For example, (S)-1-(5-((pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine derivatives and similar compounds as SHP2 inhibitors for cancer treatment.

Abstract

The present invention relates to compounds of formula (I). Compounds of formula (I) are, for example, (S)-1-(5-((pyridin-3-yl)thio)pyrazin-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine derivatives and similar compounds. The present invention also relates to compounds of formula (I) for use as Src homology phosphotyrosine phosphatase 2 (SHP2) inhibitors, for example in methods of treating cancer, cardiovascular disease, immunological disorders, autoimmune disorders, fibrosis, eye disorders, systemic lupus erythematosus, diabetes, neutropenia, and combinations thereof. The present invention also relates to pharmaceutical compositions containing said compounds and methods of synthesis thereof. JPEG2024512740000201.jpg42170

Description

[Technical Field]

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

[0002] Src homology phosphotyrosine phosphatase 2 (SHP2), encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) consisting of a C-terminal domain, a PTP domain, and two N-terminal Src homology (N-SH2) domains, contributing to multiple cellular functions including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is a positive downstream regulator of signaling for several receptor tyrosine kinases via the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol-3-kinase-AKT pathway. The protein exists in an inactive, self-inhibitory conformation stabilized by a binding network containing residues from both the N-SH2 domain and the catalytic PTP domain. Recruitment of SHP2 to an activating receptor releases the self-inhibitory conformation, resulting in catalytic activation of its phosphatase domain. In addition to its function as a phosphatase, SHP2 also acts as a docking protein for recruiting other signaling intermediates via its two amino-terminal N-SH2 domains. Since SHP2 is a positive regulator of cell signaling that leads to proliferation, differentiation, and survival, its constitutive activation is associated with carcinogenesis.

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

[0004] Both academic institutions and pharmaceutical companies have disclosed drug discovery programs that utilize SHP2 inhibitors based on various heterocyclic scaffolds.

[0005] WO2015 / 107493, WO2015 / 107494, and WO2015 / 107495 by Novartis are based on the general formula (A) shown below.

[0006] [ka]

[0007] The following compounds are disclosed.

[0008] Furthermore, Novartis has established the following general structures (B), (C), (D), and (E)

[0009] [ka]

[0010] The compounds are disclosed in WO2016 / 203404, WO2016 / 203405, and WO2017 / 216706, respectively.

[0011] The general 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.

[0012] Jacobio Pharmaceuticals has the following structures (F) and (G)

[0013] [ka]

[0014] Pyrazine derivatives of were disclosed in WO2017 / 211303 and WO2018 / 172984.

[0015] Further pyridine, pyrazine, and triazine compounds as allosteric SHP2 inhibitors have recently been disclosed by Revolution Medicines in WO2018 / 013597, WO2018 / 136264, and WO2019 / 075265.

[0016] Both WO2018 / 136265 and WO2019 / 118909 are general structure (H)

[0017] [ka]

[0018] This relates to bicyclic heteroaromatic scaffolds containing imidazopyrazine, triazolopyrazine, pyrazolopyridine, and imidazopyrimidine.

[0019] Pyrazolopyrazine and fused pyrimidine-4-one were disclosed by the Board of Directors of the University of Texas System in WO2017 / 210134 and WO2017 / 156397, respectively.

[0020] Pyrazolopyrazine was further disclosed by Relay Therapeutics in WO2018 / 081091, WO2018 / 218133, WO2018 / 057884 and WO2019 / 067843.

[0021] The imidazopyrimidines listed below are disclosed by Gilead in WO2020 / 072656:

[0022] [ka]

[0023] Therefore, SHP2 represents a very attractive target for the development of novel therapeutics for the treatment of various diseases involving SHP2. Thus, there is a need for the development of novel therapeutic agents that act as SHP2 inhibitors. The compounds of the present invention satisfy this need because they are small molecules with the ability to inhibit the activity of SHP2.

[0024] Many of the compounds disclosed in the cited patents and patent documents have the following general structure

[0025] [ka]

[0026] (In the formula, the C ring is either an aromatic or heteroaromatic ring.) It shares a heterocyclic core that is substituted with a tricyclic amine having the following properties:

[0027] Unexpectedly, the introduction of a suitable azole ring, such as pyrazole, imidazole, or triazole, with a single nitrogen atom at the left-hand bridgehead of the molecule combined with a central heterocyclic core and specific selection of substituents, enabled the identification of potent and selective SHP2 inhibitors, conferring superior pharmacokinetics in preclinical animal species and exhibiting significant plasma exposure after oral administration (both in terms of Cmax and AUC). Furthermore, the presence of either substituted or unsubstituted pyrazole moieties influenced ligand-biological target kinetics, significantly extending the residence time of SHP2 inhibitors (the time the ligand spends in contact with its biological target) by reducing koff. [Prior art documents] [Patent Documents]

[0028] [Patent Document 1] WO2015 / 107493 [Patent Document 2] WO2015 / 107494 [Patent Document 3] WO2015 / 107495 [Patent Document 4] WO2016 / 203404 [Patent Document 5] WO2016 / 203405 [Patent Document 6] WO2017 / 216706 [Patent Document 7] WO2017 / 211303 [Patent Document 8] WO2018 / 172984 [Patent Document 9] WO2018 / 013597 [Patent Document 10] WO2018 / 136264 [Patent Document 11] WO2019 / 075265 [Patent Document 12] WO2018 / 136265 [Patent Document 13] WO2019 / 118909 [Patent Document 14] WO2017 / 210134 [Patent Document 15] WO2017 / 156397 [Patent Document 16] WO2018 / 081091 [Patent Document 17] WO2018 / 218133 [Patent Document 18] WO2018 / 057884 [Patent Document 19] WO2019 / 067843 [Patent Document 20] WO2020 / 072656 [Non-patent literature]

[0029] [Non-Patent Document 1] EL Eliel and SH Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190. [Non-Patent Document 2] Berg et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977:66:1~19 [Non-licensed Document 3] T. Matozaki, Y. Murata, Y. Saito, H. Okazawa, H. Ohnishi, Cancer Sci, 100(2009), pages 1786~1793 [Non-licensed Document 4] YN Chen, MJ LaMarche, HM Chan, P. Fekkes, J. Garcia-Fortanet, MG Acker, etc., Nature, 535(2016), pages 148~152 [Non-licensed Document 5] S. Mainardi, A. Mulero-Sanchez, A. Prahallad, G. Germano, A. Bosma, P. Krimpenfort, et al., Nat Med, 24(2018), pages 961~9 [Non-licensed Document 6] DA Ruess, GJ Heynen, KJ Ciecielski, J. Ai, A. Berninger, D. Kabacaoglu, et al., Nat Med, 24(2018), pages 954~960 [Non-licensed Document 7] GS Wong, J. Zhou, JB Liu, Z. Wu, X. Xu, T. Li, et al., Nat Med, 24(2018), pages 968~977 [Non-licensed Document 8] M. Tajan, A. de Rocca Serra, P. Valet, T. Edouard, A. Yart, Eur J Med Genet, 58(2015), pages 509~525 [Non-licensed Document 9] RJ Salmond, DR Alexander, Trends Immunol, 27(2006), pages 154~160) [Non-licensed Document 10] W. Liu, W. Guo, L. Shen, Z. Chen, Q. Luo, X. Luo et al., Oncotarget, 8(2017), pp. 7586-7597 [Non-Patent Document 11] Bagdanoff et al., J. Med. Chem. 2019, 62, 1781~1792 [Non-Patent Document 12] T. Greene and PGM Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991 [Non-Patent Document 13] YP Chen et al., Nature(535)2016 [Overview of the Initiative] [Problems that the invention aims to solve]

[0030] The present invention relates to heterocyclic compounds that are useful as SHP2 inhibitors and for treating conditions mediated by SHP2.

[0031] The inventors have found that a compound having a general formula including a five-membered condensed heteroaromatic ring having a specific nitrogen pattern on the left side of the molecule exhibits enzyme IC50 for SHP2 inhibition in the low nanomolar or low micromolar range. 50 Values ​​and Cell IC 50 As is evident from both values, it was found to act as a particularly potent SHP2 inhibitor. More specifically, the compounds of the present invention are characterized by a suitable azole ring, such as pyrazole, imidazole, or triazole, in which one nitrogen is located at the left-hand bridgehead position of the molecule, combined with a central heterocyclic core and a particular selection of substituents.

[0032] Therefore, the objective of the present invention is the general formula (I):

[0033] [ka]

[0034] [In the formula, X1 is CR1 or N, X2 is CR2 or N, X3 is CR3 or N, and at least one of X1, X2 and X3 is N, R1, R2 and R3 are each H, halogen, OC 1~3 alkyl, or optionally substituted with NH2, OH or halogen C 1~3 alkyl, or optionally selected from R1 and R2 together with the carbon atom to which they are attached form a fused 5-, 6- or 7-membered saturated or partially unsaturated ring optionally containing one or two heteroatoms selected from O, S and N, and are optionally substituted at each occurrence with one or more substituents selected from halogen, OH, NH2, OCH3, C 1~3 alkyl, or optionally R2 and R3 together with the carbon atom to which they are attached form a fused 5-, 6- or 7-membered saturated or partially unsaturated ring optionally containing one or two heteroatoms selected from O, S and N, and are optionally substituted at each occurrence with halogen, OH, NH2, OCH 3、 C 1~3 alkyl, or optionally substituted with one or more substituents selected from X4 is CR5R6, O, S, or X4 is a bond, R4 is aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaryl ring, and said aryl, heteroaryl, partially unsaturated aryl, partially unsaturated heteroaryl ring are each C(O)CH3, C(O)OCH3, OH, halogen, NH2, NH-C 1~6 alkyl, N(C 1~6 alkyl)2, C 1~6 alkyl, C 3~5 cycloalkyl, haloC 1~6 alkyl, hydroxyC 1~6 alkyl, CONR'R'', CN, haloC 1~6 alkoxy, C 1~6The molecule is optionally substituted with one or more substituents independently selected from alkoxy, saturated 5- or 6-membered heterocyclic rings, aryl, or heteroaryl rings, wherein each saturated 5- or 6-membered heterocyclic ring, aryl, or heteroaryl ring is optionally substituted with one or more CH3, NH2, halogen, or OH groups, and R' and R'' are independently H or C groups. 1~6 Alkyl, preferably H or CH3, R5 and R6 are independently H and C 1~6 Selected from alkyl, OH, and halogen, Cy-X4-R4 is represented by the following general formulas (A) to (M)

[0035] [ka]

[0036] (In the formula, - R7 is H, C 1~3 From alkyl and NH2, preferably selected from H, CH3 and NH2, - R8 is H, halogen, C 1~3 Alkyl, and the C 1~3 The alkyl group is optionally substituted with one or more halogens or OH groups. - R9, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 18 , R 21 and R 26 Each instance of appearance is independently determined by H, halogen, and C. 1~6 Alkyl or Halo C 1~6 Selected from alkyl groups, - R 12 , R 17 , R 19 and R 20 It is selected from H and CH3, - R 23 and R 27 H and C are independent of each other. 1~6 Alkyl and hydroxy C 1~6 Selected from alkyl groups, - R 24 H, C 1~6 Alkyl, Halo C 1~6 It is an alkyl or halogen, - R 25 H, halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl or hydroxy C 1~6 It is alkyl, - Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are each independently selected from N and C. [corresponds to one of the following] The compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0037] A further objective of the present invention is, X1 is CR1, X2 is CR2, and X3 is CR3. R1, R2, R3, R4 and X4 are as defined above. Cy-X4-R4 is given by the following general formulas (A')~(M),

[0038] [ka]

[0039] (In the formula, - R7 is H, C 1~3 From alkyl and NH2, preferably selected from H, CH3 and NH2, - R8 is H, halogen, C 1~3 Alkyl, and the C 1~3 The alkyl group is optionally substituted with one or more halogens or OH groups. - R9, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 18 , R 21 and R 26 Each instance of appearance is independently determined by H, halogen, and C. 1~6 Alkyl or Halo C 1~6Selected from alkyl groups, - R 12 , R 17 , R 19 and R 20 It is selected from H and CH3, - R 23 and R 27 H and C are independent of each other. 1~6 Alkyl and hydroxy C 1~6 Selected from alkyl groups, - R 24 H, C 1~6 Alkyl, Halo C 1~6 It is an alkyl or halogen, - R 25 H, halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl or hydroxy C 1~6 It is alkyl, - R 28 is H, halogen or C 1~3 It is alkyl, R 29 It is a heteroaryl, - Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are each independently selected from N and C. A compound of general formula (I) corresponding to any of the above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0040] In a preferred embodiment, the compound of formula (I) described in claim 1 is a compound of general formula (IA), (IB), (IC), or (ID)

[0041] [ka]

[0042] It is a compound of [the compound].

