Azole derivatives as SHP2 inhibitors

Abstract

The present invention relates to novel compounds capable of inhibiting SHP2 phosphatase activity. The compounds of the present invention are useful in the treatment of conditions associated with SHP2 disorder. The invention also relates to a pharmaceutical composition containing the compound and a synthesis method thereof.

Description

Technical Field

[0001] The present invention relates to novel compounds capable of inhibiting SHP2 phosphatase activity. The compounds of the present invention can be used to treat diseases associated with SHP2 disorders. The present invention also relates to pharmaceutical compositions containing the compounds and methods for synthesizing the same. Background Art

[0002] Src homology phosphotyrosine phosphatase 2 (SHP2), encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) composed of a C-terminal domain, a PTP domain, and two N-terminal Src homology (N-SH2) domains that contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is a positive regulator of downstream signaling of several receptor tyrosine kinases through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositide-3-kinase-AKT pathways. The protein exists in an inactive, autoinhibited conformation that is stabilized by a binding network involving residues from the N-SH2 domain and the catalytic PTP domain. SHP2 recruitment to activated receptors releases the autoinhibited conformation and leads to catalytic activation of its phosphatase domain. In addition to its function as a phosphatase, SHP2 acts as a docking protein through its two amino-terminal N-SH2 domains to recruit other signaling intermediates. Since SHP2 is a positive regulator of cell signaling leading to proliferation, differentiation, and survival, its constitutive activation has been implicated in carcinogenesis.

[0003] SHP2 has emerged as an attractive therapeutic target for the treatment of a variety of diseases, such as Noonan syndrome, Leopard syndrome, juvenile myeloid leukemia, glioblastoma, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers.

[0004] Both academic institutions and pharmaceutical companies have publicized drug discovery programs to develop SHP2 inhibitors based on different heterocyclic scaffolds.

[0005] Novartis' WO2015 / 107493, WO2015 / 107494 and WO2015 / 107495 disclose compounds of the general formula (A) shown below:

[0006]

[0007] Novartis also disclosed compounds of the basic structures (B), (C), (D) and (E) shown below, which are disclosed in WO2016 / 203404, WO2016 / 203405 and WO2017 / 216706, respectively:

[0008]

[0009] The basic structure E disclosed in WO2017 / 216706 and the compounds identified therein are 2-amino-3H-imidazo[4,5-b]pyridine 5- or 6-thiol derivatives.

[0010] Jacobio Pharmaceuticals (Jacobio Pharmaceuticals Group Co., Ltd.) disclosed pyrazine derivatives of structures (F) and (G) shown below in WO2017 / 211303 and WO2018 / 172984:

[0011]

[0012] Recently, Revolution Medicines disclosed other pyridine, pyrazine and triazine compounds as allosteric SHP2 inhibitors in WO2018 / 013597, WO2018 / 136264 and WO2019 / 075265.

[0013] WO2018 / 136265 and WO2019 / 118909 both relate to bicyclic heteroaromatic skeletons, including imidazopyrazine, triazolopyrazine, pyrazolopyridine, imidazopyrimidine in the basic structure (H):

[0014]

[0015] The Regents of the University of Texas System disclosed pyrazolopyrazines and ring-fused pyrimidin-4-ones in WO2017 / 210134 and WO2017 / 156397, respectively.

[0016] Relay Therapeutics further disclosed pyrazolopyrazines in WO2018 / 081091, WO2018 / 218133, WO2018 / 057884 and WO2019 / 067843.

[0017] Gilead (Gilead Sciences) disclosed the following imidazopyrimidine in WO2020 / 072656:

[0018]

[0019] Therefore, SHP2 is an attractive target for the development of new therapies for the treatment of various diseases associated with it. Therefore, there is a need to develop new therapeutic agents that are SHP2 inhibitors. The compounds of the present invention meet this need because they are small molecules that can inhibit the activity of SHP2.

[0020] Many of the compounds disclosed in the cited patents and patent applications share a heterocyclic core with the basic structure shown below, which is substituted with a tricyclic amine, where ring C is an aromatic or heteroaromatic ring:

[0021]

[0022] Surprisingly, the introduction of a suitable azole ring, such as pyrazole or pyrrole, with one nitrogen at the bridgehead on the left side of the molecule, in combination with a specifically selected central heterocyclic core and substituents, enables the identification of potent and selective SHP2 inhibitors that have excellent pharmacokinetics in preclinical animal species and exhibit significant exposure in plasma (both Cmax and AUC) after oral administration. The compounds of the present invention may also have improved ligand-bio-target kinetics due to the presence of a substituted or unsubstituted azole moiety, greatly extending the residence time of the SHP2 inhibitor (the time the ligand is in contact with its biological target) by reducing its koff. In addition, many of the compounds disclosed herein are SHP2 inhibitors that can penetrate the BBB to reach their targets and can be used to treat tumors originating from or spreading to the CNS. SUMMARY OF THE INVENTION

[0023] The present invention relates to heterocyclic compounds that can be used as SHP2 inhibitors and can be used to treat SHP2-mediated disorders.

[0024] The inventors have found that compounds with a general formula including a five-membered fused heteroaromatic ring and a specific nitrogen pattern on the left side of the molecule can act as particularly effective SHP2 inhibitors, as demonstrated by the IC 50 values for enzyme and cell inhibition of SHP2 in the low nanomolar or micromolar range. More specifically, the compounds of the present invention are characterized by a suitable azole ring, such as pyrazole or pyrrole, with one nitrogen at the bridgehead on the left side of the molecule, and a specifically selected central heterocyclic core and substituents.

[0025] Accordingly, an object of the present invention is a compound of formula (I):

[0026]

[0027] Wherein:

[0028] X 1 is CR 1 or N, X 2 is CR 2 and X 3 is CR 3 ; in a preferred embodiment, X 1 is N, X 2 is CR 2 and X 3 is CR 3 ;

[0029] R 1 , R 2 and R 3 Each is optionally selected from H, halogen, OC 1-3 Alkyl or C 1-3 alkyl;

[0030] X 4 O, S or X 4 is the key;

[0031] R 4 is aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaromatic ring, wherein the aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaromatic ring is optionally substituted by one or more substituents independently selected from C(O)CH 3 、C(O)OCH 3 , OH, halogen, NH 2 NH-C 1-6 Alkyl, N(C 1-6 alkyl) 2 , C 1-6 Alkyl, C 3-5 Cycloalkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, CONR'R", CN, halogenated C 1-6 Alkoxy, C 1-6 alkoxy, saturated 5 or 6 membered heterocyclic ring, aryl or heteroaryl, wherein the saturated 5 or 6 membered heterocyclic ring, aryl or heteroaryl are each optionally substituted by one or more CH 3 NH 2 , halogen or OH, and wherein R' and R" are each independently H or C 1-6 Alkyl, preferably H or CH 3 ;

[0032] Cy-X 4 -R 4 Corresponding to any one of the general formulas (A)-(F) shown below:

[0033]

[0034] in:

[0035] -R 5 Selected from H, C 1-3 Alkyl and NH 2 ; preferably selected from H, CH 3 and NH 2 ;

[0036] -R 6 , R 7 , R8 Each independently selected from H and C 1-3 alkyl;

[0037] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0038] Preferably, the compound of formula (I) is not a compound selected from the following:

[0039] -(S)-1-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0040] -(S)-1-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0041] -(S)-1-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0042] -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0043] -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0044] -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0045] -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0046] -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0047] -(S)-1-(5-((2-Amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0048] -(S)-1-(5-((2-Amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0049] -(S)-1-(5-((2-Amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0050] -(S)-1-(5-((8-Chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0051] -(S)-1-(5-((3-Chloro-2-(1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0052] -(S)-1-(5-((3-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0053] -(S)-1-(5-((8-Chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0054] -(S)-1-(5-((5-Amino-3-chloropyrazin-2-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0055] -(S)-1-(5-((3,8-Dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0056] -(S)-1-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0057] -(S)-1-(5-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0058] -(S)-1-(5-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0059] -(S)-1-(5-((8-chloro-3-nitroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0060] -(S)-N-(7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide;

[0061] -(S)-7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxamide;

[0062] -(S)-1-(5-((6-amino-2-chloropyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0063] -(S)-1-(5-((5-chloroimidazo[1,2-a]pyridin-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0064] -(S)-7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carbonitrile;

[0065] -(S)-7-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridin-2(3H)-one;

[0066] -(S)-1-(5-((3-Chloro-2-(1H-imidazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0067] -(S)-1-(6-Amino-5-((3-chloro-2-(1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0068] -(S)-1-(5-((3-Chloro-2-(4-fluoro-1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0069] -(S)-1-(5-((3-Chloro-2-(1H-pyrrol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0070] -(S)-1-(6-Amino-5-((3-chloro-2-(1H-imidazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0071] -(S)-1-(6-Amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0072] -(S)-1-(4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0073] -(S)-1-(4-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0074] -(S)-1-(4-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N-methyl-1H-pyrrole-3-carboxamide;

[0075] -(S)-7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloro-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide;

[0076] -(S)-1-(4-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;

[0077] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0078] Another object of the present invention is a compound of formula (I) as defined above, wherein X 1 is N, X 2 is CR 2 and X 3 is CR 3 .

[0079] Preferably, in the compound of formula (I) as defined above, Cy-X 4 -R 4 corresponds to formula (A), wherein R 5 and R 6 are H.

[0080] In a preferred embodiment, the compound of formula (I) as defined above is a compound of formula (IA) or (IB):

[0081]

[0082] Preferably, R 1 , R 2 and R 3 are each independently selected from H, halogen and CH 3 , preferably, R 1 , R2 and R 3 each independently selected from H, Br, Cl, F and CH 3 , more preferably, R 1 , R 2 and R 3 each independently selected from H, Br, Cl and F.

[0083] Preferably, in the compound of formula (I) as defined above, R 4 is selected from: phenyl, pyridine, pyrimidine, pyrazine, quinoline, imidazo[1,2-a]pyridine, indole, 2H-indazole, 2,3-dihydroindole, 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine, 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1,8-naphthyridine, triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridin-2(3H)-one, each of said rings being optionally substituted by one or more substituents independently selected from C(=O)CH 3 , C(=O)OCH 3 , OH, halogen, NH 2 , CF 3 , CHF 2 , C 1-3 alkyl, C 1-3 alkoxy, C(=O)NH 2 , C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3 alkyl) 2 , CN, C 3-5 cycloalkyl, aryl or heteroaryl, wherein said aryl or heteroaryl is each optionally substituted by one or more halogen, C(=O)NH 2 , C(=O)NHCH 3 , C(=O)N(CH 3 ) 2 , C 1-3 alkyl and NHC(=O)CF 3 . More preferably, R 4 is quinoline optionally substituted by one or more substituents independently selected from OH, OC 1-3 alkyl, halogen, NH 2 , CF 3 , CHF 2 , C 1-3 alkyl, C(=O)NH 2 , C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3(alkyl) 2 、CN, C 3-5 cycloalkyl

[0084] More preferably, in the compounds of general formula (I) as defined above, R 4 is selected from the group consisting of: 2,3-dichlorophenyl, 3-fluoro-2-methylpyridin-4-yl, 2,3-difluorophenyl, 5-(4-fluorophenyl)pyrazin-2-yl, 2-chloro-3-(1H)-pyrazolyl, 2-fluoro-3-methylphenyl, 4-fluorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-methylphenyl, 2-chloro-6-fluoro-3-methylphenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 3-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, tolyl, phenyl, pyridyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-3-methylphenyl, 8-methoxyquinolin-4-yl, 2,3-dihydrobenzofuran-4-yl, 5-quinolin-4-yl, 4-chloro-2-methylphenyl, 2-(trifluoromethyl)phenyl, 2,3-dihydrobenzofuran-5-yl, trifluoromethyl-benzonitrile, 2-chloro-3-(1H-imidazol-1-yl)phenyl, 2,4-difluoro-3-methylphenyl, 2,3-dihydro-1H-inden-4-yl, 2,3-dimethylphenyl, 2,5-difluorophenyl, 2,3,4-trifluorophenyl, 3,5-difluorophenyl, 3-fluorophenyl, 1,3-dihydroisobenzofuran-4-yl, 3-chloro-2-(trifluoromethyl)pyridin-4-yl, 2,4-difluoro-3-methoxyphenyl, 3-chloro-2-(trifluoromethyl)phenyl, 3-fluoro-2-methylphenyl, 3-(difluoromethyl)-2-fluorophenyl, 4-(difluoromethyl)-2-fluorophenyl, 2-fluoro-3-methoxyphenyl, quinolinyl, 5-chloro-4-methylpyridin-3-yl, 2-chlorophenyl, 2-fluoro-4-methoxyphenyl, 1-methyl-1H-benzo[d]imidazol-6-yl, 8-fluoroquinolin-5-yl, 3-cyclopropyl-2-fluorophenyl, 8-chloroquinolin-5-yl, 2-(difluoromethyl)-3-fluorophenyl, 2-(difluoromethyl)phenyl, 8-(difluoromethoxy)quinolin-5-yl, 5-(difluoromethyl)-2-fluorophenyl, 2,6-difluorophenyl, 3-fluorobenzonitrile, 2,4,5-trifluorophenyl, 4-chloro-2-fluorophenyl, 3-fluoro-2-(1H-pyrazol-1-yl)phenyl, 2-fluoro-3-(1H-pyrazol-1-yl)phenyl, 2-chloro-3-(2-(difluoromethyl)-1H-imidazol-1-yl)phenyl, 7-fluoro-2-methyl-2H-indazol-6-yl, 4-chloro-2-methyl-2H-indazol-5-yl

[0085] More preferably, R 4 is also selected from quinoline-8-carbonitrile, 8-trifluoromethyl-quinolin-5-yl and isopropyl-phenyl

[0086] Preferably, in the compound of formula (I), Cy-X 4 -R 4 corresponds to the general formula (A), where R 5 and R 6 are H and R 4 is selected from phenyl, pyridine, pyrimidine, pyrazine, quinoline, and each of said rings is optionally substituted with one or more substituents independently selected from C(=O)CH 3 、C(=O)OCH 3 、OH、OC 1-3 alkyl, halogen, NH 2 、CF 3 、CHF 2 、C 1-3 alkyl, C(=O)NH 2 、C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3 alkyl) 2 、CN、C 3-5 cycloalkyl.

[0087] Preferably, in the compound of formula (I), Cy-X 4 -R 4 corresponds to the general formula (A), where R 2 、R 3 、R 5 and R 6 are H and R 4 is selected from phenyl, pyridine, pyrimidine, pyrazine, quinoline, and each of said rings is optionally substituted with one or more substituents independently selected from C(=O)CH 3 、C(=O)OCH 3 、OH、OC 1-3 alkyl, halogen, NH 2 、CF 3 、CHF 2 、C 1-3 alkyl, C(=O)NH 2 、C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3 alkyl) 2 、CN、C 3-5 cycloalkyl.

[0088] Preferably, in the compound of formula (I), Cy-X 4 -R 4 corresponds to the general formula (A), where R 2 、R 3 、R 5 and R 6 are H and R4 is a quinoline optionally substituted with one or more substituents independently selected from OH, OC 1-3 alkyl, halogen, NH 2 , CF 3 , CHF 2 , C 1-3 alkyl, C(=O)NH 2 , C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3 alkyl) 2 , CN, C 3-5 cycloalkyl.

[0089] Preferably, in the compounds of formula (I), Cy-X 4 -R 4 corresponds to the general formula (A), wherein R 2 , R 3 , R 5 and R 6 are H and R 4 is a phenyl substituted with halogen and / or heteroaryl; more preferably, R 4 is 2-chloro-3-(1H-pyrazol-1-yl)phenyl.

[0090] Another object of the present invention is a compound of formula (I) as defined above, selected from the group consisting of:

[0091] -(S)-6-(4'-amino-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3H)-one;

[0092] -(S)-1-(5-(2,3-dichlorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0093] -(S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4(3H)-one;

[0094] -(S)-1-(5-((3-fluoro-2-methylpyridin-4-yl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0095] -(S)-2-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-(2,3-difluorophenyl)-3-methylpyrimidin-4(3H)-one;

[0096] -(S)-1-(5-((2,3-Dichlorophenyl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0097] -(S)-1-(5-(4-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0098] -(S)-1-(6-(2,3-Difluorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0099] -(S)-1-(6-(2,3-Dichlorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0100] -(S)-1-(5-((2-Chloro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0101] -(S)-6-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one;

[0102] -(S)-1-(3-(2-Fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0103] -(S)-1-(5-((4-Fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0104] -(S)-1-(3-(2-Chloro-3-fluorophenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0105] -(S)-1-(3-(3-chloro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0106] -(S)-1-(3-(2-chloro-6-fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0107] -(S)-1-(5-((2,3-dichlorophenyl)thio)-3-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0108] -(S)-1-(5-((4-(trifluoromethoxy)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0109] -(S)-1-(5-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0110] -(S)-1-(5-((3-chlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0111] -(S)-1-(5-((2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0112] -(S)-1-(5-((2,4-dichlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0113] -(S)-1-(5-((3,4-dichlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0114] -(S)-1-(5-(phenylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0115] -(S)-1-(5-(pyridin-4-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0116] -(S)-1-(5-(o-tolylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0117] -(S)-1-(5-((2-isopropylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0118] -(S)-1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine;

[0119] -(S)-1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-7'-fluoro-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine;

[0120] -(S)-1-(5-((2-chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0121] -(S)-1-(5-(2,3-dichlorophenyl)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0122] -(S)-1-(5-((2,4-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0123] -(S)-1-(5-((3-chloro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0124] -(S)-1-(5-((2-chloro-4-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0125] -(S)-1-(5-((2-chloro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0126] -(S)-1-(5-((2-Fluoro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0127] -(S)-1-(5-((8-Methoxyquinolin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0128] -(S)-1-(5-((2,3-Dihydrobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0129] -(S)-1-(5-(Quinolin-4-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0130] -(S)-1-(5-((4-Chloro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0131] -(S)-1-(5-((2-(Trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0132] -(S)-1-(5-((2,3-Dihydrobenzofuran-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0133] -(S)-3-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-2-(trifluoromethyl)benzonitrile;

[0134] -(S)-1-(5-((2-Chloro-3-(1H-imidazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0135] -(S)-1-(5-((2,4-Difluoro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0136] -(S)-1-(5-((2,3-dihydro-1H-inden-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0137] -(S)-1-(5-((2,3-dimethylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0138] -(S)-1-(5-((2,5-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0139] -(S)-1-(5-((2,3,4-trifluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0140] -(S)-1-(5-((3,5-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0141] -(S)-1-(5-((3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0142] -(S)-1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0143] -(S)-1-(5-((2,3-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0144] -(S)-1-(5-((3-chloro-2-(trifluoromethyl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0145] -(S)-1-(5-((2,4-difluoro-3-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0146] -(S)-1-(5-((3-chloro-2-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0147] -(S)-1-(5-((3-fluoro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0148] -(S)-1-(5-((3-(difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0149] -(S)-1-(5-((4-(difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0150] -(S)-1-(5-((2-fluoro-3-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0151] -(S)-1-(5-(quinolin-5-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0152] -(S)-1-(5-((5-chloro-4-methylpyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0153] -(S)-1-(5-((2-chlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0154] -(S)-1-(5-((2-fluoro-4-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0155] -(S)-1-(5-((1-methyl-1H-benzo[d]imidazol-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0156] -(S)-5-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)quinoline-8-carbonitrile;

[0157] -(S)-1-(5-((8-(Trifluoromethyl)quinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0158] -(S)-1-(5-((8-Fluoroquinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0159] -(S)-1-(5-((3-Cyclopropyl-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0160] -(S)-1-(5-((8-Chloroquinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0161] -(S)-1-(5-((2-(Difluoromethyl)-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0162] -(S)-1-(5-((2-(Difluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0163] -(S)-1-(5-((8-(Difluoromethoxy)quinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0164] -(S)-1-(5-((5-(Difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0165] -(S)-1-(5-((2,6-Difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0166] -(S)-4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-fluorobenzonitrile;

[0167] -(S)-1-(5-((2,4,5-Trifluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0168] -(S)-1-(5-(2-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0169] -(S)-1-(5-(4-Chloro-2-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0170] -(S)-1-(5-((3-Fluoro-2-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0171] -(S)-1-(5-((2-Fluoro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0172] -(S)-1-(5-((2-Chloro-3-(2-(difluoromethyl)-1H-imidazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0173] -(S)-1-(5-((7-Fluoro-2-methyl-2H-indazol-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0174] -(S)-1-(5-((4-Chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine;

[0175] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0176] Also within the scope of the present invention are compounds of formula (I*):

[0177]

[0178] wherein X 1 、X 2 、X 3 、X 4 、Cy and R 4 are as defined above.

