CN115362149B

CN115362149B - SHP2 inhibitor, composition and application thereof

Info

Publication number: CN115362149B
Application number: CN202180021101.5A
Authority: CN
Inventors: 付邦; 李因龙; 任伟; 孙中心; 王超; 吴颢; 王家炳; 丁列明
Original assignee: Betta Pharmaceuticals Co Ltd
Current assignee: Betta Pharmaceuticals Co Ltd
Priority date: 2020-04-26
Filing date: 2021-04-22
Publication date: 2024-05-14
Anticipated expiration: 2041-04-22
Also published as: CN115362149A; WO2021218752A1

Abstract

Provided herein are compounds of formula (I), methods of using the compounds as SHP2 inhibitors, and pharmaceutical compositions comprising such compounds, which are useful in the treatment of SHP2 mediated diseases.

Description

SHP2 inhibitor, composition and application thereof

Technical Field

The invention relates to a series of compounds serving as Src homology region 2-containing protein tyrosine phosphatase 2 (Src homologyregion-containing protein tyrosine phosphatase 2, SHP 2) inhibitors, a preparation method thereof and a pharmaceutical composition. The invention also relates to the use of the above compounds or pharmaceutical compositions thereof in the treatment of SHP2 mediated diseases.

Background

The Src homology 2-containing protein tyrosine phosphatase 2 (Src homologyregion 2-containing protein tyrosine phosphatase, SHP 2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, PTPN11 being the first proto-oncogene (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood、2007、109:862-867), found to encode tyrosine phosphokinase encoding SHP2 protein containing an N-terminal SHP2 domain (N-SHP 2), a C-terminal SHP2 domain (C-SHP 2), a protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and a Pro-rich motif.

In recent years, the Ras/ERK pathway is mainly considered to be one of the most important signal transduction pathways for SHP2 to function, and the mechanism (Dance M et al.The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase(ERK1/2)pathway.Cell Signal、2008、20:453-459) is approximately as follows: upon activation of the growth factor receptor, its tyrosine residues autophosphorylate, providing a docking site for the phosphotyrosine binding region SH2 of Grb2 and SHP2 (SH 2 domain-containing adaptor protein). Binding of Grb2 to phosphorylated growth factor receptors results in aggregation of SOS proteins at the membrane. SOS, a guanine nucleotide exchange factor (guanine nucleotide exchange factor, GEF), catalyzes the conversion of the membrane-bound protein Ras from inactive Ras-GDP to active Ras-GTP. Ras-GTP is further connected with a downstream signal system, and Ser/Thr kinase Raf1 and the like are activated, so that ERK is activated under the action of regulating kinase MEK, and the ERK is directly acted on target molecules of cytoplasm after activation or transferred into nucleus to regulate gene transcription, so that cells proliferate or differentiate. This process may also be affected by SHP2 binding proteins and substrates (SHP substrate-1, SHPS-1), ras-GTPase activating proteins (Ras-GAP), and other Src members.

It has been reported that SHP2 protein regulates not only Ras/ERK signaling pathway but also various signaling pathways such as JAK-STAT3, NF- κB, PI3K/Akt, RHO and NFAT, thereby regulating physiological functions such as cell proliferation, differentiation, migration and apoptosis.

SHP2 has been shown to be associated with a variety of diseases, with about 50% of Noonan syndrome patients being found with missense mutations in PTPN 11. In addition, studies have found that PTPN11 mutation is an important cause (Tartaglia m et al.NAT genet、2003、34:148-150;LOH ml et al.Blood、2004、103:2325-2331;Tartaglia m et al.Br J Haematol、2005、129:333-339;Xu R et al.Blood、2005、106:3142-3149). of JMML and multiple leukemia, and as the study of PTPN11/SHP2 is advanced, PTPN11/SHP2 has been found to be related to the occurrence of various cancers such as lung cancer, stomach cancer, colon cancer, melanoma, thyroid cancer and the like (Tang Chunlan et al.China Journal of lung cancer、2010,13:98-101;Higuchi m et al.Cancer SCI、2004、95:442-447;bentires al j m et al.Cancer Res、2004、64:8816-8820;Martinelli s et al.Cancer gene cycle et al、2006、166:124-129).

Currently, SHP2 inhibitors are of increasing interest as potential cancer therapeutic agents. There are a number of SHP2 inhibitors under development, such as TNO155 developed in nova, which entered phase I clinical trials in 2017 for the treatment of solid tumors; JAB-3068 developed by Jacobio Pharm formally obtained a new drug clinical trial of the American FDA in month 1 of 2018; the RMC-4630 developed by recourse was subjected to the first human clinical trial in half 2018. At present, no medicine aiming at the target point exists in the markets at home and abroad, so that the development of a small molecule medicine capable of targeted inhibition of SHP2 activity has great significance in providing safer and more effective SHP2 inhibitors for patients.

Disclosure of Invention

The present invention relates to a compound which is an inhibitor of Src homology 2 containing protein tyrosine phosphatase 2 (SHP 2). Such SHP2 inhibitors are useful in the treatment of cancer.

Such SHP2 inhibitors relate to compounds, or pharmaceutically acceptable salts, isomers, stereoisomers, prodrugs, chelates, non-covalent complexes, or solvates thereof, which are shown in formula I:

Wherein,

Is a single bond or a double bond

Ring A is selected from aryl or 5-10 membered heterocyclyl; wherein the 5-10 membered heterocyclyl optionally contains 1,2 or 3 heteroatoms selected independently from N, S or O;

Ring B is selected from aryl, 5-10 membered heteroaryl, or absent;

ring C is selected from 5-8 membered heterocyclyl or absent;

Wherein, when ring B is absent, X ₁ and X ₂ are independently selected from CH ₂, O or NH;

wherein, when ring B is aryl or 5-10 membered heteroaryl, X ₁ and X ₂ are independently selected from C or N;

Wherein, when ring C is absent, Y ₁ and Y ₂ are independently selected from CR ⁵ or NR ^5';

wherein, when ring C is a 5-8 membered heterocyclyl, Y _l and Y ₂ are independently selected from C or N;

Y ₃ is selected from CH, O or N;

m is selected from CH ₂, O, NH or S;

R ¹ and R ² are independently selected from hydrogen, halogen, -CN, -NO ₂ and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸、-NR¹⁹(CH₂)qNR²⁰R²¹、-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is substituted with one or more substituents selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl or-C _1-6 alkyl;

R ⁵ is selected from hydrogen, = O, C _1-6 alkyl or C _3-8 cycloalkyl;

R ^5' is selected from hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²² And R ²³ is independently hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _2-4 alkenyl, or C _2-4 alkynyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4;

Wherein, when ring C is absent, ring A is phenyl, Y ₁ is N, Y ₂ is CH, Y ₃ is N, then m is not 0, and each R ³ is not hydrogen.

In some embodiments of formula I, ring a is aryl.

In some embodiments of formula I, ring a is phenyl.

In some embodiments of formula I, ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula I, ring A is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl,

In some embodiments of formula I, ring B is absent.

In some embodiments of formula I, ring B is aryl or 5-10 membered heteroaryl.

In some embodiments of formula I, ring B is aryl.

In some embodiments of formula I, ring B is phenyl.

In some embodiments of formula I, ring B is a 5-10 membered heteroaryl.

In some embodiments of formula I, ring B is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,

In some embodiments of formula I, ring C is absent.

In some embodiments of formula I, ring C is a 5-8 membered heterocyclyl.

In some embodiments of formula I, ring C is

In some embodiments of formula I, R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

Wherein R ⁶、R⁷ and R ⁸ are independently hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl.

In some embodiments of formula I, each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷,-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl.

Wherein ,R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²² and R ²³ are independently hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl.

In some embodiments of formula I, each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is substituted with one OR more substituents selected from halogen, -OR ⁶、-NR⁷R⁸;

In some embodiments of formula I, each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula I, each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、Cl、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃、 NH₂、N(CH₃)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂

In some embodiments of formula I, each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula I, m is selected from 0, 1,2, or 3.

In some embodiments of formula I, n is selected from 0, 1, or 2.

In some embodiments of formula I, p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound has formula II, or a pharmaceutically acceptable salt, isomer, stereoisomer, prodrug, chelate, non-covalent complex or solvate thereof,

Wherein,

Is a single bond or a double bond;

Ring B is selected from aryl or 5-10 membered heteroaryl;

X ₁ and X ₂ are independently selected from C or N;

Y ₁ and Y ₂ are independently selected from CR ⁵ or NR ^5';

Y ₃ is selected from CH, O or N;

m is selected from CH, O, NH or S;

Each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)_qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is substituted with one or more substituents selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl or-C _1-6 alkyl;

R ⁵ is selected from hydrogen, = O, C _1-6 alkyl or C _3-8 cycloalkyl;

R ^5' is selected from hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²² And R ²³ is independently selected from hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _2-4 alkenyl, or C _2-4 alkynyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4;

Wherein, if Y ₁ is N, Y ₂ is CH, Y ₃ is N, then m is not 0, then R ³ is not hydrogen.

In some embodiments of formula II, wherein between Y ₁ and Y ₂ Is a double bond.

In some embodiments of formula II, wherein Y ₁ is N and Y ₂ is CH.

In some embodiments of formula II, ring a is aryl.

In some embodiments of formula II, ring a is phenyl.

In some embodiments of formula II, ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula II, ring A is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl

In some embodiments of formula II, ring B is aryl or 5-10 membered heteroaryl.