[0043] Preferably, in compounds of general formula (IA), (IB), (IC), or (ID), R1, R2, and R3 are each independently selected from H, Br, Cl, F, CH3, OCH3, and CH2OH, or R2 and R3 together form a condensed ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, and tetrahydropyrrole.

[0044] Preferably, the compound of formula (IA) has the general structure shown below.

[0045] [ka]

[0046] Take one of them.

[0047] Preferably, the compound of formula (IB) has the general structure shown below.

[0048] [ka]

[0049] Take one of them.

[0050] Preferably, the compound of formula (IC) has the general structure shown below.

[0051] [ka]

[0052] Take one of them.

[0053] Preferably, the compound of formula (ID) has the general structure shown below.

[0054] [ka]

[0055] It has.

[0056] The present invention further includes Cy-X4-R4

[0057] [ka]

[0058] The present invention provides compounds of formula (I) as defined above, selected from the above.

[0059] Preferably, X4 is S, more preferably X4 is a bond, and even more preferably X4 is O.

[0060] Preferably, R4 is selected from phenyl, pyridine, pyrimidine, pyrazine, 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, and imidazo[1,2-a]pyridine-2(3H)-one, where the rings are each C(=O)CH3, C(=O)OCH3, OH, halogen, NH2, CF3, C(=O)CH3, C 1~3 Alkyl, C(=O)NH2, C(=O)NHC 1~3 Alkyl, C(=O)N(C 1~3 Alkyl)2, CN, C 3~5 The molecule is optionally substituted with one or more substituents independently selected from cycloalkyl, aryl, or heteroaryl groups, where each aryl or heteroaryl group is one or more halogens, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2, C 1~3 Alkyl and NHC(=O)CF3 are optionally substituted.

[0061] Preferably, R4 is 2-(trifluoromethyl)pyridine-3-yl, 2-amino-3-chloropyridine-4-yl, (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-yl, 4-chloro-2-methyl-2H-indazole-5-yl, (R)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl, 3,3-difluoroindoline-1-ylethane-1-one, 8- Loroimidazo[1,2-a]pyridine-7-yl, 3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl, 3-chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)pyridine-4-yl, 2,3-dichlorophenyl, 8-chloro-2-methylimidazo[1,2-a]pyridine-7-yl, 8-chloro-2-cyanoimidazo[1,2-a]pyridine-7-yl, 5-chloroimidazo[1,2-a]pyridine-6-yl, 6-amino-2-chloropyridine-3-yl, 3-chloro-2-(1H-pyrrole-1-yl)pyridine-4 -yl, 3-chloro-2-(4-fluoro-1H-pyrazole-1-yl)pyridine-4-yl, 3-chloro-2-(1H-imidazole-1-yl)pyridine-4-yl, 5-amino-3-chloropyrazine-2-yl, 3,8-dichloroimidazo[1,2-a]pyridine-7-yl, 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-yl, 8-chloro-3-nitroimidazo[1,2-a]pyridine-7-yl, 8-chloroimidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide, 8-chloroimidazo [1,2-a]pyridine-2-carboxamide, 8-chloroimidazo[1,2-a]pyridine-2-carbonitrile, 8-chloroimidazo[1,2-a]pyridine-2(3H)-one, 3-chloropyridine-2-yl)-1H-pyrazole-4-carboxamide, 3-chloropyridine-2-yl)-1H-pyrrole-3-carboxamide, 3-chloropyridine-2-yl)-N-methyl-1H-pyrrole-3-carboxamide, 8-chloro-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide, 3-chloropyridine-2-yl)-N,Selected from the group consisting of N-dimethyl-1H-pyrazole-4-carboxamide and 8-fluoroquinoline-4-yl.

[0062] Even more comfortable, the R4

[0063] [ka]

[0064] It is one of them.

[0065] A further objective of the present invention is, - (S)-1-(5-((2-((trifluoromethyl))pyridine-3-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((2-((trifluoromethyl))pyridine-3-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - 1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-ol; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((R)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)imidazo[1,5a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(4-((3-amino-5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-yl)thio)-3,3-difluoroindoline-1-yl)ethane-1-one; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,8-dihydro-3H,6H-spiro[fl[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-(4'-amino-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-2',3'-diyl)dimethanol; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,8-dihydro-3H,6H-spiro[flo[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2-amino-3-chloropyridine-4-yl)thio)pyridazin-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((2-((trifluoromethyl))pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(3-(2-amino-3-chloropyridine-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-7'-amine; - (S)-1-(5-((8-chloro-2-methylimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-(6-((2-amino-3-chloropyridine-4-yl)thio)-3-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methylpyrazine-2-yl)methanol; - (S)-3-(2-amino-3-chloropyridine-4-yl)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methyl-1,5-dihydro-4H-pyrzolo[3,4-d]pyrimidine-4-one; - (S)-1-(5-((5-amino-3-chloropyrazine-2-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxamide; - (S)-1-(5-((6-amino-2-chloropyridine-3-yl)thio)pyrazine-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]pyridine-6-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carbonitride; - (S)-7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2(3H)-one; - (S)-1-(5-((3-chloro-2-(1H-imidazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrrole-1-yl)pyridine-4-yl)thio)pyrazine-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-imidazole-1-yl)pyridine-4-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-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)pyrazine-2-yl)thio)-3-chloropyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide; - (S)-1-(3-(4-chloro-2-methyl-2H-indazole-5-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrido[2,3-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2-amino-3-chloropyridine-4-yl)thio)pyrido[2,3-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)-1-methyl-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-5-((2-amino-3-chloropyridine-4-yl)thio)-2-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-methylpyrimidine-4(3H)-one; - (S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-chloro-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (S)-1-(5-((8-fluoroquinoline-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-fluoro-2-methylpyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1'-amine; - (S)-1-(5-((2,3-dichlorophenyl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2,3-dichlorophenyl)thio)pyridine-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-6-(1'-amino-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (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-dimethylpyrimidine-4(3H)-one; - (S)-1-(3-(3-fluoro-2-methylpyridine-4-yl)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-(2,3-dichlorophenoxy)pyridine-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; A compound of formula (I) defined above, selected from the group consisting of the above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0066] Compounds that are (S)-1-(5-((3-fluoro-2-methylpyridine-4-yl)thio)pyrazine-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1'-amine or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are also within the scope of the present invention.

[0067] Equation (I*)

[0068] [ka]

[0069] (In the formula, X1, X2, X3, X4, Cy, and R4 are as defined above.) The compounds are also within the scope of the present invention.

[0070] More preferably, the compound has the following stereochemistry

[0071] [ka]

[0072] It has.

[0073] The compounds of the present invention can be used in the form of prodrugs. A prodrug may be a pharmacologically inactive derivative of a biologically active substance ("parent drug" or "parent molecule," i.e., the compound of the present invention) that requires transformation in the body to release an active drug and has improved delivery properties than the parent drug molecule. In vivo transformation may be the result of certain metabolic processes, such as chemical or enzymatic hydrolysis of carboxylic acids, phosphoric acids, or sulfate esters, or reduction or oxidation of sensitive functional groups.

[0074] The present invention also includes all suitable isotopic variants of the compounds of the present invention. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, 2 H, 3 H, 13 C, 14 C,15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 isotopes such as F and 36 Cl are included. Certain isotope variants of the present disclosure, for example 3 radioisotopes such as H or 14 C incorporated therein are useful for drug and / or substrate tissue distribution studies. Further, substitution with isotopes such as deuterium 2 H can provide certain therapeutic advantages resulting from better metabolic stability. Isotope variants of the compounds of the present invention can generally be prepared by conventional procedures, such as by using appropriate isotope variants of suitable reagents, according to the exemplary methods and preparations described in the following description and examples.

[0075] The present invention includes within its scope compounds of formula (I) or relative salts, such as hydrates, alcoholates and solvates of the same.

[0076] The compounds disclosed herein may exist in various 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 its possible resonance forms.

[0077] 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, pages 1119-1190), and occur as racemates, racemic mixtures as well as individual diastereomers, together with all possible isomers and mixtures thereof, including optical isomers and atropisomers, and 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.

[0078] Atropisomers are stereoisomers resulting from rotational hindrance around a single bond, and compounds 77, 77a, 77b, 78, 78a, and 78b are specific examples of atropisomers according to the present invention.

[0079] The pure stereoisomer forms of the compounds and intermediates of the present invention can be obtained by applying procedures known in the art and are intended to be included within the scope of the present invention. More specifically, “pure stereoisomer form” or “stereoisomerically pure” refers to a compound having at least 80%, preferably at least 85%, of stereoisomer excess. For example, enantiomers can be separated from each other by selective crystallization of their diastereomer salts or by chromatographic techniques using a chiral stationary phase. Pure stereoisomer forms can also be derived from the corresponding pure stereoisomer forms of suitable starting materials, provided that the reaction occurs stereospecifically. The term “enantiomerically pure” shall be similarly interpreted, taking into account the enantiomer ratio.

[0080] If any variable (e.g., R1 and R2) appears more than once in any component, its definition at each appearance is independent of all other appearances. Furthermore, a combination of substituents and variables is only permissible if such a combination results in a stable compound. Lines drawn from substituents into the ring system indicate that the indicated bond can be bonded to any of the substitutable ring atoms. If the ring system is polycyclic, the bond is intended to be bonded to any of the suitable carbon atoms in adjacent rings only.

[0081] It will be understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by known art and by the methods described below. If the substituent itself is substituted with more than one group, it will be understood that these groups may be on the same carbon element or on different carbons, as long as a stable structure is formed. The phrase "optionally substituted" should be interpreted as equivalent to the phrase "not substituted or substituted with one or more substituents," in which case preferred embodiments have 0 to 3 substituents. More specifically, 0 to 2 substituents.

[0082] The expression "one or more substituents" specifically refers to one, two, three, four or more substituents, specifically one, two, three, or four substituents, and more specifically one, two, or three substituents.

[0083] As used herein, "X4 is a bond" indicates that in general formula (I), Cy is directly linked to R4 via a single bond.

[0084] As used herein, “alkyl” is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, “C 1~6 "Alkyl" is defined as a group having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, etc. Preferably, "C 1~6 "Alkyl" is "C 1~4 "Alkyl" or "C 1~3 It refers to "alkyl". 1~4 "Alkyl" is defined as a group containing one, two, three, or four carbon atoms in a linear or branched configuration. For example, "C 1~4 "Alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, etc. 1~3"Alkyl" is defined as a group containing one, two, or three carbon atoms in a linear or branched configuration. For example, "C 1~3 "Alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, etc. Preferred alkyl groups are methyl, ethyl, i-propyl, t-butyl, or i-butyl.

[0085] As used herein, “alkoxy” refers to an alkyl group of the indicated number of carbon atoms linked via oxygen crosslinking. Therefore, “alkoxy” encompasses the above definition of alkyl. 1~6 The alkoxy group is preferably a linear or branched C 1~4 Alkoxy group, more preferably C 1~3 Alkoxy group, more preferably C 1~2 It is an alkoxy group. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, or t-butoxy. Preferred alkoxy groups include methoxy, ethoxy, and t-butoxy.

[0086] The term "halo C" is used in this specification. 1~6 Alkyl," "Halo C" 1~6 "alkoxy" and "C 1~6 Variants such as "haloalkyl" are C1 1~6 Alkyl or C 1~6 This refers to an alkoxy group. 1~6 The alkoxy group is preferably a linear or branched halo C. 1~4 Alkoxy group, more preferably halo C 1~3 Alkoxy group, more preferably halo C 1~2 Alkoxy groups, such as OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2, or OCH2CF3, most notably OCF3 or OCHF2. Halo C 1~6 The alkyl group is preferably a linear or branched halo C. 1~3 Alkyl alkyl groups, more preferably halo C 1~2Alkyl groups, such as CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, or CH(CH3)CF3, most notably CF3, CHF2, or CH(CH3)CF3.