[0179] Preferably, the compound has the following stereochemistry:

[0180]

[0181] The compounds of the invention can be used in the form of prodrugs. A prodrug can be a pharmacologically inactive derivative of a bioactive substance ("parent drug" or "parent molecule", i.e., the compound of the invention), which requires in vivo conversion to release the active drug and has improved delivery properties relative to the parent drug molecule. In vivo conversion can be the result of, for example, certain metabolic processes such as chemical or enzymatic hydrolysis of carboxylic acids, phosphates or sulfates, or reduction or oxidation of labile functional groups.

[0182] The invention also includes all suitable isotopic variants of the compounds of the invention. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, respectively, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl isotopes. Certain isotopic variants of the present disclosure, such as those containing radioactive isotopes such as 3 H or 14 C, can be used for tissue distribution studies of drugs and / or substrates. In addition, substitution with isotopes (e.g., deuterium 2 H) can provide certain therapeutic advantages due to higher metabolic stability. The isotopic variants of the compounds of the invention can generally be prepared by conventional procedures, for example, using isotopic variants of suitable reagents, by the exemplary methods and preparation processes described in the following detailed description and examples.

[0183] The invention includes within its scope solvates of the compounds of formula (I) or related salts, such as hydrates, alcoholates, etc.

[0184] The compounds disclosed herein may exist in different isomeric forms, all of which are encompassed by the present invention. Specifically, any reference to a compound of the present invention is intended to include all possible resonance forms thereof.

[0185] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119 - 1190), and occur as racemates, racemic mixtures, and as individual diastereomers, where all possible isomers and their mixtures, including optical isomers and atropisomers, all such stereoisomers are included in the present invention. The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0186] Atropisomers are stereoisomers resulting from restricted rotation about a single bond: Compounds 1 and 3 are specific examples of atropisomers according to the present invention.

[0187] The pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by applying methods known in the art and are intended to be encompassed by the scope of the present invention. In particular, "pure stereoisomeric form" or "stereoisomerically pure" means a compound having a stereoisomeric excess of at least 80%, preferably at least 85%. For example, enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts or by chromatographic techniques using a chiral stationary phase. Pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of suitable starting materials, provided that the reaction occurs in a stereospecific manner. The term "enantiomerically pure" should be interpreted in a similar manner and considers the enantiomeric ratio.

[0188] When any variable (such as R 1 and R 2 etc.) occurs more than once in any moiety, its definition at each occurrence is independent of its definition at each other occurrence. Moreover, only combinations of substituents and variables that result in stable compounds are permitted. The lines drawn from substituents into the ring system indicate that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that the bond is attached only to any suitable carbon atom on the proximal ring.

[0189] It should be understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art and those methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or on different carbons, provided that a stable structure is obtained. The phrase "optionally substituted" should be considered equivalent to the phrase "unsubstituted or substituted by one or more substituents", and in such cases, preferred embodiments will have from zero to three substituents. More specifically, there are 0-2 substituents.

[0190] The expression "one or more substituents" specifically refers to 1, 2, 3, 4 or more substituents, specifically refers to 1, 2, 3 or 4 substituents, and more specifically refers to 1, 2 or 3 substituents.

[0191] As used herein, "X 4 is a bond" means that in general formula (I), Cy is directly connected to R through a single bond 4 .

[0192] As used herein, "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-6 alkyl" is intended to include groups having 1, 2, 3, 4, 5 or 6 carbons in a straight-chain or branched arrangement, specifically including methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, etc. Preferably, "C 1-6 alkyl" refers to "C 1-4 alkyl" or "C 1-3 alkyl". "C 1-4 alkyl" is defined to include groups having 1, 2, 3 or 4 carbon atoms in a straight-chain or branched arrangement. For example, "C 1-4 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. "C 1-3 alkyl" is defined to include groups having 1, 2 or 3 carbons in a straight-chain or branched arrangement. For example, "C 1-3 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, etc. Preferred alkyl groups are methyl, ethyl, isopropyl, tert-butyl or isobutyl.

[0193] As used herein, "alkoxy" represents an alkyl group having the indicated number of carbon atoms connected by an oxygen bridge. Thus, "alkoxy" encompasses the above definitions of alkyl. C 1-6 alkoxy groups are preferably straight-chain or branched C 1-4 alkoxy, more preferably C 1-3 alkoxy groups, and still more preferably C 1-2An alkoxy group. Examples of suitable alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. Preferred alkoxy groups include methoxy, ethoxy and tert-butoxy.

[0194] As used herein, the term "halo C 1-6 alkyl", "halo C 1-6 alkoxy" and variations thereof (e.g., "C 1-6 haloalkyl") refer to a C 1-6 alkyl or C 1-6 alkoxy group in which one or more (especially 1 to 3) hydrogen atoms have been replaced by a halogen atom (especially a fluorine or chlorine atom). A halo C 1-6 alkoxy group is preferably a straight-chain or branched halo C 1-4 alkoxy group, more preferably a halo C 1-3 alkoxy group, still more preferably a halo C 1-2 alkoxy, such as OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , most particularly OCF 3 or OCHF 2 . A halo C 1-6 alkyl group is preferably a straight-chain or branched halo C 1-3 alkyl group, more preferably a halo C 1-2 alkyl group, such as CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 or CH(CH 3 )CF 3 , most particularly CF 3 , CHF 2 or CH(CH 3 )CF 3 .

[0195] As used herein, the term "aryl" or "aromatic ring" refers to a monocyclic or polycyclic aromatic ring containing carbon and hydrogen atoms. If indicated, such an aromatic ring may contain one or more heteroatoms and is also referred to as a "heteroaryl" or "heteroaromatic ring", preferably 1 to 3 heteroatoms, which are independently selected from nitrogen, oxygen, and sulfur, preferably nitrogen. As is well known to those skilled in the art, heteroaromatic rings have less aromatic character than their all-carbon counterparts. Thus, for the purposes of the present invention, a heteroaryl group only needs to have a certain degree of aromatic character. Preferably, the ring component of the aryl or heteroaryl group contains 5 or 6 members (i.e., atoms). Also preferably, the aryl or heteroaryl group is a polycyclic aromatic ring. Exemplary examples of aryl groups are optionally substituted phenyl. Exemplary examples of heteroaryl according to the present invention include optionally substituted thiophene, oxazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine, pyridine, and N-oxidopyridine. Thus, examples of monocyclic aryl optionally containing one or more heteroatoms, such as one or two heteroatoms, are 5- or 6-membered aryl or heteroaryl groups, such as but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxadiazolyl, and oxazolyl. Examples of polycyclic aromatic rings optionally containing one or more heteroatoms, such as one or two heteroatoms, are 8- to 10-membered aryl or heteroaryl groups, such as but not limited to benzimidazolyl, benzofurandicarbonyl, benzofuryl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indolinyl, indazolyl, isoindolyl, isoindolinyl, isoquinolinyl, quinazolinyl, quinolinyl, quinoxalinyl, quinazolinyl, naphthyl, naphthyridinyl, and phthalazinyl. Other examples of polycyclic heteroaromatic rings according to the present invention are 2H-pyrazolo[3,4-b]pyridine, indazole, 2H-pyrazolo[3,4-c]pyridine, 6H-pyrrolo[3,4-b]pyridine, 6H-pyrrolo[3,4-b]pyrazine, 6H-pyrrolo[3,4-d]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, 1,5-naphthyridine, imidazo[1,2-a]pyridine. The preferred aryl according to the present invention is phenyl. The preferred heteroaryl according to the present invention is pyridyl.

[0196] The expressions "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted aryloxy", "optionally substituted heteroaryl-C 1-6 alkyl", "optionally substituted heteroaryl-C 1-6"Alkoxy" generally refers to an aryl, heteroaryl or aryloxy group, wherein the aromatic or heteroaromatic ring may be substituted with one or more substituents. Examples of said substituents include alkyl, alkoxy, amino, trifluoromethyl, aryl, heteroaryl, hydroxy, carboxyalkyl, etc.

[0197] The aryl or heteroaryl ring may also have a partially unsaturated structure and may thus be derived from a partially hydrogenated analogue of the aforementioned aryl or heteroaryl group, and may also be derived from an aryl or heteroaryl ring fused to a cycloalkyl or heterocycloalkyl ring. The ring may also contain a group selected from SO, 2 and C=O. Examples of said partially unsaturated aryl or heteroaryl derivatives include 2,3-dihydro-1H-indene, 2,3-dihydro-1H-inden-1-one, 2,3-dihydroisoindol-1-one, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, isoindoline, 1-methyl-indol-2-one, dihydroquinazoline, dihydroquinoxaline, 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 1,3-dihydroisobenzofuran, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazine quinazolin-4(3H)-one, 4,5,6,7-tetrahydro-1H-indazole, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine 6',7'-dihydrospiro[azetidine-3,5'-pyrrolo[1,2-a]imidazole], 2,3-dihydrobenzo[b][1,4]dioxene, benzod[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, indan-2-one, 1,2,3,4-tetrahydro-1,5-naphthyridine, 3',4'-dihydro-2'H-spiro[azetidine-3,1'-pyrrolo[1,2-a]pyrazine], 3,4-dihydroquinolin-2(1H)-one, 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, quinoxalin-2(1H)-one, 4H-pyrido[1,2-a]pyrimidin-4-one, (6aS)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine, 3,4-dihydro-2H-1,5-naphthyridin-1-yl, dihydrofuro[2,3-b]pyridinyl, etc.

[0198] It should be noted that in the definitions used throughout the specification, there may be various isomers of heterocycles. For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

[0199] It should also be noted that the position of the group on any molecular moiety used in the definition can be at any position on that moiety, provided it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl.

[0200] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0201] The term "heteroatom" refers to an atom other than carbon or hydrogen in the ring structures or saturated main chains defined herein. Typical heteroatoms include N(H), O, and S.

[0202] The expression "NH-C 1-6 alkyl", "N(C 1-6 alkyl) 2 " refers to an amino substituent in which either of the two hydrogens is replaced by a C 1-6 alkyl chain.

[0203] The expression "saturated 5- or 6-membered heterocycle" as used herein refers to a saturated 5- or 6-membered ring containing at least one heteroatom selected from S, N, or O, preferably N. Examples of the saturated 5- or 6-membered heterocycle are pyrrolidine, piperidine, morpholine, piperazine, tetrahydrofuran, tetrahydropyran, and the like.

[0204] The present invention includes the free bases of the compounds of formula (I), and their pharmaceutically acceptable salts and stereoisomers. Certain specific compounds exemplified herein are protonated salts of amine compounds. Compounds containing one or more N atoms can be protonated on any one, some, or all of the N atoms. The term "free base" refers to an amine compound in non-salt form. The pharmaceutically acceptable salts covered include not only the salts exemplified for the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compounds of formula (I). The free form of the specific salt compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable aqueous base dilution solution such as a dilute aqueous solution of NaOH, potassium carbonate, ammonia, and sodium bicarbonate. The free form may differ in certain physical properties (such as solubility in polar solvents) from their respective salt forms, but for the purposes of the present invention, acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0205] Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing basic or acidic moieties by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or an excess of an inorganic or organic acid that forms the desired salt in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base. In a preferred embodiment, the compounds of the present invention have at least one acidic proton, and the corresponding sodium or potassium salts can be formed, for example, by reaction with a suitable base.

[0206] Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids or acidic compounds and inorganic or organic bases. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Conventional non-toxic salts also include those derived from inorganic bases such as potassium hydroxide, sodium hydroxide, magnesium hydroxide or calcium hydroxide, and salts prepared from organic bases such as ethylenediamine, lysine, trimethylamine, meglumine, etc. Preferably, the pharmaceutically acceptable salts of the present invention comprise one equivalent of a compound of formula (I) and 1, 2 or 3 equivalents of an inorganic or organic acid or base. More specifically, the pharmaceutically acceptable salts of the present invention are tartrate salts, trifluoroacetate salts or chloride salts.

[0207] When the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N 1-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0208] The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail in Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.

[0209] It should also be noted that the compounds of the present invention are potentially internal salts or zwitterions because, under physiological conditions, the deprotonated acidic moieties in the compounds, such as carboxyl groups, can be anionic, and this charge can then be internally balanced by the cationic charge of the protonated or alkylated basic moieties (such as quaternary nitrogen atoms).

[0210] Preferably, the compounds of the present invention, including their salts, stereoisomers, and solvates, are SHP2 inhibitors, which means, for example, that they can inhibit the activity or function of SHP2. Then, the present invention relates to compounds useful as inhibitors of at least one SHP2 function, and methods of inhibiting at least one SHP2 function, which include the step of contacting SHP2 with a compound described herein.

[0211] “SHP2” refers to “Src homology-2-phosphatase,” also known as SH-PTP2, SH-PTP3, Syp, PTPID, PTP2C, SAP-2, or PTPN11.

[0212] SHP2 has diverse functions because SHP2 is involved in multiple signal transduction processes, such as the RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways. SHP2 mainly regulates cancer cell survival and proliferation by activating the RAS-ERK signal transduction pathway (T. Matozaki, Y. Murata, Y. Saito, H. Okazawa, H. Ohnishi, Cancer Sci, 100 (2009), pp. 1786-1793). In the RAS-ERK pathway, SHP2 acts as an upstream positive regulator, promoting the signal transduction of the RAS-RAF-ERK kinase cascade. Therefore, inhibiting SHP2 leads to ERK dephosphorylation and inhibits the pro-cancer function of the RAS-RAF-ERK pathway, thereby inhibiting cancer cell growth and inducing apoptosis. Recently, Chen et al. (Y. N. Chen, M. J. LaMarche, H. M. Chan, P. Fekkes, J. Garcia-Fortanet, M. G. Acker et al., Nature, 535 (2016), pp. 148-152) found that cancer cell lines sensitive to SHP2 depletion are also sensitive to EGFR depletion, which verified the report that RTK-driven cancer cells rely on SHP2 for survival. In addition, recent studies have shown that SHP2 is essential for mutant KRAS-driven cancer growth, and wild-type KRAS-amplified gastric and esophageal cancers can be controlled by combined inhibition of SHP2 and MEK (S. Mainardi, A. Mulero-Sanchez, A. Prahallad, G. Germano, A. Bosma, P. Krimpenfort et al., Nat Med, 24 (2018), pp. 961-9; D. A. Ruess, G. J. Heynen, K. J. Ciecielski, J. Ai, A. Berninger, D. Kabacaoglu et al., Nat Med, 24 (2018), pp. 954-960; G. S. Wong, J. Zhou, J. B. Liu, Z. Wu, X. Xu, T. Li et al., Nat Med, 24 (2018)), pp. 968-977). As a downstream target of multiple receptors, SHP2 is also involved in signal transduction in T cells (M. Tajan, A. de Rocca Serra, P. Valet, T. Edouard, A. Yart, Eur J Med Genet, 58 (2015), pp. 509-525; R. J. Salmond, D. R. Alexander, Trends Immunol, 27 (2006), pp. 154-160). It is a downstream molecule of the PD-1 signal transduction pathway, which not only inhibits T cell activation but also leads to T cell anergy.SHP2 deficiency in T cells elicits an anti-tumor immune response against colitis-associated cancer in mice (W. Liu, W. Guo, L. Shen, Z. Chen, Q. Luo, X. Luo et al., Oncotarget, 8 (2017), pp. 7586-7597). Thus, targeting SHP2 can restore or even enhance T cell function.

[0213] SHP2 inhibition can be evaluated or measured by: cell phenotypes (such as proliferative phenotypes and resistance to co-inhibition of EGFR and c-MET, mesenchymal phenotypes in BTBC cells), cell proliferation, SHP2 activity, changes in the biochemical outputs generated by active SHP2, SHP2 expression, or binding of SHP2 to its native binding partners, all of which can be monitored as metrics for SHP2 inhibition. Specifically, inhibition of SHP2 activity or function can be measured by the IC 50 (concentration of an inhibitor that reduces the activity of SHP2 to half-maximal level), as described in the assays below or in the biochemical assays for SHP2 inhibition reported, for example, in Chen et al., Nature (535) 2016 or Bagdanoff et al., J. Med. Chem, 2019, 62, 1781-1792. Preferably, the compounds of the present invention exhibit an IC 50 for SHP2 that is less than or equal to 10 μM. Preferred compounds exhibit an enzymatic IC 50 (as defined below) for SHP2 that is less than or equal to 3 μM (preferably less than or equal to 0.5 μM or between 0.5 μM and 3 μM) and / or, an IC 50 (as defined below) for SHP2 inhibition in cell-based assays that is less than or equal to 5 μM (preferably less than or equal to 1 μM or between 1 μM and 5 μM). Then, the compounds of the present invention, including their salts, tautomers, stereoisomers, and solvates, can be used in methods for inhibiting SHP2 activity. In other words, they can be used for preventing and / or treating any disorder that can be ameliorated by inhibiting SHP2.

[0214] In a preferred embodiment, the compounds as defined above or their pharmaceutically acceptable salts, solvates or stereoisomers are used to inhibit SHP2 activity. The inhibition of SHP2 activity can be measured relative to an appropriate control, such as a subject affected by a disease or disorder mediated by SHP2 activity or a subject who has undergone the entire course of treatment of a disease or disorder mediated by SHP2 activity. Preferably, relative to an appropriate control, the compounds of the present invention inhibit SHP2 activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%. More preferably, relative to an appropriate control, the compounds of the present invention inhibit SHP2 activity by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%.

[0215] Even more preferably, relative to an appropriate control, the compounds of the present invention inhibit SHP2 activity by more than 90%, such as about 92%, 94%, 95%, 98%, 99% or 100%.

[0216] Therefore, the compounds of the present invention can be used for treating diseases and for conducting biological tests, cell tests, biochemical tests, etc.

[0217] An object of the present invention is the compounds as defined above or their pharmaceutically acceptable salts, solvates or stereoisomers for medical use.

[0218] Preferably, the compounds as defined above or their pharmaceutically acceptable salts, solvates or stereoisomers are used to inhibit SHP2 activity. The inhibition of SHP2 activity further leads to the dephosphorylation of ERK and the inhibition of the pro-cancer function of the RAS-RAF-ERK pathway. Then, the inhibition of SHP2 activity can be measured by the dephosphorylation of ERK, wherein the phosphorylation of ERK can be evaluated by any method known in the art, such as those described in the examples below. The dephosphorylation of ERK can be measured with reference to any appropriate control.

[0219] More preferably, the compounds as defined above or their pharmaceutically acceptable salts, solvates or stereoisomers are used for treating and / or preventing diseases or disorders mediated by SHP2 activity. Preferably, the diseases or disorders mediated by SHP2 activity are selected from the group consisting of: cancer, cardiovascular diseases, immune disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof. Preferably, the diseases or disorders mediated by SHP2 activity are selected from the group consisting of: Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and combinations thereof. Preferably, any of the said cancers is a primary cancer or cancer metastasis.

[0220] A disease or disorder mediated by SHP2 activity represents a condition in a subject, wherein modulating, especially inhibiting, SHP2 activity can prevent, inhibit, ameliorate, slow down or eradicate the condition and / or its symptoms. Treatment of the disease or disorder may include administering to a subject in need a therapeutically effective amount of a compound of formula (I) according to the present invention.

[0221] In diseases or disorders mediated by SHP2 activity, mutations are frequently observed at the N-SH2 / PTP binding site (such as E76D / E76K), resulting in constitutively active proteins and abnormal proliferation. Cancers carrying "PTPN11 mutations" include, but are not limited to: N58Y; D61Y, V; E69K; A72V, T, D; E76G, Q, K (all); G60A; D61Y; E69V; F71K; A72V; T73I; E76G, K; R289G; G503V (AML); G60R, D61Y, V, N; Y62D; E69K; A72T, V; T73I; E76K, V, G, A, Q; E139D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; A72V; E76A (MDS); Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (lung cancer); R138Q (melanoma); E76G (colon cancer). The compounds of the present invention can exhibit affinity for wild-type SHP2 at low concentrations and are also active against mutant forms of the protein.

