 380.42, experimental value: 381.1.

¹ H NMR(400MHz,DMSO)δ8.41(d,J＝4.0Hz,1H),7.41–7.34(m,2H),7.18(t,J＝8.9Hz,2H),7.12-7.09(m,1H),7.02(dd,J＝5.1,1.5Hz,1H),4.19(t,J＝4.0Hz,2H),3.80(s,2H),3.65(s,2H),3.60(s,3H),2.92(t,J＝5.4Hz,2H),2.41(s,3H)。

EXAMPLE 43 preparation of Compounds 2-55

As shown in fig. 43, the specific synthetic steps are as follows:

step 1:1- (4-bromopyridin-2-yl) propan-2-one

To a solution of 4-bromo-2-methylpyridine (3g, 17.4 mmol) in THF (30 mL) was added LDA (13mL, 26mmol, 2N). The reaction mixture was stirred at-78 ℃ for 1h. N-methoxy-N-methylacetamide (2.69g, 26mmol) was added. The reaction mixture was stirred at 25 ℃ for 15h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₈ H ₈ BrNO:214.06, experimental value: 214.0.

step 2:1- (4- (5-benzyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) propan-2-one

To 2- (4-fluorophenyl) -5- (1-methylphenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ]]To a solution of pyrazine (6 g,13.9 mmol) in dioxane (30 mL) and water (5 mL) were added 1- (4-bromopyridin-2-yl) propan-2-one (2g, 9.3 mmol), potassium carbonate (2.57g, 18.6 mmol) and tetrakis (triphenylphosphine) palladium (1g, 0.9 mmol). The reaction mixture was stirred at 100 ℃ for 18h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and eluted with PE/EtOAc (1. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₇ H ₂₅ FN ₄ O:440.52, experimental value: 441.1.

and step 3:1- (4- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) propan-2-ol

To 1- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-3-yl radicals]To a solution of pyridin-2-yl } propan-2-one (1200 mg) in MeOH (30 mL) was added Pd/C (100 mg). The reaction mixture was stirred at 25 ℃ for 15h. Filtering the solution and collecting the filtrate. The reaction mixture was concentrated under pressure to yield the product. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₀ H ₂₁ FN ₄ O:352.41, experimental value: 353.8.

and 4, step 4:1- (2- (4-fluorophenyl) -3- (2- (2-hydroxypropyl) pyridin-4-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

To 1- {4- [2- (4-fluorophenyl) -4H,5H,6H, 7H-pyrazolo [1,5-a ] at 0 deg.C]Pyrazin-3-yl radicals]Pyridin-2-yl } propan-2-ol (300mg, 0.85mmol) and NaHCO ₃ (143mg, 1.7 mmol) to a solution of THF (10 mL) and water (10 mL) was added acetyl acetate (174mg, 1.7 mmol). The reaction mixture was stirred at 25 ℃ for 5h. The residue was extracted with THF (10 ml × 2). The reaction mixture was concentrated under pressure. The residue was purified by general preparative HPLC to give the product.

¹ H NMR(400MHz,MeOD)δ8.40(d,J＝5.3Hz,1H),8.32(s,1H),7.41(dd,J＝8.7,5.4Hz,2H),7.18–7.00(m,4H),4.30(dt,J＝34.8,5.2Hz,2H),4.10(ddd,J＝20.0,12.4,5.7Hz,3H),2.82(qd,J＝13.3,6.5Hz,2H),2.21(d,J＝35.0Hz,3H),1.21–1.11(m,3H)。

EXAMPLE 44 preparation of Compounds 2-56

As shown in fig. 44, the specific synthetic steps are as follows:

step 1:7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2, 3-dihydrofuro [3,2-b ] pyridine

To 3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine (100mg, 0.34mmol) in dioxane (5 mL) and water (0.5 mL) was added 7- (3, 4-tetramethylcyclopentylboran-1-yl) -2, 3-dihydrofuro [3,2-b ]]Pyridine (85.11mg, 0.35mmol), pd (dppf) Cl ₂ (10 mg,10% w/w)) and K ₃ PO ₄ (144.34mg, 0.68mmol). Placing the mixture in N ₂ Stirring was carried out at 90 ℃ for 4h under an atmosphere. The reaction mixture is diluted with water and the aqueous phase is extracted twice with EA, the organic phases are combined and concentrated under pressure. Purification of the residue by preparative TLC to give milkWhite solid product (77.92mg, 68.6%).