[0087] As used herein, the terms “aryl” or “aromatic ring” mean a monocyclic or polycyclic aromatic ring containing carbon and hydrogen atoms. If necessary, such an aromatic ring may also be referred to in this context as a “heteroaryl” or “heteroaromatic ring,” and may contain one or more heteroatoms, preferably 1 to 3, independently selected from nitrogen, oxygen, and sulfur, preferably nitrogen. As is well known to those skilled in the art, heteroaryl rings have a lower aromaticity than their total carbon counterpart. Therefore, for the purposes of the present invention, the heteroaryl group only needs to have some degree of aromaticity. Preferably, the ring components of the aryl or heteroaryl group contain 5 or 6 members (i.e., atoms). More preferably, the aryl or heteroaryl group is a polycyclic aromatic ring. An exemplary example of an aryl group is optionally substituted phenyl. Exemplary examples of heteroaryl groups according to the present invention include optionally substituted thiophene, oxazole, thiazole, thiadiazole, imidazole, pyrazole, pyrimidine, pyrazine, pyridine, and pyridine N-oxide. Therefore, examples of monocyclic aryl groups containing one or more heteroatoms, for example, one or two heteroatoms at will, include, but are not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxadiazolyl, and oxazolyl, as well as any 5 or 6-membered aryl or heteroaryl group.Examples of polycyclic aromatic rings containing one or more heteroatoms, for example, one or two heteroatoms at will, include, but are not limited to, 8- to 10-membered aryl or heteroaryl groups such as benzimidazolyl, benzofranyl, benzofuranyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzoisoxazolyl, benzoisothiazolyl, indolyl, indolinyl, indolidinyl, indazolyl, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolyl, quinazolinyl, quinolyl, quinoxalinyl, quinolidinyl, naphthyl, naphthylidinyl, 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-d]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, 1,5-naphthyridine, and 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.

[0088] Expressions: "Aryl substitution by choice", "Heteroaryl substitution by choice", "Aryloxy substitution by choice", "Heteroaryl-C substitution by choice" 1~6 "Alkyl", "Optionally substituted heteroaryl-C" 1~6 "Alkoxy" collectively refers to aryl, heteroaryl, or aryloxy groups in which an aromatic or heteroaromatic ring may be substituted with one or more substituents. Examples of such substituents include alkyl, alkoxy, amino, trifluoromethyl, aryl, heteroaryl, hydroxyl, carboxyalkyl, and similar groups.

[0089] The aryl or heteroaryl ring can also have a partially unsaturated structure and can therefore be derived from partially hydrogenated analogs of the aryl or heteroaryl groups listed above, but can also be derived from aryl or heteroaryl rings fused with a cycloalkyl or heterocycloalkyl ring. The ring may also contain a group selected from SO, SO2 and C=O. Examples of the partially unsaturated aryl or heteroaryl derivatives include 2,3-dihydro-1H-indene, 2,3-dihydro-1H-indene-1-one, 2,3-dihydroisoindole-1-one, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, isoindoline, 1-methylindole-2-one, dihydroquinazoline, dihydroquinoxaline, 2,3-dihydrobenzofuran, benzo[d [1,3]dioxol, 1,3-dihydroisobenzofuran, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, 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'-dihydrospi Ro[azetidine-3,5'-pyrrolo[1,2-a]imidazole], 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d]oxazole-2(3H)-one, 2H-benzo[b][1,4]oxazine-3(4H)-one, indorin-2-one, 1,2,3,4-tetrahydro-1,5-naphthiridine, 3',4'-dihydro-2'H-spiro[azetidine-3,1'-pyrrolo[1,2-a]pyrazine], 3,4-dihydroquinoli Examples include n-2(1H)-one, 4-methyl-2H-benzo[b][1,4]oxazine-3(4H)-one, quinoxaline-2(1H)-one, 4H-pyrido[1,2-a]pyrimidine-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-naphthyridine-1-yl, dihydrofl[2,3-b]pyridinyl, and similar compounds.

[0090] It should be noted that various heterocyclic isomers may exist within the definitions used throughout this specification. For example, pyrrolyl may be lH-pyrrolyl or 2H-pyrrolyl.

[0091] It should also be noted that the position of a group on any molecular part used in the definition can be anywhere on such part, as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl.

[0092] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine, of which fluorine, chlorine, and bromine are preferred.

[0093] The term "heteroatom" refers to an atom other than carbon or hydrogen in a ring structure or saturated skeleton as defined herein. Typical heteroatoms include N(H), O, and S.

[0094] The expression "C" used in this specification 1~6 Alkyl-NH2", C 1~6 Alkyl-NH(CH3)", C 1~6 Alkyl-N(CH3)2", C 1~6 "Alkyl-NHCOCH3" is defined as a molecule in which one hydrogen atom is substituted with a group of the formula NH2, NH(CH3), N(CH3)2, or NHCOCH3, respectively, and C 1~6 Refers to alkyl. Preferably the "C 1~6 "Alkyl-" is "C 1~3 It is "alkyl-" and therefore includes alkyl groups of 1, 2, or 3 carbon atoms.

[0095] The expression "NH-C" used in this specification 1~6 Alkyl," "N(C) 1~6 "Alkyl)2" means that one of the two hydrogen atoms is C 1~6 This refers to an amino substituent substituted with an alkyl chain.

[0096] As used herein, the term “saturated five- or six-membered heterocyclic ring” refers to a saturated five- or six-membered ring containing at least one heteroatom selected from S, N, or O, preferably N. Examples of such saturated five- or six-membered heterocyclic rings include pyrrolidine, piperidine, morpholine, piperazine, tetrahydrofuran, tetrahydropyran, and similar rings.

[0097] The present invention includes compounds of formula (I) and any of formulas (II) to (VI), as well as their pharmaceutically acceptable salts and free bases of stereoisomers. Some of the specific compounds illustrated herein are protonated salts of amine compounds. Compounds containing one or more N atoms can be protonated with any one, some, or all of the N atoms. The term “free base” refers to the unsalted form of the amine compound. The pharmaceutically acceptable salts included include not only the salts illustrated for the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula (I). The free forms of the specific salt compounds described can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous solution of a base such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but the acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the present invention.

[0098] pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric amount or excess amount of a desired salt-forming inorganic or organic acid in a suitable solvent or a variety of solvent combinations. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base. In preferred embodiments, the compounds of the present invention have at least one acidic proton, and the corresponding sodium or potassium salt can be formed, for example, by reaction with a suitable base.

[0099] Therefore, 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 a basic compound with an inorganic or organic acid, or an acidic compound with an inorganic or organic base. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as 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, and the like. Conventional non-toxic salts include those derived from inorganic bases such as potassium, sodium hydroxide, magnesium, or calcium hydroxide, and salts prepared from organic bases such as ethylenediamine, lysine, tromethamine, meglumine, and the like. Preferably, the pharmaceutically acceptable salts of the present invention contain one equivalent of the compound of formula (I) and one, two, or three equivalents of an inorganic or organic acid or base. More specifically, the pharmaceutically acceptable salts of the present invention are tartrates, trifluoroacetates, or chloride salts.

[0100] When the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base, including inorganic and organic bases. Examples of salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc, and the like. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and arginine, betaine, caffeine, choline, N,N 1 Examples of basic ion exchange resins include dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine, and similar materials.

[0101] The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is more fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1~19.

[0102] Under physiological conditions, the deprotonated acidic portion of a compound, such as a carboxyl group, may be anionic. In this case, the electron charge of this anionic portion may lose its internal balance with the cationic charge of a protonated or alkylated basic portion, such as a quaternary nitrogen atom. Therefore, it should be noted that the compounds of the present invention may potentially be internal salts or zwitterions.

[0103] Preferably, the compounds of the present invention, including salts, stereoisomers, and solvates thereof, are SHP2 inhibitors, meaning, for example, that they can inhibit the activity or function of SHP2. In this case, the present invention relates to compounds for use as inhibitors of at least one SHP2 function, and to a method for inhibiting at least one SHP2 function, comprising the step of contacting SHP2 with the compounds described herein.

[0104] "SHP2" stands for "Src homology-2-phosphatase" and is also known as SH-PTP2, SH-PTP3, Syp, PTPID, PTP2C, SAP-2, or PTPN11.

[0105] The functions of SHP2 are diverse, as it is involved in multiple signaling processes, including the RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways. SHP2 primarily regulates cancer cell survival and proliferation by activating the RAS-ERK signaling 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 a positive regulator upstream, promoting signaling in the RAS-RAF-ERK kinase cascade. Therefore, SHP2 inhibition leads to dephosphorylation of ERK and suppression of the oncogenic function of the RAS-RAF-ERK pathway, resulting in inhibited cell growth and induction of apoptosis in cancer cells. Recently, Chen et al. (YN Chen, MJ LaMarche, HM Chan, P. Fekkes, J. Garcia-Fortanet, MG Acker et al., Nature, 535 (2016), pp. 148-152) found that cancer cell lines sensitive to SHP2 depletion are also sensitive to EGFR depletion, thus confirming the report that RTK-driven cancer cells depend on SHP2 for survival. Furthermore, recent studies have shown that SHP2 is required for the growth of mutant KRAS-driven cancers, and that wild-type KRAS-amplified gastroesophageal cancer can be controlled through a combination of SHP2 and MEK inhibition (S. Mainardi, A. Mulero-Sanchez, A. Prahallad, G. Germano, A. Bosma, P. Krimpenfort et al., Nat Med, 24 (2018), pp. 961-969; DA Ruess, GJ Heynen, KJ Ciecielski, J. Ai, A. Berninger, D. Kabacaoglu et al., Nat Med, 24 (2018), pp. 954-960; GS Wong, J. Zhou, JB Liu, Z. Wu, X. Xu, T. Li et al., Nat Med, 24 (2018), pp. 968-977).As a downstream target of several receptors, SHP2 is also involved in T cell signaling (M. Tajan, A. de Rocca Serra, P. Valet, T. Edouard, A. Yart, Eur J Med Genet, 58 (2015), pp. 509-525; RJ Salmond, DR Alexander, Trends Immunol, 27 (2006), pp. 154-160). It is a downstream molecule of the PD-1 signaling pathway that not only suppresses T cell activation but also induces T cell anergy. SHP2 deficiency in T cells triggered an antitumor 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). Therefore, targeting SHP2 may restore or even improve T cell function.

[0106] SHP2 inhibition can be evaluated or measured by cellular phenotypes (e.g., proliferation and resistance phenotypes to EGFR and c-MET co-inhibition, mesenchymal phenotypes in BTBC cells), and cell proliferation, SHP2 activity, changes in biochemical consequences caused by active SHP2, SHP2 expression, or binding of SHP2 to its native binding partner can be monitored as measures of SHP2 inhibition. More specifically, inhibition of SHP2 activity or function can be evaluated using the assays described herein or the biochemical assays for SHP2 inhibition reported by, for example, Chen et al., Nature (535) 2016 or Bagdanoff et al., J. Med. Chem. 2019, 62, 1781-1792, as described in IC 50 This can be measured by (the concentration of the inhibitor that reduces the activity of SHP2 to a semi-maximal level). Preferably, the compound of the present invention is IC2 for SHP2. 50 This indicates that the concentration is 10 μM or less. Preferred compounds are enzyme IC2 for SHP2 as defined below in this specification. 50 The concentration is 3 μM or less (preferably 0.5 μM or less or 0.5 μM to 3 μM), and / or the inhibition of SHP2 in the cell-based assay as defined below herein results in IC50 This indicates that the concentration is 5 μM or less (preferably 1 μM or less or 1 μM to 5 μM). In this case, the compounds of the present invention, including salts, tautomers, stereoisomers, and solvates thereof, may be for use in methods of inhibiting SHP2 activity. In other words, they may be for use in the prevention and / or treatment of any condition that is remission by SHP2 inhibition.

[0107] In preferred embodiments, the compounds defined above or their pharmaceutically acceptable salts, solvates, or stereoisomers are for use in inhibiting SHP2 activity. Inhibition of SHP2 activity can be measured in appropriate controls, such as subjects affected by diseases or disorders mediated by SHP2 activity, or subjects undergoing treatment for diseases or disorders mediated by SHP2 activity. Preferably, the compounds of the present invention inhibit SHP2 activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in appropriate controls. More preferably, the compounds of the present invention inhibit SHP2 activity by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in appropriate controls.

[0108] More preferably, the compounds of the present invention inhibit SHP2 activity by more than 90%, for example, about 92%, 94%, 95%, 98%, 99%, or 100% of a suitable control.

[0109] Therefore, the compounds of the present invention can be used for the treatment of diseases and for performing biological assays, cell assays, biochemical assays or the like.

[0110] The object of the present invention is the compounds defined above or their pharmaceutically acceptable salts, solvates, or stereoisomers for medical use.

[0111] Preferably, the compounds defined above or their pharmaceutically acceptable salts, solvates, or stereoisomers are for use in inhibiting SHP2 activity. Inhibition of SHP2 activity further results in the dephosphorylation of ERK and the suppression of the oncogenic function of the RAS-RAF-ERK pathway. In this case, inhibition of SHP2 activity can be measured by the dephosphorylation of ERK, where ERK phosphorylation can be evaluated by any method known in the art, such as as described in the examples below. Dephosphorylation of ERK can be measured against any suitable control.