[0222] Another aspect of the present invention relates to a compound of the present invention as defined above, including any pharmaceutically acceptable salt, solvate or stereoisomer thereof, for use in a method for preventing / treating an SHP2-mediated disorder and / or a disorder mediated by the oncogenic function of the RAS-RAF-ERK pathway.

[0223] Another aspect of the present invention relates to a method for preventing / treating an SHP2-mediated disorder, the method comprising the step of administering to a patient in need a therapeutically effective amount of a compound of the present invention, including any pharmaceutically acceptable salt, solvate or stereoisomer thereof, as defined above. In another aspect, the present invention relates to a method for preventing / treating an SHP2-mediated disorder, the method comprising the step of administering to a patient in need a therapeutically effective amount of a chemotherapeutic agent and a therapeutically effective amount of a compound of the present invention as further defined below.

[0224] Another aspect of the present invention relates to the use of a compound of the present invention as defined above, including any pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the prevention / treatment of an SHP2-mediated disorder.

[0225] In another aspect of the present invention, there is provided a compound, salt, solvate, stereoisomer as defined above for use in the treatment and / or prevention of a disease or condition selected from the group consisting of cancer, cardiovascular disease, immune disorders, fibrosis, eye disorders, systemic lupus erythematosus, diabetes, neutropenia, and combinations thereof. Preferably, the disease or condition is selected from the group consisting of Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combinations thereof. Preferably, the cancer is a primary cancer or a cancer metastasis.

[0226] In certain embodiments, the present invention relates to the aforementioned use / method, wherein the disorder is selected from Noonan syndrome (NS) and Leopard syndrome (LS).

[0227] In another embodiment, the present invention relates to the aforementioned uses / methods, wherein the SHP2-mediated disorder is a disorder caused by dysregulated cell proliferation, including cancer. The cancer may be hormone-dependent or hormone-resistant, such as breast cancer. Preferably, the cancer is RTK-driven or KRAS-driven, such as KRAS-amplified gastroesophageal cancer. In certain embodiments, the cancer is a solid tumor. In other embodiments, the cancer is a lymphoma or leukemia or glioma. In certain embodiments, the cancer is a drug-resistant phenotype of a cancer disclosed herein or known in the art. The cancer may be primary or metastatic. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis may also be treated using the compositions and methods disclosed herein. Precancerous neoplasia may also be treated using the compositions and methods disclosed herein.

[0228] The compounds of the present invention can be used for treating cancers selected from, but not limited to, the following: juvenile myelomonocytic leukemia (JMML); acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); B-cell acute lymphoblastic leukemia (B-ALL); neuroblastoma cells; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer, head and neck cancer; ovarian cancer; prostate cancer; cancers of the following sites: oral cavity and pharynx (lip, tongue, mouth, larynx, pharynx), stomach, small intestine, large intestine, colon, rectum, liver and biliary tract; pancreatic cancer, bone cancer, connective tissue cancer, skin cancer, cervical cancer, uterine cancer, endometrial cancer, testicular cancer, bladder cancer, kidney cancer and other urological tissue cancers, including renal cell carcinoma (RCC); gastroesophageal cancer (preferably gastroesophageal cancer with KRAS amplification), eye cancer, brain cancer, spinal cord cancer, other components of the central and peripheral nervous systems and cancers of related structures such as meninges; thyroid and other endocrine adenocarcinomas, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and hematopoietic system malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and lymphomas including lymphocytes, granulocytes and monocytes. Other types of cancers that can be treated with the compounds and methods of the present invention include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, urogenital cancer, glioblastoma multiforme, hemangioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphatic system cancer, lymphoma, lymphangiosarcoma, lymphatic endothelial sarcoma, medullary thyroid cancer, medulloblastoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteosarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid cancer, uveal melanoma, Wilms' tumor, anaplastic large cell lymphoma, colon cancer associated with colitis.

[0229] The compounds of the present invention can be used to treat any other diseases or conditions associated with abnormal SHP2 activity. Accordingly, other aspects of the present invention relate to a method of treating a patient, preferably a human, suffering from a disorder selected from the following: NS; LS; JMML; AML; MDS; B-ALL; neuroblastoma cells; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer; head and neck cancer. The present invention also relates to the use of the compounds of the present invention in the preparation of a medicament for treating a disorder selected from the following: NS; LS; JMML; AML; MDS; B-ALL; neuroblastoma cells; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer; head and neck cancer.

[0230] In a further embodiment of the present invention, the compound of formula (I) is an SHP2 inhibitor capable of penetrating the BBB to reach its target and treat a human suffering from a brain tumor and / or brain metastases. This is particularly important because the low survival rate of patients with tumors originating in or spreading to the brain is due to the inability of chemotherapeutic / targeted agents to penetrate the blood-brain barrier (BBB) and the radio / chemical resistance of the tumor itself. The BBB plays a key role in brain homeostasis, but it also significantly hinders the penetration of most small molecule inhibitors. With the increasing interest in developing selective and potent inhibitors for treating brain tumors and brain metastases, there is an urgent need to overcome the problem of crossing the BBB. In a preferred embodiment, the present invention relates to an SHP2 inhibitor capable of penetrating the BBB to reach its target and treat a human suffering from a tumor originating in or spreading to the brain.

[0231] The compounds of the present invention, including any pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof, can be effectively combined with any other known therapies capable of preventing / treating diseases or conditions mediated by SHP2 activity. Such therapies may include radiotherapy. Such therapies may also include administering another pharmacologically active compound, or two or more other pharmacologically active compounds, especially compounds having activity in the prevention / treatment of cancer, also referred to as "anticancer drugs" or "chemotherapeutic agents". For example, the compounds of the present invention as defined above, including any pharmaceutically acceptable salts, tautomers, solvates or stereoisomers thereof, can be administered simultaneously, sequentially or separately in combination with any one or more other pharmacologically active compounds. For simultaneous administration, the compounds of the present invention and one or more other pharmacologically active compounds can be formulated in the same composition.

[0232] The classes of anticancer drugs that can be combined with the compounds of the present invention include, but are not limited to: alkylating agents, antimetabolites, antimitotics, checkpoint inhibitors, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, anti-steroids and anti-androgens, mTOR inhibitors, tyrosine kinase inhibitors, etc. Chemotherapeutic agents include, for example, mitotic inhibitors (such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine) and other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2,4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine. Such combinations can provide significant therapeutic advantages, including synergistic activity.

[0233] Alkylating agents are compounds that act by adding alkyl groups to the guanine bases of DNA molecules, which prevent the strands of the double helix from connecting as they should, resulting in DNA strand breaks and affecting the reproductive ability of cancer cells. Antimetabolites are drugs that interfere with one or more enzymes or their reactions required for DNA synthesis. Antimitotics are drugs that block cell growth by stopping mitosis. Checkpoint inhibitors are an immunotherapy that blocks proteins that stop the immune system from attacking cancer cells. Topoisomerase inhibitors are compounds that block the action of topoisomerases (topoisomerase I and II), which are enzymes that control changes in DNA structure during the normal cell cycle by catalyzing the breakage and reconnection of the phosphodiester backbone of DNA strands. Aromatase inhibitors are a class of drugs that act by inhibiting the action of aromatase, which converts androgens to estrogens through the aromatization process. Angiogenesis inhibitors are substances that inhibit the growth of new blood vessels and are used to treat cancer and other diseases involving blood vessel proliferation. mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine / threonine-specific protein kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family. mTOR regulates cell metabolism, growth, and proliferation through the formation and signal transduction of two protein complexes, mTORC1 and mTORC2. The most well-known mTOR inhibitors are the so-called rapalogs (rapamycin and its analogs), which have shown tumor responses in clinical trials against various tumor types.

[0234] Accordingly, a preferred object of the present invention is the combined use of a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as defined above with at least one other therapeutic agent.

[0235] In any case, the multiple therapeutic agents (where at least one is a compound disclosed herein) can be administered in any order or even simultaneously.

[0236] Preferably, the at least one other therapeutic agent is selected from the group consisting of:

[0237] (a) alkylating agents, preferably selected from carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN);

[0238] (b) antimetabolites, preferably selected from cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytarabine (ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and raltitrexed;

[0239] (c) antimitotic agents, which are usually plant alkaloids and terpenoids or their derivatives, preferably selected from taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunine;

[0240] (d) checkpoint inhibitors such as the anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; the anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T cell immunoglobulin and mucin domain-containing protein-3), and / or OX40 (tumor necrosis factor receptor superfamily member 4);

[0241] (e) topoisomerase inhibitors, preferably selected from camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN);

[0242] (f) cytotoxic antibiotics, preferably selected from actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) aromatase inhibitors, preferably selected from aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR) and exemestane (AROMASIN);

[0243] (g) angiogenesis inhibitors, preferably selected from genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN);

[0244] (h) anti-steroids and anti-androgens, such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) and nilutamide (NILANDRON);

[0245] (i) tyrosine kinase inhibitors, preferably selected from imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR) and axitinib (INLYTA);

[0246] (j) mTOR inhibitors, such as everolimus, temsirolimus (TORISEL) and sirolimus; (12) monoclonal antibodies, such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN);

[0247] (k) Other agents such as amsacrine; Bacillus Calmette-Guérin (B-C-G) vaccine; buserelin; chloroquine; clodronate, pamidronate and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; folinic acid; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer sodium (especially when used in combination with phototherapy and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES) and dienestrol; progesterones such as medroxyprogesterone acetate (MPA) and megestrol acetate; testosterone; 5-fluoro-2,4(1H,3H)-pyrimidinedione and combinations thereof.

[0248] The present invention also provides pharmaceutical formulations comprising the compounds of the present invention. Specifically, another object of the present invention is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof as defined above, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient. Preferably, the at least one additional therapeutic agent in the pharmaceutical composition is selected from those indicated above.

[0249] In a preferred embodiment, the pharmaceutical combination or composition of the present invention is used for the treatment and / or prevention of diseases or disorders as defined herein, especially diseases or disorders mediated by SHP2 activity and / or diseases or disorders selected from the group consisting of: cancer, cardiovascular diseases, immune disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof.

[0250] The present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, such as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs. The compositions of the present invention can be prepared according to any method known in the art of pharmaceutical composition manufacture, and the compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain a mixture of the active ingredient and a pharmaceutically acceptable non-toxic excipient suitable for the preparation of tablets. These excipients may be, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrating agents (such as microcrystalline cellulose), croscarmellose sodium, corn starch or alginic acid; binders (such as starch, gelatin, polyvinylpyrrolidone or gum arabic); and lubricants (such as magnesium stearate, stearic acid or talc). Tablets may be uncoated or may be coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, water-soluble taste masking materials (such as hydroxypropyl-methylcellulose or hydroxypropylcellulose) or delayed release materials, such as ethylcellulose, cellulose acetate butyrate, may be used.

[0251] Preparations for oral use may also be made as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier (such as polyethylene glycol) or an oily medium (such as peanut oil, liquid paraffin or olive oil).

[0252] The aqueous suspension contains a mixture of an active material and an excipient suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; the dispersing agent or wetting agent may be a naturally occurring phospholipid (such as lecithin), or a condensation product of an alkylene oxide and a fatty acid (such as polyethylene glycol stearate), or a condensation product of ethylene oxide and a long-chain fatty alcohol (such as heptadecaethyleneoxycetanol), or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol (such as polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride (such as polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more colorants, one or more flavoring agents, and one or more sweetening agents (such as sucrose, saccharin or aspartame).

[0253] The oily suspension can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those shown above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as butylated hydroxyanisole or α-tocopherol.

[0254] The dispersible powders and granules suitable for the preparation of an aqueous suspension by adding water provide the active ingredient, which is mixed with a dispersing agent or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are listed by those mentioned above. Additional excipients may also be present, such as sweetening agents, flavoring agents and colorants. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0255] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or groundnut oil), or a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0256] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such preparations may also contain demulcents, preservatives, flavoring agents, coloring agents, and antioxidants.

[0257] The pharmaceutical composition can be in the form of a sterile injectable aqueous solution. Acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.

[0258] The sterile injectable preparation can also be a sterile oil-in-water microemulsion, where the active ingredient is dissolved in the oil phase. For example, the active ingredient can first be dissolved in a mixture of soybean oil and lecithin. Then the oil solution is introduced into a mixture of water and glycerol and processed to form a microemulsion.

[0259] The injectable solution or microemulsion can be introduced into the bloodstream of a patient by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS TM Model 5400 intravenous pump.

[0260] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension formulated in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. In addition, sterile non-volatile oils are often used as solvents or suspending media. For this purpose, various low-irritant non-volatile oils can be employed, including synthetic glycerol monoesters or diesters. In addition, fatty acids such as oleic acid are also used in the preparation of injectables.

[0261] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and thus melt in the rectum and release the drug. These materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0262] For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds of the present invention are used. For the purposes of this application, topical application should include mouthwashes and gargles.

[0263] The compounds of the present invention can be administered intranasally by topical use of a suitable intranasal carrier and delivery device, or by the transdermal route using transdermal skin patches of those forms known to those of ordinary skill in the art. For administration in the form of a transdermal delivery system, the dose administration will of course be continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention can also be delivered in the form of suppositories using matrices such as cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0264] The compounds of the present invention can exist in the form of liposomes or other microparticles or other nanoparticles, which are designed to target the compounds. Acceptable liposomes can be neutral, negatively charged or positively charged, and their charge is a function of the charge of the liposome components and the pH of the liposome solution. Liposomes can generally be prepared using a mixture of phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol. Polyethylene glycol can be added to improve the blood circulation time of the liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

[0265] When the compounds of the present invention are administered to a human subject, the daily dose will generally be determined by the prescribing physician and will generally vary depending on the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms. Generally, a dose level of about 0.01 mg / kg to about 150 mg / kg body weight can be used to treat the above conditions.

[0266] As used herein, the term "composition" is intended to encompass a product containing a specific amount of specific ingredients, as well as a product directly or indirectly obtained by combining specific amounts of specific ingredients.

[0267] Another object of the present invention relates to an in vitro method of inhibiting SHP2 with the compounds of the present invention. For example, this may help to evaluate whether any given compound is an inhibitor / activator of SHP2 and thus also acts on the ERK pathway.

[0268] Another object of the present invention relates to a kit comprising at least one other pharmaceutically acceptable vial or container of other types, which contains one or more doses of the compounds of the present invention, including any pharmaceutically acceptable salts, solvates or stereoisomers thereof, or contains the pharmaceutical composition of the present invention and optionally a) instructions for use thereof in mammals and / or b) an infusion bag or container containing a pharmaceutically acceptable diluent.

[0269] In certain embodiments, the compounds or compositions of the present invention are administered parenterally, intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically, intranasally or systemically.

[0270] In certain embodiments, the patient to whom the compounds or compositions of the invention are administered is a mammal, preferably a primate, more preferably a human.

[0271] In accordance with standard pharmaceutical practice, the compounds of the invention can be administered to a mammal, preferably a human, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition. In one embodiment, the compounds of the invention can be administered to an animal. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0272] As used herein, the term "prevention" refers to the absence of the development of a disease or disorder (if it has not occurred), or the absence of further development of a disease or disorder (if a disease or disorder has already developed). The ability to prevent some or all of the symptoms associated with a disease or disorder is also contemplated. As used herein, any reference to "treatment" includes the improvement of at least one symptom of the disease or disorder to be treated. Such improvement is evaluated by comparison with the same symptom before administration of the compounds or compositions of the invention.

[0273] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or agent that elicits the biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal or human.

[0274] The invention will be described by the following non-limiting examples and biological data.

[0275] Materials and Methods

[0276] chemical composition

[0277] As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its well-known meaning.

[0278] Abbreviations

[0279] AcOH: acetic acid; AlCl 3 : aluminum chloride; BnBr: benzyl bromide; BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; Boc 2 O: di-tert-butyl dicarbonate; 1-BuOH: 1-butanol; Cs 2 CO 3: Cesium carbonate; CuI: Copper(I) iodide; DAST: N,N-Diethyl-1,1,1-trifluoro-1-thionium tetrafluoroborate; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: Dichloromethane; DIPEA: N,N-Diisopropylethylamine; DMA: N,N-Dimethylacetamide; DME: 1,2-Dimethoxyethane; DMF: N,N-Dimethylformamide; DMP: Dess Martin periodinane; DMSO: Dimethyl sulfoxide; ES + : Electrospray positive ionization; Et 2 O: Diethyl ether; EtOAc: Ethyl acetate; EtOH: Ethanol; EtONa: Sodium ethoxide; HBTU: (2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HCl: Hydrochloric acid; h: Hour; H 2 O: Water; HPLC: High performance liquid chromatography; IPA: Isopropyl alcohol; K 2 CO 3 : Potassium carbonate; KOH: Potassium hydroxide; K 3 PO 4 : Potassium phosphate; LCMS: Liquid chromatography - mass spectrometry; LiAlH 4 : Lithium aluminum hydride; LDA: Lithium diisopropylamide; MeCN: Acetonitrile; MeI: Methyl iodide; MeOH: Methanol; min: Minute; MsCl: Methanesulfonyl chloride; MW: Microwave; NaBH 4 : Sodium borohydride; NaHCO 3 : Sodium hydrogen carbonate; NaH: Sodium hydride; NaNO 2 : Sodium nitrite; NaOH: Sodium hydroxide; NaOMe: Sodium methoxide; Na 2 SO 4 : Sodium sulfate; Na 2 S 2 O 3 : Sodium thiosulfate; NH 4 HCO 2 : Ammonium formate; N 2： Nitrogen; NMP: 1-Methyl-2-pyrrolidone; Pd / C: Palladium on carbon; Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2 : [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Selectfluor: (1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); POCl 3: Phosphorus oxychloride; RP: Reverse phase; RT: Retention time; rt: Room temperature; Rochelle salt solution: L(+)-Potassium sodium tartrate; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; Ti(OEt) 4 : Ethyl titanate; Sat.: Saturated; Sol.: Solution; TsCl: 4-Toluenesulfonyl chloride; UPLC: Ultra performance liquid chromatography; Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

[0280] LC-MS analysis was performed using an Acquity UPLC Waters system equipped with an SQD spectrometer, a single quadrupole mass detector, and a TUV detector, using column 1: ACQUITY UPLC BEH C18 (2.1×50 mm, id = 1.7 μm); column 2: ACQUITY UPLC HSS T3, RP18 (2.1×50 mm, id = 1.8 μm). The column temperature was 40 °C or 33 °C. The sample temperature was 25 °C or 33 °C. Phase A consisted of H 2 O (HiPerSolv Chromanorm water for HPLC-MS VWR) + 0.1% HCOOH; phase B consisted of MeCN (HiPerSolv Chromanorm acetonitrile, super gradient VWR, suitable for UPLC / UHPLC instruments) + 0.1% HCOOH; flow rate: 0.5 mL / min; UV detection (DIODE array) at 200 nm; ESI+ and ESI- detection, in the range of 100 - 1000 m / z.

[0281] Method 1: Column 1, run time: 3 minutes, run gradient: 5% B to 100% B in 2.8 min + 100% B for 0.2 min, equilibration time: 0.8 min, ionization mode: ESI+.

[0282] Method 2: Column 2, run time: 3 minutes, run gradient: 0% B to 45% B in 2.8 min + 100% B for 0.2 min, equilibration time: 0.8 min, ionization mode: ESI + 。

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296] Intermediates 1 and 2: (R)-2-Methyl-N-((S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propane-2-sulfinamide--2,2,2-trifluoroacetaldehyde and (S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0297]

[0298] Intermediate 1: (R)-2-Methyl-N-((S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propane-2-sulfinamide--2,2,2-trifluoroacetaldehyde

[0299] Step 1: 1-Benzyl-1H-pyrazole-3-carbaldehyde

[0300] Heat a suspension of 1H-pyrazole-5-carbaldehyde (1.42 g, 14.78 mmol), K 2 CO 3 (5.10 g, 36.95 mmol) and BnBr (3 mL, 25.26 mmol) in dry MeCN (27 mL) for 12 h at 70 °C. Dilute the mixture with toluene and wash with H 2 O and brine. Dry the organic layer over Na 2 SO 4 , filter and remove the solvent in vacuo. Purify the residue by flash chromatography on silica gel (from cyclohexane containing 0% to 20% EtOAc) to afford the title compound as a yellow oil (1.86 g, 68%). 1 HNMR (400 MHz, DMSO-d 6)δ 9.87 (s, 1H), 8.06 (s, 1H), 7.42 - 7.26 (m, 5H), 6.81 (s, 1H), 5.48 (s, 2H); LCMS (ES + ) Method 1: m / z 187 (M + H) + , RT 1.60 min.

