JPWO2019167000A5

JPWO2019167000A5 -

Info

Publication number: JPWO2019167000A5
Application number: JP2020544607A
Authority: JP
Publication date: 2023-06-26
Anticipated expiration: 2039-03-01

Description

本発明のさらなる態様によれば、式（Ｉ）の化合物、またはその互変異性体、立体異性体、Ｎ－オキシド、薬学的に許容される塩、もしくは溶媒和物を調製する方法であって、
前記方法は、
（ａ）式（Ａ）の化合物：

［式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｑ、Ｘ、ａ、ｂは、式（Ｉ）の化合物について上記で定義したとおりであり、
Ｐは、保護基（例えば、２－（トリメチルシリル）エトキシメチル；ＳＥＭ）を表すか、または水素であり、
Ｚは、金属残基（例えば、ハロゲン化亜鉛、例えば、塩化亜鉛）または脱離基（例えば、ハロゲン、例えば、ヨウ素または臭素）である。］
またはその保護誘導体を、式（Ｂ）の化合物：

［式中、
Ｒ^８、Ｒ^９、Ｒ^１０、Ａ、ｃは、式（Ｉ）の化合物について上記で定義したとおりであり、
Ｖは、金属またはメタロイド残基（例えば、ボロン酸、ボロン酸ピナコール、ハロゲン化マグネシウムまたはハロゲン化亜鉛、例えば、ボロン酸、ボロン酸ピナコール）または脱離基（例えば、ハロゲン）を表す。］
またはその保護体とカップリングさせ、次いで、保護基を除去するのに適した脱保護反応を実施する工程、
（ｂ）式（Ｃ）の化合物：

［式中、
Ｒ^８、Ｒ^９、Ｒ^１０、Ａ、ｃは、式（Ｉ）の化合物について上記で定義したとおりであり、
Ｘは、ＣＨであり、
Ｐは、保護基（例えば、２－（トリメチルシリル）エトキシメチル；ＳＥＭ）を表すか、または水素であり、
Ｌは、脱離基（例えば、塩化物）である。］
またはその保護誘導体を、式（Ｄ）の化合物：

［式中、
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｑ、ａ、ｂは、式（Ｉ）の化合物について上記で定義したとおりである。］
またはその保護誘導体とカップリングさせる工程、
（ｃ）式（Ｋ）の化合物：

［式中、
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｑ、ａ、ｂおよびｃは、式（Ｉ）の化合物について上記で定義したとおりであり、
Ｐは、アミン保護基（例えば、２－（トリメチルシリル）エトキシメチル；ＳＥＭ）、Ｎ，Ｎ－ジメチルスルファモイルまたは水素を表し、
Ｌ^３は、脱離基（例えば、ハロゲン、例えば、臭素）である。］
またはその保護誘導体を、
（ｉ）金属触媒（例えば、（１，３－ジイソプロピルイミダゾール－２－イリデン）（３－クロロピリジル）パラジウム（ＩＩ）ジクロリド）の存在下で、式ＣＨ_３Ｍ（式中、Ｍは金属である。）の有機金属種（例えば、ＣＨ_３－Ｚｎ－Ｈａｌ、ここで、Ｈａｌはハロゲンであり、例えば、塩化物、臭化物またはヨウ化物である。）と反応させて、Ｒ^１が－ＣＨ_３である式（Ｉ）の化合物を得る工程、または
（ｉｉ）光酸化還元触媒（例えば、［Ｉｒ｛ｄＦＣＦ_３ｐｐｙ｝_２（ｂｐｙ）］ＰＦ_６）、金属触媒（例えば、塩化ニッケル（ＩＩ）エチレングリコールジメチルエーテル錯体）、リガンド（例えば、４，４’－ジ－ｔｅｒｔ－ブチル－２，２’－ジピリジル）、塩基（例えば、リン酸二カリウム）、および光源（例えば、青色ＬＥＤ）の存在下で、ボロン酸アルキル（例えば、カリウム（２－トリメチルシリル）－エトキシメチルトリフルオロボレート）と反応させて、Ｒ^１が－ＣＨ_２ＯＨである式（Ｉ）の化合物を得る工程のいずれかの工程、
（ｄ）式（Ｒ）の化合物：