[0112] More preferably, the compounds defined above or their pharmaceutically acceptable salts, solvates, or stereoisomers are for use in the treatment and / or prevention of diseases or disorders mediated by the activity of SHP2. Preferably, the diseases or disorders mediated by the activity of SHP2 are selected from the group consisting of cancer, cardiovascular disease, immunological disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, neutropenia, and combinations thereof. Even more preferably, the diseases or disorders mediated by the activity of SHP2 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, pancreatic cancer, and combinations thereof. Preferably, any of the cancers is primary or metastatic.

[0113] Diseases or disorders mediated by SHP2 activity refer to conditions in subjects in which modulation, more specifically inhibition, of SHP2 activity can prevent, inhibit, alleviate, slow down, or eliminate the condition and / or overall symptoms. Treatment of such diseases or disorders may include administering a therapeutically effective amount of a compound of formula (I) according to the present invention to a subject in need.

[0114] In diseases or disorders mediated by SHP2 activity, mutations are often observed at the N-SH2 / PTP interface (e.g., E76D / E76K), leading to constitutively active proteins and abnormal proliferation. Cancers harboring "PTPN11 mutations" include 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, Examples include, but are not limited to, 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 can also be active against variant forms of the protein.

[0115] Another aspect of the present invention relates to compounds of the present invention, including any pharmaceutically acceptable salts, solvates, or stereoisomers thereof as defined above, for use in methods for preventing / treating SHP2-mediated disorders (plural) mediated by the oncogenic function of the RAS-RAF-ERK pathway.

[0116] Another aspect of the present invention relates to a method for preventing / treating SHP2-mediated disorders, comprising administering a therapeutically effective amount of the compound of the present invention, including any pharmaceutically acceptable salt, solvate, or stereoisomer thereof as defined above herein, to a patient in need. Another aspect relates to a method for preventing / treating SHP2-mediated disorders, comprising administering a therapeutically effective amount of a chemotherapeutic agent, further defined below, in combination with a therapeutically effective amount of the compound of the present invention, to a patient in need.

[0117] Another aspect of the present invention relates to the use of the compounds of the present invention, including any pharmaceutically acceptable salts, solvates, or stereoisomers thereof as defined above herein, in the prevention / treatment of SHP2-mediated disorders.

[0118] In yet another aspect of the present invention, compounds, salts, solvates, and stereoisomers defined above are provided for use in the treatment and / or prevention of diseases or disorders selected from the group consisting of cancer, cardiovascular disease, immunological disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, neutropenia, and combinations thereof. Preferably, the disease or disorder 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, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, and combinations thereof. Preferably, the cancer is primary cancer or metastatic cancer.

[0119] In certain embodiments, the present invention relates to the aforementioned use / method of selecting the disorder from Noonan syndrome (NS) and Leopard syndrome (LS).

[0120] In further embodiments, the present invention relates to the aforementioned uses / methods in which the SHP2-mediated disorder is due to dysregulated cell proliferation, including cancer. The cancer may be hormone-dependent or hormone-resistant, as in the case of breast cancer. Preferably, the cancer is RTK-driven or KRAS-driven, such as KRAS-proliferating gastroesophageal cancer. In certain embodiments, the cancer is a solid tumor. In other embodiments, the cancer is a lymphoma, leukemia, or glioma. In certain embodiments, the cancer is a drug-resistant phenotype of cancer disclosed herein or known in the art. The cancer may be primary or metastatic. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis can also be treated using the compositions and methods disclosed herein. Precancerous neoplasms can also be treated using the compositions and methods disclosed herein.

[0121] The compounds of the present invention are used in juvenile myelomonocytic leukemia (JMML); acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); B-cell acute lymphoblastic leukemia (B-ALL); neuroblastoma; esophagus; breast cancer; lung cancer; colon cancer; stomach cancer, head and neck cancer; ovarian cancer; prostate cancer; cancers of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), stomach, small intestine, large intestine, colon, rectum, liver and bile duct; cancers of the pancreas, bone, connective tissue, skin, cervix, uterus, endometrium, testes, bladder, kidney and other urinary tract tissues including renal cell carcinoma (RCC); gastroesophageal cancer (preferably KR It can be used to treat cancers of the following: AS-amplified gastroesophageal cancer; cancers of the eyes, brain, spinal cord, and other components of the central and peripheral nervous system, as well as related structures such as the meninges; cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, and hematopoietic malignancies including leukemias such as chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML), as well as lymphomas including lymphocytic, granulocytic, and monocytic types. Further types of cancer that can be treated using the compounds and methods of the present invention include adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, undifferentiated astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary cancer, glioblastoma multiforme, angioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphoid cancer, lymphoma, lymphangiosarcoma, lymph This includes, but is not limited to, intraductal sarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pineal glandoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synoviomas, thyroid cancer, uveal melanoma, Wilms' tumor, anaplastic large cell lymphoma, and colitis-related cancers.

[0122] The compounds of the present invention may be useful in treating any other disease or condition associated with abnormal activity of SHP2. Therefore, in a further embodiment, the present invention relates to a method for treating a patient, preferably a human, who has a disorder selected from NS;LS;JMML;AML;MDS;B-ALL;neuroblastoma;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 manufacture of pharmaceuticals for the treatment of disorders selected from NS;LS;JMML;AML;MDS;B-ALL;neuroblastoma;esophageal cancer;breast cancer;lung cancer;colon cancer;gastric cancer;head and neck cancer.

[0123] The compounds of the present invention, comprising any pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, can be usefully combined with any other known therapeutic agent useful for the prevention / treatment of diseases or disorders mediated by the activity of SHP2. Such therapeutic agents may include radiotherapy. Such therapeutic agents may also include the administration of another pharmacologically active compound or two or more other pharmacologically active compounds, more specifically compounds active in the prevention / treatment of cancer, also referred to as “anticancer drugs” or “chemotherapeutic agents.” For example, the compounds of the present invention, comprising any pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof as defined above, may 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 may be formulated in the same composition.

[0124] Classes of anticancer drugs that can be combined with the compounds of the present invention include, but are not limited to, alkylating agents, antimetabolites, mitotic inhibitors, checkpoint inhibitors, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, antisteroids and antiandrogens, mTOR inhibitors, tyrosine kinase inhibitors, and others. Examples of chemotherapeutic agents include taxanes, vinca alkaloids, mitotic inhibitors such as paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, or vinflunin, and other anticancer agents such as cisplatin, 5-fluorouracil, or 5-fluoro-2-4(lH,3H)-pyrimidinedione (5FU), flutamide, or gemcitabine. Such combinations can provide significant advantages in treatment, including synergistic activity.

[0125] Alkylating agents are compounds that work by adding alkyl groups to the guanine bases of DNA molecules, preventing the double helix strands from linking as they should, thus causing breaks in the DNA strands and affecting the ability of cancer cells to proliferate. Antimetabolites are drugs that interfere with one or more enzymes or reactions necessary for DNA synthesis. Mitotic inhibitors are a type of drug that blocks cell growth by stopping mitosis. Checkpoint inhibitors are a type of immunotherapy that blocks proteins that stop the immune system from attacking cancer cells. Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases (topoisomerases I and II), enzymes that control changes in DNA structure by catalyzing the breakdown and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Aromatase inhibitors are a class of drugs that work by inhibiting the action of aromatase, an enzyme that converts androgens to estrogens through a process called aromatization. Angiogenesis inhibitors are substances that inhibit the growth of new blood vessels and are used to treat cancers and other diseases that involve the proliferation of blood vessels. mTOR inhibitors are a class of drugs that inhibit the mammalian target (mTOR) of rapamycin, a serine / threonine-specific protein kinase belonging to the phosphatidylinositol-3 kinase (PI3K)-related kinase (PIKK) family. mTOR regulates cellular metabolism, growth, and proliferation by forming two protein complexes, mTORC1 and mTORC2, and signaling through these complexes. The most established mTOR inhibitors are the so-called rapalogs (rapamycin and its analogues), which have shown tumor responses in clinical trials for various tumor types.

[0126] Therefore, a preferred object of the present invention is the compounds defined above or pharmaceutically acceptable salts, solvates, or stereoisomers thereof for use in combination with at least one further therapeutic agent.

[0127] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously.

[0128] Preferably, the at least one further therapeutic agent is (a) Alkylating agents including, but not limited to, 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 including, but not limited to, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (Cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and larcitrexed; (c) Taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); mitotic inhibitors, including but not limited to vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunin, which are often plant alkaloids and terpenoids or derivatives thereof; (d) Anti-PD-1 or PD-L1 antibodies such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); and checkpoint inhibitors such as 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, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN); (f) Cytotoxic antibiotics including, but not limited to, actinomycin D (dactinomycin, cosmegene), bleomycin (blenoxane), doxorubicin (adriamycin), daunorubicin (cerubidine), epirubicin (ellence), fludarabine (fludarabine), idarubicin, mitomycin (mitosol), mitoxantrone (novantronone), and plicamycin; aromatase inhibitors including, but not limited to, aminoglutethimide, anastrozole (arimidex), letrozole (femara), borozole (rivizor), and exemestane (aromasin); (g) Angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); (h) Antisteroids and antiandrogens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), and nilutamide (NILANDRON); (i) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) Amsacrin; Calmette-Guéran bacillus (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, Pamidronate and other bisphosphonates; Colchicine; Demethoxypyridine; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Lebamisol; Ronidamine; Mesna; Metformin; Mitotane (o,p'-DDD, LYSODREN); No Codazole; octreotide (SANDOSTATIN); perifosine; porfimer (specifically 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; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione, and other agents such as combinations thereof. It is selected from the group consisting of the following.

[0129] The present invention further provides pharmaceutical preparations comprising the compounds of the present invention. More specifically, a further object of the present invention is a pharmaceutical composition comprising the compounds defined above or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, alone or in combination with at least one further therapeutic agent and at least one pharmaceutically acceptable excipient. Preferably, the at least one further therapeutic agent in the pharmaceutical composition is selected from those shown above.

[0130] In preferred embodiments, the pharmaceutically acceptable combinations or compositions of the present invention are intended for use in the treatment and / or prevention of diseases or disorders as defined herein, more particularly diseases or disorders mediated by the activity of SHP2, and / or diseases or disorders selected from the group consisting of cancer, cardiovascular disease, immunological disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, neutropenia, and combinations thereof.

[0131] The present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft 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 production, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pharmaceutically refined and tasty preparations. Tablets contain the active ingredient in mixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet production. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques that mask the unpleasant taste of the drug or delay its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, water-soluble taste-masking materials such as hydroxypropyl methylcellulose or hydroxypropylcellulose, or time-delaying substances such as ethylcellulose or cellulose acetate / butyrate can be used.

[0132] Formulations for oral use may also be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as flexible gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0133] The aqueous suspension contains the active material in mixture with excipients suitable for the preparation of the aqueous suspension. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic. Dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxides and long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxides and partial esters derived from fatty acids and anhydrous hexitol such as polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin, or aspartame.

[0134] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners, such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those mentioned above, can be added to provide an oral preparation with a pleasant mouthfeel. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0135] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives to provide an active ingredient. Suitable dispersants or wetting agents and suspending agents are illustrated by those already described above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0136] 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 peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and anhydrous hexitol, such as sorbitan monooleate, and condensation products of the partial ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants.

[0137] The syrup and elexyl can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, colorants, and antioxidants.

[0138] The pharmaceutical composition may be in the form of a sterile aqueous solution for injection. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.

[0139] The sterile injection preparation may also be a sterile oil-in-water microemulsion in which 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. The oily solution is then introduced into a mixture of water and glycerol and treated to form a microemulsion.

[0140] The injectable solution or microemulsion can be introduced into the patient's bloodstream 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 compound. Continuous intravenous delivery devices can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS® Model 5400 intravenous pump.

[0141] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular or subcutaneous administration. This suspension can be formulated according to the known art using the preferred dispersants or wetting agents and suspending agents described above. The sterile injection preparation may also be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. In addition, sterile fixatives are conventionally used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic mono or diglycerides, can be used. Furthermore, fatty acids such as oleic acid have applications in injection preparations.

[0142] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Examples of such materials include cocoa butter, glycerin-gelatinized, hydrogenated vegetable oil, and mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights.

[0143] For topical use, creams, ointments, jellies, solutions, or suspensions containing the compound of the present invention are used. For this application, topical application may include mouthwash and gargle.

[0144] The compounds of the present invention can be administered in an intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via a transdermal route using transdermal skin patches as is well known to those skilled in the art. For administration in the form of a transdermal delivery system, the dosage is naturally continuous rather than intermittent throughout the entire drug regimen. The compounds of the present invention can also be delivered as suppositories using bases such as cocoa butter, glycerin-gelatinized, hydrogenated vegetable oil, and mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights.