[0301] Step 2: 1-(tert-Butyl) 4-ethyl 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate

[0302] At -78 °C, LDA (2N in THF; 6 mL, 12.0 mmol) was added to a stirred solution of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (2.45 g, 9.52 mmol) in dry THF (20 mL). After 10 min, a solution of 1-benzyl-1H-pyrazole-3-carbaldehyde (1.86 g, 9.99 mmol) in dry THF (5 mL) was slowly added. After 5 min, the mixture was allowed to warm to room temperature. After 20 min, the mixture was diluted with toluene and adjusted to pH = 6 with 2N HCl at 0 °C. The organic layer was washed with H 2 O, brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to obtain the crude compound (4.35 g) as a yellow viscous solid, which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.72 (d, J = 2.2 Hz, 1H), 7.36 - 7.24 (m, 3H), 7.24 - 7.13 (m, 2H), 6.17 (d, J = 2.2 Hz, 1H), 5.47 (d, J = 5.5 Hz, 1H), 5.26 (s, 2H), 4.64 (d, J = 5.5 Hz, 1H), 4.04 - 3.92 (m, 2H), 3.92 - 3.76 (m, 2H), 2.77 - 2.55 (m, 2H), 1.93 - 1.79 (m, 1H), 1.59 - 1.30 (m, 12H), 1.12 (t, J = 7.1 Hz, 3H); LCMS (ES + ) Method 1: m / z 444 (M + H) + , RT 2.05 min.

[0303] Step 3: 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0304] At 0 °C, LiAlH 4(1N in THF; 7.2 mL, 14.4 mmol) was added to a stirred solution of 1-(tert-butyl) 4-ethyl 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (5.28 g, 11.9 mmol) in dry THF (30 mL). After 1.5 h, LiAlH 4 (1N in THF; 1 mL, 2.0 mmol) was added. After 30 min, the mixture was quenched by slowly adding 5% citric acid solution (to pH = 6) and Rochelle salt solution at 0 °C and diluted with toluene. The organic layer was washed with H 2 O(x2) and brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to afford the crude product as a colorless solid (4.7 g), which was used in the next step without purification. LCMS (ES + ) Method 1: m / z 402 (M+H) + , RT 1.77 min.

[0305] Step 4: tert-Butyl 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[0306] At 0 °C, dry DIPEA (3.1 mL, 17.8 mmol) and MsCl (0.95 mL, 12.3 mmol) were added to a stirred solution of tert-butyl 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (4.7 g, 11.71 mmol) in DCM (60 mL). After 5 min, the mixture was diluted with DCM and 5% citric acid solution was added at 0 °C. Then the organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (from cyclohexane containing 20% to 70% EtOAc) to afford the title compound as a white spongy solid (3.1 g, 56% over 3 steps). 1 H NMR (400 MHz, DMSO-d 6)δ 7.76 (d, J = 2.1 Hz, 1H), 7.36 - 7.23 (m, 3H), 7.23 - 7.16 (m, 2H), 6.23 (d, J = 2.2 Hz, 1H), 5.42 (d, J = 4.9 Hz, 1H), 5.29 (s, 2H), 4.63 (d, J = 4.9 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H), 4.18 (d, J = 9.7 Hz, 1H), 3.51 (br dd, J = 15.9, 13.8 Hz, 2H), 3.21 - 2.96 (m, 5H), 1.57 - 1.31 (m, 13H). LCMS(ES + ) Method 1: m / z 480 (M + H) + , RT 1.93 min.

[0307] Step 5: tert-Butyl 4'-hydroxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0308] At 120 °C, a solution of tert-butyl 4-((1-benzyl-1H-pyrazol-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (3.70 g, 7.71 mmol) in 1-BuOH (64 mL) was heated in a sealed tube for 3 h, then cooled to room temperature and treated with NH 4 HCO 2 (1.46 g, 23.15 mmol) and 10 wt% Pd / C (0.41 g, 0.39 mmol). The mixture was heated under reflux for 15 min and then stirred at room temperature for 2 h. The mixture was filtered through a pad of α-cellulose and washed with EtOAc and MeOH. The volatiles were removed under reduced pressure and the product was purified by flash chromatography on silica gel (from 20% to 100% EtOAc + petroleum ether containing 3% MeOH) to afford the title compound as a white solid (1.40 g, 61% over 2 steps). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (d, J = 1.8 Hz, 1H), 6.11 (d, J = 1.8 Hz, 1H), 5.52 (d, J = 7.0 Hz, 1H), 4.61 (d, J = 7.0 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.66 - 3.54 (m, 2H), 3.15 (br d, J = 9.3 Hz, 2H), 1.79 - 1.67 (m, 1H), 1.55 - 1.31 (m, 12H); LCMS(ES + ) Method 1: m / z 294 (M + H) + , RT 1.43 min.

[0309] Step 6: tert-Butyl 4'-oxo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0310] At 0 °C, DMP (2.5 g, 6.01 mmol) was added portionwise to a stirred solution of tert-butyl 4'-hydroxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.6 g, 5.45 mmol) in DCM (24 mL). The resulting mixture was warmed to room temperature. After 1 h, the mixture was diluted with DCM and washed with 10% Na 2 S 2 O 3 solution, H 2 O and brine. The organic layer was dried over Na 2 SO 4 and filtered, and the solvent was removed under reduced pressure to afford a yellow solid. The residue was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound as an off-white solid (1.25 g, 78%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.90 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 4.53 (s, 2H), 3.94 (br d, J = 13.5 Hz, 2H), 2.97 (br s, 2H), 1.75 - 1.59 (m, 4H), 1.42 (s, 9H); LCMS (ES + ) Method 1: m / z 292 (M+H) + , RT 1.73 min.

[0311] Step 7: (R,Z)-tert-Butyl 4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0312] At 100 °C, a solution of tert-butyl 4'-oxo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (980 mg, 2.17 mmol) and (R)-(-)-tert-butylsulfinamide (790 mg, 6.52 mmol) in Ti(OEt) 4 (4 mL) was heated for 1 h. The mixture was cooled to room temperature, diluted with EtOAc and H 2 O, and the precipitated solid was filtered and washed with EtOAc. The organic layer was washed with H 2 O (x3), brine, dried over Na 2 SO 4Dry, filter and remove the solvent under reduced pressure. The residue was purified by flash chromatography on silica gel (from petroleum ether containing 20% EtOAc to 100% EtOAc) to afford the title compound as a pale yellow solid (740 mg, 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 4.46 (d, J = 2.9 Hz, 2H), 3.98 (br d, J = 13.7 Hz, 2H), 3.09 - 2.80 (m, 2H), 1.63 - 1.86 (m, 4H), 1.42 (s, 9H), 1.20 (s, 9H); LCMS (ES + ) Method 1: m / z 395 (M+H) + , RT 1.91 min.

[0313] Step 8: (S)-4'-(((R)-tert-Butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester

[0314] -50 °C, NaBH 4 (0.23 g, 6 mmol) was added to a dry THF (15 mL) solution of (S,Z)-4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester (1.57 g, 3.97 mmol). After 5 min, the mixture was allowed to warm to room temperature. After 1.5 h, an additional portion of NaBH 4 (30 mg, 0.79 mmol) was added and after 30 min, the mixture was diluted with EtOAc and H 2 O at 0 °C. The organic layer was washed with brine, dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to afford a pale yellow solid which was dissolved in EtOH (16 mL) and heated at 75 °C for 1 h (an 88 / 12 diastereomeric ratio was observed by UPLC-MS). The mixture was then evaporated under reduced pressure and the product was purified by flash chromatography on silica gel (from DCM containing 0% to 100% EtOAc + 3% MeOH) to afford the title compound as a white solid (908 mg, 62%, diastereomeric ratio = 97 / 3). 1 HNMR (400 MHz, DMSO-d 6)δ 7.46 (d, J = 1.7 Hz, 1H), 6.07 (d, J = 1.6 Hz, 1H), 5.93 (d, J = 10.0 Hz, 1H), 4.43 (d, J = 9.9 Hz, 1H), 4.19 - 4.11 (m, 1H), 4.08 - 3.96 (m, 2H), 3.82 (br t, J = 14.0 Hz, 2H), 3.12 - 2.80 (m, 2H), 1.80 - 1.55 (m, 3H), 1.41 (s, 9H), 1.15 (s, 9H); LCMS (ES + ) Method 1: m / z 397 (M + H) + , RT 1.66 min.

[0315] Step 9: (R)-2-Methyl-N-((S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propane-2-sulfinamide - 2,2,2-trifluoroacetaldehyde

[0316] At room temperature, TFA (0.2 mL, 2.61 mmol) was added to a dry DCM (1.5 mL) solution of (S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester (90 mg, 0.23 mmol). After 2 h, the mixture was evaporated under reduced pressure to afford a colorless solid (95 mg, quantitative). 1 1H NMR (400 MHz, DMSO-d 6 )δ 8.68 - 8.24 (m, 3H), 7.48 (d, J = 1.8 Hz, 1H), 6.20 - 6.04 (m, 2H), 4.52 (d, J = 10.0 Hz, 1H), 4.14 (dd, J = 19.3, 11.3 Hz, 2H), 3.44 - 3.18 (m, 2H), 3.17 - 2.89 (m, 2H), 2.07 - 1.65 (m, 4H), 1.30 - 1.09 (m, 9H); LCMS (ES + ) Method 1: m / z 297 (M + H) + , RT 0.89 min.

[0317] Intermediate 2: (S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0318] Step 10: (S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0319] At room temperature, HCl (4N in 1,4-dioxane; 2.3 mL, 9.2 mmol) was added to a stirred solution of tert-butyl (S)-4'-(((S)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (908 mg, 2.29 mmol) in DCM (5 mL). After 2 h, the product was filtered, washed with DCM, and dried under reduced pressure to afford a pale yellow solid (463 mg, 75%). 1 H NMR (DMSO-d 6 +TFA) δ 8.97 (br s, 2H), 8.76 (br s, 3H), 7.54 (d, J = 1.7 Hz, 1H), 6.33 (d, J = 1.7 Hz, 1H), 4.59 - 4.45 (m, 1H), 4.41 - 4.18 (m, 2H), 3.38 (br d, J = 12.7 Hz, 1H), 3.29 - 3.10 (m, 2H), 3.10 - 2.87 (m, 1H), 2.17 - 1.80 (m, 3H), 1.80 - 1.65 (m, 1H); LCMS (ES + ) Method 2: m / z 193 (M+H) + , RT 0.54 min.

[0320] Intermediate 3: (S)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0321]

[0322] Step 1: tert-butyl (S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0323] Dry DIPEA (0.4 mL, 2.3 mmol) was added to a suspension of Intermediate 2 (200 mg, 0.75 mmol) and Boc 2 O (412 mg, 1.89 mmol) in dry DCM (3 mL). After 3 h, the mixture was diluted with DCM and washed with 5% citric acid solution, H 2 O and brine. The organic layer was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to petroleum ether containing 50% EtOAc) to afford the title compound as a colorless solid (225 mg, 76%). LCMS (ES + ) Method 1: m / z 393 (M+H)+ , RT 1.95 min.

[0324] Step 2: (S)-4'-((tert-Butoxycarbonyl)amino)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester

[0325] At 50 °C, Selectfluor (53 mg, 0.29 mmol) was added to a stirred solution of (S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester (65 mg, 0.17 mmol) in dry DMF (1.3 mL). After 5 h, the mixture was diluted with toluene and washed with H 2 O (x2) and brine. The organic layer was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (from 20% to 65% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a pale yellow solid (10 mg, 14%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.57 (d, J = 9.7 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 4.85 (d, J = 9.6 Hz, 1H), 4.01 (s, 2H), 3.69 - 3.48 (m, 2H), 3.26 - 2.97 (m, 2H), 1.66 - 1.47 (m, 4H), 1.37 (s, 18H). LCMS (ES + ) Method 1: m / z 411 (M + H) + , RT 2.06 min.

[0326] Step 3: (S)-3'-Fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0327] Following the procedure described for the synthesis of Intermediate 2 in Step 10, the title compound was prepared starting from (S)-4'-((tert-butoxycarbonyl)amino)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylic acid tert-butyl ester (starting from Step 2; 10 mg, 0.02 mmol) to afford a white powder (5 mg, 73%). LCMS (ES + ) Method 1: m / z 211 (M + H) + , RT 0.34 min.

[0328] Intermediate 4: 3-(2,3-dichlorophenyl)-6-hydroxy-2-methylpyrimidin-4(3H)-one

[0329]

[0330] Step 1: N-(2,3-dichlorophenyl)acetamidine

[0331] At 0 °C, treat a solution of 2,3-dichloroaniline (1.62 g, 10 mmol) in dry DCE (10 mL) and MeCN (0.78 mL) with AlCl 3 (1.47 g, 11 mmol). Stir the reaction mixture at 0 °C for 10 min, then at 100 °C for 18 h. After cooling, treat the reaction mixture with ice H 2 O and extract with DCM. Add NaOH (2N) to the mixture to adjust the pH to 10 and extract the aqueous phase with DCM. The combined organic layers are dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound as a brown oil (1.62 g, 80%), which is used as a crude product without further purification. LCMS (ES + ) Method 1: m / z 203 (M+H) + , RT 1.15 min.

[0332] Step 2: 3-(2,3-dichlorophenyl)-6-hydroxy-2-methylpyrimidin-4(3H)-one

[0333] Treat a suspension of N-(2,3-dichlorophenyl)acetamidine (1.61 g, 7.93 mmol) in EtOH (8 mL) with diethyl malonate (2.42 mL, 15.86 mmol) and EtONa (20% solution in EtOH; 8.88 mL, 23.78 mmol), and stir the resulting mixture in a sealed tube at 120 °C for 18 h. Cool the reaction mixture to 25 °C and remove the volatiles under reduced pressure. Add H 2 O to the residue, cool the mixture to 0 °C and acidify to pH ~2 with HCl (6N). Warm the mixture to 25 °C and stir for 1 h. Collect the formed solid by vacuum filtration, wash with Et 2 O, and dry under reduced pressure to afford the title compound (955 mg, 44%). LCMS (ES + ) Method 1: m / z 271 (M+H) + , RT 1.08 min.

[0334] Intermediate 5: 6-chloro-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4(3H)-one

[0335]

[0336] Heat a solution of 3-(2,3-dichlorophenyl)-6-hydroxy-2,5-dimethylpyrimidin-4(3H)-one (prepared using diethyl 2-methylmalonate as the reagent in Step 2 as reported in the synthesis of Intermediate 4; 360 mg, 1.26 mmol) in POCl 3 (4 mL) at 100 °C for 48 h. Cool the reaction mixture to room temperature and concentrate it under reduced pressure. Add ice H 2 O to the mixture and extract the mixture with DCM. Wash the organic layer with saturated NaHCO 3 solution, dry over Na 2 SO 4 , filter and concentrate in vacuo. Purify the crude product by flash chromatography (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound as a white powder (194 mg, 51%). 1 H NMR (DMSO-d 6 ) δ 7.93 (d, J = 7.9 Hz, 1H), 7.75 - 7.65 (m, 2H), 2.13 (s, 6H); LCMS (ES + ) Method 1: m / z 303 (M+H) + , RT 1.90 min.

[0337] Intermediate 6: 6-chloropyrido[2,3-b]pyrazin-2-yl 4-nitrobenzenesulfonate

[0338]

[0339] Treat a solution of 6-chloropyrido[2,3-b]pyrazin-2(1H)-one (1.0 g, 5.5 mmol) in DMF (10 mL) with TEA (0.92 mL, 6.6 mmol) and 4-nitrobenzenesulfonyl chloride (1.2 g, 5.51 mmol). Stir the mixture at room temperature for 1 h, then pour it into H 2 O, filter off the formed precipitate and dry to afford the title product as a brown solid (1.87 g, 92%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.52 - 5.50 (m, 5H), 8.01 (d, J = 8.7 Hz, 1H). LCMS (ES + ) Method 1: m / z 367 (M+H) + , RT 1.78 min.

[0340] Intermediate 7: Sodium 5-chloropyrazine-2-thiolate

[0341]

[0342] Step 1: Methyl 3-((5-chloropyrazin-2-yl)thio)propionate

[0343] Charge methyl 3-mercaptopropionate (200 uL, 1.60 mmol), 2-chloro-5-iodopyrazine (350 mg, 1.46 mmol), DIPEA (648 uL, 3.64 mmol), Xantphos (42.1 mg, 0.07 mmol), Pd 2 (dba) 3 (33.3 mg, 0.04 mmol) and 1,4-dioxane (4.4 mL) into a pressure tube and degas the mixture and heat at 95 °C for 2 h. After cooling, the reaction mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to petroleum ether containing 50% EtOAc) to afford the title compound as a yellow powder (330 mg, 97%). LCMS (ES + ) Method 1: m / z 233 (M+H) + , RT 1.66 min.

[0344] Step 2: Sodium 5-chloropyrazine-2-thiolate

[0345] Add NaOMe (20% w / w solution in MeOH; 0.21 mL, 0.85 mmol) to a solution of methyl 3-((5-chloropyrazin-2-yl)thio)propionate (330 mg, 0.71 mmol) in MeOH (2 mL) and stir the mixture at room temperature for 3 h, then evaporate under reduced pressure to give a residue which was treated with Et 2 O (30 mL). The solution was placed at -20 °C for 18 h. The precipitate formed was filtered and washed with Et 2 O and DCM to afford the title compound as a yellow powder (119 mg, 99%). LCMS (ES + ) Method 1: m / z145 (M+H) - RT 0.74 min.

[0346] Intermediate 8: 1-(2-chloro-3-iodophenyl)-1H-pyrazole

[0347]

[0348] With Cs 2 CO 3(380 mg, 1.17 mmol) and 2-chloro-1-fluoro-3-iodobenzene (250 mg, 0.98 mmol) were treated with pyrazole (78 mg, 1.17 mmol) in a solution of DMF (6.0 mL) and stirred at 160 °C under MW irradiation for 30 min. After cooling, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with H 2 O. The organic solvent was dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford a residue which was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound as a white powder (198 mg, 67%). LCMS (ES + ) Method 1: m / z 305 (M+H) + , RT 1.83 min.

[0349] Intermediate 9: 1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-one hydrochloride

[0350]

[0351] Step 1: 1-Tosyl-1H-pyrrole-2-carbaldehyde

[0352] At 0 °C, NaH (60 wt% in mineral oil; 547 mg, 13.67 mmol) was added to a solution of 1H-pyrrole-2-carbaldehyde (1.0 g, 10.52 mmol) in dry DMF (20 mL). After 10 min, TsCl (3.1 g, 1.55 mmol) was added and the mixture was warmed to room temperature and stirred for 16 h, then diluted with EtOAc and washed with citric acid (5% aqueous solution), H 2 O and brine. The organic layer was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to afford the title compound as a light brown solid (2.5 g, 96%), which was used in the next step without further purification. LCMS (ES + ) Method 1: m / z 250 (M+H) + , RT 1.89 min.

[0353] Step 2: 1-(tert-Butyl) 4-ethyl 4-(hydroxy(1-tosyl-1H-pyrrol-2-yl)methyl)piperidine-1,4-dicarboxylate

[0354] At -78 °C, LDA (2N in THF; 5.2 mL, 10.4 mmol) was added to a dry THF (28 mL) solution of ethyl 1-(tert-butoxycarbonyl)piperidine-4-carboxylate (2.25 g, 8.7 mmol). After 10 min, a dry THF (7 mL) solution of 1-tosyl-1H-pyrrole-2-carbaldehyde (2.51 g, 10.1 mmol) was slowly added and the reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was diluted with toluene and citric acid (5% aqueous solution) at 0 °C until pH = 5. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to afford the title compound as a yellow oil (4.4 g, 99%), which was used in the next step without further purification. LCMS (ES + ) Method 1: m / z 507 (M+H) + , RT 2.35 min.