［式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｑ、ａ、ｂ、ｃ、Ａは、式（Ｉ）の化合物について上記で定義したとおりであり、
Ｌ^１は、適切な脱離基（例えば、ハロゲン）を表す。］
またはその保護誘導体を、ヒドラジンまたはヒドラジン保護誘導体を使用して環化する工程、
を含み、
いずれの場合も、引き続き必要に応じて脱保護工程を含んでいてもよく、あるいは
前記方法は、（ｅ）式（Ｉ）の化合物の保護誘導体を脱保護する工程を含み、あるいは
前記方法は、（ｆ）式（Ｉ）の化合物またはその保護誘導体を、式（Ｉ）のさらなる化合物またはその保護誘導体へ相互変換する工程を含み、あるいは
前記方法は、（ｇ）必要により、式（Ｉ）の化合物の薬学的に許容される塩を形成する工程を含んでもよい、前記方法を提供する。
According to a further aspect of the invention, a method of preparing a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, comprising: ,
The method includes:
(a) a compound of formula (A):

[In the formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Q, X, a, b are as defined above for compounds of formula (I);
P represents a protecting group (e.g. 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen;
Z is a metal residue (eg zinc halide, eg zinc chloride) or a leaving group (eg halogen, eg iodine or bromine). ]
or a protected derivative thereof, a compound of formula (B):

[In the formula,
R ⁸ , R ⁹ , R ¹⁰ , A, c are as defined above for compounds of formula (I);
V represents a metal or metalloid residue (eg boronic acid, pinacol boronate, magnesium or zinc halide, eg boronic acid, pinacol boronate) or a leaving group (eg halogen). ]
or coupling with its protected form, followed by a suitable deprotection reaction to remove the protecting group;
(b) a compound of formula (C):

[In the formula,
R ⁸ , R ⁹ , R ¹⁰ , A, c are as defined above for compounds of formula (I);
X is CH;
P represents a protecting group (e.g. 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen;
L is a leaving group (eg chloride). ]
or a protected derivative thereof, a compound of formula (D):

[In the formula,
^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , Q, a, b are as defined above for compounds of formula (I). ]
or coupling with a protected derivative thereof;
(c) compounds of formula (K):

[In the formula,
^R2 , ^R3 ^, ^R4 , ^R5 , ^R6 , ^R7 , R8, ^R9 , ^R10 , Q, a, b and c are as defined above for compounds of formula (I); ,
P represents an amine protecting group (eg 2-(trimethylsilyl)ethoxymethyl; SEM), N,N-dimethylsulfamoyl or hydrogen;
^L3 is a leaving group (eg halogen, eg bromine). ]
or a protected derivative thereof,
(i) in the presence of a metal catalyst such as (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride of the formula CH ₃ M, where M is a metal .) with an organometallic species (eg, CH ₃ —Zn—Hal, where Hal is a halogen, such as chloride, bromide, or iodide) to give R ¹ is —CH ₃ . obtaining a compound of formula (I), or
(ii) photoredox catalysts (e.g. [Ir{ _dFCF3ppy } ₂ (bpy)] _PF6 ), metal catalysts (e.g. nickel(II) chloride ethylene glycol dimethyl ether complex), ligands (e.g. 4,4') -di-tert-butyl-2,2'-dipyridyl), a base (e.g. dipotassium phosphate), and a light source (e.g. a blue LED), an alkyl boronate (e.g. potassium (2-trimethylsilyl) -ethoxymethyltrifluoroborate) to give compounds of formula (I) wherein R ¹ is -CH ₂ OH,
(d) compounds of formula (R):

[In the formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Q, a, b, c, A are defined above for compounds of formula (I) as defined,
L ¹ represents a suitable leaving group (eg, halogen). ]
or cyclizing a protected derivative thereof using hydrazine or a hydrazine protected derivative;
including
In either case, optionally followed by a deprotection step, or
(e) deprotecting the protected derivative of the compound of formula (I), or
( f ) interconverting a compound of formula (I) or a protected derivative thereof to a further compound of formula (I) or a protected derivative thereof, or
(g ) optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

Claims

Compounds of formula (I):