[0145] The compounds of the present invention can be presented in liposomes or other microparticles or nanoparticles designed to target the compounds. Acceptable liposomes can be neutral, negatively charged, or positively charged, with the charge being a function of the charge of the liposome components and the pH of the liposome solution. Liposomes can typically be prepared using a mixture of phospholipids and cholesterol. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphotidylglycerol, and phosphatidylinositol. Polyethylene glycol may be added to improve the blood circulation time of the liposomes. Acceptable nanoparticles include albumin nanoparticles and gold nanoparticles.

[0146] When the compounds according to the present invention are administered to human subjects, the daily dose is usually determined by the prescribing physician, and the dose generally varies according to the individual patient's age, weight, sex and response, as well as the severity of the patient's symptoms. Generally, a dose level of approximately 0.01 mg / kg to approximately 150 mg / kg body weight is useful for treating the above-mentioned conditions.

[0147] As used herein, the term “composition” is intended to encompass products containing the specified components in specified amounts, as well as any products resulting directly or indirectly from combinations of the specified components in specified amounts.

[0148] Another object of the present invention relates to an in vitro method for inhibiting SHP2 with the compounds of the present invention. This may be useful, for example, for evaluating whether any given compound is an inhibitor / activator of SHP2 and therefore also acts in the ERK pathway.

[0149] A further object of the present invention relates to a kit comprising at least one pharmaceutically acceptable vial or other type of container containing one or more doses of the compound or pharmaceutical composition of the present invention, comprising any pharmaceutically acceptable salt, solvate or stereoisomer thereof, and optionally a) instructions for use thereof in mammals and / or b) a pharmaceutically acceptable diluent.

[0150] In certain embodiments, the compounds or compositions of the present invention are administered parenterally, intramuscularly, intravenously, subcutaneously, orally, pulmonaryly, intrathecally, topically, intranasally, or systemically.

[0151] In certain embodiments, the patient administered with the compound or composition of the present invention is a mammal, preferably a primate, and more preferably a human.

[0152] The compounds of the present invention can be administered to mammals, preferably humans, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in pharmaceutical compositions according to standard pharmacokinetics. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or via parenteral, rectal, and topical routes including intravenous, intramuscular, intraperitoneal, subcutaneous, and intravenous, intramuscular, intraperitoneal, and subcutaneous.

[0153] As used herein, the term “prevention” means no progression of the disorder or disease if nothing is happening, or no further progression of the disorder or disease if it is already progressing. The ability to prevent some or all of the symptoms associated with the disorder or disease is also considered. Any reference to “treatment” or “treating” as used herein includes remission of at least one symptom of the disease / disorder being treated. Such remission should be evaluated in comparison to the same symptom before administration of the compound or composition of the present invention.

[0154] As used herein, the term “therapeutic dose” means the amount of an active compound or pharmaceutical product that elicits a biological or drug response in a tissue, system, animal, or human, as sought by a researcher, veterinarian, physician, or other clinician.

[0155] The present invention is described by the following non-limiting examples and biological data.

[0156] Materials and methods chemical properties The following abbreviations used herein have the meanings set forth below. If an abbreviation is not defined, it has the generally accepted meaning.

[0157] Abbreviation AcCl: Acetyl chloride; AcOH: Acetic acid; AlCl3: Aluminum chloride; BOP: Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; B2Pin2: 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane); Boc2O: Di-tert-butyldicarbonate; t-BuLi: Tert-butyllithium; 1-BuOH: 1-Butanol; t-BuOK: Tert-butoxide potassium; CDI: 1,1'-Carbonyldiimidazole; CDCl3: Deuterated chloride Chloroform; CHCl3: Chloroform; mCPBA: Methachloroperoxybenzoic acid; Cs2CO3: Cesium carbonate; CsF: Cesium fluoride; CuBr: Copper bromide; CuI: Copper iodide; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: Dichloromethane; DEAD: Diethyl azodicarboxylate; DIAD: Diisopropyl azodicarboxylate; DIPEA: N,N-Diisopropylethylamine; DMA: Dimethylacetamide; DMAP: 4-(dimethylamino)pyridine; DME: Dimethoxyethane; DMF: Dimethylformamide; DMSO: Dimethyl sulfoxide; ES + :Electrospray cationization; Et2O:Diethyl ether; Â:Ethyl acetate; EtOH:Ethanol; EtONa:Sodium ethoxide; HCl:Hydrochloric acid; h:Time; H2:Hydrogen; HBF4:Tetrafluoroboric acid; HCO2H:Formic acid; H2O:Water; H2SO4:Sulfuric acid; HPLC:High-performance liquid chromatography; I2:Iodine; IPA:Isopropyl alcohol; K2CO3:Potassium carbonate; KOAc:Potassium acetate; KOH:Potassium hydroxide; K3PO4:Potassium phosphate; LCMS:Liquid chromatography-mass spectrometry; LiAlH4:Lithium aluminum hydride; LDA:Lithium diisopropylamide; MeCN:Acetonitrile; MgSO4:Magnesium sulfate; MeI: Iodomethane; MeOH: Methanol; min: Minute; MW: Microwave; NaBH4: Sodium borohydride; NaHCO3: Sodium bicarbonate; NCS: N-Chlorosuccinimide; NIS: N-Iodosuccinimide; NaH: Sodium hydride; NaNO2: Sodium nitrite; NaOH: Sodium hydroxide; NaOMe: Sodium methoxide; Na2SO4: Sodium sulfate; Na2S2O3: Sodium thiosulfate; NaOtBu: Sodium 2-methylpropane-2-oleate; NBS: N-bromosuccinimide; NH4HCO2: Ammonium formate; NH4OH: Ammonium hydroxide; N 2: Nitrogen; PPh3: Triphenylphosphine; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2·DCM: Complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DCM; Pd(OH)2: Palladium hydroxide; Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0); POCl3: Phosphoryl chloride; RP: Reverse phase; RT: Retention time; rt: Room temperature; RuPhos: Dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine; SE M: Trimethylsilylethoxymethyl; TCDI: 1,1'-thiocarbonyldiimidazole; TEA: Triethylamine; [(t-Bu)3PH]BF4: Tri-tert-butylphosphonium tetrafluoroborate; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; THF: Tetrahydrofuran; Ti(OEt)4: Titanium ethoxide; Sat.: Saturated; Sol.: Solution; TsCl: 4-toluenesulfonyl chloride; ULC: Ultrahigh-performance liquid chromatography; Xantphos: 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0158] LC-MS analysis, Column 1: ACQUITY UPLC BEH SHIELD, RP 18 (2.1×50mm, id=1.7μm); Column 2: ACQUITY UPLC HSS T3, RP 18(2.1×50mm, id=1.8μm); Column 3: ACQUITY UPLC BEH SHIELD, RP 18 (2.1 × 100 mm, id = 1.7 μm) and column 4: Phenomenex Kinetex EVO RP 18 Analysis was performed using a 3×50 mM (id=2.6 μm) sample in a UPLC Acquity Waters system equipped with an SQD spectrometer, a single quadrupole mass detector, and a TUV detector. Column temperature: 40°C or 33°C. Sample temperature: 25°C or 33°C. Phase A consisted of H2O (HiPerSolv Chromanorm for HPLC-MS, Water, VWR) + 0.05% TFA; Phase B consisted of MeCN (HiPerSolv Chromanorm, Acetonitrile SuperGradient, VWR, suitable for ULC / UHPLC instruments) + 0.05% TFA; Phase A2 consisted of H2O (HiPerSolv Chromanorm for HPLC-MS, Water, VWR) / MeCN (HiPerSolv Chromanorm, Acetonitrile SuperGradient, VWR, suitable for ULC / UHPLC instruments) 95 / 5v / v + 20mM NH4HCO2 buffer, pH=7.4; Phase B2 consisted of H2O (HiPerSolv Chromanorm for HPLC-MS, Water, VWR) / MeCN (HiPerSolv Chromanorm, Acetonitrile SuperGradient (VWR) consists of 20 / 80v / v + 20mM NH4HCO2 buffer, pH=7.4; flow rate: 0.5mL / min or 1.8mL / min; UV detection (diode array) 200nm; ESI+ and ESI- detection in the 100~1000m / z range.

[0159] Method 1: Column 1, Run time: 3 min, Run gradient: 2.80 min from 5%B to 100%B + 0.2 min to 100%B, Equilibrium time: 0.8 min, Ionization mode: ESI + . Method 2: Column 2, Run time: 3 min, Run gradient: 2.80 min from 0%B to 45%B + 0.2 min to 100%B, Equilibrium time: 0.8 min, Ionization mode: ESI+ . Method 3: Column 3, Run time: 6 minutes, Run gradient: 5%B to 100%B in 5 minutes + 100%B in 1 minute, Equilibrium time: 2 minutes. Ionization mode: ESI + . Method 4: Column 1, Run time: 3 minutes, Run gradient: 2.80 minutes from 40%B to 100%B + 0.2 minutes to 100%B, Equilibrium time: 0.8 minutes. Ionization mode: ESI + . Method 5: Column 4, Run time: 2 minutes, Run gradient: 1.84 minutes from 5% B2 to 95% B2, Equilibrium time: 0.16 minutes. Ionization mode: ESI + Method 6 (2-minute GRAD10 LUNA HILIC AB): Column 4, Run time: 2 minutes, Run gradient: 1.5 minutes from 92%B to 70%B, Equilibrium time: 0.5 minutes. Ionization mode: ESI + Method 7 (5-minute GRAD10 LUNA HILIC AB): Column 4, Run time: 5 minutes, Run gradient: 4.2 minutes from 92%B to 70%B, Equilibrium time: 0.8 minutes. Ionization mode: ESI + Method 8 (5-minute normalized A2B2 ELS EVO): Column 4, Run time: 5 minutes, Run gradient: 4.75 minutes from 0% B2 to 95% B2, Equilibrium time: 0.25 minutes. Ionization mode: ESI + Method 9 (A2B2 EVO over 5 minutes): Column 4, Run time: 5 minutes, Run gradient: 4.75 minutes from 50% B2 to 100% B2, Equilibrium time: 0.25 minutes. Ionization mode: ESI +

[0160] Method for producing the compound of the present invention The present invention also includes a method for preparing the compounds of the present invention. The following scheme is an example of a synthetic route that can be employed to prepare the compounds of the present invention.

[0161] In the reaction schemes described below, it may be useful to protect reactive functional groups, such as amino, imino, hydroxyl, thio, or carboxyl groups, to avoid their unwanted participation in the reaction. Conventional protecting groups can be used according to standard practice. See, for example, T. Greene and PGM Wuts, "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991.

[0162] Those skilled in the art will readily understand that certain compounds of the present invention can be converted to other compounds of the present invention by standard chemical methods (e.g., by chlorination / dechlorination).

[0163] The following examples were synthesized using appropriate starting materials, following the scheme and procedure or variations thereof described below (Table 1).

[0164] [Table 1A]

[0165] [Table 1B]

[0166] [Table 1C]

[0167] [Table 1D]

[0168] [Table 1E]

[0169] [Table 1F]

[0170] [Table 1G]

[0171] [Table 1H]

[0172] [Table 1I]

[0173] [Table 1J]

[0174] [Table 1K]

[0175] An exemplary and non-restrictive method for the synthesis of specific examples is reported below.

[0176] [ka]

[0177] Intermediate 1: tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate Step 1: 1-benzyl-1H-pyrazole-3-carbaldehyde A suspension of 1H-pyrazole-5-carbaldehyde (1.42 g, 14.78 mmol), K2CO3 (5.10 g, 36.95 mmol), and benzyl bromide (3.0 mL, 25.26 mmol) in dry MeCN (27 mL) was heated at 70°C for 12 hours. The mixture was diluted with toluene and washed with H2O (×2) and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel (0% to 20% siRNA in cyclohexane) to obtain the title compound as a yellow oil (1.86 g, 68%). 1 H NMR (300 MHz, DMSO-d6) 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 minutes.

[0178] Step 2: 1-(tert-butyl)4-ethyl4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate LDA (2N in THF; 6 mL, 12 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) at -78°C. After 10 minutes, 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 minutes, the mixture was warmed to room temperature. After 20 minutes, the mixture was diluted with toluene and adjusted to pH=6 with 2N HCl at 0°C. The organic layer was washed with H2O (×2) and brine, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the crude compound as a yellow viscous solid, which was used in the next step without purification (4.35 g). 1H NMR (300 MHz, DMSO-d6) 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 minutes.