[0355] Step 3: tert-Butyl 4-(hydroxy(1-tosyl-1H-pyrrol-2-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate

[0356] At 0 °C, LiAlH 4 (2N in THF; 6 mL, 12.0 mmol) was added to a dry THF (24 mL) solution of 1-(tert-butyl) 4-ethyl 4-(hydroxy(1-tosyl-1H-pyrrol-2-yl)methyl)piperidine-1,4-dicarboxylate (5 g, 9.8 mmol), and the reaction mixture was stirred at this temperature for 2 h, then diluted with toluene and quenched by slowly adding citric acid (5% aqueous solution) until pH = 6. The aqueous phase was extracted with toluene and the organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to afford the title compound as a brown viscous solid (3.9 g, 85%). LCMS (ES + ) Method 1: m / z 465 (M+H) + , RT 1.99 min.

[0357] Step 4: tert-Butyl 4-(hydroxy(1-tosyl-1H-pyrrol-2-yl)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[0358] At 0 °C, a solution of tert-butyl 4-(hydroxymethyl)-4-[(oxidanyl)[1-(phenylmethyl)-1H-pyrazol-3-yl]methyl]piperidine-1-carboxylate (3.9 g, 8.4 mmol) in DCM (50 mL) was treated with dry DIPEA (1.8 mL, 10.3 mmol) and MsCl (0.65 mL, 8.4 mmol) and stirred at this temperature for 30 min, then quenched with citric acid (5% aqueous solution) and diluted with DCM. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (from cyclohexane containing 0% EtOAc to cyclohexane containing 70% EtOAc) to afford the title compound as a pale red spongy solid (1.5 g, 34%). LCMS (ES + ) Method 1: m / z 543 (M+H) + , RT 2.06 min.

[0359] Step 5: tert-Butyl 4-(((methylsulfonyl)oxy)methyl)-4-(1-tosyl-1H-pyrrole-2-carbonyl)piperidine-1-carboxylate

[0360] At 0 °C, a solution of tert-butyl 4-(hydroxy(1-tosyl-1H-pyrrole-2-yl)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (900 mg, 1.66 mmol) in DCM (8 mL) was treated with DMP (774 mg, 1.82 mmol) and stirred at this temperature for 1 h, then diluted with DCM and washed with NaHCO 3 (saturated solution), H 2 O and brine. The organic layer was dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. Purification by flash chromatography on silica gel (from cyclohexane containing 0% EtOAc to cyclohexane containing 70% EtOAc) afforded the title compound as a pale orange spongy solid (525 mg, 59%). LCMS (ES + ) Method 1: m / z 541 (M+H) + , RT 2.16 min.

[0361] Step 6: tert-Butyl 1'-oxo-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1-carboxylate

[0362] NaOH (4N, 10 mL, 40 mmol) was added to a stirred solution of tert-butyl 4-(((methylsulfonyloxy)methyl)-4-(((tetrahydro-2H-pyran-2-yl)oxy)(1-tosyl-1H-pyrrol-2-yl)methyl)piperidine-1-carboxylate (525 mg, 0.97 mmol) in MeOH (10 mL), and the mixture was stirred at 60 °C for 2 h, then cooled to room temperature and diluted with EtOAc and H 2 O. The organic layer was washed with H 2 O, brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to afford the title compound as a light brown solid (281 mg, 99%). LCMS (ES + ) Method 1: m / z 291 (M+H) + , RT 1.71 min.

[0363] Step 7: 1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-one hydrochloride

[0364] HCl (4N in 1,4-dioxane; 1.5 mL, 6 mmol) was added to a solution of 1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-one hydrochloride (280 mg, 0.96 mmol) in DCM (7 mL) and the reaction mixture was stirred at room temperature for 4 h, then evaporated under reduced pressure to give a residue which was suspended in Et 2 O and filtered. The solvent was removed under reduced pressure to afford the title compound as a purple powder (214 mg, 98%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (brs, 1H), 8.98 - 8.61 (m, 1H), 7.47 - 7.41 (m, 1H), 6.75 (dd, J = 1.0, 3.9 Hz, 1H), 6.62 (dd, J = 2.2, 4.0 Hz, 1H), 4.40 (s, 2H), 3.47 - 3.39 (m, 2H), 3.06 (br d, J = 9.6 Hz, 2H), 2.17 - 1.92 (m, 2H), 1.92 - 1.74 (m, 2H). LCMS (ES + ) Method 1: m / z 191 (M+H) + , RT 0.62 min.

[0365] Intermediates 10 and 11: 1-(2-fluoro-6-iodophenyl)-1H-pyrazole and 1-(2-fluoro-3-iodophenyl)-1H-pyrazole

[0366]

[0367] Following the procedure reported for the synthesis of Intermediate 8, the title compound was prepared using 1,2-difluoro-3-iodobenzene under MW irradiation in acetone at 90 °C for 16 h. Intermediate 10: (32 mg, 53%); LCMS (ES + ) Method 1: m / z 289 (M+H) + , RT 1.59 min. Intermediate 11: (9 mg, 15%); LCMS (ES + ) Method 1: m / z 289 (M+H) + , RT 1.88 min.

[0368] Intermediate 12: 1-(2-chloro-3-iodophenyl)-2-(difluoromethyl)-1H-imidazole

[0369]

[0370] Step 1: 1-(2-chloro-3-iodophenyl)-1H-imidazole-2-carbaldehyde

[0371] The title compound (32 mg, 25%) was prepared following the procedure reported for the synthesis of Intermediate 8. LCMS (ES + ) Method 1: m / z 333 (M+H) + , RT 1.58 min.

[0372] Step 2: 1-(2-chloro-3-iodophenyl)-2-(difluoromethyl)-1H-imidazole

[0373] At 0 °C, a solution of 1-(2-chloro-3-iodophenyl)-1H-imidazole-2-carbaldehyde (21 mg, 0.06 mmol) in DCM (0.6 mL) was treated with DAST (26 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 h, then cooled back to 0 °C and treated with NaHCO 3 (saturated solution) and DCM. The organic layer was washed with brine, dried over Na 2 SO 4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to petroleum ether containing 70% EtOAc) to afford the title compound (10 mg, 45%). LCMS (ES + ) Method 1: m / z 355 (M+H) + , RT 1.74 min.

[0374] Intermediate 13: 5-bromo-4-fluoro-2-methyl-2H-indazole

[0375]

[0376] Step 1: 5-Bromo-4-fluoro-1H-indazole

[0377] Add a solution of NaNO 2 (84 mg, 1.23 mmol) in H 2 O (1 mL) to a cold solution of 4-bromo-3-fluoro-2-methylaniline (100 mg, 0.49 mmol) in AcOH (2.2 mL). Warm the reaction mixture to room temperature and stir for 18 h. Add H 2 O to precipitate the product and wash the residue with petroleum ether to afford the title compound as an orange powder (68 mg, 65%). LCMS (ES + ) Method 1: m / z 215 (M+H) + , RT 1.55 min.

[0378] Step 2: 5-Bromo-4-fluoro-2-methyl-2H-indazole

[0379] Treat a solution of 5-bromo-4-fluoro-1H-indazole (68 mg, 0.31 mmol) in EtOAc (1.5 mL) with trimethyloxonium tetrafluoroborate (51 mg, 0.34 mmol) and stir at room temperature for 2 h, then add H 2 O. Filter the resulting precipitate and wash with H 2 O and petroleum ether to afford the title compound as a brown oil (63 mg, 88%). LCMS (ES + ) Method 1: m / z 229 - 231 (M+H) + , RT 1.60 min.

[0380] Intermediate 14: Sodium 4-chloro-2-methyl-2H-indazole-5-thiolate

[0381]

[0382] Step 1: 5-Bromo-4-chloro-1H-indazole

[0383] Treat a solution of 4-bromo-3-chloro-2-methylaniline (867 mg, 3.93 mmol) in AcOH (17 mL) with a solution containing NaNO 2 (339 mg, 4.91 mmol) in H 2 O (1.5 mL). Stir the mixture at room temperature for 1 h. Concentrate the solvent under reduced pressure and suspend the residue in H 2 O, filter and wash with H 2Washed with O and n - heptane. The phases were separated, and the organic phase was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (gradient elution with cyclohexane containing 0 - 30% EtOAc) to afford the title compound as a pale orange solid (328 mg, 36%). LCMS (ES + ) Method 1: m / z 231 (M + H) + , RT 1.59 min.

[0384] Step 2: 5 - Bromo - 4 - chloro - 2 - methyl - 2H - indazole

[0385] A solution of 5 - bromo - 4 - chloro - 1H - indazole (1.49 g, 6.45 mmol) in EtOAc (32 mL) was treated with trimethyloxonium tetrafluoroborate (1.43 g, 9.65 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 5 h. Upon completion, the mixture was quenched with saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution with n - heptane containing 0 - 30% EtOAc) to afford the title compound as an orange solid (0.9 g, 57%). 1 1H NMR (500 MHz, DMSO - d 6 ): δ 8.49 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 4.16 (s, 3H). LCMS (ES + ) Method 1: m / z 245 (M + H) + , RT 1.69 min.

[0386] Step 3: 2 - Ethylhexyl 3 - ((4 - chloro - 2 - methyl - 2H - indazol - 5 - yl)thio)propanoate

[0387] At 130 °C, 3 - mercaptopropanoic acid 2 - ethylhexyl ester (139 μL, 0.61 mmol), 5 - bromo - 4 - chloro - 2 - methyl - 2H - indazole (100 mg, 0.41 mmol), DIPEA (145 μL, 0.81 mmol), Xantphos (24 mg, 0.04 mmol) and Pd 2 (dba) 3A solution of (22 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was stirred for 1.5 h. After cooling, the mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (gradient elution with petroleum ether containing 0 - 50% EtOAc) to give the title compound as a yellow oil (150 mg, 96%). LCMS (ES + ) Method 1: m / z 383 (M+H) + , RT 2.58 min.

[0388] Step 4: Sodium 4-chloro-2-methyl-2H-indazole-5-thiol

[0389] A solution of 2-ethylhexyl 3-((4-chloro-2-methyl-2H-indazol-5-yl)thio)propionate (125 mg, 0.33 mmol) in MeOH (6 mL) was treated with NaOMe (25 wt% in MeOH; 328 μL, 0.36 mmol) and stirred at room temperature for 1 h, then evaporated under reduced pressure to give a residue, which was dissolved in H 2 O and washed with Et 2 O. The aqueous phase was diluted with MeCN and lyophilized to give the title compound as a yellow powder (72 mg, 99%). LCMS (ES + ) Method 1: m / z 199 (M+H) + , RT 1.59 min. Example

[0390] Example 1: (S)-6-(4'-Amino-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3H)-one

[0391]

[0392] BOP (16 mg, 0.04 mmol) and DBU (0.01 mL, 0.09 mmol) were added to a suspension of intermediate 3 (9 mg, 0.03 mmol) and intermediate 4 (8 mg, 0.03 mmol) in dry MeCN (0.1 mL). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a white powder (3 mg, 23%). 1 1H NMR (400 MHz, DMSO-d 6) δ 8.55 (br s, 3H), 7.81 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 3.7 Hz, 1H), 7.58 - 7.51 (m, 2H), 5.51 (s, 1H), 4.67 (br s, 1H), 4.36 (br d, J = 11.6 Hz, 1H), 4.23 (br d, J = 11.8 Hz, 1H), 4.18 - 4.14 (m, 1H), 3.33 - 3.27 (m, 1H), 3.15 - 3.08 (m, 1H), 2.01 (s, 3H), 1.84 - 1.56 (m, 4H). LCMS (ES + ) Method 1: m / z 463 (M + H) + , RT 1.21 min.

[0393] Example 2: (S)-1-(5-(2,3 - dichlorophenoxy)pyrazin - 2 - yl)-4'H,6'H - spiro[piperidine - 4,5'-pyrrolo[1,2 - b]pyrazole]-4'-amine

[0394]

[0395] Step 1: 2 - chloro - 5-(2,3 - dichlorophenoxy)pyrazine

[0396] A mixture of 2 - bromo - 5 - chloropyrazine (33 mg, 0.17 mmol), 2,3 - dichlorophenol (31 mg, 0.19 mmol), Cs 2 CO 3 (78 mg, 0.24 mmol), CuI (3 mg, 0.017 mmol) and 2 - (dimethylamino)acetic acid (2 mg, 0.017 mmol) in 1,4 - dioxane (0.9 ml) was degassed and heated at 115 °C for 12 h. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as a white powder (28 mg, 60%). LCMS (ES + ) Method 1: m / z 275 (M + H) + , RT 2.34 min.

[0397] Step 2: (S)-1-(5-(2,3 - dichlorophenoxy)pyrazin - 2 - yl)-4'H,6'H - spiro[piperidine - 4,5'-pyrrolo[1,2 - b]pyrazole]-4'-amine

[0398] Heat a solution of Intermediate 2 (32 mg, 0.12 mmol), 2-chloro-5-(2,3-dichlorophenoxy)pyrazine (28 mg, 0.1 mmol) and DIPEA (0.09 mL, 0.51 mmol) in NMP (0.5 mL) at 120 °C for 12 h. After cooling, the reaction mixture was concentrated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc to EtOAc containing 0% MeOH to 100% MeOH) to give a residue, which was purified by preparative HPLC-MS (from 25% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a white powder (1.4 mg, 33%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (br s, 3H), 8.13 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.24 (s, 1H), 4.41 - 4.36 (m, 1H), 4.29 (br d, J = 11.4 Hz, 1H), 4.15 (br d, J = 11.2 Hz, 1H), 4.11 - 4.01 (m, 1H), 3.18 - 3.12 (m, 1H), 3.03 - 2.97 (m, 1H), 1.81 - 1.54 (m, 5H). LCMS (ES + ) Method 1: m / z 431 (M + H) + , RT 1.54 min.

[0399] Example 3: (S)-6-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazol]-1-yl)-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4(3H)-one

[0400]

[0401] Step 1: (S)-N-((S)-1-(1-(2,3-Dichlorophenyl)-2,5-dimethyl-6-oxo-1,6-dihydropyrimidin-4-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazol]-4'-yl)-2-methylpropane-2-sulfinamide

[0402] The solution of intermediate 5 (90 mg, 0.3 mmol), intermediate 1 (182 mg, 0.35 mmol) and DIPEA (0.3 mL, 1.77 mmol) in DMF (1 mL) was heated at 100 °C for 12 h. The reaction mixture was filtered through a Celite pad, washed with EtOAc and concentrated in vacuo. The residue was used in the next step without further purification (105 mg). LCMS (ES + ) Method 1: m / z 579 (M+H) + , RT 1.90 min.

[0403] Step 2: (S)-6-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4(3H)-one

[0404] The solution of (S)-N-((S)-1-(1-(2,3-dichlorophenyl)-2,5-dimethyl-6-oxo-1,6-dihydropyrimidin-4-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide in MeOH (1 mL) was treated with MeOH (3 M, 0.5 mL) containing HCl for 1 h. The solvent was evaporated in vacuo and the residue was purified directly by reverse-phase chromatography (from 15% to 35% MeCN / H 2 O + 0.1% TFA) to give the title compound as a white solid (35 mg, 25%). The above mixture of atropisomers was separated by chiral SFC on a TM Prep 15 Waters using IA (1x25 cm) column (flow rate: 10 ml / min, T col = 40 °C, P col : 120 bar, modifier: 30% MeOH (+0.1% TEA) for 3 min, 30 - 35% for 6 min, 35 - 40% for 11 min, 40 - 30% for 2 min, 30% for 2 min; using CO 2 as the supercritical fluid); the title compound as a white powder (5.8 mg; 18%) was obtained as the second eluate (RT = 14.9 min). 1 1H NMR (400 MHz DMSO-d 6)δ 7.81 (t, J = 5.2 Hz, 1H), 7.55 (d, J = 4.6 Hz, 2H), 7.40 (s, 1H), 6.05 (brs, 1H), 4.15 (br d, J = 11.0 Hz, 1H), 3.99 - 3.94 (m, 2H), 3.77 - 3.69 (m, 2H), 3.20 - 3.14 (m, 2H), 1.99 (s, 3H), 1.98 (m, 1H), 1.92 (s, 3H), 1.92 - 1.90 (m, 2H), 1.75 - 1.61 (m, 3H), 1.52 - 1.48 (m, 1H). LCMS(ES + ) Method 1: m / z 459 (M + H) + , RT 1.09 min.

[0405] Example 4: (S)-1-(5-((3-Fluoro-2-methylpyridin-4-yl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0406]

[0407] Step 1: 2-Ethylhexyl 3-((5-chloro-3-methylpyrazin-2-yl)thio)propionate

[0408] To Pd 2 (dba) 3 (11 mg, 0.01 mmol), 2-Bromo-5-chloro-3-methylpyrazine (100 mg, 0.48 mmol), 2-Ethylhexyl 3-mercaptopropionate (0.12 mL, 0.53 mmol), Xantphos (13.9 mg, 0.024 mmol) and DIPEA (0.17 mL, 0.96 mmol) in 1,4-dioxane (2.4 mL) was degassed and stirred at 95 °C for 1 h, then cooled and filtered through a pad of Celite, washed with EtOAc. The solvent was concentrated under reduced pressure to afford a residue which was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound (166 mg, 99%). LCMS(ES + ) Method 1: m / z 345 (M + H) + , RT 2.50 min.

[0409] Step 2: Sodium 5-chloro-3-methylpyrazine-2-thiol

[0410] NaOMe (20% w / w solution in MeOH; 0.58 mL, 0.58 mmol) was added to a solution of 2-ethylhexyl 3-((5-chloro-3-methylpyrazin-2-yl)thio)propionate (166 mg, 0.48 mmol) in MeOH (1.4 mL). The mixture was stirred at room temperature for 2 h and then evaporated under reduced pressure. A mixture of Et 2 O and H 2 O (20 mL) was added to the residue. The aqueous phase was separated and lyophilized to afford the title compound as a yellow powder (87 mg, 99%). LCMS (ES + ) Method 1: m / z 161 (M+H) + , RT 1.08 min.

[0411] Step 3: 5-Chloro-2-((3-fluoro-2-methylpyridin-4-yl)thio)-3-methylpyrazine

[0412] A suspension of 4-bromo-3-fluoro-2-methylpyridine (25 mg, 0.13 mmol), sodium 5-chloro-3-methylpyrazine-2-thiolate (48 mg, 0.13 mmol), Pd 2 (dba) 3 (3 mg, 0.03 mmol), Xantphos (4 mg, 0.01 mmol) and DIPEA (0.05 mL, 0.26 mmol) in 1,4-dioxane (0.7 mL) was degassed and heated at 85 °C for 1 h, then cooled and filtered through a Solka Floc pad, washed with EtOAc / MeOH. The solvent was concentrated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from EtOAc containing 0% MeOH to 100% MeOH) to afford the title compound (12 mg, 34%). LCMS (ES + ) Method 1: m / z 270 (M+H) + , RT 1.98 min.

[0413] Step 4: (S)-1-(5-((3-fluoro-2-methylpyridin-4-yl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0414] Heat a solution of Intermediate 2 (15 mg, 0.04 mmol), 5-chloro-2-((3-fluoro-2-methylpyridin-4-yl)thio)-3-methylpyrazine (12 mg, 0.04 mmol) and DIPEA (0.04 mL, 0.22 mmol) in DMF (0.2 mL) at 90 °C for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure to afford a residue, which was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to give the title compound as a yellow powder (4.5 mg, 24%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (br s, 3H), 8.35 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.60 (s, 1H), 6.64 (t, J = 5.6 Hz, 1H), 6.32 (s, 1H), 4.48 - 4.24 (m, 5H), 3.37 - 3.29 (m, 1H), 3.24 - 3.16 (m, 1H), 2.45 (s, 3H), 2.43 (s, 3H), 1.85 - 1.66 (m, 4H). LCMS (ES + ) Method 1: m / z 426 (M+H) + , RT 1.20 min.