In some embodiments of formula II, ring B is aryl.

In some embodiments of formula II, ring B is phenyl.

In some embodiments of formula II, ring B is a 5-10 membered heteroaryl.

In some embodiments of formula II, ring B is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl

In some embodiments of formula II, R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is substituted with one or more substituents selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

Wherein R ⁶、R⁷ and R ⁸ are independently selected from hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl.

In some embodiments of formula II, each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷,-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

Wherein ,R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²² and R ²³ are independently selected from hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl.

In some embodiments of formula II, each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is substituted with one OR more substituents selected from halogen, -OR ⁶、-NR⁷R⁸;

In some embodiments of formula II, each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula II, each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、C_l、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃、 NH₂、N(CH₃)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂.

In some embodiments of formula II, each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula II, m is selected from 0, 1, 2, or 3.

In some embodiments of formula II, n is selected from 0,1, or 2.

In some embodiments of formula II, p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound has formula II', or a pharmaceutically acceptable salt, isomer, stereoisomer, prodrug, chelate, non-covalent complex or solvate thereof.

Wherein,

Is a single bond or a double bond;

ring A is aryl or 5-10 membered heterocyclyl; wherein the 5-10 membered heterocyclyl contains 1,2 or 3 heteroatoms selected from N, S or O;

X ₁ and X ₂ are selected from CH ₂, O or NH;

y ₁ and Y ₂ are selected from CR ⁵ or NR ^5';

Y ₃ is selected from CH, O or N;

m is selected from CH, O, NH or S;

each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸、-NR¹⁹(CH₂)qNR²⁰R²¹、-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

R ⁵ is selected from hydrogen, = O, C _1-6 alkyl or C _3-8 cycloalkyl;

R ^5' is selected from hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4;

In some embodiments of formula II', ring a is aryl.

In some embodiments of formula II', ring a is phenyl.

In some embodiments of formula II', ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula II', ring A is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl,

In some embodiments of formula II', R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

In some embodiments of formula II', each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸、-NR¹⁹(CH₂)qNR²⁰R²¹、-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

In some embodiments of formula II', each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is optionally substituted with one OR more substituents independently selected from halogen, -OR ⁶、-NR⁷R⁸;

In some embodiments of formula II', each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula II', each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、C_l、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃、 NH₂、N(CH₃)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂.

In some embodiments of formula II', each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula II', m is selected from 0, 1, 2, or 3.

In some embodiments of formula II', n is selected from 0, 1, or 2.

In some embodiments of formula II', p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound is formula III, or a pharmaceutically acceptable salt, isomer, stereoisomer, prodrug, chelate, non-covalent complex, or solvate thereof.

Wherein,

Ring A is aryl or 5-10 membered heterocyclyl; wherein the 5-10 membered heterocyclyl optionally contains 1,2 or 3 heteroatoms selected independently from N, S or O;

ring B is aryl or 5-10 membered heteroaryl;

X ₁ and X ₂ are independently selected from C or N;

Y ₃ is selected from CH, O or N;

m is selected from CH, O, NH or S;

Each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹, C _3-8 cycloalkyl, 3-8 membered heterocyclyl or-C _1-6 alkyl;

R ^5' is selected from hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4.

In some embodiments of formula III, R ^5' is selected from hydrogen.

In some embodiments of formula III, ring a is aryl.

In some embodiments of formula III, ring a is phenyl.

In some embodiments of formula III, ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula III, ring A is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl,

In some embodiments of formula III, ring B is aryl or 5-10 membered heteroaryl.

In some embodiments of formula III, ring B is aryl.

In some embodiments of formula III, ring B is phenyl.

In some embodiments of formula III, ring B is a 5-10 membered heteroaryl.

In some embodiments of formula III, ring B is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,

In some embodiments of formula III, R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

In some embodiments of formula III, each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷,-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

In some embodiments of formula III, each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is optionally substituted with one OR more substituents independently selected from halogen, -OR ⁶、-NR⁷R⁸;

In some embodiments of formula III, each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula III, each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、C_l、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃、 NH₂、N(CH₃)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂.

In some embodiments of formula III, each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula III, m is selected from 0, 1, 2, or 3.

In some embodiments of formula III, n is selected from 0, 1, or 2.

In some embodiments of formula III, p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound is a compound of formula IV or a pharmaceutically acceptable salt, isomer, stereoisomer, prodrug, chelate, non-covalent complex or solvate thereof,

Wherein,

Is a single bond or a double bond;

Ring B is selected from aryl or 5-10 membered heteroaryl;

X ₁ and X ₂ are independently selected from C or N;

Y ₃ is selected from CH, O or N;

m is selected from CH, O, NH or S;

Z ₁ is selected from CH or N;

z ₂ is selected from CH, CH2, N or NH;

Each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4.

In some embodiments of formula IV, ring a is aryl.

In some embodiments of formula IV, ring a is phenyl.

In some embodiments of formula IV, ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula IV, ring A is thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl

In some embodiments of formula IV, ring B is selected from aryl or 5-10 membered heteroaryl.

In some embodiments of formula IV, ring B is aryl.

In some embodiments of formula IV, ring B is phenyl.

In some embodiments of formula IV, ring B is a 5-10 membered heteroaryl.

In some embodiments of formula IV, ring B is selected from thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl

In some embodiments of formula IV, Z ₁ is selected from N; z ₂ is selected from CH.

In some embodiments of formula IV, Z ₁ is selected from N; z ₂ is selected from N.

In some embodiments of formula IV, Z ₁ is selected from N; z ₂ is selected from CH ₂.

In some embodiments of formula IV, R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

In some embodiments of formula IV, each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷,-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

In some embodiments of formula IV, each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is optionally substituted with one OR more substituents independently selected from halogen, -OR ⁶、-NR⁷R⁸;

Wherein R6, R7 and R8 are independently hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl.

In some embodiments of formula IV, each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula IV, each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、C_l、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃, NH₂、N(CH₃)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂.

In some embodiments of formula IV, each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula IV, m is selected from 0, 1, 2, or 3.

In some embodiments of formula IV, n is selected from 0,1, or 2.

In some embodiments of formula IV, p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound has formula IV', or a pharmaceutically acceptable salt, isomer, stereoisomer, prodrug, chelate, non-covalent complex or solvate thereof,

Wherein,

Is a single bond or a double bond;

Ring A is aryl or a 5-10 membered heterocyclyl; wherein the 5-10 membered heterocyclyl optionally contains 1,2 or 3 heteroatoms selected independently from N, S or O;

X ₁ and X ₂ are independently selected from CH ₂, O or NH;

Wherein when ring C is absent, Y ₁ and Y ₂ are independently selected from CR ⁵ or NR ^5';

Y ₃ is selected from CH, O or N;

m is selected from CH, O, NH or S;

Z ₁ is selected from CH or N;

Z ₂ is selected from CH, CH ₂, N or NH;

Each R ³ and R ⁴ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸,-NR¹⁹(CH₂)qNR²⁰R²¹,-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹, C _3-8 cycloalkyl, 3-8 membered heterocyclyl or-C _1-6 alkyl;

R ⁵ is selected from hydrogen, = O, C _1-6 alkyl or C _3-8 cycloalkyl;

R ^5' is selected from hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²² And R ²³ is selected from hydrogen, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _2-4 alkenyl, or C _2-4 alkynyl;

m is selected from 0,1, 2,3 or 4;

n is selected from 0, 1,2,3 or 4;

p is selected from 1, 2, 3 or 4;

q is selected from 1, 2, 3 or 4.

In some embodiments of formula IV', ring a is aryl.

In some embodiments of formula IV', ring a is phenyl.

In some embodiments of formula IV', ring a is a 5-10 membered heterocyclyl.

In some embodiments of formula IV', ring A is selected from thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl or isoquinolinyl,

In some embodiments of formula IV', Z ₁ is selected from N; z ₂ is selected from CH.

In some embodiments of formula IV', Z ₁ is selected from N; z ₂ is selected from N.

In some embodiments of formula IV', Z ₁ is selected from N; z ₂ is selected from CH ₂.

In some embodiments of formula IV', R ¹ and R ² are independently selected from hydrogen, halogen, and C _1-6 alkyl; wherein C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、-OR⁶、-NR⁷R⁸;

In some embodiments of formula IV', each R ³ is independently selected from hydrogen, halogen, -CN, -NO ₂、＝O、C_1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl 、-OR⁶、-NR⁷R⁸、-SR⁹、-C(＝O)OR¹⁰、-C(＝O)NR¹¹R¹²、-S(＝O)₂R¹³、-S(＝O)₂OR¹⁴、-S(＝O)₂NR¹⁵R¹⁶、-O(CH₂)_POR¹⁷、-O(CH₂)_PNR¹⁷R¹⁸、-NR¹⁹(CH₂)qNR²⁰R²¹、-NR²²(CH₂)qOR²³; wherein C _1-6 alkyl, C _3-8 cycloalkyl, aryl, 3-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO ₂、＝O、-OR⁶、-NR⁷R⁸、-SR⁹、C_3-8 cycloalkyl, 3-8 membered heterocyclyl, or-C _1-6 alkyl;

In some embodiments of formula IV', each R ⁴ is independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, -OR ⁶; wherein C _1-6 alkyl is optionally substituted with one OR more substituents independently selected from halogen, -OR ⁶、-NR⁷R⁸;

In some embodiments of formula IV', each R ¹ and R ² is independently selected from hydrogen, halogen, CH ₂ OH.