[0179] Step 3: tert-butyl 4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)-4(hydroxymethyl)piperidine-1-carboxylate LiAlH4 (2N in THF; 7.2 mL, 14.4 mmol) was added to a stirred solution of 1-(tert-butyl)4-ethyl4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (5.28 g, 11.90 mmol) in dry THF (30 mL) at 0°C. After 1.5 hours, LiAlH4 (2N in THF; 1 mL, 2.0 mmol) was added. After 30 minutes, the mixture was quenched at 0°C by slowly adding a 5% citric acid solution (to pH=6) and a Rochelle salt solution, and diluted with toluene. The organic layer was washed with H2O (×2) and brine, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a crude product as a colorless solid, which was used in the next step without purification (4.70 g). LCMS (ES) + ) Method 1: m / z 402(M+H) + , RT 1.77 minutes.

[0180] Step 4: tert-butyl 4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (4.70 g, 11.71 mmol) in DCM (60 mL), dried DIPEA (3.1 mL, 17.8 mmol) and methanesulfonyl chloride (0.950 mL, 12.27 mmol) were added at 0°C. After 5 minutes, the mixture was diluted with DCM and a 5% citric acid solution was added at 0°C. The organic layer was then washed with H2O and brine, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (20% to 70% siRNA in cyclohexane) to obtain the title compound as a white spongy solid (3.15 g, 56% obtained over 3 steps). 1 H NMR (300 MHz, DMSO-d6) 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 minutes.

[0181] Step 5: tert-butyl 4'-hydroxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate A solution of tert-butyl 4-((1-benzyl-1H-pyrazole-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (3.7 g, 7.71 mmol) in 1-BuOH (64 mL) was heated in a sealed tube at 120 °C for 3 hours, then cooled to room temperature, and ammonium formate (1.46 g, 23.15 mmol) and Pd / C 10% by weight (0.41 g, 0.39 mmol) were added. The mixture was heated under reflux for 15 minutes, then stirred at room temperature for 2 hours. The mixture was filtered on an alpha-cellulose pad and washed with butyl and MeOH. Volatile substances were removed under reduced pressure, and the product was purified by flash chromatography on silica gel (20% to 100% butyl + 3% MeOH in petroleum ether) to obtain the title compound as a white solid (1.40 g, 61% over 2 steps). 1 H NMR (300 MHz, DMSO-d6) 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 minutes.

[0182] Step 6: tert-butyl4'-oxo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate To a stirred solution of tert-butyl 4'-hydroxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.60 g, 5.45 mmol) in 24 mL of DCM, Dess-Martin periodinane (2.55 g, 6.01 mmol) was gradually added at 0°C. The resulting mixture was warmed to room temperature. After 1 hour, the mixture was diluted with DCM and washed with 10% Na2S2O3 solution, H2O, and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a yellow solid. The residue was purified by flash chromatography on silica gel (0% to 100% siRNA in petroleum ether) to obtain the title compound as a grayish-white solid (1.25 g, 78%). 1 H NMR (300 MHz, DMSO-d6) 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 minutes.

[0183] Step 7: tert-butyl(R,Z)-4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 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 at 100 °C for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and H₂O, and the solid precipitated. The mixture was filtered and washed with ethyl acetate. The organic layer was washed with H₂O (×3) and brine, dehydrated with Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (20% to 100% ethyl acetate in petroleum ether) to obtain the title compound as a pale yellow solid (740 mg, 86%). 1 H NMR (300 MHz, DMSO-d6) 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 minutes.

[0184] Step 8: tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate NaBH4 (227 mg, 6.00 mmol) was added at -50°C to a solution of tert-butyl(S,Z)-4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.57 g, 3.97 mmol) in dry THF (15 mL). After 5 minutes, the mixture was warmed to room temperature. After 1.5 hours, NaBH4 (30 mg, 0.79 mmol) was added, and after an additional 30 minutes, the mixture was diluted with siRNA and H2O at 0°C. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain a pale yellow solid, which was dissolved in EtOH (16 mL) and heated at 75°C for 1 hour (diastereomer ratio observed by ULC-MS: 88 / 12). The mixture was then evaporated under reduced pressure, and the product was purified by flash chromatography on silica gel (0% to 100% siRNA + 3% MeOH in DCM) to obtain the title compound as a white solid (908 mg, 62%; diastereomer ratio = 97 / 3). 1 H NMR (300 MHz, DMSO-d6) 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, LCMS (ES) + ) Method 1: m / z 397 (M+H) + , RT 1.66 minutes. Intermediates 2, 3, 4 and 5

[0185] [ka]

[0186] Intermediate 2: (R)-2-methyl-N-((S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propan-2-sulfinamide 2,2,2-trifluoroacetate

[0187] [ka]

[0188] Intermediate 2 was prepared according to method A: TFA (0.2 mL, 2.61 mmol) was added at room temperature to a solution of tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (intermediate 1; 90 mg, 0.227 mmol) in dry DCM (1.5 mL). After 2 hours, the mixture was evaporated under reduced pressure to obtain a colorless solid (95 mg, quantitative). 1 H NMR (300 MHz, DMSO-d6) δ 8.68-8.24 (m, 2H), 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); + ) Method 1: m / z 297 (M+H) + , RT 0.89 minutes. Intermediate 3: (R)-2-methyl-N-((S)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propan-2-sulfinamide 2,2,2-trifluoroacetate

[0189] [ka]

[0190] Intermediate 3 was prepared using tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (prepared using 3-methyl-1H-pyrazole-5-carbaldehyde as a starting material, in the same procedure as for intermediate 1; 138 mg, 0.34 mmol) as a starting material, according to Method A. The product was purified by flash chromatography on a C18 cartridge (0% to 30% MeCN / H2O + 0.1% TFA), ground with ELISA, and the title compound was obtained as a beige solid (68 mg, 65%). LCMS (ES + ) Method 1: m / z 311(M+H) + , RT 0.98 min. Intermediate 4: (R)-N-((S)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide 2,2,2-trifluoroacetate

[0191] [ka]

[0192] Intermediate 4 was prepared using tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (160 mg; 0.38 mmol, prepared using 3-methoxy-1H-pyrazole-5-carbaldehyde as a starting material in the same procedure as for intermediate 1, 160 mg; 0.38 mmol) as a starting material, according to Method A. The product was purified by flash chromatography on a C18 cartridge (0% to 20% MeCN / H2O + 0.1% TFA), ground with ethyl acetate, and the title compound was obtained as a beige solid (85 mg, 51%). LC-MS (ES) + ) Method 1: m / z 327(M+H) + , RT 0.81 min. Intermediate 5: (S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride

[0193] [ka]

[0194] Intermediate 5 was prepared according to method B: HCl (4N in 1,4-dioxane; 2.3 mL, 9.2 mmol) was added at room temperature 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 (intermediate 1; 908 mg, 2.29 mmol) in DCM (5 mL). After 2 hours, the product was filtered, washed with DCM, and dried under reduced pressure to obtain a pale yellow solid (463 mg, 75%). 1 H NMR (DMSO-d6+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 LCMS (ES) + ) Method 2: m / z 193 (M+H) + , RT 0.54 minutes. Intermediates 6, 7, 8 and 9

[0195] [ka]

[0196] Intermediate 6: (S)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Step 1: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate Dried DIPEA (0.40 mL, 2.30 mmol) was added to a suspension of (S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (intermediate 5; 200 mg, 0.75 mmol) and Boc2O (412 mg, 1.89 mmol) in dried DCM (3 mL). After 3 hours, the mixture was diluted with DCM and washed with 5% citric acid solution, H2O, and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 50% siRNA in petroleum ether) to obtain the title compound as a colorless solid (225 mg, 76%). LCMS (ES + ) Method 1: m / z 393(M+H) + RT 1.95 min. LCMS(ES + ) Method 1: m / z 393(M+H) + , RT 1.95 minutes. Step 2A: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0197] [ka]

[0198] N-chlorosuccinimide (54.5 mg, 1.05 mmol) was added to a stirred solution of tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (152 mg, 0.39 mmol) in dry DMF (1.7 mL) at 50°C. After 2.5 hours, the mixture was diluted with toluene and washed with H2O (×2) and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the title compound as a pale yellow solid (158 mg, 95%). 1 H NMR (300 MHz, DMSO-d6) δ 7.62-7.51 (m, 2H) 4.86 (d, J=9.7 Hz, 1H), 4.17-4.02 (m, 2H), 3.71-3.52 (m, 2H), 3.32-3.08 (m, 2H), 1.72-1.52 (m, 4H), 1.46 (s, 18H); LCMS (ES + ) Method 1: m / z 427 (M+H) + , RT 2.14 minutes. Step 4: (S)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride (intermediate 6)

[0199] [ka]

[0200] (S)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was obtained as a white solid (112 mg, quantitatively) using tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (158 mg, 0.370 mmol) as a starting material, according to Method B (used to prepare intermediate 5). LCMS (ES) + ) Method 1: m / z 227(M+H) + , RT 0.36 min. Intermediate 7: (S)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Step 2B: tert-butyl(S)-3'-bromo-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0201] [ka]

[0202] tert-butyl(S)-3'-bromo-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate was prepared using NBS (53 mg, 0.30 mmol) and tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (intermediate 6, prepared as step 1; 110 mg, 0.28 mmol) as starting materials to obtain a yellow solid (132 mg, quantitative). 1 H NMR (DMSO-d6) δ 7.54 (s, 1H), 7.48 (d, J=9.7 Hz, 1H), 4.77 (d, J=9.8 Hz, 1H), 4.06 (d, J=3.8 Hz, 2H), 3.44-3.64 (m, 2H), 3.05-3.27 (m, 2H), 1.48-1.68 (m, 4H), 1.41 (d, J=1.9 Hz, 18H); LCMS (ES + ) Method 1: m / z 471 (M+H) + , RT 2.16 minutes Step 4: (S)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride (intermediate 7)

[0203] [ka]

[0204] (S)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared using tert-butyl(S)-3'-bromo-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (from step 2B; 17 mg, 0.04 mmol) as a starting material, according to method B, to obtain a white powder (12 mg, 80%). LCMS(ES) + ) Method 1: m / z 271(M+H) + , RT 0.37 min. Intermediate 8: (S)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Step 2C: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate

[0205] [ka]

[0206] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (53 mg, 0.298 mmol) was added at 50°C to a stirred solution of tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (intermediate 6, prepared as step 1; 65 mg, 0.17 mmol) in dry DMF (1.3 mL). After 5 hours, the mixture was diluted with toluene and washed with H2O (×2) and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (20% to 65% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow solid (10 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) 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 minutes. Step 4: (S)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride (intermediate 8)

[0207] [ka]

[0208] (S)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared using tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (from step 2C; 10 mg, 0.02 mmol) as a starting material, according to method B, to obtain a white powder (5 mg, 73%). LCMS(ES) + ) Method 1: m / z 211(M+H) + , RT 0.34 min.

[0209] Intermediate 9: (S)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Step 3: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate In a sealed microwave vial, a solution of tert-butyl(S)-3'-bromo-4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (80 mg, 0.170 mmol), CsF (52 mg, 0.34 mmol), trimethylboroxine (0.09 mL, 0.68 mmol), and Pd(PPh3)4 (19.6 mg, 0.02 mmol) in degassed dried 1,4-dioxane (1 mL) was heated at 105 °C for 5 hours under an N2 atmosphere. The mixture was diluted with ELISA and washed with H2O (×2). The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a C18 cartridge (10% to 55% MeCN in H2O) to obtain the title compound as a pale yellow powder (16 mg, 22%). LC-MS (ES) + ) Method 1: m / z 407(M+H) + , RT 1.99 minutes.

[0210] Step 4: (S)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (intermediate 9) (S)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared as a white powder (8 mg, 77%) using tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (from step 3; 15 mg, 0.04 mmol) as a starting material, according to Method B (used to prepare intermediate 5). LCMS(ES) + ) Method 1: m / z 207(M+H) + , RT 0.36 min Intermediate 10: (S)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine

[0211] [ka]

[0212] Step 1: (S)-2'methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine dihydrochloride (S)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared using (R)-2-methyl-N-((S)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)propan-2-sulfinamide (54 mg, 0.17 mmol) as a starting material, according to Method B (similar procedure used to prepare intermediate 5), to obtain a white powder (42 mg, 86%). LCMS(ES + ) Method 1: m / z 211(M+H) + , RT 0.37 min.

[0213] Step 2: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate was prepared using (S)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine as a starting material, following the procedure used in intermediate step 1, to obtain the title compound as a white powder (34 mg, 54%). LCMS(ES) + ) Method 1: m / z 407(M+H) + , RT 1.94 minutes.