[In the formula,
X is CH or N;
R ¹ is hydrogen, —CH ₃ or —CH ₂ OH, provided that when X is N, R ¹ is selected from —CH ₃ and —CH ₂ OH;
^R2 and ^R3 are
(i) independently selected from hydrogen and C _1-4 alkyl, or
(ii) together form a 1-3 membered bridging group selected from C _1-3 alkylene, C _2-3 alkenylene, methylene-NR ^q -methylene and methylene-O-methylene, wherein said bridging group is optionally substituted with a group selected from C _1-4 alkyl, hydroxy and halogen, R ^q is selected from hydrogen, C _1-4 alkyl, hydroxy and halogen;
is either
Q is C or N;
If Q is C,
(i) R ⁴ ^is hydrogen or C _1-4 alkyl (eg methyl) optionally substituted with amino C _1-4 alkyl (eg —CH ₂ NH ₂ ); is hydrogen, amino, hydroxy or C _1-4 alkyl (eg methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxy and amino C _1-4 alkyl ( —CH ₂ OH), with the proviso that both R ⁴ and R ⁵ must not be selected from amino and C _1-4 alkyl substituted with amino, or
(ii) R ⁴ and R ⁵ together with Q form a 4- to 6-membered nitrogen-containing heterocycle;
is either
If Q is N,
^R4 is absent,
^R5 is hydrogen, and
R ² and R ³ together form a 1- to 3-membered bridging group;
R ⁶ and R ⁷ are independently selected from halogen (eg fluorine), C _1-4 alkyl (eg —CH ₃ ) and hydroxy, provided that when Q is N, R ⁶ or R ⁷ is halogen is neither hydroxy nor hydroxy, a is selected from 0, 1 and 2, b is selected from 0, 1 and 2,
Ring A is
(i) a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring) optionally containing 1 or 2 additional heteroatoms selected from N, O and S, or (ii) ) a 6-membered aromatic nitrogen-containing heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O and S, or
(iii) a 6-membered non-aromatic nitrogen-containing heterocycle optionally containing 1 or 2 additional heteroatoms selected from N and S;
is either
R ⁸ is selected from haloC _1-4 alkyl (eg —CF ₃ ), —CH ₃ and halogen (eg chlorine or fluorine);
R ⁹ is selected from hydrogen, C _1-4 alkyl (eg —CH ₃ ), haloC _1-4 alkyl (eg —CF ₃ ) and halogen (eg chlorine);
R ¹⁰ is halogen, cyano, cyanoC _1-4 alkyl (eg —CH ₂ —CN), hydroxy, =O(oxo), C _1-4 alkyl (eg —CH ₃ , —CH(CH ₃ ) ₂ or —CH ₂ CH ₃ ), haloC _1-4 alkyl (for example —CHF ₂ ), C _1-4 alkoxy (for example —OCH ₃ , —OCH ₂ CH ₃ and —OCH(CH ₃ ) ₂ ), HydroxyC _1-4 alkyl (for example -CH ₂ C(CH ₃ ) ₂ OH, -CH(CH ₃ )CH ₂ OH, -CH(CH ₃ )OH, -CH ₂ CH ₂ OH or -CH ₂ OH) , C _1-4 alkoxyC _1-4 alkylene (for example —CH ₂ —O—CH ₃ or —CH ₂ —CH ₂ —O—CH ₃ ), C _1-4 alkylsulfone (for example —SO ₂ CH ₃ ), amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino (eg —N(CH ₃ ) ₂ ), amino-C _1-4 alkylene (eg —CH ₂ NH ₂ ), —C _{1 -4} alkylene-C(=O)NH _(2-q) (C _1-6 alkyl) _q , -C _0-4 alkylene-NHC(=O)C _1-6 alkyl, sulfonamide C _0-4 alkylene ( For example, —SO ₂ NR ^x ₂ or —CH ₂ SO ₂ NR ^x ₂ , where R ^x is independently selected from H and C _1-6 alkyl), 3-6 membered cycloalkyl, O, a 5- or 6-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from N and S and optionally substituted with a substituent selected from C _1-4 alkyl; C _1-4 alkyl substituted with 3-6 membered cycloalkyl, containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, substituted selected from C _1-4 alkyl containing 1 or 2 heteroatoms selected from C _1-4 alkyl substituted with a 5- or 6-membered unsaturated heterocyclic group optionally substituted with a group, O, N and S, and C _1- C _1-4 alkyl substituted by a 4- to 6-membered saturated heterocyclic group optionally substituted by a substituent selected from 4 alkyl, and 1 _or 2 hetero selected from O, N and S independently selected from 4-6 membered saturated heterocyclic groups containing atoms and optionally substituted with substituents selected from C _1-4 alkyl, q is selected from 0, 1 and 2; and c is selected from 0, 1, 2 and 3; ]
or a tautomer or solvate or pharmaceutically acceptable salt thereof.