In some embodiments of formula IV', each R ³ is independently selected from hydrogen 、OCH₃、OCH₂CH₃、C_l、NH₂、CN、-CONH₂、OCHF₂、-COOCH₃、CH₃、CH₂OH、CH₂CH₂OH、OH、-SO₂CH₃、CF₃、F、OCF₃、-SO₂NH₂、CH(OH)CH₃、 NH₂、N(CH3)₂、CH(CH₃)₂、OCH₂CH₂N(CH₃)₂、OCH₂CH₂OCH₃、N(CH₃)CH₂CH₂N(CH₃)₂.

In some embodiments of formula IV', each R ⁴ is independently selected from hydrogen, CN, F, OCH ₃.

In some embodiments of formula IV', m is selected from 0, 1, 2, or 3.

In some embodiments of formula IV', n is selected from 0, 1, or 2.

In some embodiments of formula IV', p is selected from 1 or 2.

In some embodiments of formula I, wherein the compound is:

(S) -1'- (3- (1- (pyrazin-2-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (thiophen-2-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (4-fluorophenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (3, 5-difluorophenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2, 6-dimethoxyphenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (pyrimidin-5-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (pyridin-3-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine ] -1-amine hydrochloride;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) phenol;

(S) -1'- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2-chlorophenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -6-methoxy-1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1-amino-1 '- (3- (1- (3, 5-dimethoxyphenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine ] -6-carbonitrile;

(S) -1'- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -6-methoxy-1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -6-fluoro-1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -2- (1- (6- (1-amino-5, 6-difluoro-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) benzonitrile;

(R) -8- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -8-azaspiro [4.5] decan-1-amine;

(R) -8- (3- (1- (thiophen-2-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1-oxa-8-azaspiro [4.5] decan-4-amine;

(R) -1'- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -3H-spirocyclic [ benzofuran-2, 4' -piperidin ] -3-amine;

(S) -1'- (3- (1- (2-aminopyrimidin-5-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -methyl 4- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) benzoate;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) -1-methylpyridin-2 (1H) -one;

(S) -1'- (3- (1- (3- (difluoromethoxy) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) benzonitrile;

(S) -1'- (3- (1- (o-tolyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) - (2- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) phenyl) methanol;

(S) -1'- (3- (1- (2-methoxyphenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (3, 5-dimethoxyphenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (2, 2-difluoro-1-phenylvinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S, E) -3- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -3-phenylpropan-2-en-1-ol;

(S) -1'- (3- (1- (2-methylpyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2-chlorophenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) phenol;

(S) -1'- (3- (1- (2- (methylsulfonyl) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) -2-methoxyphenol;

(S) -1'- (3- (3- (trifluoromethyl) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2-fluorophenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (3, 4-dimethoxyphenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2- (trifluoromethyl) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (2- (trifluoromethoxy) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) benzonitrile;

(S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) pyridinonitrile;

(S) -1'- (3- (3- (trifluoromethoxy) phenyl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (quinolin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) vinyl) -4-methoxy-1-methylpyridin-2 (1H) -one;

(S) -1'- (3- (1- (2-methylthiazol-5-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-aminopyrimidin-5-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-hydroxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzamide;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (difluoromethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzonitrile;

(S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzoic acid methyl ester;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (o-tolyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (hydroxymethyl) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-methoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3, 5-dimethoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (2, 2-difluoro-1-phenylvinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S, E) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (3-hydroxy-1-phenylprop-1-en-1-yl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-methylpyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chlorophenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-hydroxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (methylsulfonyl) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-hydroxy-2-methoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (trifluoromethyl) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3, 5-difluorophenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-fluorophenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3, 4-dimethoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (trifluoromethyl) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (trifluoromethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzonitrile;

(S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) pyridine carbonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (trifluoromethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (quinolin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4-methoxy-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-methylthiazol-5-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1-phenylvinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (thiophen-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (thiazol-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-methylisoxazol-5-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (thiophen-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-chlorothien-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5- (hydroxymethyl) thiophen-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4-methylthiazol-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (1-methyl-1H-imidazol-5-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-methoxypyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4-hydroxy-2-oxo-1, 2-dihydropyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-chloro-2-methoxypyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-methoxy-6-methylpyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-methyl-1H-indazol-5-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzenesulfonamide;

6- (S) -1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (1-hydroxyethyl) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-cyclopropylphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (dimethylamino) pyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) pyridine amide;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -4, 5-dihydro-6H-pyrrolo [3,4-d ] thiazol-6-one;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) thiazole-5-carbonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5- (hydroxymethyl) thiazol-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) thiazole-4-carboxamide;

(S) -2- (1- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) thiazole-4-carbonitrile;

(S) -2- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) thiophene-3-carbonitrile;

(S) -5- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) thiophene-3-carbonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5- (hydroxymethyl) -4-methylthiophene-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -5- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -4-methylthiophene-2-carbonitrile;

(S) -N- (3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) phenyl) acetamide;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dihydro-benzo [ b ] [1,4] dioxin-6-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-hydroxy-5-methoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 2-difluorobenzo [ d ] [1,3] dioxin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-hydroxy-2-methoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-fluoro-5-methoxyphenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-fluoro-5- (trifluoromethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-oxo-1, 2-dihydropyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-ethoxypyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6-methoxypyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-methoxy-1H-pyrrolo [2,3-c ] pyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-aminopyrimidin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (trifluoromethyl) pyrimidin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) pyrimidine-2-carbonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 6-dimethylpyrimidin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-cyclopropyl-1H-pyrazol-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -5- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) pyridine carbonitrile;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -5-methylpyridinenitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-amino-5- (trifluoromethyl) pyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-amino-5-chloropyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-methylpyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloro-6- (hydroxymethyl) pyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6- (2-hydroxyethyl) pyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6- (3-hydroxy-oxolan-3-yl) pyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

6- (S) -1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (1-hydroxyethyl) pyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6-isopropylpyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

methyl (S) -4- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) pyridinecarboxylic acid ester;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (hydroxymethyl) pyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (difluoromethyl) pyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4- (trifluoromethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 6-dimethylpyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6- (hydroxymethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

6- (S) -1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6- (1-hydroxyethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6- (2-hydroxyethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4- (difluoromethyl) pyridin-2-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (2- (dimethylamino) ethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-hydroxy-5- (2-methoxyethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4- (2-methoxyethoxy) phenyl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-fluoro-2-methylpyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-fluoro-2-hydroxypyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-amino-5-fluoropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (methylamino) pyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-fluoro-2-methylpyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6-amino-4-fluoropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dichloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (4-chloropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-chloro-2-fluoropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloro-5-methylpyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 5-dichloropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5, 6-dichloropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-chloro-5-hydroxypyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (quinolin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dichlorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-chloro-2-methylpyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (methylsulfonyl) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzenesulfonamide;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (methylsulfonyl) pyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6-chloro-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -methyl 5- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -2-oxo-1, 2-dihydropyridine-3-carboxylate;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5- (hydroxymethyl) -6-oxo-1, 6-dihydropyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-fluoro-3-methoxyphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloro-3-methoxyphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -2-fluorobenzonitrile;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -2-chlorobenzonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-chloro-6-methylpyridin-3-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -5-chloropyridine carbonitrile;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (2-methoxyethoxy) pyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

6- (S) -1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2- (tetrahydrofuran-3-yl) oxy) pyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dihydro-1, 4] dioxo [2,3-b ] pyridin-8-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (5-chloro-2-methoxypyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-chlorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-fluorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (difluoromethyl) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-methoxyphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (hydroxymethyl) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (2- (dimethylamino) ethyl) (methyl) amino) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (pyrrolidin-1-yl) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-morpholinophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3- (morpholinomethyl) phenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-6-fluoro-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (1-phenylvinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-difluorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (6-methylpyridin-2-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloro-3-methylphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1-phenylvinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1- (6-methylpyridin-3-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1- (thiazol-5-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -6- (1-amino-6-methoxy-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1-phenylvinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one;

(S) -2- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methyl-5- (1-phenylvinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -2- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -5- (1- (6-amino-5-chloropyridin-3-yl) vinyl) -3-methyl-3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -2- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3-methyl-5- (1- (thiophen-2-yl) vinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -2- (1-amino-6-fluoro-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3-methyl-5- (1-phenylvinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -2- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (1-phenylvinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -2- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (1- (3-methoxyphenyl) vinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -5- (1- (2- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 7-dihydro-3H-pyrrolo [2,3-d ] pyrimidin-5-yl) vinyl) nicotinonitrile;

(S) -2- (1-amino-6-methoxy-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -5- (1-phenylvinyl) -3, 7-dihydro-4H-pyrrolo [2,3-d ] pyrimidin-4-one;

(S) -1'- (9- (1-phenylvinyl) -2, 7-dihydro-3H-imidazo [1,2-c ] pyrazolo [4,3-e ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1-phenylvinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (2-methylpyridin-4-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (pyrimidin-5-yl) vinyl) -7H pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (2-methoxyphenyl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (2, 6-dimethoxyphenyl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -2- (1- (5- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-9-yl) vinyl) benzonitrile

(S) -1'- (9- (1- (2- (trifluoromethyl) phenyl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (thiazol-2-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (thiophen-2-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (3, 5-difluorophenyl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -1'- (9- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(R) -8- (9- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -7H pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine;