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₁₉ H ₁₇ FN ₄ O:336.37, experimental value: 337.

step 2:1- (3- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

To a solution of 7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2, 3-dihydrofuro [3,2-b ] pyridine (35mg, 0.10 mmol) in DCM (65 mL) at 0 deg.C was added TEA (20.24mg, 0.20 mmol), followed by the dropwise addition of acetyl chloride (8.64mg, 0.10 mmol). The mixture was stirred at 25 ℃ for 2h. The reaction mixture was diluted with water and the aqueous phase was extracted twice with DCM, the organic phases were combined and concentrated under pressure. The residue was purified by general preparative HPLC to give the product as a white solid (30.95mg, 78.6%).

The chemical formula is as follows: calculated value (M + H) ⁺ )：C ₂₁ H ₁₉ FN ₄ O ₂ 378.41, experimental value: 339.

EXAMPLE 45 preparation of Compounds 2-57

As shown in fig. 45, the specific synthetic steps are as follows:

step 1:1- (3- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

7-bromo-2, 3-dihydrofuro [3,2-b ] under nitrogen atmosphere at room temperature]Pyridine (68mg, 0.34mmol,1.0 equiv.) and 2- (4-fluorophenyl) -5-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] s]To a stirred mixture of pyrazine (121mg, 0.34mmol,1.0 equiv.) in toluene (15 mL) was added Cs ₂ CO ₃ (230mg, 0.69mmol,2.0 equiv.) and Pd (dppf) Cl ₂ CH ₂ Cl ₂ (28mg, 0.034mmol,0.1 equivalent). The resulting mixture was stirred at 100 ℃ for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1]Pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a]Pyrazin-5 (4H) -yl) ethan-1-one (36mg, 28%).

EXAMPLE 46 preparation of Compounds 2-58

As shown in fig. 46, the specific synthetic steps are as follows:

step 1:1- (3-bromo-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-5 (4H) -yl) ethan-1-one

To a solution of 7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4,5-b ] pyridine (150mg, 0.51mmol) in DCM (10 mL) at 0 deg.C was added TEA (103.21mg, 1.02mmol) followed by acetyl chloride (40.04mg, 0.51mmol) dropwise. The mixture was stirred at 25 ℃ for 2h. The reaction mixture was diluted with water and the aqueous phase was extracted twice with DCM, the organic phases were combined and concentrated under pressure. The residue was purified by preparative TLC to give a milk white solid product (147.14mg, 85.9%).

The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₄ H ₁₃ BrFN ₃ O:338.18, experimental value: 339.

and 2, step: 7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4,5-b ] pyridine

To 1- (3-bromo-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1,5-a ]]To a solution of pyrazin-5 (4H) -yl) ethan-1-one (35mg, 0.10 mmol) in dioxane (3 mL) and water (0.5 mL) was added 2-methyl-7- (3, 4-tetramethylcyclopentylboran-1-yl) -2, 3-dihydroisoxazolo [4,5-b ]]Pyridine (28.40mg, 0.11mmol), pd (dppf) Cl ₂ (3.5mg, 10% w/w) and K ₃ PO ₄ (42.45mg, 0.20mmol). Mixing the mixture in N ₂ Stirring was carried out at 90 ℃ for 4h under an atmosphere. The reaction mixture was diluted with water and the aqueous phase was extracted twice with EA, the organic phases were combined and concentrated under pressure. The residue was purified by general preparative HPLC to give the product as a white solid (15.27mg, 37.5%).

The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₁ H ₂₀ FN ₅ O ₂ :393.42, experimental values: 394.

EXAMPLE 47 preparation of Compounds 2-59

As shown in fig. 47, the specific synthetic steps are as follows:

step 1:7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4,5-b ] pyridine

To 3-bromo-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a]Pyrazine (100mg, 0.34mmol) in dioxane (5 mL) and water (0.5 mL) was added 2-methyl-7- (3, 4-tetramethylcyclopentylboran-1-yl) -2, 3-dihydroisoxazolo [4,5-b ]]Pyridine (87.78mg, 0.34mmol), pd (dppf) Cl ₂ (10mg, 10% w/w)) and K ₃ PO ₄ (144.34mg, 0.68mmol). Mixing the mixture in N ₂ Stirred at 85 ℃ for 6h under an atmosphere. The reaction mixture was diluted with water and the aqueous phase was extracted twice with EA, the organic phases were combined and concentrated under pressure. The residue was purified by preparative TLC to give the product as a grey solid (85.31mg, 71.9%).