A compound of claim 1, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof,
X is CH or N;
R ¹ is hydrogen, —CH ₃ or —CH ₂ OH, provided that when X is N, R ¹ is selected from —CH ₃ and —CH ₂ OH;
^R2 and ^R3 are
(i) independently selected from hydrogen and C _1-4 alkyl, or
(ii) together form a 1-3 membered bridging group selected from C _1-3 alkylene, C _2-3 alkenylene, methylene-NR ^q -methylene and methylene-O-methylene, wherein said bridging group is optionally substituted with a group selected from C _1-4 alkyl, hydroxy and halogen, R ^q is selected from hydrogen, C _1-4 alkyl, hydroxy and halogen;
is either
Q is C or N;
If Q is C,
(i) R ⁴ ^is hydrogen or C _1-4 alkyl (eg methyl) optionally substituted with amino C _1-4 alkyl (eg —CH ₂ NH ₂ ); is hydrogen, amino or C _1-4 alkyl (eg methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxy and amino ( _eg —CH ₂ OH), provided that both R ⁴ and R ⁵ are not selected from amino and C _1-4 alkyl substituted with amino, or
(ii) R ⁴ and R ⁵ together with Q form a 4- to 6-membered nitrogen-containing heterocycle;
is either
If Q is N,
^R4 is absent,
R ⁵ is hydrogen, and
R ² and R ³ together form a 1- to 3-membered bridging group;
R ⁶ and R ⁷ are independently selected from halogen (eg fluorine), C _1-4 alkyl (eg —CH ₃ ) and hydroxy, provided that when Q is N, R ⁶ or R ⁷ is neither halogen nor hydroxy, a is selected from 0, 1 and 2, b is selected from 0, 1 and 2,
Ring A is
(i) a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring) optionally containing 1 or 2 additional heteroatoms selected from N, O and S, or (ii) ) a 6-membered aromatic nitrogen-containing heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O and S, or (iii) 1 or 2 selected from N and S any 6-membered non-aromatic nitrogen-containing heterocycle optionally containing 1 additional heteroatom,
R ⁸ is selected from haloC _1-4 alkyl (eg —CF ₃ ), —CH ₃ and halogen (eg chlorine or fluorine);
R ⁹ is selected from hydrogen, C _1-4 alkyl (eg —CH ₃ ), haloC _1-4 alkyl (eg —CF ₃ ) and halogen (eg chlorine);
R ¹⁰ is halogen, cyano, cyanoC _1-4 alkyl (eg —CH ₂ —CN), hydroxy, =O (oxo), C _1-4 alkyl (eg —CH ₃ or —CH ₂ CH ₃ ) , haloC _1-4 alkyl, C _1-4 alkoxy (eg —OCH ₃ ), hydroxyC _1-4 alkyl (eg —CH ₂ C(CH ₃ ) ₂ OH, —CH(CH ₃ )CH ₂ OH , —CH(CH ₃ )OH, —CH ₂ CH ₂ OH or —CH ₂ OH), C _1-4 alkoxyC _1-4 alkylene (for example —CH ₂ —O—CH ₃ or —CH ₂ —CH ₂ —O—CH ₃ ), C _1-4 alkylsulfone (for example —SO ₂ CH ₃ ), amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino (for example —N(CH ₃ ) ₂ ), aminoC _1-4 alkylene (eg —CH ₂ NH ₂ ), —C _1-4 alkylene-C(=O)NH _(2-q) (C _1-6 alkyl) _q , —C _1-4 Alkylene-NHC(=O)C _1-6 alkyl, sulfonamidoC _0-4 alkylene (eg —SO ₂ NR ^x ₂ or —CH ₂ SO ₂ NR ^x ₂ , where R ^x is H and C _{1- 6} alkyl), and 1 or 2 heteroatoms selected from O, N and S, optionally substituted with a substituent selected from C _1-4 alkyl 4 independently selected from ~6-membered saturated heterocyclic groups, q is selected from 0, 1 and 2, and c is selected from 0, 1 and 2;
Said compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or 2, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein X is CH.

3. The compound of claim 1 or 2, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein X is N.

4. The compound of any one of claims 1-3, wherein R ¹ is H, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

R ² and R ³ taken together,
a 1- to 3-membered bridging group selected from C _1-3 alkylene, C _2-3 alkenylene, methylene-NR ^q -methylene and methylene-O-methylene, wherein said bridging group is C _1-4 alkyl, optionally substituted with a group selected from hydroxy and halogen, wherein R ^q is selected from hydrogen and C _1-4 alkyl; or C _1-3 alkylene (eg —CH ₂ —CH _2- ), a compound according to any one of claims 1 to 5, or a tautomer, N-oxide thereof, a pharmaceutically acceptable salt or solvate.

7. The compound of any one of claims 1-6, wherein Q is C, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

R ⁴ is hydrogen or C _1-4 alkyl (eg methyl), for example R ⁴ is hydrogen and/or R ⁵ is hydrogen, amino or C _1-4 alkyl (eg methyl), C _1-4 alkyl (eg —CH ₂ OH) optionally substituted by 1 or 2 groups selected from halogen, hydroxy and amino, for example R ⁵ is amino or C _1-4 alkyl (eg methyl) optionally substituted with 1 or 2 groups selected from halogen, hydroxy and amino (eg amino) (eg _-CH ₂ OH) A compound according to any one of claims 1 to 7, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, which is.

a is 0 or 1, such as 0, or a is 1 and R ⁶ is halogen (e.g., fluorine) or hydroxy, such as a is 1 and R ⁶ is fluorine, and /or a compound according to any one of claims 1 to 8, wherein b is 0 or 1, such as 0, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof .

Ring A is
a 5-membered nitrogen-containing heterocyclic ring (such as an aromatic or non-aromatic ring) or a 6-membered aromatic optionally containing 1 or 2 additional heteroatoms selected from N, O and S a nitrogen-containing heterocycle, or a 5-membered nitrogen-containing heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O and S (e.g., an aromatic or non-aromatic ring) , or a 5-membered aromatic nitrogen-containing heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O and S, or 1 or 2 selected from N, O and S a 6-membered aromatic nitrogen-containing heterocyclic ring optionally containing 1 additional heteroatom, or a 6-membered 6-membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from The compound according to any one of claims 1 to 9, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, which is a non-aromatic nitrogen-containing heterocycle.

Below part:

is the following Table I or Table II :

is selected from, e.g., the part below:

but,

for example,

is selected from, or

for example,

A compound according to any one of claims 1 to 10, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, selected from:

R ⁸ is selected from —CF ₃ , —CH ₃ and halogen (e.g. chlorine or fluorine), for example R ⁸ is selected from halogen (e.g. chlorine) and/or R ⁹ is hydrogen, and/or R ¹⁰ is halogen, cyano, cyanoC _1-4 alkyl (eg —CH ₂ —CN), hydroxy, =O(oxo), C _1-4 alkyl (eg —CH ₃ or —CH ₂ CH ₃ ), haloC _1-4 alkyl, C _1-4 alkoxy (eg —OCH ₃ ), hydroxyC _1-4 alkyl (eg —CH(CH ₃ )CH ₂ OH, —CH(CH ₃ )OH , —CH ₂ CH ₂ OH or —CH ₂ OH), diC _1-4 alkylamino (for example —N(CH ₃ ) ₂ ), and C _1-4 alkoxyC _1-4 alkylene (for example —CH ₂ —O—CH ₃ ), for example, R ¹⁰ is from halogen, cyano, hydroxy, ═O(oxo), and C _1-4 alkyl (eg —CH ₃ or —CH ₂ CH ₃ ) or R ¹⁰ is halogen, cyano, hydroxy, ═O(oxo), C _1-4 alkoxy (eg —OCH ₃ ), diC _1-4 alkylamino (eg —N(CH ₃ ) ₂ ), and C _1-4 alkyl (eg —CH ₃ or —CH ₂ CH ₃ ), for example R ¹⁰ is hydroxy, =O(oxo) and C _1-4 alkyl ( —CH ₃ ), for example c is selected from 0, 1 or 2, for example c is 1 or 2, or tautomers, N-oxides, pharmaceutically acceptable salts or solvates thereof.