(R) -1'- (9- (1-phenylvinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -3H-spirocyclic [ benzofuran-2, 4' -piperidin ] -3-amine;

(R) -8- (9- (1-phenylvinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1-oxa-8-azaspiro [4.5] decan-4-amine;

(R) -5-fluoro-1 '- (9- (1-phenylvinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -3H-spirocyclic [ benzofuran-2, 4' -piperidin ] -3-amine;

(S) -6-methoxy-1 '- (9- (1-phenylvinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [4,3-c ] pyrimidin-5-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine;

(R) -8- (9- (1- (thiophen-3-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -1-oxa-8-azaspiro [4.5] decan-4-amine;

(R) -8- (9- (1- (2-methylpyridin-4-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine;

(S) -2-methoxy-1 '- (9- (1- (2-methylpyridin-4-yl) vinyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazol [4,3-c ] pyrimidin-5-yl) -4, 6-dihydro spiro [ cyclopentyl [ d ] thiazol-5, 4' -piperidin ] -4-amine;

(S) -1'- (9- (1-phenylvinyl) -7H imidazo [1,2-c ] pyrazolo [4,3-e ] pyrimidin-5-yl) -1, 3-dihydro spiro [ inden-2, 4' -piperidin ] -1-amine;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-methoxy-2-methylphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (3-hydroxy-2-methylphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-chloro-3-hydroxyphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-fluoro-3-hydroxyphenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2, 5-difluorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -3- (1-phenylvinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -3- (1- (6- (4-amino-4, 6-dihydro-spiro [ cyclopentylthiazole-5, 4 '-piperidine ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzonitrile;

(S) -3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentylthiazol-5, 4 '-piperidin ] -1' -yl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dichlorophenyl) vinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1-phenylvinyl) -1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -3- (1- (6- (4-amino-4, 6-dihydro-spiro [ cyclopentylthiazole-5, 4 '-piperidine ] -1' -yl) -5-methyl-4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) benzonitrile;

(S) -3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentylthiazol-5, 4 '-piperidin ] -1' -yl) -5-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -6- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -3- (1- (2, 3-dichlorophenyl) vinyl) -5-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4 (5H) -one;

(S) -2- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -3-methyl-5- (1-phenylvinyl) -3H-pyrrole [2,3-d ] pyrimidin-4 (7H) -one;

(S) -2- (4-amino-4, 6-dihydro-spiro [ cyclopentane [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) -5- (1-phenylvinyl) -3H-pyrrole [2,3-d ] pyrimidin-4 (7H) -one.

The invention also provides a pharmaceutical composition characterized by comprising a compound, a pharmaceutically acceptable salt, an isomer, a stereoisomer, a prodrug, a chelate, a non-covalent complex or a solvate of any of the invention, and at least one pharmaceutically acceptable carrier or excipient.

The invention also provides application of the compound or the pharmaceutical composition thereof in preparing medicines.

In some embodiments, the medicament is for treating, preventing, delaying or preventing cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.

In some embodiments, the medicament is for treating a disorder mediated by SHP 2.

In some embodiments, the disease is cancer.

In some embodiments, the cancer is Noonan syndrome, leopard syndrome, juvenile granulocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, and/or pancreatic cancer.

The invention also provides application of the compound or the pharmaceutical composition thereof in preparation of SHP2 inhibitors.

The invention also provides a method of treating or preventing a disorder mediated by SHP2 by administering to a patient in need thereof a compound or pharmaceutical composition of any one of the invention.

In some embodiments, the disease is cancer.

The present invention also provides a method of treating cancer by administering to a patient in need thereof a compound or pharmaceutical composition of any one of the present invention.

In some embodiments, wherein the cancer is Noonan syndrome, leopard syndrome, juvenile granulomatous leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, and/or pancreatic cancer.

The general chemical terms used in the above formulae have their usual meanings. For example, the term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, cl and Br.

As used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight or branched chain moieties. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. C _1-8, as in C _1-8 alkyl, is defined as a radical having 1, 2,3, 4, 5, 6, 7 or 8 straight-chain or branched carbon atoms

Alkenyl and alkynyl groups include straight, branched or cyclic alkenes and alkynes. Likewise, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl or alkynyl groups having 2, 3, 4, 5, 6, 7, or 8 carbon atoms in a straight or branched arrangement. Alkynyl groups include ethynyl, propynyl, and the like.

Alkoxy is an oxyether formed from the aforementioned straight, branched or cyclic alkyl groups. For example, alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, 3- (2-methyl) butoxy, 2-pentoxy, 2-methylbutoxy, neopentoxy, cyclopentoxy, n-hexoxy, 2-methylpentoxy and cyclohexyloxy.

As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or multicyclic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

As used herein, unless otherwise indicated, the term "heterocyclyl" means an unsubstituted or substituted stable three to ten membered ring system consisting of carbon atoms and one to three heteroatoms selected from N, O or S, wherein the nitrogen or sulfur heteroatoms may be oxidized and the nitrogen heteroatoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. The heterocyclic group is formed by a single bond or a single bond and a double bond. The term "heterocyclyl" represents an unsubstituted or substituted stable three-or seven-membered monocyclic system or an unsubstituted or substituted six-or ten-membered bicyclic system. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl, thiomorpholinyl oxadiazolyl, 1,2,3, 4-tetrahydroisoquinolyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl benzoxazolyl, benzopyrazole, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.

As used herein, unless otherwise indicated, the term "heteroaryl" means an unsubstituted or substituted stable five or six membered monocyclic aromatic ring system or an unsubstituted or substituted nine or ten membered benzo-fused heteroaryl ring system or bicyclic heteroaryl ring system consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Heteroaryl groups may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazole, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazole, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

The term "alkenyloxy" refers to the group-O-alkenyl, wherein alkenyl is as defined above.

The term "alkoxy" refers to the group-O-alkynyl, wherein alkynyl is as defined above.

The term "cycloalkyl" refers to a cyclic saturated alkyl chain having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents. Typical substituents include, but are not limited to, halogen (F, cl, br or I), C _1-8 alkyl, C _3-12 cycloalkyl 、-OR¹、SR¹、＝O、＝S、-C(O)R¹、-C(S)R¹、＝NR¹、-C(O)OR¹、-C(S)OR¹、-NR¹R²、-C(O)NR¹R²、 cyano, nitro 、-S(O)₂R¹、-OS(O₂)OR¹、-OS(O)₂R¹、-OP(O)(OR¹)(OR²); wherein R ¹ and R ² are independently selected from-H, lower alkyl, lower haloalkyl. In some embodiments of the present invention, in some embodiments, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy t-butoxy, -SCH ₃、-SC₂H₅, carboxaldehyde, -C (OCH ₃), cyano, nitro, CF ₃、-OCF₃, amino, dimethylamino, methylthio, sulfonyl, and acetyl.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing instant compounds are also part of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and are therefore intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of the present invention.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For pharmaceutical use, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts generally take the form of basic nitrogen protonated by inorganic or organic acids. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, saccharin, or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administration" shall include treatment of various diseases described with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted in vivo to the indicated compound upon administration to a subject. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, "prodrug design", H.Bundgaard doctor, escule, 1985.

The definition of any substituent or variable at a particular position in a molecule is independent of the definition of other positions in the molecule. It will be appreciated that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide chemically stable compounds and may be readily synthesized by techniques known in the art and as described herein.

The present invention includes that the compounds described herein may contain one or more asymmetric centers and thus may produce diastereomers and optical isomers. The present invention includes all such possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The above formula I has no clear stereochemistry at certain positions. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. In the synthetic processes used to prepare such compounds, or in the use of racemization or epimerization processes known to those skilled in the art, the product of such processes may be a mixture of stereoisomers.

When tautomers of the compounds of formula I are present, the invention includes any of the possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless specifically indicated otherwise.

When the compounds of formula I and pharmaceutically acceptable salts thereof are present in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, etc. may be used.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases that can form salts include ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compounds of the present invention are basic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are preferred, with formic acid and hydrochloric acid being particularly preferred. Since the compounds of formula I are intended for pharmaceutical use, they are provided essentially in the form of an alcohol, for example at least 60% alcohol, more suitably at least 75% alcohol, especially at least 98% alcohol (% on a weight ratio basis).

The pharmaceutical composition of the present invention comprises a compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the conditions under which the active ingredient is being administered. The pharmaceutical composition may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds of formula I or prodrugs or metabolites of the invention or pharmaceutically acceptable salts thereof may be combined as active ingredients by intimately mixing with pharmaceutical carriers according to conventional pharmaceutical formulation techniques. The carrier may take a variety of forms, such as oral or parenteral (including intravenous) depending on the form of preparation desired for administration. Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, such as capsules, buffers or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition may be presented as a powder, a granule, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or an oil-in-water liquid emulsion. In addition to the common dosage forms described above, the compounds represented by formula I or pharmaceutically acceptable salts thereof may also be administered by controlled release devices and/or delivery devices. The composition may be prepared by any pharmaceutical method. Typically, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently molded to the desired appearance.

Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt. The compound of formula I or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be solid, liquid or gaseous. Solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers such as syrup, peanut oil, olive oil, and water. Gaseous carriers such as carbon dioxide and nitrogen. In preparing the composition in oral dosage form, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to prepare oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used for producing oral solid preparations such as powders, capsules and tablets. For ease of administration, tablets and capsules are the preferred oral dosage units in which solid pharmaceutical carriers are used. Wherein the tablets may be coated by standard aqueous or non-aqueous techniques.