The chemical formula is as follows: calculated value (M + H) ⁺ )C ₁₉ H ₁₈ FN ₅ O:351.39, experimental value: 352.

and 2, step: 7- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4,5-b ] pyridine

To a solution of 7- (2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4,5-b ] pyridine (50mg, 0.14mmol) in THF (65 mL) was added paraformaldehyde (4.50mg, 0.15mmol), and the mixture was stirred at 25 ℃ for 30min. Sodium cyanoborohydride () 17.60mg, 0.28mmol) was then added at 0 deg.C. The mixture was stirred at 25 ℃ for 2h. The reaction was quenched with water and extracted twice with EA. The organic phases were combined and concentrated under pressure. The residue was purified by general preparative HPLC to give the product as a white solid (24.91mg, 47.9%).

The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₀ H ₂₀ FN ₅ O:365.41, experimental value: 366.

EXAMPLE 48 preparation of Compounds 2-60

As shown in fig. 48, the specific synthetic steps are as follows:

step 1:7- (2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) furo [3,2-b ] pyridin-2 (3H) -one

To 3-bromo-2- (4-fluorophenyl) -5-methyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]To a solution of pyrazine (30mg, 0.10 mmol) in dioxane (3 mL) and water (0.3 mL) was added 7- (3, 4-tetramethylcyclopentylboran-1-yl) furo [3,2-b ]]Pyridin-2 (3H) -one (28.29mg, 0.11mmol), pd (dppf) Cl ₂ (3mg, 10% w/w) and K ₃ PO ₄ (42.45mg, 0.20mmol). Placing the mixture in N ₂ Stirred at 90 ℃ for 4h under an atmosphere. The reaction mixture was diluted with water and the aqueous phase was extracted twice with EA, the organic phases were combined and concentrated under pressure. The residue was purified by preparative TLC to give the product as a yellow solid (16.14mg, 45.8%).

The chemical formula is as follows: calculated value (M + H +) C ₂₀ H ₁₇ FN ₄ O ₂ :364.38, experimental value: 365.

EXAMPLE 49 preparation of Compounds 2-61

As shown in fig. 49, the specific synthetic steps are as follows:

step 1:7- (5-acetyl-2- (4-fluorophenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) furo [3,2-b ] pyridin-2 (3H) -one

To 1- [2- (4-fluorophenyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H,6H, 7H-pyrazolo [1,5-a ]]Pyrazin-5-yl]Ethanone (100mg, 0.259mmol) in 1, 4-dioxane/H ₂ To a solution in O =10]Pyridin-2 (3H) -one (83.23mg, 0.389mmol), na ₂ CO ₃ (82.546mg，0.778mmol)、Pd(dppf)Cl ₂ (37.951mg, 0.0519mmol). The reaction mixture was stirred at 100 ℃ for 16h. Completion of the reaction was detected by LCMS. The solution was filtered and the filtrate was collected. The reaction mixture was concentrated under pressure. The crude material was loaded onto a silica gel column and eluted with DCM/MeOH (10. The chemical formula is as follows: calculated value (M + H) ⁺ )C ₂₁ H ₁₇ FN ₄ O ₃ :392.3, experimental values: 393.0.

example 50 biological Activity

In the presence of 1 μ L CK1 δ inhibitor (e.g., a compound of the present application) or 4% DMSO (e.g., as a control), with a composition containing 50mM Tris, 10mM MgCl ₂ CK 1. Delta. Kinase assays were performed with 1mM dithiothreitol, 100. Mu.g/mL BSA with 10. Mu.M ATP, 2nM wild-type CK 1. Delta. And 42. Mu.M peptide substrate PLRTLpSVASLPGL (Flotow et al, 1990) in buffer (40. Mu.L, pH 7.5). Incubating the reaction mixture at 25 ℃ for 85min; detection was performed as described for Kinase-Glo assay (Promega). The luminescence output was measured on a Perkin Elmer Envision microplate reader (Perkin Elmer, waltham, MA).

Bmal1-dLuc or Per2-dLuc U2OS cells were suspended in medium (DMEM supplemented with 10% fetal bovine serum, 0.29mg/mL L-glutamine, 100 units/mL penicillin, and 100mg/mL streptomycin) and plated at 200. Mu.L (10,000 cells) Per well on 96-well white solid bottom plates. After 2 days, 100. Mu.L of explant (explant) medium (DMEM supplemented with 2% B27, 10mM HEPES, 0.38mg/mL sodium bicarbonate, 0.29mg/mL L-glutamine, 100 units/mL penicillin, 100mg/mL streptomycin, 0.1mg/mL gentamicin, and 1mM fluorescein, pH 7.2) was dispensed per well followed by 1. Mu.L of the compound of the present application (dissolved in DMSO; final concentration in DMSO is 0.7%). The plate was covered with an optically clear film and set to a microplate reader (Infinite M200, tecan). Luminescence values were recorded every 1h for 3 to 4 days. The cycle parameters were obtained from the luminous rhythm by the curve fitting programs cellula rhythm or MultiCycle (Actimetrics), both programs producing similar results.