[0415] Using the above procedure, the following examples were synthesized using the corresponding starting materials: Example 6, Example 17 (starting from 5-bromo-2-chloro-3-methylpyrazine in Step 1)

[0416]

[0417] Example 5: (S)-2-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-(2,3-difluorophenyl)-3-methylpyrimidin-4(3H)-one

[0418]

[0419] Step 1: 5-bromo-2-chloropyrimidin-4(3H)-one

[0420] At 0 °C, add KOH (2N; 2.4 mL, 4.8 mmol) to a solution of 5-bromo-2,4-dichloro-pyrimidine (545 mg, 2.39 mmol) in THF (8 mL). Allow the mixture to warm to room temperature and stir at this temperature for 24 h, then quench the reaction by adjusting to pH = 1 with HCl (6N) at 0 °C and then extract with EtOAc (2x). Combine the organic layers, and pass through Na 2 SO4 Dry, filter and remove the solvent under reduced pressure to afford the title compound as a brown solid (480 mg, 95%), which was used without further purification. LCMS (ES + ) Method 1: m / z 209 (M+H) + , RT 0.81 min.

[0421] Step 2: 5-Bromo-2-chloro-3-methylpyrimidin-4(3H)-one

[0422] At 0 °C, NaH (60 wt% in mineral oil; 101 mg, 2.5 mmol) was added to a dry DME (6 mL) / DMF (1.5 mL) solution of 5-bromo-2-chloropyrimidin-4(3H)-one (480 mg, 2.29 mmol). The mixture was allowed to warm to room temperature, treated with MeI (0.29 mL, 4.58 mmol) and heated at 60 °C for 2 h. After cooling, the reaction mixture was diluted with brine and EtOAc. The organic layer was dried over Na 2 SO 4 dried, filtered and the solvent removed under reduced pressure to afford a residue which was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to petroleum ether containing 40% EtOAc) to afford the title compound as an off-white powder (300 mg, 58%). LCMS (ES + ) Method 1: m / z 223 (M+H) + , RT 1.01 min.

[0423] Step 3: tert-Butyl (S)-(1-(5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0424] A solution of intermediate 2 (32 mg, 0.11 mmol), 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (20 mg, 0.09 mmol) and DIPEA (0.12 mL, 0.72 mmol) in DMF (0.45 mL) was heated at 90 °C for 2 h. After cooling, the solvent was concentrated under reduced pressure and the residue was dissolved in DCM (0.4 mL) and treated with Boc 2 O (39 mg, 0.18 mmol) and DIPEA (23 mg, 0.18 mmol) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure to afford a residue which was purified by flash chromatography on silica gel (from 0% to 100% EtOAc + 10% MeOH in petroleum ether) to afford the title compound as a pale yellow oil (16 mg, 37%). LCMS (ES +) Method 1: m / z 479 (M+H) + , RT 1.66 min.

[0425] Step 4: (S)-2-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-(2,3-difluorophenyl)-3-methylpyrimidin-4(3H)-one

[0426] tert-Butyl (S)-(1-(5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (16 mg, 0.03 mmol), (2,3-difluorophenyl)boronic acid (10.5 mg, 0.07 mmol), Pd(dppf)Cl 2 (4.9 mg, 0.01 mmol) and K 3 PO 4 (17.7 mg, 0.08 mmol) in a suspension in a mixture of 1,4-dioxane (0.12 mL) and H 2 O (0.06 mL) was degassed and stirred at 100 °C for 45 min, then cooled and concentrated under reduced pressure. The residue was treated with HBr (33% in AcOH; 0.3 mL) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 10% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a white powder (0.4 mg, 2.8%). LCMS (ES + ) Method 1: m / z 413 (M+H) + , RT 0.97 min.

[0427] Example 7: (S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0428]

[0429] Step 1: (S)-1-(5-iodopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0430] Intermediate 2 (79 mg, 0.3 mmol), 2-chloro-5-((3-fluoro-2-methylpyridin-4-yl)thio)pyrazine (60 mg, 0.25 mmol) and DIPEA (0.22 mL, 1.25 mmol) were heated in a solution of a mixture of 1,4-dioxane (0.5 mL) and DMSO (0.3 mL) at 120 °C for 6 h. After cooling, the reaction mixture was evaporated under reduced pressure to afford the title compound, which was used crude in the next step. LCMS (ES + ) Method 1: m / z 397 (M+H) + , RT 1.06 min.

[0431] Step 2: (S)-(1-(5-Iodopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)tert-butyl carbamate

[0432] A solution of (S)-1-(5-iodopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (80 mg, 0.2 mmol) in DCM (1 mL) was treated with Boc 2 O (132 mg, 0.61 mmol) and DIPEA (209 mg, 1.61 mmol) and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound (17 mg, 11%). LCMS (ES + ) Method 1: m / z 497 (M+H) + , RT 2.22 min.

[0433] Step 3: (S)-(1-(5-(4-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)tert-butyl carbamate

[0434] To (S)-(1-(5-iodopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)tert-butyl carbamate (17 mg, 0.03 mmol), 4-fluorophenol (4.2 mg, 0.04 mmol), Cs 2 CO 3(15.6 mg, 0.05 mmol), CuI (0.7 mg, 0.003 mmol) and 2-(dimethylamino)acetic acid (0.4 mg, 0.003 mmol) in 1,4-dioxane (0.17 ml) were degassed and heated at 115 °C for 2 h. After cooling, the reaction mixture was filtered through a Solka Floc pad and concentrated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as a white powder (16 mg, 97%). LCMS (ES + ) Method 1: m / z 481 (M+H) + , RT 2.37 min.

[0435] Step 4: (S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0436] A solution of tert-butyl (S)-(1-(5-(4-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (16 mg, 0.03 mmol) in DCM (0.5 ml) was treated with TFA (0.2 mL) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to afford a residue, which was purified by preparative HPLC-MS (from 13% to 100% MeCN / H 2 O + 0.1% TFA) to give the title compound as a white powder (0.8 mg, 6%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (br s, 3H), 8.09 (s, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.12 - 7.08 (m, 2H), 6.30 (s, 1H), 4.43 (s, 1H), 4.34 (d, J = 11.4 Hz, 1H), 4.23 - 4.08 (m, 3H), 3.24 - 3.19 (m, 1H), 3.10 - 3.05 (m, 1H), 1.91 - 1.75 (m, 3H), 1.65 - 1.62 (m, 1H). LCMS (ES + ) Method 1: m / z 381 (M+H) + , RT 1.13 min.

[0437] Example 8: (S)-1-(6-(2,3-Difluorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0438]

[0439] Step 1: tert-Butyl (S)-(1-(6-chloropyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0440] A solution of intermediate 6 (100 mg, 0.27 mmol) and intermediate 2 (90 mg, 0.3 mmol) in DMA (2 mL) was treated with DIPEA (0.24 mL, 1.36 mmol) and heated at 60 °C for 2 h, then cooled to room temperature and treated with Boc 2 O (119 mg, 0.55 mmol), and stirred for 90 min. Then the mixture was diluted with EtOAC and washed with H 2 O and brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (from DCM containing 0% MeOH to DCM containing 7.5% MeOH) to give the title compound as a yellow oil (47 mg, 38%). LCMS (ES + ) Method 1: m / z 456 (M+H) + , RT 1.83 min.

[0441] Step 2: (S)-1-(6-(2,3-Difluorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0442] Heating (S)-(1-(6-chloropyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (23 mg, 0.05 mmol), (2,3-difluorophenyl)boronic acid (16 mg, 0.1 mmol), Pd(dppf)Cl 2 (8.3 mg, 0.01 mmol) and K 2 CO 3(28 mg, 0.2 mmol) in MeCN (0.5 mL) was mixed for 16 h, then cooled, diluted with EtOAC, filtered and evaporated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (from DCM with 0% MeOH to DCM with 10% MeOH) to give the Boc-protected intermediate (10 mg). The material was dissolved in DCM (1 mL) and treated with HCl (4 N in 1,4-dioxane; 0.13 mL) and stirred at room temperature for 2 h. Volatiles were removed in vacuo and the residue was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a yellow powder (5.5 mg, 25%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (s, 1H), 8.34 (br s, 3H), 8.08 (d, J = 8.6 Hz, 1H), 7.99 - 7.97 (m, 1H), 7.77 (br t, J = 7.3 Hz, 1H), 7.53 (s, 1H), 7.51 - 7.47 (m, 1H), 7.35 - 7.30 (m, 1H), 6.25 (s, 1H), 4.57 (br d, J = 13.8 Hz, 1H), 4.48 (d, J = 14.3 Hz, 1H), 4.42 (br s, 1H), 4.35 (br d, J = 11.4 Hz, 1H), 4.23 (br d, J = 11.4 Hz, 1H), 3.44 - 3.25 (m, 2H), 1.87 - 1.66 (m, 4H). LCMS (ES + ) Method 1: m / z 434 (M + H) + , RT 1.19 min.

[0443] Using the above procedure, the following examples were synthesized using the corresponding starting materials: Example 9

[0444]

[0445] Example 10: (S)-1-(5-((2-chloro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0446]

[0447] Step 1: 2-chloro-5-((2-chloro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazine

[0448] To a solution of Intermediate 7 (37 mg, 0.07 mmol), Intermediate 8 (20 mg, 0.07 mmol), Pd 2 (dba) 3 (2.4 mg, 0.003 mmol), Xantphos (3 mg, 0.01 mmol) and DIPEA (0.04 mL, 0.21 mmol) in 1,4-dioxane (0.4 mL) was degassed and heated at 110 °C for 30 min. After cooling, the solvent was removed under reduced pressure to afford a residue, which was purified by flash silica chromatography (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as a brown oil (21 mg, 99%). LCMS (ES + ) Method 1: m / z 323 (M+H) + , RT 1.95 min.

[0449] Step 2: (S)-1-(5-((2-chloro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0450] Intermediate 1 (40 mg, 0.08 mmol) and K 2 CO 3 (45 mg, 0.32 mmol) in DMA (0.5 mL) / H 2 O (0.5 mL) mixture was heated at 90 °C for 5 h. After cooling, the reaction mixture was filtered and the residue was washed with MeOH, then the solvent was concentrated under reduced pressure to give a residue, which was treated with HCl (3 N in MeOH; 0.4 mL). The mixture was stirred at room temperature for 30 min and the solvent was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a light yellow powder (4.3 mg, 14%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.41 (br s, 3H), 8.36 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.41 - 7.39 (m, 2H), 7.02 (dd, J 1 = 6.5 Hz, J 2= 2.5 Hz, 1H), 6.55 (s, 1H), 6.32 (s, 1H), 4.49 - 4.25 (m, 5H), 3.40 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 1.85 - 1.67 (m, 4H). LCMS (ES + ) Method 1: m / z 479 (M + H) + , RT 1.24 min.

[0451] Example 11: (S)-6-(4'-Amino-4'H, 6'H-spiro[piperidine-4, 5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one

[0452]

[0453] Step 1: 6-Chloro-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one

[0454] To a solution of 3-bromo-6-chloro-1-methylpyridin-2(1H)-one (20 mg, 0.09 mmol), (2,3-dichlorophenyl)boronic acid (34.3 mg, 0.18 mmol), Pd(dppf)Cl 2 (14.7 mg, 0.02 mmol) and K 3 PO 4 (114.4 mg, 0.54 mmol) in 1,4-dioxane (0.5 mL) / H 2 O (0.1 mL) mixture was degassed and heated at 90 °C for 2 h. After cooling, the reaction mixture was filtered through a SolkaFloc pad and washed with EtOAc. The solvent was concentrated under reduced pressure to afford a residue which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound as a yellow solid (16 mg, 62%). LCMS (ES + ) Method 1: m / z 288 (M + H) + , RT 1.87 min.

[0455] Step 2: (S)-6-(4'-Amino-4'H, 6'H-spiro[piperidine-4, 5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one

[0456] 6-Chloro-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one (16 mg, 0.07 mmol), intermediate 2 (26 mg, 0.09 mmol) and DIPEA (0.05 mL, 0.29 mmol) in DMA (0.45 mL) were heated at 110 °C for 24 h, then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a brown powder (6.7 mg, 21%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (br s, 3H), 7.62 - 7.60 (m, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 5.99 (d, J = 7.7 Hz, 1H), 4.55 (br s, 1H), 4.34 (br d, J = 11.2 Hz, 1H), 4.21 (d, J = 11.4 Hz, 1H), 3.50 (s, 3H), 3.30 - 3.28 (m, 1H), 3.22 - 3.19 (m, 1H), 3.00 - 2.95 (m, 1H), 2.86 - 2.80 (m, 1H), 2.07 - 1.85 (m, 3H), 1.74 - 1.71 (m, 1H). LCMS (ES + ) Method 1: m / z 444 (M + H) + , RT 1.16 min.

[0457] Example 12: (S)-1-(3-(2-Fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0458]

[0459] Step 1: N-((3-Chloropyrazin-2-yl)methyl)-2-fluoro-3-methylbenzamide

[0460] (3-Chloropyrazin-2-yl)methanamine hydrochloride (46 mg, 0.25 mmol), 2-fluoro-3-methylbenzoic acid (30 mg, 0.2 mmol), DIPEA (0.14 mL, 0.78 mmol) and HBTU (89 mg, 0.24 mmol) in DMF (0.7 mL) were stirred at room temperature for 2 h, then the solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc, washed with HCl (1N), NaHCO 3(Saturated solution) and brine wash. The organic phase was dried over Na 2 SO 4 , concentrated under reduced pressure to give the title compound as a white solid (54 mg, 99%), which was used in the next step without further purification. LCMS (ES + ) Method 1: m / z 280 (M+H) + , RT 1.52 min.

[0461] Step 2: 8-Chloro-3-(2-fluoro-3-methylphenyl)imidazo[1,5-a]pyrazine

[0462] A suspension of N-((3-chloropyrazin-2-yl)methyl)-2-fluoro-3-methylbenzamide (48 mg, 0.17 mmol) in a mixture of DMF (0.28 mL) and EtOAc (0.58 mL) was treated with POCl 3 (0.08 mL, 0.85 mmol) and stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was diluted with EtOAC (3 mL) and ice H 2 O (1 mL), washed with saturated NaHCO 3 aqueous solution, the organic phase was separated, dried over Na 2 SO 4 , and concentrated in vacuo to give the title compound as a white powder (44 mg, 99%), which was used in the next step without further purification. LCMS (ES + ) Method 1: m / z 262 (M+H) + , RT 1.75 min.

[0463] Step 3: (S)-1-(3-(2-Fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0464] A solution of 8-chloro-3-(2-fluoro-3-methylphenyl)imidazo[1,5-a]pyrazine (15 mg, 0.06 mmol), intermediate 2 (21 mg, 0.07 mmol) and DIPEA (0.03 mL, 0.17 mmol) in DMA (0.4 mL) was stirred at 110 °C for 5 h, then cooled to room temperature and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 15% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a white powder (18 mg, 75%). 1 1H NMR (400 MHz, DMSO-d 6) δ 8.42 (broad singlet, 3H), 8.11 (singlet, 1H), 7.60 (singlet, 1H), 7.55 - 7.47 (multiplet, 2H), 7.39 - 7.37 (multiplet, 1H), 7.32 (triplet, J = 7.2 Hz, 1H), 7.17 (doublet, J = 5.0 Hz, 1H), 6.33 (singlet, 1H), 4.54 - 4.43 (multiplet, 4H), 4.29 (doublet, J = 11.4 Hz, 1H), 3.58 - 3.52 (multiplet, 1H), 3.42 - 3.36 (multiplet, 1H), 2.36 (singlet, 3H), 2.00 - 1.86 (multiplet, 3H), 1.73 - 1.69 (multiplet, 1H). LCMS (ES + ) Method 1: m / z 418 (M + H) + , RT 0.77 min.

[0465] Using the above procedure, the following examples were synthesized with the corresponding starting materials: Example 14, Example 15, Example 16

[0466]

[0467]

[0468] Example 13: (S)-1-(5-((4-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0469]

[0470] Step 1: 2-bromo-5-((4-fluorophenyl)thio)pyrazine

[0471] 4-Fluorobenzenethiol (0.01 mL, 0.08 mmol), 2,5-dibromopyrazine (20 mg, 0.08 mmol) and K 2 CO 3 (12 mg, 0.08 mmol) in DMF (0.5 mL) were stirred at room temperature for 1 h and then diluted in DCM and H 2 O. The organic phase was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as a yellow powder (14 mg, 58%). LCMS (ES + ) Method 1: m / z 285 (M + H) + , RT 2.11 min.

[0472] Step 2: (S)-1-(5-((4-Fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0473] Intermediate 2 (19 mg, 0.07 mmol), 2-bromo-5-((4-fluorophenyl)thio)pyrazine (14 mg, 0.05 mmol) and K 3 PO 4 (36 mg, 0.17 mmol) were heated at 95 °C in a solution in a mixture of IPA (0.5 mL) / DMA (0.2 mL) for 12 h, then cooled, filtered through a cellulose pad and washed with MeOH. The solvent was evaporated under reduced pressure to give a residue which was purified by preparative HPLC-MS (from 25% to 100% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a yellow powder (5.6 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (br s, 4H), 8.18 (s, 1H), 7.59 (s, 1H), 7.40 (dd, J 1 = 8.6 Hz, J 2 = 5.5 Hz, 2H), 7.22 (t, J = 8.9 Hz, 2H), 6.31 (s, 1H), 4.46 (br s, 1H), 4.38 - 4.30 (m, 2H), 4.25 - 4.21 (m, 2H), 3.32 - 3.26 (m, 1H), 3.18 - 3.12 (m, 1H), 1.83 - 1.72 (m, 3H), 1.66 - 1.62 (m, 1H). LCMS (ES + ) Method 1: m / z 397 (M + H) + , RT 1.19 min.

[0474] Example 18: (S)-1-(5-((4-(Trifluoromethoxy)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0475]

[0476] Step 1: 2-Chloro-5-((4-(trifluoromethoxy)phenyl)thio)pyrazine

[0477] To 2-bromo-5-chloropyrazine (30 mg, 0.16 mmol), 4-(trifluoromethoxy)benzenethiol (30 mg, 0.16 mmol), DIPEA (0.05 mL, 0.31 mmol), Pd2 (dba) 3 (14 mg, 0.02 mmol) and a solution of Xantphos (18 mg, 0.03 mmol) in 1,4-dioxane (0.8 mL) were degassed and heated at 90 °C for 2 h, then cooled to room temperature, filtered and evaporated under reduced pressure to give a residue, which was purified by flash silica chromatography (from petroleum ether containing 0% EtOAc to petroleum ether containing 20% EtOAc) to give the title compound as a colorless oil (22 mg, 46%). LCMS (ES + ) Method 1: m / z 307 (M+H) + , RT 2.32 min.

[0478] Step 2: (S)-1-(5-((4-(trifluoromethoxy)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0479] A solution of 2-chloro-5-((4-(trifluoromethoxy)phenyl)thio)pyrazine (22 mg, 0.07 mmol), Intermediate 2 (27 mg, 0.09 mmol) and K 2 CO 3 (50 mg, 0.36 mmol) in DMA (240 μL) and H 2 O (160 μL) was degassed and then heated at 90 °C for 5 h. The mixture was cooled to room temperature, filtered and evaporated under reduced pressure to give a residue, which was purified by preparative HPLC-MS (from 25% to 100% MeCN / H 2 O + 0.1% TFA) to obtain the title compound as a yellow powder (3.5 mg, 11%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.38 (m, 2H), 8.26 (s, 1H), 7.58 (s, 1H), 7.40 - 7.34 (m, 4H), 6.30 (s, 1H), 4.44 (br s, 1H), 4.37 - 4.33 (m, 2H), 4.26 - 4.23 (m, 2H), 3.31 - 3.27 (m, 1H), 3.21 - 3.15 (m, 1H), 1.84 - 1.73 (m, 3H), 1.67 - 1.64 (m, 1H). LCMS (ES + ) Method 1: m / z 463 (M+H) + , RT 1.44 min.

[0480] Using the above procedure, the following examples were synthesized using the corresponding starting materials: Example 19; Example 20; Example 21; Example 22; Example 23; Example 24; Example 25; Example 26; Example 27.

[0481]

[0482]

[0483] Example 28: (S)-1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine

[0484]

[0485] Step 1: 2-chloro-5-((2,3-dichlorophenyl)thio)pyrazine

[0486] According to the procedure of the synthesis report for Example 18, the title compound was prepared starting from 2-chloro-5-iodopyrazine (180 mg, 0.6 mmol) in Step 1 to give the title compound as an off-white powder (144 mg, 88%). LCMS (ES + ) Method 1: m / z 291 - 293 (M+H) + , RT 2.31 min.