Tablets containing the compositions of the invention may be prepared by compression or molding with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules and mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet contains from about 0.05mg to about 5g of active ingredient and each cachet or capsule contains from about 0.05mg to about 5g of active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5mg to about 5g of the active agent, mixed with an appropriate amount of carrier material, which may be present in an amount of from about 5% to about 95% of the total composition. The unit dosage form typically contains from about 1mg to about 2g of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water, including suitable surfactants such as hydroxypropylcellulose, and dispersions in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be added to prevent detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the composition may be in the form of a sterile powder for extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form needs to be sterile and fluid efficient to facilitate injection. The pharmaceutical composition needs to be stable under the conditions of manufacture and storage; therefore, the preservation should prevent the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium such as water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), vegetable oils, and suitable mixtures thereof.

The pharmaceutical composition of the present invention is in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders, and the like. Furthermore, the composition is in a form suitable for use in a percutaneous device. These formulations may be prepared by conventional processing methods using the compounds of formula I of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment having the desired consistency is prepared by mixing the hydrophilic material with water and from about 5wt% to about 10wt% of the compound.

The pharmaceutical composition of the invention is in a form suitable for rectal administration wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be formed by first mixing the composition with a softened or melted carrier and then cooling and shaping in a mold.

In addition to the carrier ingredients described above, the pharmaceutical formulations described above may be supplemented with one or more additional carrier ingredients in appropriate amounts, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be added to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of formula I or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

Generally, dosage levels on the order of about 0.01mg/kg to about 150mg/kg body weight per day may be used to treat the following conditions, or about 0.5mg to about 7g per patient per day. For example, colon, rectal, mantle cell lymphoma, multiple myeloma, breast, prostate, glioblastoma, squamous cell esophageal, liposarcoma, T-cell lymphoma melanoma, pancreatic or lung cancer may be administered by about 0.01 to 50mg of the compound per kilogram of body weight per day, or about 0.5 to about 3.5g per patient per day.

However, lower or higher doses than those described above may be required in special cases. The specific dosage level and treatment regimen of any particular subject will depend upon a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion of drug combination, the severity and course of the particular disease undergoing therapy, the subject's disposition to the disease and the judgment of the treating physician.

These and other aspects will become apparent from the following written description of the invention.

The following examples are provided to better illustrate the invention. All parts and percentages are by weight and all temperatures are degrees celsius unless explicitly stated otherwise.

The present invention will be described in more detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that may be changed or modified to produce substantially the same result. According to the description herein, more than one assay found that the compounds of the examples inhibited ENPP1.

Detailed Description

Experimental procedures for the compounds of the present invention are provided below.

The following abbreviations are used in the examples:

AcOH: acetic acid;

DCM: dichloromethane;

DIBAL-H: diisobutyl aluminum hydride;

DI ethyl acetate: n, N-diisopropylethylamine;

DMF: dimethylformamide;

DMAP: 4-dimethylaminopyridine;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

EDTA: ethylenediamine tetraacetic acid;

HATU: hexafluorophosphate azabenzotriazole tetramethylurea;

HEPES:4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid;

LCMS: liquid chromatography-mass spectrometry;

h or hrs: an hour or hours;

PE: petroleum ether;

MeOH: methanol;

min: minutes;

NCS: n-chlorosuccinimide;

rt or R.T: room temperature;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: preparing thin layer chromatography;

1N:1mol.L-1, (2N: 2mol.L-1, etc.).

Preparation of intermediate compound M4

Step 1: preparation of Compound M4-3

LDA (2M, 6.00mL,12.00 mmol) was added dropwise to a solution of 1- (tert-butyl) 4-ethylpiperidine-1, 4-dicarboxylic acid (2.83 g,11.00 mmol) in THF (50 mL) at-78deg.C under nitrogen. The resulting mixture was stirred at this temperature for 1 hour. 2-chloro-5- (chloromethyl) thiazole (1.69 g,10.06mmol in 3mL tetrahydrofuran) was then added dropwise and stirred for 1 hour. The reaction mixture was quenched with brine (50 mL) and extracted with EA (2X 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:20, v/v elution) to give compound M4-3 (1.15 g).

Step 2: preparation of Compound M4-5

LDA (2M, 3.00mL,6.00 mmol) was added dropwise to a solution of compound M4-3 (900 mg,2.31 mmol) in THF (50 mL) at-78deg.C under nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and quenched with brine (30 mL). The resulting mixture was extracted with EA (2X 30 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound M4-5 (832 mg).

Step 3: preparation of Compounds M4-6

To a solution of M4-5 (800 mg,2.33 mmol) in 2mL of Ti (OEt) 4 was added 2-methylpropane-2-sulfinamide (847 mg,6.99 mmol) in portions and the resulting mixture was stirred at 90℃for 12.0 hours. When the reaction mixture was cooled to room temperature, the reaction mixture was cooled by adding 50mL of ice water. The mixture was extracted with EtOAc (30 mL. Times.3) and the combined organic phases washed with brine (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound M4-6 (1.02 g).

Step 4: preparation of Compound M4-7

To a solution of compound M4-6 (1.02 g,2.29 mmol) in THF (10 mL) at-50deg.C was added drop-wise BH3/THF (1M, 6.6mL,6.87 mmol). The resulting mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched by dropwise addition of brine. The layers were separated, the organic layer was washed with brine (1×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: hex=1:2, v/v elution) to give compound M4-7 (516 mg).

Step 5: preparation of Compound M4

A suspension of compounds M4-7 (500 mg,1.12 mmol), TEA (2 mL) and Pd/C (10%, 138 mg) in methanol (10 mL) was stirred under hydrogen at 40℃for 24 hours under hydrogen. The resulting mixture was filtered, and an additional portion of palladium on carbon (10%, 280 mg) was added to the filtration. The resulting mixture was stirred at 50℃for a further 16 hours. The resulting mixture was filtered, concentrated under reduced pressure and filtered. The residue was purified by silica gel chromatography (eluting with EA: hex=1:1, v/v) to give intermediate M4 (255 mg). MS:414[ M+H ] +.

A suspension of compound M4-7 (500 mg,1.12 mmol), ethyl acetate (2 mL) and Pd/C (10%, 138 mg) in MeOH (10 mL) was stirred at 40℃for 24h under hydrogen. The resulting mixture was filtered and an additional portion of Pd/C (10%, 280 mg) was added to the mixture for re-filtration. The resulting mixture was stirred at 50℃for a further 16 hours. The resulting mixture was filtered, concentrated under reduced pressure and filtered. The residue was purified by silica gel chromatography (eluting with ethyl acetate: hex=1:1, v/v) to give intermediate M4 (255 mg). MS:414[ M+H ] +.

Preparation of intermediate M5

Step 1: preparation of Compound M5-3

To a solution of M5-1 (25.00 g,189.4 mmol) in 200mL of DMF under nitrogen atmosphere was added NaH (22.7 g,567.5 mmol) in portions and the resulting mixture was stirred at 0deg.C for 1.0 h. M5-2 (54.96 g,227.1 mmol) was then slowly added. The resulting mixture was stirred at 0℃for 1.0 hour and at 60℃for a further 1.0 hour. When the reaction mixture was cooled to 0 ℃, the reaction mixture was quenched by adding 500mL of ice water. The mixture was extracted with EtOAc (500 ml×3) combined with the organic phase, washed with brine (200 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M5-3 (29.0 g) as a brown oil.

Step 2: preparation of Compound M5-5

To a solution of M5-3 (29.00 g,96.4 mmol) in 50mL of Ti (OEt) 4 was added in portions M5-4 (34.99 g,288.7 mmol) and the resulting mixture was stirred at 90℃for 12.0 hours. When the reaction mixture was cooled to room temperature, the reaction mixture was quenched by adding 500mL of ice water. The mixture was extracted with EtOAc (300 ml×3) and combined organic phases, washed with brine (200 ml×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude compound M5-5 (39.0 g) as a brown oil.

Step 3: preparation of Compounds M5-6

NaBH ₄ (6.37 g,167.5 mmol) was added in portions to a solution of M5-5 (48.00 g,118.8 mmol) in 500mL of tetrahydrofuran at-20deg.C under nitrogen. The resulting mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was cooled by adding 300mL of ice water. The mixture was extracted with ethyl acetate (300 ml×3) and the organic layers were combined. The organic layer was washed with brine (200 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M5-6 (25.4 g) as a brown oil.

Step 4: preparation of Compound M5

To a solution of M5-6 (10.0 g,24.6 mmol) in 100mL DCM was added TFA (28.04 g,246.0 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was cooled by adding 100mL of saturated NaHCO3 solution. The mixture was extracted with acetoacetic acid (100 mL. Times.3) and the organic layers were combined. The organic layer was washed with brine (100 ml×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M5 (7.64 g) as a yellow solid.

Compounds of formula (I) M5:1H NMR(500MHz,DMSO-d6)：δ7.26-7.16(m,4H),5.50(d,J＝10.0Hz,1H),4.30(d,J＝10.0Hz,1H),3.04(d,J＝16.0Hz,1H),2.87-2.80(m,2H),2.67-2.58(m,3H),1.88-1.82(m,1H),1.59-1.53(m,1H),1.37-1.34(m,1H),1.21(s,9H),1.12-12 1.09(m,1H).