The CK1 δ inhibition results (IC 50) are summarized in table 5.

TABLE 5

An "-" in table 5 indicates that the value exceeds the measurement range, e.g. the value >100000.

The CK1 δ inhibition results (EC 50) are summarized in table 6.

TABLE 6

An "-" in table 6 indicates that the value exceeds the measurement range, e.g. the value >30.

Example 51 drug transport assay

Preparation of Caco-2 cells

To each well of the Transwell insert (insert) and reservoir (reservoir) were added 50. Mu.L and 25mL of cell culture medium, respectively. Then HTS transwell plates were treated at 37 ℃ with 5% CO ₂ Incubation was continued for 1 hour, followed by cell seeding.

Caco-2 cells were diluted to 6.86X 10 with medium ⁵ Individual cells/mL and 50 μ L of cell suspension was dispensed into the filtration wells of a 96-well HTS Transwell plate. The cells were assayed at 37 ℃ and 5% CO ₂ Cell culture in a cell incubator at 95% relative humidity for 14 to 18 days. The cell culture medium was replaced every other day, starting no more than 24 hours after the initial planting.

Preparation of stock solutions

Stock solutions of 10mM test compound were prepared in DMSO. Positive control stock solutions were prepared in DMSO at a concentration of 10 mM. In this assay Digoxin (Digoxin) and propranolol (propranolol) were used as control compounds.

Assessing cell monolayer integrity

The medium was removed from the reservoir and each Transwell insert and replaced with pre-warmed fresh medium.

Trans-epithelial resistance across the monolayer (TEER) was measured using the Millicell epithelial voltage resistance measurement system (Millipore, USA).

At the end of the measurement, the plate is returned to the incubator.

TEER values were calculated according to the following formula:

TEER measurement (ohm) membrane area (cm) ² ) = TEER value (ohm cm) ² )

The TEER value should be greater than 230ohm cm ² Acceptable Caco-2 monolayers are indicated.

Analysis program

The Caco-2 plates were removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) and then incubated at 37 ℃ for 30 minutes.

Stock solutions of control and test compounds were diluted in DMSO to give a 1mM solution, and then diluted with HBSS (10 mM hepes, ph 7.4) to give a 5 μ M working solution. The final concentration of DMSO in the incubation system was 0.5%.

To determine the drug transport rate in the apical to basolateral direction, 125 μ L of a 5 μ M working solution of the control compound and test compound was added to the Transwell insert (apical chamber) and 50 μ L of the sample (D0 sample) was immediately transferred from the apical chamber to a new 96-well culture plate. The wells receiving the plates (substrate outside chamber) were filled with 235. Mu.L of HBSS (10 mM HEPES, pH 7.4).

To determine the drug transport rate from the basolateral to the apical direction, 285 μ L of a 5 μ M working solution of the control compound and test compound was added to the wells of the receiver plate (basolateral compartment) and 50 μ L of the sample (D0 sample) was immediately transferred from the basolateral compartment to a new 96-well plate. The wells of the Transwell insert (apical chamber) were filled with 75. Mu.L of HBSS (10 mM HEPES, pH 7.4). Duplicate analyses were performed.

The plates were incubated at 37 ℃ for 2 hours.

After incubation, 50 μ L of sample from the donor side (apical chamber for apical flow to basal outside (Ap → Bl) and basal lateral chamber for basal outside flow to apical (Bl → Ap)) and the receiver side (basal lateral chamber for apical flow to basal outside (Ap → Bl) and apical chamber for basal outside flow to apical (Bl → Ap)) was transferred to wells of a new 96 well plate, followed by addition of 4 volumes of cold methanol containing the appropriate Internal Standard (IS). The sample was vortexed for 5 minutes and then centrifuged at 3,220g for 40 minutes. A100. Mu.L aliquot of the supernatant was mixed with an appropriate volume of ultrapure water and then subjected to LC-MS/MS analysis.

To determine the fluorescein leakage results after a 2 hour run period, fluorescein stock solutions were prepared in water and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100. Mu.M. To each Transwell insert (apical chamber) was added 100. Mu.L of fluorescent yellow solution, followed by filling the wells receiving the plates (basolateral chamber) with 300. Mu.L of HBSS (10 mM HEPES, pH 7.4). These plates were incubated at 37 ℃ for 30 minutes. 80 μ L of sample was removed directly from the apical and basolateral wells (using basolateral channel wells) and transferred to wells of a new 96-well plate. Fluorescent yellow fluorescence signals (to monitor monolayer integrity) were measured in a luciferase reader with 485nM excitation and 530nM emission.