[0487] Step 2: 1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-one

[0488] Intermediate 9 (50 mg, 1.07 mmol), 2-chloro-5-((2,3-dichlorophenyl)thio)pyrazine (60 mg, 0.21 mmol) and K 2 CO 3 (86 mg, 0.62 mmol) in a mixture of DMA / H 2 O (6 / 4 v / v; 1 mL) were heated at 90 °C for 3 h, then cooled to room temperature, diluted with EtOAC and washed with H 2 O, citric acid (5% aqueous solution) and brine. The organic layer was dried over Na 2 SO 4 and filtered and the solvent was removed under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (from petroleum ether containing 10% EtOAc to 100% EtOAc) to give the title compound as an off-white powder (54 mg, 59%). LCMS (ES + ) Method 1: m / z 445 (M+H) +,RT 2.34 min.

[0489] Step 3: (R,Z)-N-(1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-ylidene)-2-methylpropane-2-sulfinamide

[0490] Treat a dry DME (1 mL) solution of 1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-one (53 mg, 0.12 mmol) and (R)-(-)-tert-butylsulfinamide (44 mg, 0.36 mmol) with Ti(EtO) 4 (1 mL) and heat at 100 °C for 24 h. After cooling, dilute the reaction mixture with EtOAc and H 2 O. Filter off the precipitate and wash the organic layer with H 2 O, brine, dry over Na 2 SO 4 , filter and remove the solvent under reduced pressure to give a residue, which is purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as an off-white powder (47 mg, 72%). LCMS (ES + ) Method 1: m / z 548 (M+H) + , RT 2.47 min.

[0491] Step 4: (R)-N-((S)-1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-yl)-2-methylpropane-2-sulfinamide

[0492] Add NaBH 4 (32 mg, 0.85 mmol) to a THF (1 mL) solution of (R,Z)-N-(1-(5-((3-chloro-2-(1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-ylidene)-2-methylpropane-2-sulfinamide (46 mg, 0.08 mmol) and stir the reaction mixture at room temperature for 48 h, then quench with H 2 O at 0 °C. Stir the reaction mixture at this temperature for 20 min, then treat with EtOAc and allow the mixture to warm to room temperature. The organic layer is dried over Na 2 SO 4The solvent was removed by drying, filtering and under reduced pressure to afford the title compound as a pale yellow solid (46 mg; 99%), which was used in the next step without further purification. LCMS (ES + ) Method 1: m / z 550 (M+H) + , RT 2.39 min.

[0493] Step 5: (S)-1-(5-((2,3-Dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine

[0494] HCl (4N in 1,4-dioxane; 0.7 mL, 2.8 mmol) was added to a solution of (R)-N-((S)-1-(5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-yl)-2-methylpropane-2-sulfonamide (46 mg, 0.08 mmol) in a MeCN / H 2 O (1.2 / 1 v / v; 2.2 mL) mixture and the mixture was stirred at room temperature for 5 min, then diluted with H 2 O and EtOAc and basified to pH = 10 with KOH (10N) at 0 °C. The aqueous phase was extracted with EtOAc and the organic layers were combined, dried over Na 2 SO 4 dried, filtered and the solvent was removed under reduced pressure to afford a residue which was purified by flash column chromatography on silica gel (from EtOAc containing 0% MeOH to EtOAc containing 10% MeOH) to afford the title compound as a yellow solid (11.5 mg; 30%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d, J = 1.1 Hz, 1H), 8.37 - 8.10 (m, 4H), 7.46 (dd, J = 1.3, 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.88 (dd, J = 1.4, 8.1 Hz, 1H), 6.80 (dd, J = 1.1, 2.5 Hz, 1H), 6.19 - 6.14 (m, 1H), 6.11 - 6.06 (m, 1H), 4.41 - 4.15 (m, 4H), 4.14 - 4.01 (m, 1H), 3.44 - 3.32 (m, 1H), 3.30 - 3.15 (m, 1H), 1.88 - 1.64 (m, 3H), 1.63 - 1.52 (m, 1H). LCMS (ES + ) Method 1: m / z 446 (M+H) + , RT 1.69 min.

[0495] Using the above procedure, the following examples were synthesized using the corresponding starting materials: Example 29.

[0496]

[0497] Example 30: (S)-1-(5-((2-chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0498]

[0499] Step 1: (S)-1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0500] A solution of intermediate 2 (47 mg, 0.18 mmol), 2,5-dibromopyrazine (35 mg, 0.15 mmol) and TEA (0.1 mL, 0.74 mmol) in DMA (0.6 mL) was heated at 80 °C for 12 h, then cooled to room temperature and diluted with EtOAC and NaOH (1 N). The organic phase was washed with H 2 O, dried over Na 2 SO 4 and evaporated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (from DCM containing 0% MeOH to DCM containing 5% MeOH) to afford the title compound (24 mg, 47%). LCMS (ES + ) Method 1: m / z 349 (M+H) + , RT 0.83 min.

[0501] Step 2: tert-Butyl (S)-(1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0502] A mixture of (S)-1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (24 mg, 0.07 mmol) and Boc 2 O (30 mg, 0.14 mmol) in DCM (0.3 mL) was stirred at room temperature for 1 h, then washed with H 2 O, brine, dried over Na 2 SO 4 and evaporated under reduced pressure to afford the title compound (30 mg, 99%). LCMS (ES + ) Method 1: m / z 449 (M+H) +, RT 1.89 min.

[0503] Step 3: 2-Ethylhexyl 3-((5-((S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)propionate

[0504] A suspension of tert-butyl (S)-(1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (30 mg, 0.07 mmol), 2-ethylhexyl 3-mercaptopropionate (0.02 mL, 0.08 mmol), Pd 2 (dba) 3 (6.1 mg, 0.01 mmol), Xantphos (7.7 mg, 0.01 mmol) and TEA (0.03 mL, 0.2 mmol) in toluene (0.8 mL) was degassed and heated at 90 °C for 2 h, then cooled to room temperature and evaporated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to afford the title compound as a yellow oil (34 mg, 87%). LCMS (ES + ) Method 1: m / z 587 (M+H) + , RT 2.65 min.

[0505] Step 4: Sodium (S)-5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-thiolate

[0506] A solution of 2-ethylhexyl 3-((5-((S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)propionate (34 mg, 0.06 mmol) in MeOH (0.5 mL) was treated with NaOMe (25 wt% in MeOH; 53 μL, 0.06 mmol) and stirred at room temperature for 45 min, then concentrated under reduced pressure to give a residue, which was triturated with a mixture of petroleum ether / EtOAc (10 / 1 v / v) to afford the title compound as a pale yellow powder (24 mg, 99%). LCMS (ES + ) Method 1: m / z 403 (M+H) + , RT 1.32 min.

[0507] Step 5: tert-Butyl (S)-(1-(5-((2-chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0508] A suspension of 2-chloro-1-fluoro-3-iodobenzene (18 mg, 0.07 mmol), sodium (S)-5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-thiolate (25 mg, 0.06 mmol), Pd 2 (dba) 3 (3 mg, 0.003 mmol), DIPEA (0.02 mL, 0.12 mmol) and Xantphos (3.4 mg, 0.01 mmol) in 1,4-dioxane (0.6 mL) was degassed and heated at 90 °C for 1 h, then cooled to room temperature and evaporated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound as a yellow solid (6 mg, 19%). LCMS (ES + ) Method 1: m / z 532 (M+H) + , RT 2.28 min.

[0509] Step 6: (S)-1-(5-((2-chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0510] A solution of (R)-N-((S)-1-(5-((2-chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (6 mg, 0.011 mmol) in DCM (0.5 mL) was treated with TFA (0.2 mL) and stirred at room temperature for 10 min, then evaporated under reduced pressure to afford a residue, which was purified by preparative HPLC-MS (from 20% to 100% MeCN / H 2 O + 0.1% TFA) to obtain the title compound as a yellow powder (4 mg, 82%). 1 1H NMR (400 MHz, DMSO-d 6)δ 8.51 (s, 1H), 8.38 (br s, 3H), 8.32 (s, 1H), 7.59 (s, 1H), 7.31 - 7.28 (m, 2H), 6.84 - 6.77 (m, 1H), 6.31 (s, 1H), 4.50 - 4.24 (m, 5H), 3.40 - 3.20 (m, 2H), 1.90 - 1.64 (m, 4H). LCMS (ES + ) Method 1: m / z 431 (M + H) + , RT 1.31 min.

[0511] Example 31: (S)-1-(5-(2,3-dichlorophenyl)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0512]

[0513] Step 1: 2-chloro-5-(2,3-dichlorophenyl)pyrazine

[0514] To a mixture of 2-bromo-5-chloropyrazine (70 mg, 0.36 mmol), (2,3-dichlorophenyl)boronic acid (69 mg, 0.36 mmol), Pd(dppf)Cl 2 (26 mg, 0.036 mmol) and K 3 PO 4 (230 mg, 1.09 mmol) in a mixture of 1,4-dioxane (0.9 mL) and H 2 O (90 μL) was degassed and heated at 100 °C for 1 h, then cooled and filtered through a cellulose pad, which was washed with EtOAc. The solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound (20 mg, 21%). LCMS (ES + ) Method 1: m / z 259 (M + H) + , RT 2.17 min.

[0515] Step 2: (S)-1-(5-(2,3-dichlorophenyl)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0516] Using intermediate 2 (20 mg, 0.08 mmol) and K 2 CO 3(53 mg, 0.39 mmol) was treated with a solution of 2-chloro-5-(2,3-dichlorophenyl)pyrazine (20 mg, 0.08 mmol) in DMF (0.4 mL) and stirred at 100 °C for 1 h, then cooled and filtered over a cellulose pad, and washed with a mixture of EtOAc / MeOH. The solvent was removed under reduced pressure to afford a residue, which was purified by preparative HPLC-MS (from 17% to 45% MeCN / H 2 O + 0.1% TFA) to give the title compound as a yellow powder (9.6 mg, 30%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (s, 1H), 8.43 (s, 1H), 8.40 (br s, 3H), 7.70 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.55 - 7.53 (m, 1H), 7.49 - 7.45 (m, 1H), 6.32 (s, 1H), 4.48 - 4.25 (m, 5H), 3.37 - 3.31 (m, 1H), 3.23 - 3.17 (m, 1H), 1.89 - 1.78 (m, 3H), 1.69 - 1.66 (m, 1H). LCMS (ES + ) Method 1: m / z 415 (M + H) + , RT 1.22 min.

[0517] Example 32: (S)-1-(5-((2,4-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0518]

[0519] Step 1: (S)-1-(5-((2,4-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0520] 2-Chloro-5-(2,4-difluorophenyl)thio-pyrazine (prepared according to the same procedure reported in Step 1 of Example 10; 25 mg, 0.1 mmol), Intermediate 2 (35 mg, 0.12 mmol) and K 2 CO 3 (67 mg, 0.48 mmol) in a solution of DMA (320 μL) and H 2 O (180 μL) was heated at 95 °C for 3 h, then cooled, filtered, washed with a minimal amount of DMSO and purified by preparative HPLC-MS (from 17% to 45% MeCN / H 2Purified with O + 0.1% TFA to obtain the title compound as a light yellow powder (3.4 mg, 8%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.31 (br s, 3H), 8.18 (s, 1H), 7.58 (s, 1H), 7.52 - 7.46 (m, 1H), 7.39 (t, J = 9.1 Hz, 1H), 7.16 - 7.12 (m, 1H), 6.30 (s, 1H), 4.44 (s, 1H), 4.37 - 4.19 (m, 4H), 3.30 - 3.25 (m, 1H), 3.17 - 3.11 (m, 1H), 1.83 - 1.70 (m, 3H), 1.65 - 1.62 (m, 1H). LCMS (ES + ) Method 1: m / z 415 (M + H) + , RT 1.27 min.

[0521] Using the above procedure, the following examples were synthesized using the corresponding starting materials: Example 33; Example 34; Example 35; Example 36; Example 37; Example 38; Example 39; Example 40; Example 41; Example 42; Example 43; Example 44; Example 45; Example 46; Example 47; Example 48; Example 49; Example 50; Example 75; Example 76; Example 77; Example 80; Example 81; Example 82

[0522]

[0523]

[0524]

[0525] Example 51: (S)-1-(5-((3-Fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0526]

[0527] Step 1: 2-Chloro-5-((3-fluorophenyl)thio)pyrazine

[0528] With Cs 2 CO 3(27 mg, 0.08 mmol) and 3-fluorobenzenethiol (11 mg, 0.08 mmol) were treated with a solution of 2-chloro-5-iodopyrazine (20 mg, 0.08 mmol) in DMSO (0.8 mL). The mixture was degassed and irradiated with blue light (Penn Photoreactor) at room temperature for 5 h. Subsequently, the solvent was evaporated under reduced pressure to afford a residue, which was purified by flash column chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound (6 mg, 30%). LCMS (ES + ) Method 1: m / z 241 (M+H) + , RT 2.07 min.

[0529] Step 2: (S)-1-(5-((3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0530] The title compound was prepared according to the procedure reported in Step 1 of the synthesis of Example 32 and was obtained as a white powder (2.4 mg, 24%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 8.30 (bs, 3H), 8.27 (s, 1H), 7.58 (s, 1H), 7.41 - 7.35 (m, 1H), 7.10 - 7.05 (m, 3H), 6.29 (s, 1H), 4.43 (br s, 1H), 4.35 (br d, J = 12.5 Hz, 2H), 4.28 - 4.23 (m, 2H), 3.35 - 3.32 (m, 1H), 3.23 - 3.17 (m, 1H), 1.88 - 1.73 (m, 3H), 1.68 - 1.64 (m, 1H). LCMS (ES + ) Method 1: m / z 397 (M+H) + , RT 1.22 min.

[0531] Example 52: (S)-1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0532]

[0533] Step 1: Methyl 3-((1,3-dihydroisobenzofuran-4-yl)thio)propionate

[0534] The title compound was prepared according to the procedure reported in Step 1 of the synthesis of Intermediate 7 and obtained as a yellow powder (31 mg, 65%). LCMS (ES + ) Method 1: m / z 239 (M-H) - , RT 1.63 min.

[0535] Step 2: Sodium 1,3-dihydroisobenzofuran-4-thiolate

[0536] A solution of methyl 3-(1,3-dihydroisobenzofuran-4-ylthio)propionate (31 mg, 0.13 mmol) in MeOH (0.37 mL) was treated with NaOMe (25% in MeOH; 34 mg, 0.16 mmol) and stirred at room temperature for 2 h, then concentrated under reduced pressure to give a residue, which was treated with Et 2 O. After stirring for 30 min, the precipitate was separated by filtration and dried to give the title compound as a yellow powder (22.6 mg, 99%). LCMS (ES + ) Method 1: m / z 153 (M+H) + , RT 1.51 min.

[0537] Step 3: 2-Chloro-5-((1,3-dihydroisobenzofuran-4-yl)thio)pyrazine

[0538] The title compound was obtained starting from 2-chloro-5-iodopyrazine according to the procedure reported in Step 1 of the synthesis of Example 18 (15 mg, 91%). LCMS (ES + ) Method 1: m / z 265 (M+H) + , RT 1.89 min.

[0539] Step 4: (S)-1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0540] The title compound was prepared according to the procedure reported in Step 2 of the synthesis of Example 18 and was obtained as a yellow powder (6.2 mg, 26%). 1 1H NMR (400 MHz, DMSO-d 6)δ 8.35 (broad singlet, 3H), 8.28 (singlet, 1H), 8.07 (singlet, 1H), 7.48 (singlet, 1H), 7.20 - 7.15 (multiplet, 2H), 7.06 (broad doublet, J = 7.2 Hz, 1H), 6.20 (singlet, 1H), 4.95 (singlet, 2H), 4.81 (singlet, 2H), 4.35 (broad singlet, 1H), 4.27 - 4.10 (multiplet, 4H), 3.21 - 3.15 (multiplet, 1H), 3.07 - 3.02 (multiplet, 1H), 1.75 - 1.63 (multiplet, 3H), 1.55 - 1.52 (multiplet, 1H). LCMS (ES + )Method 1: m / z 421 (M + H) + , RT 1.09 min.

[0541] Using the above procedure, the following examples were synthesized with the corresponding starting materials: Example 53; Example 54; Example 55; Example 56; Example 57; Example 58; Example 59; Example 60; Example 61; Example 62; Example 63; Example 64; Example 65; Example 66; Example 67; Example 68; Example 69; Example 70; Example 71; Example 72; Example 73; Example 74; Example 83; Example 84

[0542]

[0543]

[0544]

[0545] Example 78: (S)-1-(5-(3-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0546]

[0547] Step 1: (S)-1-(5-Bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0548] Stir a solution of 2,5-dibromopyrazine (100 mg, 0.42 mmol), intermediate 2 (111 mg, 0.42 mmol) and DIPEA (0.37 mL, 2.1 mmol) in DMF (2.1 mL) at 85 °C for 5 h, then cool, dilute in EtOAc and wash with NaOH (1N). After removing the solvent under reduced pressure, the title compound was obtained and used as a crude product (146 mg, 99%). LCMS (ES +) Method 1: m / z 349 (M+H) + , RT 1.28 min.

[0549] Step 2: tert-Butyl (S)-(1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0550] Stir a solution of (S)-1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (146 mg, 0.42 mmol) and Boc 2 O (182 mg, 0.84 mmol) in DCM (1.7 mL) at room temperature for 12 h. Then wash the mixture with H 2 O, brine, dry it over Na 2 SO 4 dry, filter and then evaporate the solvent under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound (40 mg, 21%). LCMS (ES + ) Method 1: m / z 449 (M+H) + , RT 1.89 min.

[0551] Step 3: tert-Butyl (S)-(1-(5-(3-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate

[0552] Stir a solution of tert-Butyl (S)-(1-(5-bromopyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (20 mg, 0.04 mmol), 2-fluorophenol (5 mg, 0.04 mmol), N,N-dimethylglycine (0.5 mg, 0.004 mmol), CuI (0.8 mg, 0.004 mmol) and Cs 2 CO 3 (20 mg, 0.06 mmol) in 1,4-dioxane (0.22 mL) at 115 °C for 2 h, then cool, filter on a Solka Floc pad and wash with EtOAc. Then evaporate the solvent under reduced pressure to give a residue, which is purified by flash chromatography on silica gel (from petroleum ether containing 0% EtOAc to 100% EtOAc) to give the title compound (16 mg, 75%). LCMS (ES + ) Method 1: m / z 481 (M+H) +, RT 2.07 min.

[0553] Step 4: (S)-1-(5-(3-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0554] A solution of tert-butyl (S)-(1-(5-(3-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (16 mg, 0.03 mmol) in DCM (0.2 mL) was treated with TFA (67 μL) and stirred at room temperature for 2 h, then evaporated and purified by preparative HPLC-MS (from 15% to 30% MeCN / H 2 O + 0.1% TFA) to afford the title compound as a pale yellow powder (5.3 mg, 42%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (br s, 3H), 8.11 (s, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.31 - 7.28 (m, 1H), 7.21 - 7.16 (m, 3H), 6.25 (s, 1H), 4.39 (br s, 1H), 4.30 (br d, J = 11.4 Hz, 1H), 4.17 - 4.10 (m, 2H), 4.02 (br d, J = 14.5 Hz, 1H), 3.18 - 3.12 (m, 1H), 3.03 - 2.97 (m, 1H), 1.80 - 1.69 (m, 3H), 1.58 - 1.55 (m, 1H). LCMS (ES + ) Method 1: m / z 381 (M + H) + , RT 1.13 min.

[0555] Using the above procedure, Example 79 was synthesized using the corresponding starting materials:

[0556]

[0557] biology

[0558] SHP2 Inhibitory Enzyme Assay

[0559] The experiment was conducted as described by YP Chen et al., Nature (535) 2016. Using the following buffer, a 20 μL / well assay volume was assembled in a 384-well black polystyrene low-binding microplate (Greiner): 60 mM HEPES pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA pH 8, 0.05% Tween-20, 5 mM DTT. The SHP-2 enzyme (synthesized by Origene, Met1–Leu525, catalog number TP750155) was used at a final concentration of 0.5 nM. The enzyme was activated by 500 nM IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide; Wang et al., iScience 25, 104009, April 15, 2022, https: / / doi.org / 10.1016 / j.isci.2022.104009) and incubated with 75 μM DiFMUP (Sigma) as the substrate.