Preparation of intermediate compound M6

Step 1: preparation of Compound M6-3

M6-2 (19.5 g,114.0 mmol) and K ₂CO₃ (26.2 g,189.8 mmol) were added to a solution of M6-1 (19.5 g,95.2 mmol) in 100mL MeCN. The resulting mixture was stirred at 90℃for 3.0 hours. Upon cooling to room temperature, the solid was filtered and washed with EtOAc (50 ml×2), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M6-3 (5.9 g).

Step 2: preparation of Compound M6-4

To a solution of M6-3 (1.5 g,7.7 mmol) in 15mL of toluene was added dropwise PBr ₃ (1.1 mL). The resulting mixture was stirred at 105℃for 12 hours. The reaction mixture was concentrated and quenched with 15mL of water. The pH was adjusted to 9 with 4M NaOH solution. The mixture was then extracted with EtOAc (50 ml×2) and the organic layers were combined. The organic layer was washed with brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound M6-4 (1.5 g).

Step 3: preparation of Compound M6-6

NaH (271mg, 6.8 mmol) was added in portions to a solution of M6-5 (450 mg,3.4 mmol) in 6mL DMF at 0deg.C and the resulting mixture stirred at 60deg.C for 1.0 h. The mixture was then cooled to room temperature and M6-4 (1.2 g,3.7 mmol) was slowly added. The resulting mixture was stirred at 60℃for a further 1.0 hour. After the reaction was completed, the reaction mixture was cooled to 0 ℃ and quenched by addition of 30mL of ice water. The organic phase extracts were combined with EtOAc (30 ml×3), washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M6-6 (160 mg).

Step 4: preparation of Compound M6-7

To a solution of M6-6 (160 mg,0.55 mmol) in 2mL DCE at 0deg.C was added drop wise ACE Cl (155 mg,1.4 mmol) and the resulting mixture was stirred at room temperature for 2.0 hours. The mixture was then concentrated, the residue was dissolved in 4mL of methanol, and the mixture was stirred at 80 ℃ for 3 hours. The resulting mixture was concentrated again and the residue was dissolved in 4mL DCM. (BOC) ₂ O (242 mg,1.1 mmol) and DIPEA (239 mg,1.9 mmol) were then added to the mixture and the resulting mixture was stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was cooled by adding 30mL of ice water. The mixture was extracted with EtOAc (30 ml×3), the organic phases were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M6-7 (25 mg).

Step 5: preparation of Compound M6

The procedure for synthesizing compound M6 from intermediate M6-7 is the same as that of M5-3 to M5

Preparation of intermediate compound M11

Step 1: preparation of Compound M11-3

To a solution of M11-2 (2.83 g,18.1 mmol) in 50mL THF at-78deg.C under nitrogen was added dropwise LDA (2M, 6 mL) in THF/Hex. After stirring the resulting mixture for 1.0 hour, a solution of M11-1 (1.56 g,6.1 mmol) in 3mL THF was slowly added. The resulting mixture was stirred for another 1.0 hour. The reaction mixture was cooled by adding 50mL of brine. The organic layer was combined with EtOAc (30 ml×3), washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M11-3 (1.44 g) as a pale yellow oil.

Step 2: preparation of Compound M11-4

To 50g PPA was added M11-3 (1.9 g,5.04 mmol) and the resulting mixture was stirred at 130℃for 2 hours. The reaction mixture was cooled to room temperature by adding 50mL of ice water. The mixture was adjusted to ph=8 with 4M NaOH solution, extracted with EtOAc (150 ml×2) combined with the organic layer, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M11-4 (1.04 g) as a pale yellow solid.

Step 3: preparation of Compound M11-5

To a solution of M11-4 (1.0 g,4.3 mmol) in 50mL of ethanol was added TEA (2.0 mL) and BoC ₂ 0 (2.1 g,9.6 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of 50mL brine, extracted with EtOAc (150 ml×2) and combined organic layers, and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M11-5 (1.2 g) as a pale yellow solid.

Step4: preparation of Compound M11

The procedure for synthesizing compound M11 from intermediate M11-5 is the same as that of M5-3 to M5

Preparation of intermediate compounds M7, M8, M9 and M10

The following compounds (e.g., M7, M8, M9 and M10) were synthesized using the procedure described above (e.g., M11) or modified with the corresponding starting materials.

Preparation of intermediate compound M15

To a solution of SM1 (560 mg,2.0 mmol) in 20mL DMF was added M5 (640 mg,2.2 mmol) and DIPEA (860 mg,6.6 mmol). The resulting mixture was stirred at 80℃for 3 hours. When cooled to room temperature, the reaction mixture was quenched by addition of 20mL of brine, extracted with EtOAc (100 ml×3) and combined organic layers, and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M15 (990 mg) as a pale yellow solid.

Preparation of intermediate compounds M16, M17, M18, M19 and M20

The following compounds (e.g., M16, M17, M18, M19 and M20) were synthesized using the procedure described above (e.g., M15) or modified procedures with the corresponding starting materials.

EXAMPLE 9 Synthesis of (S) -1'- (3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2,4' -piperidin ] -1-amine (A9)

Step 1: preparation of Compound A9-2

To a solution of A9-1 (2.07 g,10.0 mmol) in 30mL of toluene under nitrogen protection were added ethynyl trimethylsilane (1.0 g,10.1 mmol), TEA (2.02 g, 20.0 mmol), cuI (190 mg,1.0 mmol) and Pd (PPh ₃)₂Cl₂ (105 mg, 0.15 mmol) the resulting mixture was stirred at 60℃for 5.0 h.

Step 2: preparation of Compound A9-3

To a solution of A9-2 (1.12 g,5.0 mmol) in 20mL MeCN was added K2CO3 (1.38 g,10.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled by adding 100mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound A9-3 (720 mg) as a yellow solid.

Step 3: preparation of Compounds A9-4

To a solution of A9-3 (455 mg,3.0 mmol) in 10mL THF under nitrogen was added tributylane (1.5 g,5.1 mmol) and Pd (PPh ₃)₂Cl₂ (75 mg.0.075 mmol) the resulting mixture was stirred at room temperature for 24 hours.

Step 4: preparation of Compound A9

M15 (400 mg,0.7 mmol), cuI (106 mg,0.7 mmol) and Pd (PPh ₃)₂Cl₂ (49 mg.0.07 mmol) were added to a solution of A9-4 (444 mg,1.0 mmol) in 10mL dry DMF the resulting mixture was stirred at 80℃for 0.5 hours, when cooled to room temperature the reaction mixture was quenched by addition of 100mL HCl (3N) and stirred at room temperature for a further 2 hours, the mixture was neutralized to pH=8 with NaOH (2N) solution, the mixture was extracted with EtOAc (100 mL×3) combined with an organic layer, washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

Preparation of Compounds A1-A47

The following compounds (e.g., A1-A47) were synthesized using the A9 procedure described above or modified procedures with the corresponding starting materials.

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Compounds of formula (I) A5:1H NMR(500MHz,DMSO-d6)δ8.60(d,J＝5.1Hz,4H),8.50(s,1H),7.77–7.48(m,1H),7.42–7.16(m,5H),6.84(d,J＝2.3Hz,1H),6.68(d,J＝8.3Hz,3H),5.32(d,J＝2.2Hz,1H),4.48–4.25(m,4H),3.62(s,6H),3.43(s,1H),3.37–3.20(m),4H),3.01(d,J＝16.1Hz,1H),1.82(dd,J＝13.0,3.6Hz,2H),1.58(d,J＝15.7Hz,2H).

Preparation of intermediate M21

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Step 1: preparation of Compound M21-2

To 30mL of dioxane solution of M21-1 (3.15 g,10.0 mmol) was added 20mL of sodium hydroxide (4M) solution. The resulting mixture was stirred at room temperature for 24 hours. The mixture was neutralized with HCl (1N) solution to ph=7. The solid was filtered and washed with water and dried under vacuum to give compound M21-2 (2.1 g) as a pale yellow solid.

Step 2: preparation of Compound M21

To a solution of M21-2 (578mg, 2.0 mmol) in 20mL DMF was added M5 (640 mg,2.2 mmol) and DIP ethyl acetate (860 mg,6.7 mmol). The resulting mixture was stirred at 100℃for 3 hours. After cooling to room temperature, the mixture was quenched with 20mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M21 (860 Mg).

EXAMPLE 47 Synthesis of 6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -3- (1- (2-amino-3-chloropyridin-4-yl) vinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one (B1)

M21 (340 mg,0.7 mmol), cuI (106 mg,0.7 mmol) and Pd (PPh 3) 2Cl2 (49 mg.0.07 mmol) were added to a solution of A9-4 (444 mg,1.0 mmol) in 10mL anhydrous DMF. The resulting mixture was stirred at 110℃for 0.5 h. When cooled to room temperature, the reaction mixture was quenched by addition of 100mL HCl (3N) and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized to ph=8 with sodium hydroxide (2N) solution. The mixture was extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound B1 (190 mg) as a pale yellow solid.

Preparation of Compounds B1-B150

The following compounds (B1-B150) were synthesized using the procedure B1 described above or using a modified procedure of the corresponding starting materials

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Compounds of formula (I) B16:¹H NMR(500MHz、DMSO-d₆)δ12.77(s、1H)、8.32(s、3H)、7.49–7.27(m、4H)、7.28–7.14(m、4H)、5.47(d、J＝1.7Hz、1H)、4.23(d、J＝13.7Hz、2H)、3.96(s、1H)、3.32–3.13(m、2H)、3.09(d、J＝15.7Hz、1H)、2.70(d、J＝15.8Hz、1H)、1.88–1.59(m、2H)、1.48(d、J＝13.2Hz、1H)、1.17(d、J＝13.4Hz、1H).