Data analysis

The apparent permeability coefficient (P) of the Caco-2 drug transport assay can be calculated using the formula _app ) In units of centimeters/second:

P _app ＝(V _A x [ medicine)] _{Receiving body} ) /(area × time × [ drug)] _{Initial, donor} )

Wherein V _A Volume of receiving well (mL), area is the surface area of the membrane (0.143 cm for a Transwell-96 well-permeable support) ² ) And time is the total transit time (in seconds).

The efflux rate will be determined using the following formula:

efflux ratio = P _app(B-A) /P _app(A-B)

Wherein P is _app(B-A) Denotes the apparent permeability coefficient in the direction from the outside of the substrate to the tip, and P _app(A-B) Indicating the apparent permeability coefficient in the direction from the top to the outside of the substrate.

Recovery can be determined using the following formula:

recovery% = (V) _A X [ medicine] _{Receiver body} +V _D X [ medicine] _Donor )/(V _D X [ medicine] _{Initial, donor} )

Wherein V _A Volume in the receiving well (in mL) (0.235 mL for flow from the top to the outside of the base (Ap → Bl) and 0.075mL for flow from the outside of the base to the top (Bl → Ap)), V _D Is the volume in the donor well (in mL) (0.075 mL for flow from the apical end to the outer side of the base (Ap → Bl) and 0.235mL for flow from the outer side of the base to the apical end (Bl → Ap)).

The yellow leakage rate can be calculated in percent (%) using the following formula:

% LY leakage rate =100 × [ LY × [] _{Receiver body} /([LY] _{Donor body} +[LY] _{Receiving body} )

LY leak rates <1% were acceptable, indicating an acceptable Caco-2 monolayer.

P _app(B-A) 、P _app(A-B) And the efflux ratio are summarized in table 7.

TABLE 7

Compound (I)	P _app(A-B) (10 ^-6 ，cm/s)	P _app(B-A) (10 ^-6 ，cm/s)	Efflux rate
				Digoxin	0.30	16.98	56.52
Propranolol	26.55	13.63	0.51
				2-43	8.5	30.8	3.6
2-50	19.25	17.32	0.9
				2-52	22.76	23.87	1.05

Example 52 intrinsic Clearance analysis

1. The main solution was prepared according to table 8.

TABLE 8

Reagent	Reserve concentration	Volume of	Final concentration
				Phosphate buffer	200mM	200μL	100mM
Ultra pure H ₂ O	-	106μL	-
				MgCl ₂ Solutions of	50mM	40μL	5mM

2. Three independent experiments were performed as follows. a) Using NADPH: mu.L of 20mg/mL liver microsomes and 40. Mu.L of 10mM NADPH were added to the incubation. The final concentrations of microsomes and NADPH were 0.5mg/mL and 1mM, respectively. b) Without NADPH: 10. Mu.L of 20mg/mL liver microsomes and 40. Mu.L of ultrapure H ₂ And adding O for cultivation. The final concentration of microsomes was 0.5mg/mL. c) NADPH-free heat-inactivated microsomes: 10 μ L of 20mg/mL heat-inactivated liver microsomes and 40 μ L of ultrapure H ₂ And adding O for cultivation. The final concentration of microsomes was 0.5mg/mL.

3. The reaction was started by adding 4. Mu.L of a 200. Mu.M test compound solution or a control compound solution at a final concentration of 2. Mu.M and was carried out at 37 ℃.

4. Aliquots of 50. Mu.L were taken from the reaction solution at 0, 15, 30, 45 and 60 min. The reaction was stopped by adding 4 volumes of cold acetonitrile containing internal standards (100 nM alprazolam, 200nM labetalol, 200nM caffeine and 2. Mu.M tyroprofen). The sample was centrifuged at 3,220g for 40 minutes. Mixing 100 μ L of the supernatant with 100 μ L of ultrapure H ₂ O mixed and then subjected to LC-MS/MS analysis.

5. Data analysis

All calculations were performed using Microsoft Excel.

The peak area was determined from the extracted ion chromatogram. The slope value k was determined by linear regression of the curve of the natural logarithm of the remaining percentage of parent drug versus incubation time.