[0214] Step 3: tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate was prepared using tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (32 mg, 0.08 mmol) as a starting material, following the procedure used in intermediate step 6, step 2A, to obtain a pale yellow solid (33 mg, 95%). LCMS(ES) + ) Method 1: m / z 441(M+H) + , RT 2.19 minutes.

[0215] Step 4: (S)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (intermediate 10) (S)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared using tert-butyl(S)-4'-((tert-butoxycarbonyl)amino)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (30 mg, 0.07 mmol) as a starting material, according to Method B, to obtain a white powder (19 mg, 83%). LCMS(ES + ) Method 1: m / z 241(M+H) + , RT 0.44 min. Intermediate 11: 2-chloro-6-((2-(trifluoromethyl)pyridine-3-yl)thio)-1H-imidazo[4,5-b]pyrazine

[0216] [ka]

[0217] Step 1: 5-Bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-one A solution of 5-bromo-2,3-pyrazinediamine (4.1 g, 21.7 mmol) and CDI (7.0 g, 43.4 mmol) in THF (120 mL) was heated at 60°C for 72 hours. Then, a second dose of CDI (7.0 g, 43.4 mmol) was added, and heating at 60°C was continued for 24 hours. After cooling, the mixture was concentrated under vacuum, and the residue was purified by reverse-phase chromatography (gradient elution of 0-50% MeCN (+0.1% TFA) / H2O (+0.1% TFA)). The volatile matter was evaporated to obtain the residue, which was ground with MeCN and filtered to obtain the title compound as a beige solid (3.04 g, 65%). 1 H NMR (DMSO-d6) δ 11.98 (br s, 1H), 11.91 (br s, 1H), 7.98 (s, 1H). LCMS (ES + ) m / z 215, 217 (M+H) + .

[0218] Step 2: 5-[(2-(trifluoromethyl)pyridine-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-one A solution of 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-one (1.0 g, 4.65 mmol) in 1,4-dioxane (47 mL) was degassed with N2 for 5 minutes, and then Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.27 g, 0.47 mmol), 2-(trifluoromethyl)pyridine-3-thiol (1.19 g, 5.12 mmol), and DIPEA (1.62 mL, 9.3 mmol) were added sequentially. The reaction mixture was degassed further with N2 for 5 minutes and heated at 100°C for 2 hours. After cooling, the mixture was concentrated under vacuum, and the residue was treated with MeCN to obtain a precipitate, which was filtered off to obtain the title compound as a beige solid (1.33 g, 91%). 1 H NMR (DMSO-d6) δ 11.96 (br s, 2H), 8.56 (d, J=3.7 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.58 (dd, J=8.2 and 4.5 Hz, 1H). LCMS (ES + ) m / z 314 (M+H) + .

[0219] Step 3: 2-Chloro-6-[(2-(trifluoromethyl)pyridine-3-yl)thio]-1H-imidazo[4,5-b]pyrazine (intermediate 11) A solution of 5-[(2-(trifluoromethyl)pyridine-3-yl)thio]-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-one (1.3 g, 4.15 mmol) in POCl3 (20 mL, 0.21 mol) was heated in a sealed vial at 120°C for 8 hours. After cooling, the mixture was concentrated under vacuum to obtain the residue, which was purified by reverse-phase chromatography (gradient elution of 0-100% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow solid (TFA salt; 0.26 g, 19%). 1H NMR (DMSO-d6) δ 8.71 (d, J=3.9 Hz, 1H), 8.55 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.70 (dd, J=8.1 and 4.6 Hz, 1H). LCMS (ES + ) m / z 332 (M+H) + . Intermediate 12: 3-Chloro-4-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine-6-yl)thio)pyridine-2-amine

[0220] [ka]

[0221] Step 1: 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-thione A solution of 5-bromopyrazine-2,3-diamine (5.0 g, 26.5 mmol) in 1,4-dioxane (55 mL) was treated with TCDI (6.6 g, 37.0 mmol). The mixture was heated at 50°C for 16 hours. After cooling, the reaction mixture was concentrated under vacuum and purified on silica gel (eluted with 0-50% ethyl acetate / petroleum ether) to obtain the title compound as a yellow solid (5.4 g, 79%). 1 H NMR (DMSO-d6) δ 13.62 (br s, 2H), 8.22 (s, 1H). LCMS (ES + ) m / z 231, 233 (M+H) + .

[0222] Step 2: 6-bromo-2-(methylthio)-1H-imidazo[4,5-b]pyrazine A solution of 5-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyrazine-2-thion (3.0 g, 13.0 mmol) in H2O (85 mL) was treated with NaOH (799 mg, 19.5 mmol) at room temperature and stirred at this temperature until the starting material was completely dissolved. Then, MeI (1.2 mL, 19.5 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. A solution of 2N NaOH was added until clear, the aqueous solution was washed with CHCl3, concentrated, and acidified to pH=6.5 with 6N aqueous HCl. The resulting precipitate was filtered and washed with H2O to obtain the title compound as a pale yellow solid (1.8 g, 56%). 1 H NMR (DMSO-d6) δ 7.76 (s, 1H), 2.55 (s, 3H). LCMS (ES + ) m / z 245, 247 (M+H) + .

[0223] Step 3: 6-Bromo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine mCPBA (4.2 g, 18.4 mmol) was gradually added at 0°C to a solution of 6-bromo-2-(methylthio)-1H-imidazo[4,5-b]pyrazine (1.8 g, 7.3 mmol) in DCM (70 mL), and the resulting reaction mixture was stirred at room temperature for 3 hours. After adding 6N aqueous HCl (10 mL), the mixture was extracted with a CHCl3 / EtOH 95:5 solution (3 × 150 mL). The organic phase was washed with H2O and brine. The dried organic layer was concentrated under vacuum, and the residue was purified on reversed-phase silica gel (eluted with 0-50% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white solid (1.5 g, 75%). 1 H NMR (DMSO-d6) δ 8.79 (s, 1H), 3.56 (s, 3H). LCMS (ES + ) m / z 277, 279 (M+H) + .

[0224] Step 4: 2-Ethylhexyl 3-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine-6-yl)thio)propanoate In a pressure tube, 6-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine (800 mg, 2.9 mmol), 2-ethylhexyl 3-mercaptopropanoate (722 μL, 3.2 mmol), DIPEA (1.0 mL, 5.8 mmol), Xantphos (83 mg, 0.14 mmol), and Pd2(dba)3 (66 mg, 0.07 mmol) were placed in 1,4-dioxane (15 mL). The mixture was degassed with N2, sealed, and heated at 100°C for 30 minutes. After cooling, the mixture was concentrated under vacuum and purified on silica gel (eluted in petroleum ether at 10-100% (siRNA + 10% MeOH)) to obtain the title compound as a pale yellow solid (993 mg, 75%). LC-MS (ES) + )m / z 415(M+H) + .

[0225] Step 5: 3-Chloro-4-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine-6-yl)thio)pyridine-2-amine (intermediate 12) A solution of 2-ethylhexyl 3-((2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine-6-yl)thio)propanoate (100 mg, 0.24 mmol), 3-chloro-4-iodopyridine-2-amine (73.7 mg, 0.29 mmol), XantPhos (6.9 mg, 0.012 mmol), and Pd2(dba)3 (5.5 mg, 0.006 mmol) was dissolved in N2-1,4-dioxane (1.4 mL) and DMF (1.0 mL). Then potassium 2-methylpropane-2-oleate (40.6 mg, 0.36 mmol) and DIPEA (0.08 mL, 0.48 mmol) were added, and the mixture was stirred at 100°C for 1 hour. After cooling, the mixture was concentrated under vacuum and purified on silica gel (eluted with 5-100% (Ã + 20% MeOH) in Ã) to obtain the title compound as a yellow solid (75 mg, 87%). LC-MS (ES) + )m / z 356(M+H) + . Intermediate 13: 6-Chloro-3-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-amine

[0226] [ka]

[0227] Step 1: 2-Ethylhexyl 3-((2-(trifluoromethyl)pyridine-3-yl)thio)propanoate A mixture of 3-bromo-2-trifluoromethylpyridine (712 mg, 3.15 mmol), 2-ethylhexyl 3-sulfanylpropanoate (0.79 mL, 3.47 mmol), Pd2(dba)3 (289 mg, 0.32 mmol), and Xantphos (183 mg, 0.32 mmol) in degassed dried 1,4-dioxane (7 mL) was mixed with DIPEA (1.7 mL, 9.76 mmol) under an N2 atmosphere, and the resulting mixture was heated at 100 °C for 1 hour. After removing volatiles under reduced pressure, the residue was purified by flash chromatography on silica gel (0% to 20% butyl in cyclohexane) to obtain 2-ethylhexyl 3-((2-(trifluoromethyl)pyridine-3-yl)thio)propanoate as an orange solid (809 mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (br d, J=4.2 Hz, 1H), 8.17 (br d, J=8.3 Hz, 1H), 7.72-7.65 (m, 1H), 3.95 (d, J=5.5 Hz, 2H), 3.42-3.33 (m, 2H), 2.69 (t, J=6.5 Hz, 2H), 1.34-1.18 (m, 9H), 0.89-0.79 (m, 6H). LCMS (ES + ) Method 3: m / z 364 (M+H) + , RT 2.08 minutes.

[0228] Step 2: Potassium 2-(trifluoromethyl)pyridine-3-thiolate A solution of 2-ethylhexyl 3-((2-(trifluoromethyl)pyridine-3-yl)thio)propanoate (500 mg, 1.38 mmol) in dry THF (4 mL), cooled to -78°C, was added to a suspension of t-BuOK (463 mg, 4.13 mmol) in dry THF (20 mL). After stirring at -78°C for 20 minutes, the reaction mixture was quenched with aqueous K2CO3 solution (2 M, 0.25 mL) and gradually warmed to room temperature (a brownish solid precipitated). The solid was filtered off, washed with THF (×2), and dried under reduced pressure to obtain the product as a brownish solid (300 mg, 98%). 1 H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=4.0 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 6.77 (dd, J=8.1, 4.2 Hz, 1H). LCMS (ES + ) Method 1: m / z 180 (M+H) + , RT 1.69 minutes.

[0229] Step 3: 6-Chloro-3-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-amine (intermediate 13) To a solution of 2-amino-3-bromo-6-chloropyrazine (464 mg, 2.23 mmol) and potassium 2-(trifluoromethyl)pyridine-3-thiolate (484 mg, 2.23 mmol) in degassed dried 1,4-dioxane (10 mL), Pd2(dba)3 (204 mg, 0.22 mmol) and Xantphos (129 mg, 0.22 mmol) were sequentially added under an N2 atmosphere in a sealed tube, followed by the addition of dried DIPEA (1 mL, 5.74 mmol). The resulting mixture was refluxed for 1 hour. The volatile matter was evaporated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (0% to 30% siRNA in cyclohexane) to obtain the title compound as a yellow solid (390 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.5, 1.0 Hz, 1H), 8.00-7.94 (m, 1H), 7.74-7.68 (m, 2H), 7.16 (s, 2H). LCMS (ES + ) Method 1: m / z 307, 309 (M+H) + , RT 1.96 minutes. Intermediate 14: 3-((2-amino-3-chloropyridine-4-yl)thio)-6-chloropyrazine-2-amine

[0230] [ka]

[0231] Step 1: 3-Chloro-4-iodopyridine-2-amine A solution of 3-chloro-2-fluoro-4-iodopyridine (2.0 g, 7.77 mmol) in 1,4-dioxane (8 mL) and 30% NH4OH in H2O (20 mL, 155.3 mmol) was refluxed for 3 hours. The mixture was diluted with siRNA and H2O, the phases were separated, and the aqueous layer was extracted with siRNA (3 × 10 mL). The collected organic layer was washed with brine (× 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-chloro-4-iodopyridine-2-amine as a brownish solid (1.96 g, quantitative). 1 H NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=5.1 Hz, 1H), 7.11 (d, J=5.1 Hz, 1H), 6.56 (s, 2H). LCMS (ES + ) Method 1: m / z 255 (M+H) + , RT 0.92 minutes.