Compounds of formula (I) B20:¹H NMR(500MHz、DMSO-d₆)δ10.90(s、1H)、8.51(s、2H)、7.69(m、3H)、7.58(d、J＝7.9Hz、2H)、7.45–7.23(m、3H)、6.81(s、1H)、5.79(s、1H)、4.49–3.99(m、4H)、3.36–3.12(m、3H)、2.97(d、J＝16.1Hz、1H)、1.76(d、J＝6.1Hz、2H)、1.51(d、J＝11.0Hz、2H).

Compounds of formula (I) B28:¹H NMR(500MHz、DMSO-d₆)δ12.95(s、1H)、7.46(dd、J＝16.3、7.8Hz、3H)、7.39–7.20(m、5H)、6.73(s、1H)、5.77(s、1H)、4.23(d、J＝21.4Hz、2H)、3.33(s、3H)、3.28–3.07(m、3H)、2.95–2.80(m、1H)、1.83–1.61(m、1H)、1.49(d、J＝13.5Hz、1H)、1.39–1.16(m、2H).

Compounds of formula (I) B33:¹H NMR(500MHz、DMSO-d₆)δ10.87(s、1H)、8.59(d、J＝5.4Hz、1H)、7.60(d、J＝7.4Hz、1H)、7.50–7.17(m、9H)、6.57(s、1H)、5.69(d、J＝1.5Hz、1H)、4.51–4.11(m、4H)、3.36–3.12(m、3H)、2.97(d、J＝16.0Hz、1H)、1.78(dt、J＝12.9、3.6Hz、2H)、1.50(t、J＝13.8Hz、2H).

Preparation of intermediate compound M22

Step 1: preparation of Compound M22-2

To a solution of M22-1 (3.15 g,10.0 mmol) in 30mL of DCM was added (2- (chloromethoxy) ethyl) trimethylsilane (2.0 g,12.0 mmol) and DIP ethyl acetate (2.58 g,20.0 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched by the addition of 100mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M22-2 (3.61 g).

Step 2: preparation of Compound M22-3

To a solution of M22-2 (2.20 g, 5.0 mmol) in 20mL THF was added 4mL sodium hydroxide (5M) solution. The resulting mixture was stirred at room temperature for 7.5 hours. The reaction mixture was quenched by the addition of 100mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with brine (100 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M22-3 (1.61 g).

Step 3: preparation of Compound M22-4

To a solution of M22-3 (1.28 g,3.0 mmol) in 10mL of DMF was added MeI (0.56 g,4.0 mmol) and K ₂CO₃ (0.82 g,6.0 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with 100mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with brine (100 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M22-4 (0.81 g).

Step4: preparation of Compound M22

To a solution of M22-4 (441 mg,1.0 mmol) in 10mL dioxane was added 3mL of HCl (4M) in dioxane. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was quenched with 10mL of water and neutralized to ph=8 with sodium hydroxide (2N) solution. The solid was filtered, washed with brine (10 mL. Times.2), and dried in vacuo to give compound M22 (210 mg).

Preparation of intermediate compound M23

To a solution of M22 (620 mg,2.0 mmol) in 20mL DMF was added M5 (640 mg,2.2 mmol) and DIP ethyl acetate (860 Mg,6.6 mmol). The resulting mixture was stirred at 90℃for 3 hours. When cooled to room temperature, the reaction mixture was quenched with 20mL of water. The mixture was extracted with ethyl acetate (100 ml×3), the organic layers were combined, washed with brine (100 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M23 (810 mg).

Preparation of intermediate compounds M24 and M25

The following compounds (M24 and M25) were synthesized using the procedure of M21, M22 and M23 described above or using modified procedures of the corresponding starting materials

EXAMPLE 178 Synthesis of 6- (1-amino-1, 3-dihydro-spiro [ inden-2, 4 '-piperidin ] -1' -yl) -5-methyl-3- (1-phenylvinyl) -1, 5-dihydro-4H-pyrazolo [3,4-d ] pyrimidin-4-one (C1)

Step 1: preparation of Compound C1-2

To a solution of C1-1 (510 mg,5.0 mmol) in 10mL of anhydrous tetrahydrofuran under nitrogen was added tributyl (1.5 g,5.0 mmol) and Pd (PPh 3) ₂ Cl2 (210 mg.0.3 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched by addition of 100mL of water and extracted with ethyl acetate (100 ml×3), the organic layers combined and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound C1-2 (1.31 g).

Step 2: preparation of Compounds C1-3

M23 (350 mg,0.7 mmol), cuI (106 mg,0.7 mmol) and Pd (PPh 3) ₂ Cl2 (49 mg.0.07 mmol) were added to a solution of C1-2 (393 mg,1.0 mmol) in 10mL anhydrous DMF under nitrogen. The resulting mixture was stirred at 80℃for 0.5 h. When cooled to room temperature, the reaction mixture was quenched by addition of 100mL of water, extracted with ethyl acetate (100 ml×3) in combination with the organic layer, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound C _1-3 (310 mg) as a pale yellow solid.

Step 3: preparation of Compound C1

To a solution of C1-3 (278 mg,0.5 mmol) in dioxane was added 4mL of HCl (4M) in dioxane. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was quenched by addition of 100mL of NaHCO3 saturated solution, extracted with ethyl acetate (100 ml×3), combined with the organic layer and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound C ₁ (190 mg) as a pale yellow solid.

Preparation of Compounds C1-C4, D1-D4 and E1-E4

The following compounds (C1-C4, D1-D4 and E1-E4) were synthesized using the procedure C ₁ described above or using modified procedures of the corresponding starting materials.

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Preparation of intermediate compound M26

Step 1: preparation of Compound M26-2

To a solution of M26-1 (3.15 g,10.0 mmol) in 30mL dioxane was added 2-aminoethanol (2.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The solid was filtered, washed with dioxane and dried under vacuum to give compound M26-2 (2.44 g) as a white solid.

Step 2: preparation of Compound M26

To a solution of M26-2 (1.7 g,5.0 mmol) in 20mL of CHCl ₃ was added SOCl ₂ (2.0 mL). The resulting mixture was stirred at 80℃for 6 hours. Upon cooling to room temperature, the reaction mixture was quenched by addition of 100mL of water and extracted with DCM (100 ml×2), the organic layers were combined, washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M26 (964.5 mg).

Preparation of intermediate compound M27

Step 1: preparation of Compound M27-1

To a solution of M26-1 (3.15 g,10.0 mmol) in 30mL ethanol was added hydrazine hydrate (80%) (3.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The solid was filtered, washed with ethanol and dried under vacuum to give compound M27-1 (2.75 g) as a pale yellow solid.

Step 2: preparation of Compound M27

To a solution of M27-1 (1.55 g,5.0 mmol) in 20mL dioxane was added triethoxymethane (2.0 mL). The resulting mixture was stirred at 60℃for 5 hours. When cooled to room temperature, the reaction mixture was quenched by addition of 100mL of water, extracted with DCM (100 ml×2), combined with the organic layer and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M27 (1.30 g) as a pale yellow solid.

Preparation of intermediate M28

Step 1: preparation of Compound M28-1

To a solution of M26-1 (3.15 g,10.0 mmol) in 30mL of methanol was added 2, 2-dimethoxyethylamine (2.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The solid was filtered and washed with methanol and dried under vacuum to give compound M28-1 (3.45 g) as a yellow solid.

Step 2: preparation of Compound M28

AcOH (2.0 mL) was added to a solution of M28-1 (1.92 g,5.0 mmol) in 20mL dioxane. The resulting mixture was stirred at 90℃for 5 hours. Upon cooling to room temperature, the reaction mixture was quenched by addition of 100mL of saturated NaHCO ₃ solution, extracted with DCM (100 ml×2), combined with the organic layer and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound M28 (767 mg) as a pale yellow solid

Example 190 (S) -1'- (9- (1-Phenylvinyl) -2, 7-dihydro-3H-imidazo [1,2-c ] pyrazolo [4,3-e ] pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidin ] -1-amine (F1)

Step 1: preparation of Compound F1-1

To a solution of M26 (643 mg,2.0 mmol) in 20mL DMF was added M5 (670 mg,2.2 mmol) and DIP ethyl acetate (860 mg,6.6 mmol). The resulting mixture was stirred at 80℃for 3 hours. When cooled to room temperature, the reaction mixture was quenched by addition of 20mL of brine, extracted with ethyl acetate (100 ml×3) and combined organic layers, and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound F1-1 (893 mg).

Step 2: preparation of Compound F1-2

C1-2 (393 mg,1.0 mmol), cuI (106 mg,0.7 mmol) and Pd (PPh ₃)₂Cl₂ (49 mg, 0.07 mmol) were added to a solution of F1-1 (413 mg,0.7 mmol) in 10mL of anhydrous DMF under nitrogen, the resulting mixture was stirred at 80℃for 1.5 hours, when cooled to room temperature, the reaction mixture was quenched by the addition of 100mL of water and extracted with ethyl acetate (100 mL. Times.3), the combined organic layers were washed with brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by silica gel chromatography to give compound F1-2 (330 mg) as a pale yellow solid

Step 3: preparation of Compound F1

To a solution of F1-2 (283 mg,0.5 mmol) in 10mL dioxane was added 4mL of HCl (4M) in dioxane. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was quenched by addition of 100mL of saturated NaHCO ₃ solution, extracted with ethyl acetate (100 ml×3), combined with the organic layer and washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound F1 (208 mg) as a pale yellow solid.