the compound is
1-[exo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3 .2.1] octan-3-yl]methanamine;
exo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2. 1] octan-3-amine;
endo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2. 1] octan-3-amine;
1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]piperidin-4-amine;
1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-4-methylpiperidin-4-amine;
endo-9-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-9-azabicyclo[3.3. 1] nonane-3-amine;
{4-amino-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]piperidin-4-yl} methanol;
endo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-methyl-8-azabicyclo[ 3.2.1] octan-3-amine;
4-chloro-5-(3-{3,8-diazabicyclo[3.2.1]octan-8-yl}-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2-methyl- 2H-indazole;
7-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-2,7-diazaspiro[3.5] Nonane;
1-{1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-2-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl]-4-methyl piperidin-4-yl}methanamine;
rac-(1S,2R,3R,5R)-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl ]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
endo-8-[7-(7-chloro-1,3-benzothiazol-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2.1 ] octan-3-amine;
1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-2-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl]-4-methylpiperidine-4 - an amine;
endo-8-[7-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3 .2.1] octan-3-amine;
7-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-1,7-diazaspiro[3.5] Nonane;
endo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-2-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[ 3.2.1] octan-3-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-7-chloro- N,N-dimethyl-1,3-benzothiazol-2-amine;
5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro- 2,3-dihydro-1,3-benzoxazol-2-one;
exo-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-2-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[ 3.2.1] octan-3-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-5-chloro- 2-methyl-3,4-dihydroquinazolin-4-one;
7-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-8-chloro- N,N-dimethylquinolin-2-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-7-chloro- 2,3-dihydro-1,3-benzothiazol-2-one;
endo-8-[7-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3. 2.1] octan-3-amine;
7-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-5,5-difluoro-2,7- diazaspiro[3.5]nonane;
endo-8-[7-(4-chloro-2-ethyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2. 1] octan-3-amine;
endo-8-[7-(8-chloro-2-methoxyquinolin-7-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2.1]octane -3-amine;
exo-8-[7-(4-chloro-2-ethyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2. 1] octan-3-amine;
(3R,4R)-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-fluoropiperidine -4-amine;
(3S,4S)-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-fluoropiperidine -4-amine;
(3S,4S)-4-amino-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]piperidine -3-ol;
(3S,4R)-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-fluoropiperidine -4-amine;
(3R,4S)-1-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-fluoropiperidine -4-amine;
{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo [2,3-b]pyrazin-2-yl}methanol;
7-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-8-chloro- 1,2-dihydroquinolin-2-one;
2-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-3 ,4-dichloro-2H-indazol-2-yl)ethan-1-ol;
(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro -2-methyl-2H-indazol-3-yl)methanol;
endo-8-[7-(4-fluoro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2. 1] octan-3-amine;
endo-8-{7-[7-chloro-2-(oxolan-3-yl)-1,3-benzothiazol-6-yl]-5H-pyrrolo[2,3-b]pyrazin-3-yl} -8-azabicyclo[3.2.1]octan-3-amine;
exo-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azabicyclo[ 3.2.1] octan-3-amine;
exo-8-[7-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3. 2.1] octan-3-amine;
endo-8-[7-(5-chloro-3-methoxy-2-methylquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2 .1] octan-3-amine;
endo-8-{7-[7-chloro-2-(methoxymethyl)-1,3-benzothiazol-6-yl]-5H-pyrrolo[2,3-b]pyrazin-3-yl}-8- azabicyclo[3.2.1]octan-3-amine;
(6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-7-chloro -1,3-benzothiazol-2-yl)methanol;
endo-8-{7-[4-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl]-5H-pyrrolo[2,3-b]pyrazin-3-yl}-8-azabicyclo [3.2.1] octan-3-amine;
endo-8-{7-[4-chloro-2-(oxetan-3-yl)-2H-indazol-5-yl]-5H-pyrrolo[2,3-b]pyrazin-3-yl}-8- azabicyclo[3.2.1]octan-3-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-5-chloro- 2-methyl-1,2-dihydroisoquinolin-1-one;
endo-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azabicyclo[ 3.2.1] octan-3-amine;
2-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2H-indazol-2-yl)-N,N-dimethylacetamide;
endo-8-[7-(4-chloro-7-fluoro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[ 3.2.1] octan-3-amine;
endo-8-[7-(4-chloro-2-methyl-2H-1,2,3-benzotriazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8 - azabicyclo[3.2.1]octan-3-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-5-chloro- 2,3-dimethyl-3,4-dihydroquinazolin-4-one;
1-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2H-indazol-2-yl)-2-methylpropan-2-ol;
endo-8-[7-(3,4-dichloro-1H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2.1] octan-3-amine;
endo-8-[7-(4-chloro-2,7-dimethyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3. 2.1] octan-3-amine;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-5-chloro- 3-methyl-3,4-dihydroquinazolin-4-one;
2-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2H-indazol-2-yl)-N-methylacetamide;
3-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2H-indazol-2-yl)-N,N-dimethylpropanamide;
6-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-7-chloro- N,N-dimethyl-1,3-benzothiazole-2-carboxamide;
2-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2H-indazol-2-yl)-N-tert-butylacetamide;
2-(5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4 -chloro-2-methyl-2H-indazol-3-yl)acetonitrile;
5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro- 2-methyl-2H-indazole-3-carbonitrile;
(1S,2R,3R,5R)-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]- 2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
(1R,2S,3S,5S)-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]- 2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
(1S,2R,3S,5R)-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]- 2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
5-{3-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro- 3,3-difluoro-2,3-dihydro-1H-indol-2-one;
(1R,2S,3R,5S)-8-[7-(4-chloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]- 2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
endo-8-(7-{4-chloro-2-[(1-methyl-1H-imidazol-2-yl)methyl]-2H-indazol-5-yl}-5H-pyrrolo[2,3-b] pyrazin-3-yl)-8-azabicyclo[3.2.1]octan-3-amine;
endo-8-(7-{4-chloro-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2H-indazol-5-yl}-5H-pyrrolo[ 2,3-b]pyrazin-3-yl)-8-azabicyclo[3.2.1]octan-3-amine;
endo-8-(7-{4-chloro-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-2H-indazol-5-yl}-5H-pyrrolo[2,3-b] pyrazin-3-yl)-8-azabicyclo[3.2.1]octan-3-amine;
6-{3-[(3R,4S)-4-amino-3-fluoropiperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-5-chloro-2-methyl -1,2-dihydroisoquinolin-1-one;
5-{3-[(3R,4S)-4-amino-3-fluoropiperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro-2-methyl -2,3-dihydro-1H-isoindol-1-one;
(1R,2S,3S,5S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazine-6 -yl]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