In vitro half-life (in vitro t) _1/2 ) Determined by the slope value:

ex vivo t _1/2 ＝-(0.693/k)

In vitro t using the formula _1/2 (min) into in vitro intrinsic clearance (in vitro CL) _int In μ L/min/mg protein) (average of two determinations):

in vitro CL _int = 0.693 × incubation volume (μ l)/(t ex vivo) _1/2 * Amount of protein (mg)

In vitro t using the formula _1/2 (min) conversion to amplified unbound intrinsic clearance (amplified CL) _int In mL/min/kg) (average of two determinations):

the scale factors for predictive values of intrinsic clearance in liver microsomes are summarized in table 9.

TABLE 9

Iwatsubo et al, davies and Morris,1993, 10 (7) pages 1093-1095.

Barter et al, 2007, curr Drug Metab,8 (1), pages 33-45; iwatsubo et al, 1997, JPET,283, pages 462-469.

Papp (B-A), papp (A-B) and efflux rates are summarized in Table 10.

Watch 10

While preferred embodiments of the present application have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. The present invention is not intended to be limited to the specific examples provided in the specification. While the invention has been described with reference to the foregoing specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Further, it is to be understood that all aspects of the present invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the application described herein may be employed in practicing the invention. It is therefore contemplated that the present invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the application and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula I:

wherein Ar is ¹ Is optionally via one or more R ₁ Aryl substituted by a substituent, and R ₁ Each independently selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethyl, perfluoroalkoxy, hydroxyl, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxide, wherein the substituent on the sulfur atom is alkyl, sulfonamide,

amino and N-monosubstituted or N, N-disubstituted amino,

wherein the substituents on the amino nitrogen are selected from the group consisting of: hydride ions, hydrocarbyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl, hydrocarboyl, arylsulfonyl and alkylsulfonyl groups, or wherein the amino nitrogen forms a 5-to 8-membered heterocyclyl or heteroaryl ring group with the two substituents attached thereto;

wherein X ₁ 、X ₂ And X ₃ Each independently is C or N;

R ₇ is absent or is-CN;

a is absent and is

Or a ring A, or a ring B,

wherein R is ₂ is-NH ₂ -CN or Z, in the presence of a catalyst,

wherein-X is-O, -S or-NQ,

-Y is a hydride ion, a hydrocarbyl or a hydrocarbyl aryl,

wherein R is ₃ Is a halogen or a-CN group,

wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group in which up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and optionally said ring A is substituted by R ₄ Substituent group(s), and R ₄ Is = O;

b is absent and is

Or a ring (B) of a cyclic structure,

Wherein R is ₁₀ Is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said R ₁₀ Optionally via R ₈ Substituted by a substituent, said R ₈ The substituent being C ₁ -C ₆ An alkyl group, which is a radical of an alkyl group,

wherein R is ₅₂ Independently selected from the group consisting of: azido, hydride ion, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and aryl substituted with one or more substituents selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylalkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyl, alkoxycarbonyl-alkyl, heterocyclooxy, hydroxycarbonyl-alkyl, heterocyclooxy, cyclohydrocarbylthio, cyclohydrocarbyloxy, cyclohydrocarbylthio, etcCycloalkylamino, heteroarylalkoxy, heteroarylalkylthio, heteroarylalkylamino, arylalkoxy, arylalkylthio, arylalkylamino, heterocyclyl, heteroaryl, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, arylalkylacyl, hydrocarbyloxy, arylalkylacyloxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkoxy, hydrocarbylthio, hydrocarbylalkoxyalkylthio, hydrocarbyloxycarbonyl, hydroxycarbonylalkoxy, hydrocarbyloxycarbonylalkyl, alkylhydroxycarbonylthio, hydrocarbyloxycarbonylalkoxy, hydrocarbyloxycarbonylalkoxythio, amino, alkylcarbonylamino, arylcarbonylamino, cycloalkylcarbonylamino, heterocyclocarbonylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, heterocycloalkoxy, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroaryl-sulfonylamino, heteroarylalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino and N-monosubstituted or N, N-disubstituted aminoalkyl,

wherein the substituents on the amino hydrocarbyl nitrogen are selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl and hydrocarbonacyl radicals, or wherein the aminoalkyl nitrogen forms, with the two substituents attached thereto, a 5-to 8-membered heterocyclyl or heteroaryl ring radical,