[0560] Briefly, serial dilutions of DMSO assay compounds were transferred to the bottom of the assay plate. After incubating for 30 minutes, SHP2 was added together with the IRS1 peptide, the DiFMUP substrate was added to the reaction and incubated at room temperature for 30 minutes. Finally, 5 μL of 160 μM bpV (bisperoxo[1,10-phenanthroline]oxovanadate [V], Sigma) was added to stop and quench the reaction. Fluorescence was detected by a microplate reader (Envision, PerkinElmer) according to the DiFMUP excitation and emission wavelengths. The lower the fluorescence, the higher the SHP2 inhibition.

[0561] The activity of each compound dilution was calculated as the percentage of inhibition between the vehicle (DMSO, 0% inhibition) and no enzyme (100% inhibition). The percentage of inhibition was fitted to the compound dilution using a four-parameter logistic regression. The inflection point (i.e., the concentration at which half-maximal inhibition is reached) is the IC 50 .

[0562] The IC 50 of the compounds of the present invention in the SHP2 inhibitory enzyme assay is shown in Table 2. Note: A indicates IC 50 less than or equal to 0.05 μM; B indicates IC 50 greater than 0.05 μM and less than or equal to 0.3 μM.

[0563] Table 2 - SHP2 Inhibition of the Compounds of the Present Invention

[0564]

[0565]

[0566] Phosphorylated-ERK cell assay

[0567] ERK phosphorylation was detected using the "Advanced Phospho-ERK1 / 2 (Thr202 / Tyr204)" TR-FRET kit (Cisbio, catalog number #64AERPEG / H) according to the manufacturer's reagents and instructions.

[0568] Briefly, 20,000 KYSE-520 cells / well (DSMZ ACC 371) were plated in 6 μL of RPMI-1640 (Invitrogen) growth medium in 384 white low-volume high-alkalinity TC microplates (Greiner). After overnight incubation, the cells were treated with serial dilutions of the compound in DMSO and incubated at 37 °C for 2 h. After incubation, 2 μL / well of 4X lysis buffer (Cisbio 64KL1FDF) was added and incubated with the cells for 30 min with gentle shaking. Finally, the lysate was combined with 2 μL / well of Eu cryptate (donor) and D2 (acceptor) conjugated antibody (from Cisbio kit #64AERPEG / H) diluted 1:100 in detection buffer (from Cisbio kit #64AERPEG / H). The plates were then sealed and incubated at room temperature in the dark. After overnight incubation, the TR-FRET signal was detected on a suitable reader (Envision, PerkinElmer). The lower the TR-FRET signal, the higher the inhibition of SHP2 in the cells.

[0569] The activity of each compound dilution was calculated as the percentage between cells treated with the vehicle DMSO and cell-free, 0% inhibition, and 100% inhibition. The percentage of activity was fit to the compound dilution using four-parameter logistic regression. The inflection point (i.e., the concentration at which half-maximal inhibition is achieved) is the IC 50 .

[0570] The IC 50 of the compounds of the present invention in the phospho-ERK cell assay 50 Results are shown in Table 3. Note: "+" indicates that the IC 50 is equal to or higher than 0.5 μM; "++" indicates that the IC 50 is less than 0.5 μM and higher than or equal to 0.1 μM; "+++" indicates that the IC

[0571] Table 3 - pERK Activity of Compounds of the Present Invention

[0572]

[0573]

[0574] Binding kinetics assay by surface plasmon resonance (SPR)

[0575] The N-terminally biotinylated recombinant SHP2 protein (AviTag-G4SG4S-SHP2(1-525)) was custom-produced by VIVA Biotech Co., Ltd. The binding kinetic rate constants were measured by SPR using a Biacore T200 instrument. The recombinant SHP2 protein was diluted to 5 μg / mL in HBS-P+ buffer and then captured on an S series streptavidin sensor chip up to 5000 RU. The binding of compounds was evaluated by a single-cycle kinetics program (SCK): The compounds were diluted (3-fold dilution from 300 to 3.7 nM) in HBS-EP+ supplemented with 2% DMSO, injected onto the ligand for 120 s, and then the dissociation rate was measured for 3600 s at 50 μL / min and 25 °C. The sensorgrams were analyzed by the Biacore T200 evaluation software: The binding rate constants (kon, koff) and affinity (KD) were calculated by curve fitting according to the 1:1 Langmuir model. Each molecule was tested in triplicate on separate flow cells. The results are reported in Table 4 below.

[0576] Table 4

[0577]

[0578] Determination of brain permeability in Sprague-Dawley rats

[0579] After intravenous administration, the total brain levels in Sprague-Dawley rats were measured by Cbrain@8h / Cplasma@8h, expressed as the brain / plasma ratio (K p ,brain) (see Pharmaceutical Research, Vol. 25, No. 8, August 2008 DOI: 10.1007 / s11095-007-9502-2; Pharmaceutical Research (2022) 39:1321–1341 https: / / doi.org / 10.1007 / s11095-022-03246-6). The unbound fraction of each molecule in the biological matrix was determined by in vitro plasma and brain binding assays. K puu ,brain was calculated by the following equation:

[0580] K puu ,brain = Cbrain@8h / Cplasma@8h × (f u ,brain / f u ,plasma)

[0581] The in vitro plasma and brain binding assays were performed on a RED (rapid equilibrium dialysis) device.

[0582] The unbound fraction (fu) of each molecule in brain homogenate and plasma was calculated as the ratio of the buffer side reaction to the brain homogenate / plasma side reaction. An IV study design was used as an in vivo screening model to determine the brain permeability of each molecule. Male juvenile SD rats (n = 3) were dosed intravenously with each molecule at a dose of 0.2 mg / kg, which was dissolved in DMSO / propylene glycol / water, 20:60:20 (v / v / v). Plasma samples were collected via the tail vein at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours post-dose, and the brain tissue was harvested at the 8-hour time point and homogenized in 3 volumes of water. All samples were stored at ~ -80 °C prior to LC / MS / MS analysis. At the 8-hour time point, the unbound brain-to-plasma ratio was generated to identify molecules with a K puu , brain value > 0.3, which indicates good brain passive permeability. Table 4 above reports the results for representative compounds.

Claims

1. A compound of formula (I): Wherein: X 1 is CR 1 or N; X 2 is CR 2 ; X 3 is CR 3 ; R 1 、 R 2 and R 3 each independently selected from H, halogen, OC 1-3 alkyl or C 1-3 alkyl; preferably, R 1 、 R 2 and R 3 are each independently selected from H and halogen; X 4 is O, S or a bond; R 4 is an aryl, heteroaryl, partially unsaturated aryl, or partially unsaturated heteroaromatic ring, and the aryl, heteroaryl, partially unsaturated aryl, or partially unsaturated heteroaromatic ring is optionally substituted with one or more substituents independently selected from C(O)CH 3 , C(O)OCH 3 , OH, halogen, NH 2 , NH-C 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-5 cycloalkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, CONR’R”, CN, halo-C 1-6 alkoxy, C 1-6 alkoxy, a saturated 5- or 6-membered heterocycle, aryl, or heteroaryl, where the saturated 5- or 6-membered heterocycle, aryl, or heteroaryl is each optionally substituted with one or more CH 3 , NH 2 , halogen, or OH, and where R’ and R” are each independently H or C 1-6 alkyl, preferably H or CH 3 ; Cy-X 4 -R 4 corresponds to any one of the general formulas (A)-(F) shown below: Wherein: -R 5 Selected from H, C 1-3 alkyl, and NH 2 ; preferably selected from H, CH 3 and NH 2 ; -R 6 , R 7 , R 8 are each independently selected from H and C 1-3 alkyl; Or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Provided that the compound of formula (I) is not a compound selected from the following: -(S)-1-(6-Amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-methyl-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-chloro-2-(1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((5-amino-3-chloropyrazin-2-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloro-3-nitroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-N-(7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide; -(S)-7-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxamide; -(S)-1-(5-((6-Amino-2-chloropyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((5-Chloroimidazo[1,2-a]pyridin-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-7-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carbonitrile; -(S)-7-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridin-2(3H)-one; -(S)-1-(5-((3-Chloro-2-(1H-imidazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-Amino-5-((3-chloro-2-(1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-Chloro-2-(4-fluoro-1H-pyrazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-Chloro-2-(1H-pyrrol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-Amino-5-((3-chloro-2-(1H-imidazol-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-Amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-1H-pyrazole-4-carboxamide; -(S)-1-(4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-1H-pyrrole-3-carboxamide; -(S)-1-(4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N-methyl-1H-pyrrole-3-carboxamide; -(S)-7-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-8-chloro-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide; -(S)-1-(4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

2. The compound of formula (I) according to claim 1, wherein, X 1 is N.

3. The compound of formula (I) according to any one of claims 1 or 2, wherein, R 4 selected from: phenyl, pyridine, pyrimidine, pyrazine, quinoline, imidazo[1,2-a]pyridine, indole, 2H-indazole, 2,3-dihydroindole, 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazine, 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1,8-naphthyridine, triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridin-2(3H)-one, wherein each ring is optionally substituted with one or more substituents independently selected from C(=O)CH 3 、C(=O)OCH 3 、OH, halogen, NH 2 、CF 3 、CHF 2 、C 1-3 alkyl, C 1-6 alkoxy, C(=O)NH 2 、C(=O)NHC 1-3 alkyl, C(=O)N(C 1-3 alkyl) 2 、CN, C 3-5 cycloalkyl, aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more of the following groups: halogen, C(=O)NH 2 、C(=O)NHCH 3 、C(=O)N(CH 3 ) 2 、C 1-3 alkyl and NHC(=O)CF 3 .

4. The compound of formula (I) according to any one of the preceding claims, wherein, R 4 Selected from the group consisting of: 2,3-dichlorophenyl, 3-fluoro-2-methylpyridin-4-yl, 2,3-difluorophenyl, 5-(4-fluorophenyl)pyrazin-2-yl, 2-chloro-3-(1H)-pyrazolyl, 2-fluoro-3-methylphenyl, 4-fluorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-methylphenyl, 2-chloro-6-fluoro-3-methylphenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 3-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, tolyl, phenyl, pyridyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-3-methylphenyl, 8-methoxyquinolin-4-yl, 2,3-dihydrobenzofuran-4-yl, 5-quinolin-4-yl, 4-chloro-2-methylphenyl, 2-(trifluoromethyl)phenyl, 2,3-dihydrobenzofuran-5-yl, trifluoromethyl-benzonitrile, 2-chloro-3-(1H-imidazol-1-yl)phenyl, 2,4-difluoro-3-methylphenyl, 2,3-dihydro-1H-inden-4-yl, 2,3-dimethylphenyl, 2,5-difluorophenyl, 2,3,4-trifluorophenyl, 3,5-difluorophenyl, 3-fluorophenyl, 1,3-dihydroisobenzofuran-4-yl, 3-chloro-2-(trifluoromethyl)pyridin-4-yl, 2,4-difluoro-3-methoxyphenyl, 3-chloro-2-(trifluoromethyl)phenyl, 3-fluoro-2-methylphenyl, 3-(difluoromethyl)-2-fluorophenyl, 4-(difluoromethyl)-2-fluorophenyl, 2-fluoro-3-methoxyphenyl, quinolinyl, 5-chloro-4-methylpyridin-3-yl, 2-chlorophenyl, 2-fluoro-4-methoxyphenyl, 1-methyl-1H-benzo[d]imidazol-6-yl, 8-fluoroquinolin-5-yl, 3-cyclopropyl-2-fluorophenyl, 8-chloroquinolin-5-yl, 2-(difluoromethyl)-3-fluorophenyl, 2-(difluoromethyl)phenyl, 8-(difluoromethoxy)quinolin-5-yl, 5-(difluoromethyl)-2-fluorophenyl, 2,6-difluorophenyl, 3-fluorobenzonitrile, 2,4,5-trifluorophenyl, 4-chloro-2-fluorophenyl, 3-fluoro-2-(1H-pyrazol-1-yl)phenyl, 2-fluoro-3-(1H-pyrazol-1-yl)phenyl, 2-chloro-3-(2-(difluoromethyl)-1H-imidazol-1-yl)phenyl, 7-fluoro-2-methyl-2H-indazol-6-yl, 4-chloro-2-methyl-2H-indazol-5-yl.

5. The compound of formula (I) as defined in claim 1, which is selected from: -(S)-6-(4'-Amino-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3H)-one; -(S)-1-(5-(2,3-Dichlorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-6-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4(3H)-one; -(S)-1-(5-((3-Fluoro-2-methylpyridin-4-yl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-2-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-(2,3-difluorophenyl)-3-methylpyrimidin-4(3H)-one; -(S)-1-(5-((2,3-dichlorophenyl)thio)-6-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(4-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-(2,3-difluorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(6-(2,3-dichlorophenyl)pyrido[2,3-b]pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-chloro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-1-methylpyridin-2(1H)-one; -(S)-1-(3-(2-fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(3-(2-chloro-3-fluorophenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(3-(3-chloro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(3-(2-chloro-6-fluoro-3-methylphenyl)imidazo[1,5-a]pyrazin-8-yl)-4'H,6'H-spiro[piperidine -4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-dichlorophenyl)thio)-3-methylpyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-(trifluoromethoxy)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-(Trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-Chlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-Fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,4-Dichlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3,4-Dichlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(Phenylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(Pyridin-4-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(o-Tolylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-Isopropylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-Dichlorophenyl)thio)pyrazin-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine; -(S)-1-(5-((2,3-Dichlorophenyl)thio)pyrazin-2-yl)-7'-fluoro-1'H,3'H-spiro[piperidine-4,2'-pyrrolizine]-1'-amine; -(S)-1-(5-((2-Chloro-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(2,3-Dichlorophenyl)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,4-Difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-chloro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-chloro-4-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-chloro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-fluoro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-methoxyquinolin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-dihydrobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(quinolin-4-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-chloro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-dihydrobenzofuran-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-3-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-2-(trifluoromethyl)benzonitrile; -(S)-1-(5-((2-chloro-3-(1H-imidazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,4-difluoro-3-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-dihydro-1H-inden-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-dimethylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,5-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3,4-trifluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3,5-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((1,3-dihydroisobenzofuran-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,3-difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-chloro-2-(trifluoromethyl)pyridin-4-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,4-difluoro-3-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-chloro-2-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-fluoro-2-methylphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-(difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-(difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-fluoro-3-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(quinolin-5-ylthio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((5-chloro-4-methylpyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-chlorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-fluoro-4-methoxyphenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((1-methyl-1H-benzo[d]imidazol-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-5-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)quinoline-8-carbonitrile; -(S)-1-(5-((8-(trifluoromethyl)quinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-fluoroquinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-cyclopropyl-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-chloroquinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-(difluoromethyl)-3-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-(Difluoromethyl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((8-(Difluoromethoxy)quinolin-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((5-(Difluoromethyl)-2-fluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2,6-Difluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-4-((5-(4'-Amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazin-2-yl)thio)-3-fluorobenzonitrile; -(S)-1-(5-((2,4,5-Trifluorophenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(2-Fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-(4-Chloro-2-fluorophenoxy)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((3-Fluoro-2-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-Fluoro-3-(1H-pyrazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((2-Chloro-3-(2-(difluoromethyl)-1H-imidazol-1-yl)phenyl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((7-Fluoro-2-methyl-2H-indazol-6-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; -(S)-1-(5-((4-Chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

6. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as defined in any one of the preceding claims, which is an inhibitor of SHP2, preferably a brain-penetrant inhibitor of SHP2.

7. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as defined in any one of the preceding claims, which is for medical use.

8. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as described in any one of the preceding claims, which is used in the treatment and / or prevention of diseases or disorders mediated by SHP2 activity.

9. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as described in any one of the preceding claims, which is used in the treatment and / or prevention of diseases or disorders selected from the group consisting of: cancer, cardiovascular diseases, immune disorders, autoimmune diseases, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes, neutropenia and combinations thereof.

10. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof for the use as claimed in claim 8 or 9, wherein, the diseases or disorders are selected from the group consisting of: Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, brain cancer and combinations thereof.

11. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof for the use as claimed in claim 9 or 10, wherein, the cancer is primary cancer or cancer metastasis.

12. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof for the use as claimed in any one of claims 8-11, wherein, the use is in combination with radiotherapy or in combination with at least one additional therapeutic agent, preferably, the at least one additional therapeutic agent is selected from the group consisting of: (a) alkylating agents, which are preferably selected from carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa and cyclophosphamide (ENDOXAN); (b) antimetabolites, which are preferably selected from cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytarabine (ara-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX) and raltitrexed; (c) Antimitotic agents, which are generally plant alkaloids and terpenoids or their derivatives, preferably selected from taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE) and vinflunine; (d) Checkpoint inhibitors such as the anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 and MPDL3280A; the anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T cell immunoglobulin and mucin domain-containing protein-3) and / or OX40 (tumor necrosis factor receptor superfamily member 4); (e) Topoisomerase inhibitors, preferably selected from camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON) and etoposide (EPOSIN); (f) Cytotoxic antibiotics, preferably selected from actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) Aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR) and exemestane (AROMASIN); (g) Angiogenesis inhibitors, preferably selected from genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN); (h) Anti-steroids and anti-androgens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN) and nilutamide (NILANDRON); (i) Tyrosine kinase inhibitors, preferably selected from imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR) and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL) and sirolimus; (12) Monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) Other agents such as amsacrine; Bacillus Calmette-Guérin (B-C-G) vaccine; buserelin; chloroquine; clodronate, pamidronate and other bisphosphonates; colchicine; demecolcine; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; folinic acid; leuprorelin (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer sodium (especially in combination with phototherapy and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES) and dienestrol; progesterones such as medroxyprogesterone acetate (MPA) and megestrol acetate; testosterone; 5-fluoro-2,4(1H,3H)-pyrimidinedione and combinations thereof.

13. A pharmaceutical composition comprising a compound as defined in any one of claims 1-5 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, alone or in combination with at least one additional therapeutic agent, and at least one pharmaceutically acceptable excipient, preferably said at least one additional therapeutic agent being selected from the group consisting of: (a) Alkylating agents, preferably selected from carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa and cyclophosphamide (ENDOXAN); (b) Antimetabolites, preferably selected from cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytarabine (ara-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), folinic acid (FUSILEV), methotrexate (RHEUMATREX) and raltitrexed; (c) Antimitotic agents, which are usually plant alkaloids and terpenoids or their derivatives, preferably selected from taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE) and vinflunine; (d) Checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); inhibitors targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T cell immunoglobulin and mucin domain-containing protein-3), and / or OX40 (tumor necrosis factor receptor superfamily member 4); (e) Topoisomerase inhibitors, which are preferably selected from camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN); (f) Cytotoxic antibiotics, which are preferably selected from actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) Aromatase inhibitors, which are preferably selected from aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR), and exemestane (AROMASIN); (g) Angiogenesis inhibitors, which are preferably selected from genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); (h) Anti-steroids and anti-androgens, such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), and nilutamide (NILANDRON); (i) Tyrosine kinase inhibitors, which are preferably selected from imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors, such as everolimus, temsirolimus (TORISEL), and sirolimus; (12) Monoclonal antibodies, such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) Other agents such as aclarubicin; Bacillus Calmette-Guérin (B-C-G) vaccine; buserelin; chloroquine; clodronate, pamidronate and other bisphosphonates; colchicine; demecolcine; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; folinic acid; leuprorelin (LUPRON); levamisole; lonidamine; mesna; metformin; mitotane (o,p'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer sodium (especially when used in combination with phototherapy and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); oestrogens such as oestradiol, diethylstilbestrol (DES) and dienestrol; progestogens such as medroxyprogesterone acetate (MPA) and megestrol acetate; testosterone; 5-fluoro-2,4(1H,3H)-pyrimidinedione and combinations thereof.

14. The pharmaceutical composition according to claim 13 for use in an application as defined in any one of claims 8 to 11.

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