(3R,4S)-1-[7-(7-chloro-1-methyl-1H-1,3-benzodiazol-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl ]-3-fluoropiperidin-4-amine;
(3R,4S)-1-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]- 3-fluoropiperidin-4-amine;
5-{3-[(3R,4S)-4-amino-3-fluoropiperidin-1-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-4-chloro-3-methyl -2,3-dihydro-1,3-benzothiazol-2-one;
6-{3-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5H-pyrrolo[2,3-b ]pyrazin-7-yl}-5-chloro-3-methyl-3,4-dihydroquinazolin-4-one;
rac-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2- methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2-methyl- 2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2-methyl- 2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2-ethyl- 2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-4-fluoro- 2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-methoxyquinoxaline -6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[3,8-diazabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3 ,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-4-fluoro- 2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H - pyrazolo[3,4-b]pyrazin-5-yl}methanol;
rac-(1S,2S,3S,5R)-3-amino-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3 , 4-b]pyrazin-6-yl]-8-azabicyclo[3.2.1]octan-2-ol;
4-chloro-5-(6-{3,9-diazabicyclo[3.3.1]nonan-9-yl}-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)- 2-methyl-2H-indazole;
(1R,2S,3S,5S)-8-[3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazine-6 -yl]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
(1R,2S,3S,5S)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazine -6-yl]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
7-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,7-diazaspiro [ 3.5] nonane;
(1R,2S,3S,5S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl] -2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
7-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[3 ,4-b]pyrazin-3-yl}-8-chloro-N,N-dimethylquinoxalin-2-amine;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-2-ethyl- 4-fluoro-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(7-chloro-2-methyl- 1,3-benzothiazol-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2,3- dimethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-methoxy- 2-methylquinolin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[4-chloro-2-(propane -2-yl)-2H-indazol-5-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2- ethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
(1R,2S,3S,5S)-8-[7-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl ]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-bromo-4-fluoro- 2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
(1R,2S,3S,5S)-8-[7-(5-chloro-3-methoxyquinoxalin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-2-fluoro -8-azabicyclo[3.2.1]octan-3-amine;
endo-8-[7-(5-chloro-3-methoxyquinoxalin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-8-azabicyclo[3.2.1]octane -3-amine;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-2,4- dimethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-methoxyquinoxaline -6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
[6-(4-amino-4-methylpiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b] pyrazin-5-yl]methanol;
(6-{2,8-diazaspiro[4.5]decan-8-yl}-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4 -b]pyrazin-5-yl)methanol;
[3-(5-chloro-3-methoxyquinoxalin-6-yl)-6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1H-pyrazolo[3,4-b] pyrazin-5-yl]methanol;
{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3, 4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(7-chloro-1,3- benzothiazol-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
endo-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl] -8-azabicyclo[3.2.1]octan-3-ol;
{6-[endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazole-5- yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1H-pyrazolo[3,4 -b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(dimethyl amino)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
8-chloro-7-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)- 2-methoxyquinoxaline;
1-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine;
(1S,2S,3S,5R)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl] -2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
{3-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-7-(3,4-dichloro-2- methyl-2H-indazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[7-chloro-2-(dimethyl amino)-1,3-benzothiazol-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[3 ,4-b]pyrazin-3-yl}-4-chloro-2-methyl-2H-indazole-3-carbonitrile;
6-[3,9-diazabicyclo[3.3.1]nonan-9-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3, 4-b]pyrazin-5-yl}methanol;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-(hydroxymethyl)-1H- pyrazolo[3,4-b]pyrazin-3-yl}-4-chloro-2-ethyl-2H-indazole-3-carbonitrile;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[3 ,4-b]pyrazin-3-yl}-4-chloro-2-ethyl-2H-indazole-3-carbonitrile;
{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)- 1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-(hydroxymethyl)-1H- pyrazolo[3,4-b]pyrazin-3-yl}-4-chloro-2-methyl-2H-indazole-3-carbonitrile;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(dimethyl amino)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl] -1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
(6-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[ 3,4-b]pyrazin-3-yl}-7-chloro-1,3-benzothiazol-2-yl)methanol;
{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-1H-pyrazolo [3,4-b]pyrazin-5-yl}methanol;
{6-[endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H- pyrazolo[3,4-b]pyrazin-5-yl}methanol;
endo-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azabicyclo[3.2 .1] octan-3-amine;
7-{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}- 8-chloro-N,N-dimethylquinoxalin-2-amine;
8-chloro-7-(6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)- N,N-dimethylquinoxalin-2-amine;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(5-chloro-3-ethoxyquinoxaline -6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
(1R,2S,3S,5S)-8-[3-(5-chloro-3-ethoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl] -2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(7-chloro-2-methyl- 1,3-benzothiazol-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-2,4- dimethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(3-chloro-2,4-dimethyl-2H-indazol-5-yl)-1H - pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[7-chloro-2-(methoxy methyl)-1,3-benzothiazol-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(propane -2-yloxy)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-methyl-1H-pyrazolo[3 ,4-b]pyrazin-3-yl}-4-chloro-2-(propan-2-yl)-2H-indazole-3-carbonitrile;
(1S,2S,3S,5R)-8-[3-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)-5-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[5-chloro-3-(morpholine -4-yl)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;
(1R,2S,3S,5S)-8-{3-[5-chloro-3-(morpholin-4-yl)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl}-2-fluoro-8-azabicyclo[3.2.1]octan-3-amine;
5-{6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-(hydroxymethyl)-1H- pyrazolo[3,4-b]pyrazin-3-yl}-4-chloro-2-(propan-2-yl)-2H-indazole-3-carbonitrile; and {6-[(1R,2S,3S, 5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-[3-(azetidin-1-yl)-5-chloroquinoxalin-6-yl] -1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, or a tautomer, N-oxide, pharmaceutically acceptable salt or Solvate.

A compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and one or more (eg species) with other therapeutic agents (eg, anticancer agents).

wherein said compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof and one or more other therapeutic agents are administered sequentially or concurrently; 15. A pharmaceutical combination according to Item 14.

A medicament comprising a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a combination medicament according to claim 14 Composition.

Uses for:
or prevention or treatment of a condition or condition mediated by SHP2; or prevention or treatment of a condition or condition described herein; or prevention or treatment of cancer; prevention or treatment of cancer, used in combination with a therapeutic agent (e.g., an anticancer agent) or therapy; or hepatocellular carcinoma, melanoma, esophageal cancer, renal cancer, colon cancer, colorectal cancer cancer, lung cancer, mesothelioma, lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer or prostate cancer. , a pharmaceutical combination according to claim 14 or a pharmaceutical composition according to claim 16 .

A process for preparing a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-13. and
(a) a compound of formula (A):

[In the formula,
R ⁸ , R ⁹ , R ¹⁰ , A, c are as defined above for compounds of formula (I);
V represents a metal or metalloid residue (eg boronic acid, pinacol boronate, magnesium or zinc halide, eg boronic acid, pinacol boronate) or a leaving group (eg halogen). ]
or coupling with its protected form, followed by a suitable deprotection reaction to remove the protecting group, or
(b) a compound of formula (C):

[In the formula,
^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , Q, a, b are as defined above for compounds of formula (I). ]
or a protected derivative thereof , followed by optionally performing a suitable deprotection reaction to remove the protecting group , or
(c) compounds of formula (K):

[In the formula,
^R2 , ^R3 ^, ^R4 , ^R5 , ^R6 , ^R7 , R8, ^R9 , ^R10 , Q, a, b and c are as defined above for compounds of formula (I); ,
P represents an amine protecting group (eg 2-(trimethylsilyl)ethoxymethyl; SEM), N,N-dimethylsulfamoyl or hydrogen;
^L3 is a leaving group (eg halogen, eg bromine). ]
or a protected derivative thereof,
(i) in the presence of a metal catalyst such as (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride of the formula CH ₃ M, where M is a metal .) with an organometallic species (eg, CH ₃ —Zn—Hal, where Hal is a halogen, such as chloride, bromide, or iodide) to give R ¹ is —CH ₃ . obtaining a compound of formula (I), or
(ii) photoredox catalysts (e.g. [Ir{ _dFCF3ppy } ₂ (bpy)] _PF6 ), metal catalysts (e.g. nickel(II) chloride ethylene glycol dimethyl ether complex), ligands (e.g. 4,4') -di-tert-butyl-2,2'-dipyridyl), a base (e.g. dipotassium phosphate), and a light source (e.g. a blue LED), an alkyl boronate (e.g. potassium (2-trimethylsilyl) -ethoxymethyltrifluoroborate) to give protected derivatives of compounds of formula (I) wherein R ¹ is -CH ₂ OH , followed by an optional deprotection reaction suitable for removing the protecting groups. or _
(d) compounds of formula (R):

[In the formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Q, a, b, c, A are defined above for compounds of formula (I) as defined,
L ¹ represents a suitable leaving group (eg, halogen). ]
or cyclizing a protected derivative thereof using hydrazine or a hydrazine protected derivative , followed by optionally performing a suitable deprotection reaction to remove the protecting group , or
( e) deprotecting the protected derivative of the compound of formula (I), or
(f) interconverting a compound of formula (I) or a protected derivative thereof to a further compound of formula (I) or a protected derivative thereof , followed by optionally a suitable deprotection reaction to remove the protecting group; or _
(g) forming a pharmaceutically acceptable salt of a compound of formula (I) from a compound of formula (I).