wherein R is ₆ Is C ₁ -C ₆ Alkyl or R ₆₁ ，

Wherein R is ₆₁ Independently selected from the group consisting of: an azido group, a hydride ion, a hydrocarbyl group, an amido group, a hydrocarbylamino group, a halohydrocarbyl group, a perhalohydrocarbyl group, and an aryl substituent optionally substituted with one or more substituents selected from the group consisting of: halogen, alkyl, alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylalkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyl, alkoxycarbonylalkyl, heterocyclooxy, hydroxycarbonylalkyl, heterocycloothio, heterocyclooamino, cycloalkyloxy, cycloalkylthio, heterocyclooxy, and heterocyclooxyCycloalkylamino, heteroarylalkoxy, heteroarylalkylthio, heteroarylalkylamino, arylalkoxy, arylalkylthio, arylalkylamino, heterocyclyl, heteroaryl, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, arylhydrocarbonyl, hydrocarbyloxy, arylalkyloxy, hydroxyalkyl, hydroxyalkoxyl, hydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylalkoxy, hydrocarbyloxycarbonylalkyl, alkylhydroxycarbonylthio, hydrocarbyloxycarbonylalkoxy, hydrocarbyloxycarbonylalkoxythio, amino, alkylcarbonylamino, arylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, heterocycloalkoxy, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino and N-monosubstituted or N, N-disubstituted aminoalkyl,

wherein the substituents on the nitrogen atom of the amino hydrocarbyl group are selected from the group consisting of: alkyl, aryl, arylalkyl, cycloalkyl, arylalkyloxycarbonyl, alkyloxycarbonyl and hydrocarboyl groups, or wherein the aminoalkyl nitrogen forms a 5-to 8-membered heterocyclyl or heteroaryl ring group with the two substituents attached thereto, and

wherein ring B is 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring B is optionally substituted by R ₉ Is substituted by a substituent, and the R ₉ Is PMB, wherein PMB represents a group

2. The method of claim 1, wherein R ₁ Is F.

3. The method of any one of claims 1-2, wherein the compound of formula I comprises the one R ₁ And (4) a substituent.

4. The method of any one of claims 1 to 3, wherein R ₃ Is F or-CN.

5. The method of any one of claims 1-4, wherein A is selected from the group consisting of:

6. the method of any one of claims 1 to 5, wherein R ₅ is-COO-CH ₂ CH ₃ or-CO-R ₁₀ 。

7. The method of claim 6, wherein R ₁₀ Is composed of

8. The method of claim 7, wherein R ₈ is-CH ₃ 。

9. The method of any one of claims 1 to 8, wherein R ₆ is-CH ₃ 。

10. The method of any one of claims 1-9, wherein B is selected from the group consisting of:

11. the method of any one of claims 1 to 10, wherein the compound is selected from the group consisting of:

12. the method of any one of claims 1 to 11, wherein X ₁ Is C, X ₂ Is C, X ₃ Is N, R ₇ Is absent, A is

And B is

Wherein R is ₂ Is Z, Z is-NR ₂₃ R ₂₄ ，

R ₂₃ Is hydride ion or C ₁ -C ₆ A hydrocarbon group, R ₂₄ Independently selected from the group consisting of: hydride ions, lower alkyl, aryl lower alkyl, hydroxy lower alkyl and 2-pyridyl lower alkyl, 3-pyridyl lower alkyl and 4-pyridyl lower alkyl;

Ar ¹ is aryl substituted by halogen or halogeno, lower alkyl or alkoxy;

R ₆ is R ₆₁ ，R ₆₁ Is hydride ion or C ₁ -C ₆ A hydrocarbyl group; and is

R ₅ Is R ₅₂ ，R ₅₂ Is a hydride ion or a lower alkyl group.

13. The method of any one of claims 1 to 12, wherein X ₁ Is C, X ₂ Is C, X ₃ Is N, R ₇ Is absent, A is

And B is

Wherein R is ₂ Is Z, Z is-OR ₂₅ ，

R ₂₅ Is a hydride ion, C ₁ -C ₆ Alkyl or aryl lower alkyl;

Ar ¹ aryl independently substituted with halogen, lower alkyl or alkoxy;

R ₆ is R ₆₁ ，R ₆₁ Is C ₁ -C ₆ A hydrocarbyl group; and is provided with

R ₅ Is R ₅₂ ，R ₅₂ Is a hydride ion.

14. The method of any one of claims 1 to 13, wherein X ₁ Is C, X ₂ Is C, X ₃ Is N, R ₇ Is absent, A is

And B is

Wherein R is ₂ is-CN;

Ar ¹ is aryl substituted by halogen, lower alkyl or alkoxy;

R ₆ is R ₆₁ ，R ₆₁ Is lower alkyl; and is

R ₅ Is R ₅₂ ，R ₅₂ Is a hydride ion or a lower alkyl group.