Preparation of Compounds G1-G23 and H1

The following compounds (G1-G23 and H1) were synthesized using the F1 procedure described above or using a modified procedure of the corresponding starting materials.

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EXAMPLE 228 SHP2 allosteric inhibitor enzyme Activity assay

SHP2 is activated by binding of a dityramidal phosphoryl peptide to its Src homology 2 (SH 2) domain. Subsequent activation steps result in the release of an auto-inhibitory interface of SHP2, which in turn activates SHP2 Protein Tyrosine Phosphatase (PTP), which can be used for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored in a rapid fluorometric format using an alternative difmeup.

SHP2 is activated by binding of a double tyrosine phosphorylated peptide to its Src homology 2 (SH 2) domain. Subsequent activation steps result in release of the SHP2 autorepression interface, which in turn activates SHP2 Protein Tyrosine Phosphatase (PTP) and can be used for substrate recognition and reaction catalysis. Monitoring of catalytic activity of SHP2 using alternative difmep in rapid fluorescence analysis format

The measurement procedure was as follows:

(1) The compound formula comprises the following components:

The final test concentrations of the compounds of the invention (10 mM stock) were 10. Mu.M, 3.333. Mu.M, 1.111. Mu.M, 0.3704. Mu.M, 0.1235. Mu.M, 0.0412. Mu.M, 0.0137. Mu.M, 0.0046. Mu.M, 0.0015. Mu.M, 0.00. Mu.M, by dilution of the compounds of the invention with 100% DMSO and assay buffer to appropriate fold;

(2) Preparing an enzyme reaction working solution:

SHP2 enzyme biopsies were performed in 96-well black polystyrene plates (flat bottom, low flange, non-binding surface) (PERKI ELMER, cat# 6005270) using 50 μl of final reaction volume at room temperature and the following assay buffer conditions: 60mM HEPES, 75mM NaCl, 75mM KCl, 0.05% BRIJ-35, 1mM EDTA, 5mM DTT.

(3) Enzyme-catalyzed reaction and data monitoring:

Compounds of the present invention were added to corresponding 96-well plates without providing compounds and enzymes as blank test wells. SHP2-activating peptide (irs1_py1172 (dPEG 8) pY 1222) was thawed on ice, 0.5 μm was added to each well, and then 0.2ng SHP2 protein sample was added to the corresponding well plate and incubated for 1 hour at room temperature. The substrate DiFMUP (Invitrogen, cat #D6567) was added to the reaction at room temperature for 1 hour. Fluorescence signals were monitored using an enzyme reader (Envision, PERKI ELMER) using excitation and emission wavelengths of 340nm and 450nm, respectively.

(4) Data analysis:

The calculation formula is as follows:

Inhibition ratio% = [1- (conversion_sample-conversion_min)/(conversion_max-conversion_min) ]×100%

Wherein: convergence_sample is the Conversion reading of the sample; convertion_min is the average of the blank wells and represents the Conversion reading without enzyme wells; convertion_max is the mean of the positive control well ratio and represents the Conversion reading for wells without compound inhibition. The IC50 values of compounds for enzyme activity were calculated using log (inhibitor) vs. response-Variable slope fit efficacy curves of analytical software GRAPHPAD PRISM.

Results are expressed as IC50, the inhibitory activity of the compounds on SHP2 is shown in table 1, the IC50 values of the compounds of the invention, as exemplified in the examples, are within the following ranges: "A" represents "IC50 is less than or equal to 100nM"; "B" represents "100nM < IC50.ltoreq.500 nM"; "C" represents IC50 > 500nM.

TABLE 1

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Example 229 cell proliferation assay

The effect of the compounds of the present invention on proliferation of leukemia cells MV-4-11 and lung cancer cells NCI-H358 was evaluated using an in vitro cell test. The detection method used in this assay is CELL TITER-GLO (CTG) luminescence, and the number of living cells can be detected by quantitatively measuring ATP. Since ATP is involved in various enzymatic reactions in the living body and is an index of metabolism of living cells, its content directly reflects the number and state of cells, cellTiter-Glo reagent was added during the experiment. Cell culture medium, measuring luminescence value, the luminescence value is proportional to the amount of ATP, and ATP is directly related to the number of living cells; thus, cell viability can be observed by detecting ATP content.

The measurement procedure was as follows:

(1) Cell plating:

Taking a bottle of NCI-H358 cells in logarithmic growth phase, counting after digesting the resuspended cells, inoculating the cell density into a 96-well ultra-low adhesion plate, inoculating 2000 cells into each well, inoculating into a 37 ℃ plate, adding into a 5% CO ₂ incubator for 24 hours, and treating;

taking a bottle of logarithmic MV-4-11 cells, counting after collecting the cells, inoculating the cell density into a 96-well plate, inoculating 4000 cells into each well, placing the plate into a 37 ℃ and 5% CO ₂ incubator for 24 hours, and then adding the compound of the invention for treatment;

(2) Cell compounding treatment:

The compounds of the invention were formulated for cell therapy at final concentrations of 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM, 0nM. To low, the well plate was placed in a 5% CO2 incubator at 37℃for 120 hours. Only medium without cell wells was added as a blank; the concentration of compound in the control group was 0nM.

(3) CTG detection:

MV-4-11 cell: after 120 hours of cell culture, 50. Mu.L of the cells were added to each well Luminescent Cell Viability Assay solution, gently shake for 2min, incubate at room temperature for 10min and read the assay value for each well on a multifunctional microplate reader.

NCI-H358 cells: after 96 hours of cell culture, 50. Mu.L of the cells were added to each wellLuminescent Cell Viability Assay solution, gently shake 2min, incubate at room temperature for a further 10min, incubate move to 96 well write plate and read assay value for each well on multifunctional enzyme reader.

(4) Data analysis:

the rejection ratio is calculated from the emissions value readings,

Percentage inhibition = (1- (management group value-blank group value)/(control group value-blank group value) ×100

GRAPHPAD PRISM log (inhibitor) versus response-variable slope fit quantization curve and calculate IC50 for compounds inhibiting cell proliferation as shown in table 2, compounds of the present disclosure as exemplified in the examples show IC50 values in the following ranges: "A" represents "IC50 is less than or equal to 100nM"; "B" represents "100nM < IC50.ltoreq.500 nM"; "C" represents IC50 > 500nM.

Table 2

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Example 230 in vitro Metabolic stability in human, rat, monkey and canine liver microsomes

Buffer solution:

1900mg of MgCl ₂ are dissolved in ultra pure water having a final volume of 400 mL.

17.42G K ₂HPO₄ and 13.65g KH ₂PO₄, respectively, were dissolved in a final volume of 1000mL of ultra pure water. K ₂HPO₄ and KH ₂PO₄ were mixed to prepare 100mM potassium Phosphate (PBS) buffer. The pH of the final solution was adjusted to pH 7.30.+ -. 0.10.

Reaction stop protocol:

Cold acetonitrile (including 10ng/mL labetalol and 10ng/mL glibenclamide) was stored at 4 ℃.

Preparing a working solution:

Verapamil (positive control) and test compound stock solutions were diluted to 50 μm and 200 μm concentrations, respectively, using MeOH/ACN/H ₂ O solutions (1:1:2, v/v/v).

Program

1) Add 40. Mu.L MgCl ₂ and 306. Mu.L PBS to 96 plate wells (blank, composite, NADPH well-free compound)

2) To the wells, 4 μl of the compound working fluid (blank: 4 μl PBS buffer) (note: the volume of DMSO in the final culture system is less than or equal to 0.5 percent)

3) Mu.L of microsomes (20 mg/mL) was added to each well. The mixture was heated at 37.0℃for 10 minutes.

4) The reaction was started by adding 40. Mu.L of 10mM NADPH working solution. The total volume was 400. Mu.L.

5) Samples of 50. Mu.L were taken from the reaction solution at 0, 5, 15, 45 minutes. The reaction solution was quenched by the addition of 400. Mu.L of a stop solution.

6) The sampling plate was shaken for about 10 minutes. 5 minutes.

7) The sample was centrifuged at 3200RCF for 10 minutes. Then 50. Mu.L was transferred to a new plate diluted with 200. Mu. L H2O for LC/MS/MS analysis.

Data analysis

T1/2 and CL are calculated using the first order kinetic equation:

k= -slope

t1/2＝0.693/k

Clint=k/C protein

Where k represents the elimination constant, which is calculated from a log-linear plot of percent remaining versus time. t1/2 represents half-life. Protein C is the concentration of liver microsomes.

The results of the metabolic stability of human, rat, monkey, canine liver microsomes are shown in table 3.

TABLE 3

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Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -2-fluorobenzonitrile; or (b)

(S) -3- (1- (6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -4-oxo-4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) vinyl) -2-chlorobenzonitrile.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

3. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment, delay or prevention of cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.

4. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment of a disorder mediated by SHP 2.

5. The use according to claim 4, wherein the disease is cancer.

6. The use according to claim 5, characterized in that the cancer is Noonan syndrome, leopard syndrome, childhood granulocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma and/or pancreatic cancer.

7. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 2 for the preparation of an inhibitor of SHP 2.