15. A method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula II:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

X ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₅ and X ₆ Each independently being C or N,

R ₂ is absent or is = O,

R ₃ is absent or is a-CN group,

a is absent and is

Or a ring (A) of the cyclic structure,

wherein R is ₄ Is a halogen, and the halogen is a halogen,

wherein R is ₅ Selected from the group consisting of: -NH ₂ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ alkyl-OH and C ₁ -C ₆ alkyl-O-CO-C ₁ -C ₆ An alkyl group, which is a radical of an alkyl group,

wherein ring A is 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring A is optionally substituted by R ₆ Substituted by a substituent, said R ₆ Is the range of = O,

b is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said B is optionally substituted by one or more R ₇ Is substituted by a substituent group, and

wherein R is ₇ Each independently selected from the group consisting of: CO-C ₁ -C ₆ Alkyl, bn, = O, C ₁ -C ₆ Alkyl, CO-NH-C ₁ -C ₆ Alkyl radical、CO-C ₁ -C ₆ alkyl-CN, R ₈ 、R ₈ -C ₁ -C ₆ Alkyl and CO-R ₈ -C ₁ -C ₆ Alkyl radical, wherein R ₈ Is a 4 to 7 membered cycloalkyl or heterocycloalkyl or 5 to 6 membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-.

16. The method of claim 15, wherein R ₁ Is F.

17. The method of any one of claims 15 to 16, wherein n is 1.

18. The method of any one of claims 15 to 16, wherein n is 2.

19. The method of any one of claims 15-18, wherein R ₄ Is F.

20. The method of any one of claims 15-19, wherein R ₅ Selected from the group consisting of: -NH ₂ 、-CH ₃ 、-CH ₂ -NH-CH ₃ 、-CH ₂ -OH and-CH ₂ -O-CO-CH ₃ 。

21. The method of any one of claims 15-20, wherein a is selected from the group consisting of:

22. the method of any one of claims 15-21, wherein R ₇ Each independently selected from the group consisting of: -Bn, = O, -CH ₃ 、-CO-CH ₃ 、-CO-CH ₂ -CH ₃ 、-CO-CH-(CH ₃ ) ₂ 、-CO-NH-CH ₃ 、-CO-CH ₂ -CN、R ₈ 、R ₈ -CH ₃ and-CO-R ₈ -CH ₃ Wherein R is ₈ Is composed of

23. The method of any one of claims 15-22, wherein R ₇ The number of (2) is 1 or 2.

24. The method of any one of claims 15-23, wherein B is selected from the group consisting of:

25. the method of any one of claims 15 to 24, wherein the compound is selected from the group consisting of:

26. a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula III:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

X ₁ and X ₂ Each independently being C or N,

a is absent and is

Or a ring A, or a ring B,

ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring C is optionally substituted by R ₃ Substituent(s) substituted, R ₃ Is the range of = O,

c is

Or a ring C, or a ring of the formula,

wherein R is ₄ is-CN, -COO-C ₁ -C ₆ An alkyl group or an amide group,

R ₅ is C ₁ -C ₆ Alkyl radical, and

ring C is 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said ring C is optionally substituted by R ₆ Substituent group, R ₆ Is = O.

27. The method of claim 26, wherein R ₁ Is F.

28. The method of any one of claims 26 to 27, wherein n is 1.

29. According to claim 26The method of any one of to 28, wherein R ₂ is-CH ₃ 。

30. The method of any one of claims 26 to 29, wherein a is

31. The method of any one of claims 26-30, wherein R ₄ is-CN, -CO-NH ₂ or-COO-CH ₃ 。

32. The method of any one of claims 26 to 31, wherein R ₅ is-CH ₃ 。

33. The method of any one of claims 26-32, wherein C is selected from the group consisting of:

34. the method of any one of claims 26 to 33, wherein the compound is selected from the group consisting of:

35. a method of inhibiting CK1 δ or CK1 e activity comprising administering an effective amount of a compound of formula IV:

wherein R is ₁ Is a halogen, and the halogen is a halogen,

n is 0, 1 or 2,

R ₂ is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are replaced by a heteroatom selected from = N-and-O-, and said R ₂ Optionally via R ₃ Is substituted by a substituent, and R ₃ Is = O.

36. The method of claim 35, wherein R ₁ Is F.

37. The method of any one of claims 35 to 36, wherein n is 1.

38. The method of any one of claims 35 to 37, wherein R ₂ Is composed of

39. The method of any one of claims 35 to 38, wherein the compound is one of:

40. the method of any one of claims 1 to 39, wherein the method is an in vitro method, an ex vivo method, or an in vivo method.

41. A method of treating a neurological and/or psychiatric disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the disease or condition is a mood disorder, a sleep disorder, or a circadian rhythm disorder.

43. The method of claim 42, wherein the mood disorder is selected from the group consisting of: depression and bipolar disorder.