[0232] Step 2: Methyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate To a solution of 3-chloro-4-iodopyridine-2-amine (1.96 g, 7.70 mmol) and methyl 3-mercaptopropionate (0.92 mL, 8.48 mmol) in degassed dried 1,4-dioxane (30 mL), Pd2(dba)3 (1 g, 1.15 mmol) and [(t-Bu)3PH]BF4 (334 mg, 1.15 mmol) were sequentially added, followed by degassed dried DIPEA (4.0 mL, 23.76 mmol) under an N2 atmosphere. The mixture was stirred at 90°C for 2 hours. Volatile substances were removed under reduced pressure, and the residue was purified by flash chromatography on silica (20% to 100% butyl in petroleum ether) to obtain methyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate as an orange solid (1.8 g, 93%). 1 H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J=5.3 Hz, 1H), 6.57 (d, J=5.4 Hz, 1H), 6.25 (s, 2H) 3.64 (s, 3H), 3.22 (t, J=7.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H); LCMS (ES + ) Method 1: m / z 247 (M+H) + , RT 0.98 minutes.

[0233] Step 3: 2-amino-3-bromo-6-chloropyrazine To a solution of methyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate (1.8 g, 7.29 mmol) in EtOH (22 mL), EtONa (20 wt% solution in EtOH, 3.6 mL, 9.24 mmol) was added at 0°C. The mixture was gradually warmed to room temperature. After 30 minutes, EtOH was removed under reduced pressure, and the residue was diluted with DCM (50 mL). A precipitate of the product was observed, and the solid was filtered and washed with DCM (×3) to obtain the title compound as a red solid (1.3 g, 92%). 1 H NMR (300 MHz, DMSO-d6) δ 7.03 (d, J=5.4 Hz, 1H), 6.46 (d, J=5.3 Hz, 1H), 5.01 (s, 2H). LCMS (ES +) Method 1: m / z 161,163 (M+H) + , RT 0.56 minutes.

[0234] Step 4: 3-((2-amino-3-chloropyridine-4-yl)thio)-6-chloropyrazine-2-amine (intermediate 14) To a solution of 2-amino-3-bromo-6-chloropyrazine (419 mg, 2.01 mmol) and sodium 2-amino-3-chloropyridine-4-thiolate (367 mg, 2.01 mmol) in degassed dried 1,4-dioxane (8 mL), Pd2(dba)3 (184 mg, 0.20 mmol) and [(t-Bu)3PH]BF4 (58.5 mg, 0.202 mmol) were sequentially added under an N2 atmosphere, followed by the addition of dried DIPEA (0.87 mL, 5.02 mmol). The resulting mixture was stirred at 105°C for 1.5 hours. Volatile substances were removed under reduced pressure, and the residue was purified by flash chromatography on a C18 cartridge (5 to 45% MeCN + 0.1% HCO2H in H2O) to obtain the title product as an orange solid (116 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.70 (d, J=5.3 Hz, 1H), 7.17 (s, 2H), 6.39 (s, 2H), 5.97 (d, J=5.3 Hz, 1H). LCMS (ES + ) Method 1: m / z 288 (M+H) + , RT 1.13 minutes. Intermediate 15: Sodium (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate

[0235] [ka]

[0236] Step 1: Methyl(S)-3-((6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate Methyl(S)-3-((6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)propanoate was prepared using intermediate 30 (70 mg, 0.23 mmol) as a starting material, following the procedure used in step 1 of intermediate 13. The compound was purified by flash chromatography on a C18 cartridge (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow solid (68 mg, quantitative). LCMS (ES) + ) Method 1: m / z 295(M+H) + , RT 1.12 minutes.

[0237] Step 2: Sodium (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate (intermediate 15) Sodium (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-thiolate was prepared using (S)-3-((6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-yl)thio)propanoate (68 mg, 0.23 mmol) as a starting material, following the procedure used in intermediate step 3, to obtain the title compound as a white powder (35 mg, 66%). 1 LCMS (ES) + ) Method 1: m / z 209 (M+H) + , RT 1.64 minutes. Intermediates 16 and 17: 3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-amine (16) and (S)-4-((5-chloropyrazine-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (17)

[0238] [ka]

[0239] Step 1: Methyl 3-((5-chloropyrazine-2-yl)thio)propanoate Methyl 3-((5-chloropyrazine-2-yl)thio)propanoate was prepared using 2-bromo-5-chloropyrazine (640 mg, 3.31 mmol) and methyl 3-mercaptopropionate (428 mg, 3.56 mmol) as starting materials, following the procedure used in intermediate 13 step 1. The compound was purified by flash chromatography on silica gel (0% to 40% butyl in petroleum ether) to obtain the title compound as a yellow solid (710 mg, 92%). LCMS (ES) + ) Method 1: m / z 233(M+H) + , RT 1.80 minutes.

[0240] Step 2: Sodium 5-chloropyrazine-2-thiolate Sodium 5-chloropyrazine-2-thiolate was prepared using methyl 3-((5-chloropyrazine-2-yl)thio)propanoate (710 mg, 3.05 mmol) as a starting material, following the procedure used in intermediate step 3, to obtain the title compound as a yellow powder (457 mg, 88%). LC-MS (ES) + )m / z 147(M+H) + .

[0241] Step 3A: 3-Chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-amine (Intermediate 16) Starting with 3-chloro-4-iodopyridine-2-amine (430 mg, 1.69 mmol) and sodium 5-chloropyrazine-2-thiolate (250 mg, 1.48 mmol), intermediate 16 was prepared according to the procedure used in intermediate 13 step 1. This intermediate was purified by flash chromatography on a C18 cartridge (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow powder (263 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=1.4 Hz, 1H), 8.65 (d, J=1.4 Hz, 1H), 7.81 (d, J=5.2 Hz, 1H), 6.51 (s, 2H), 6.45 (d, J=5.3 Hz, 1H); LCMS (ES + ) Method 1: m / z 274 (M+H) + , RT 1.16 minutes.

[0242] Step 3B: (S)-4-((5-chloropyrazine-2-yl)thio)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (intermediate 17) Intermediate 17 was prepared using intermediate 30 (100 mg, 0.33 mmol) and sodium 5-chloropyrazine-2-thiolate (59 mg, 0.35 mmol) as starting materials, following the procedure used in step 1 of intermediate 13. The product was purified by flash chromatography on a C18 cartridge (5% to 45% MeCN / H2O + 0.1% TFA) to obtain the title compound as a brown powder (60 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=1.5 Hz, 1H), 8.38 (d, J=1.4 Hz, 1H), 7.66 (d, J=5.3 Hz, 1H), 6.54 (d, J=5.3 Hz, 1H), 4.49 (dd, LCMS (ES) + ) Method 1: m / z 321 (M+H) + , RT 1.23 minutes. Intermediate 18: 8-bromo-5-chloroimidazo[1,2-c]pyrimidine

[0243] [ka]

[0244] Step 1: 5-Bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidine-4-amine Aminoacetaldehyde dimethyl acetal (1.5 mL, 13.76 mmol) was added at 0°C to a solution of 5-bromo-2,4-dichloropyrimidine (2.05 g, 8.99 mmol) and dried TEA (2.0 mL, 14.35 mmol) in EtOH (15 mL). The mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was concentrated, then diluted with siRNA and washed with H2O (×2). The organic layer was washed with brine (×2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a white powder (2.63 g, 98%). 1 H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.65 (br t, J=5.7 Hz, 1H), 4.58 (t, J=5.4 Hz, 1H), 3.48 (t, J=5.7 Hz, 2H), 3.31-3.26 (m, 6H); LCMS (ES + ) Method 1: m / z 296 (M+H) +, RT 1.62 minutes.

[0245] Step 2: 8-Bromoimidazo[1,2-c]pyrimidine-5-ol A suspension of 5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidine-4-amine (2.63 g, 8.86 mmol) in concentrated H2SO4 (8 mL) was stirred at 75°C for 40 minutes. The mixture was cooled to 0°C, and 5N NaOH (50 mL) was added until a precipitate was observed (pH=6). The solid was filtered, and the filtrate was extracted with ₹ (3 × 5 mL). The collected organic layer was washed with brine (× 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain a beige powder (1.52 g; 80%). 1 LCMS (ES) + ) Method 1: m / z 214 (M+H) + , RT 0.64 minutes.

[0246] Step 3: 8-bromo-5-chloroimidazo[1,2-c]pyrimidine (intermediate 18) In a sealed microwave vial, dried DIPEA (1.6 mL, 9.2 mmol) was added at 0°C to a suspension of 8-bromoimidazo[1,2-c]pyrimidine-5-ol (380 mg, 1.78 mmol) in POCl3 (8 mL, 85.6 mmol). The mixture was stirred at 115°C for 9 hours, cooled, and slowly added to a stirred mixture of cold H2O and RINKAN. The organic layer was washed with H2O (2 × 10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by flash chromatography on a C18 cartridge (0% to 35% MeCN / H2O + 0.1% TFA) to obtain the title compound as a beige powder (170 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ 8.22-8.18 (m, 2H), 7.85 (d, J=1.5 Hz, 1H). LCMS (ES + ) Method 1: m / z 232 (M+H) + , RT 1.21 minutes. Intermediate 19: (R)-2-methyl-N-((S)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)propan-2-sulfinamide bis(2,2,2-trifluoroacetate)

[0247] [ka]

[0248] Step 1: 1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbaldehyde A suspension of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbaldehyde (1.0 g, 7.34 mmol) in dry MeCN (20.0 mL) was treated with K2CO3 (2.54 g, 18.36 mmol) and benzyl bromide (1.48 mL, 12.49 mmol), and heated at 70°C for 18 hours. After cooling, the reaction mixture was diluted with toluene (200 mL), washed with H2O (2×) and brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash chromatography (gradient elution of 0-20% siRNA in petroleum ether) to obtain the title compound (1.5 g, 90%). 1 H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.44-7.14 (m, 5H), 5.35 (s, 2H), 5.17 (t, J=5.7 Hz, 1H), 4.50 (d, J=5.7 Hz, 1H), 2.71-2.39 (m, 4H).LCMS (ES + ) Method 2: m / z 227 (M+H) + , RT 1.68 minutes.

[0249] Step 2: 1-(tert-butyl)4-ethyl4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate A solution of 1-(tert-butyl)4-ethylpiperidine-1,4-dicarboxylate (1.3 g, 2.69 mmol) cooled to -78°C in dry THF (11.2 mL) was treated with LDA (2N in THF; 3.31 mL, 6.63 mmol). The reaction mixture was stirred at this temperature for 10 minutes, and then treated with a solution of 1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbaldehyde (1.5 g, 6.63 mmol) in dry THF (2.8 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated NH4Cl solution at 0°C and extracted with ELISA (2×). The combined organic materials were washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether). The title compound was obtained as a white powder (1.3 g, 41%).

[0250] Step 3: tert-butyl 4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate A solution of 1-(tert-butyl)4-ethyl4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (1.3 g, 2.69 mmol) in dry THF (6.8 mL), cooled to 0°C, was treated with LiAlH4 (1N in THF; 3.23 mL, 3.23 mmol), and the mixture was stirred at 0°C for 4 hours. The reaction product was slowly quenched with citric acid (10% aqueous solution), then diluted with ELISA, and washed with saturated Rochelle salt solution. The phases were separated, the organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a white solid (1.11 g, 93%), which was used as the crude product in the next step. LCMS(ES) + ) Method 2: m / z 442(M+H) + , RT 1.83 minutes.

[0251] Step 4: tert-butyl 4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate A solution of tert-butyl 4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.11 g, 2.51 mmol) cooled to 0°C in dry DCM (9.5 mL) was treated with DIPEA (1.32 mL, 7.54 mmol) and methanesulfonyl chloride (0.42 mL, 5.52 mmol). The mixture was stirred at 0°C for 50 minutes and then quenched with citric acid (10% aqueous solution; 50 mL). The phases were separated, the organic layer was washed with H2O (50 mL) and brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% ethyl acetate in petroleum ether). The title compound was obtained as a brownish solid (789 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.26 (m, 3H), 7.18 (br d, J=7.0 Hz, 2H), 5.33 (d, J=4.2 Hz, 1H), 5.14 (s, 2H), 4.53 (d, J=4.2 Hz, 1H), 4.32 (d, J=9.7 Hz, 1H), 4.19 (d, J=9.7 Hz, 1H), 3.58-3.45 (m, 2H), 3.15 (s, 3H), 3.12-3.05 (m, 2H), 2.60-2.53 (m, 2H), 2.44-2.39 (m, 2H), 1.58-1.40 (m, 4H), 1.36 (s, 9H), 1.36-1.33 (m, 2H). LCMS (ES + ) Method 2: m / z 520 (M+H) + , RT 1.95 minutes.

[0252] Step 5: tert-butyl 8-hydroxy-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate A solution of tert-butyl 4-((1-benzyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (789 mg, 1.52 mmol) in 1-BuOH (9.2 mL) was heated in a sealed tube at 120°C for 2 hours. Ammonium formate (287.2 mg, 4.55 mmol) and Pd(OH)2 (100 mg, 0.71 mmol) were carefully added, and the mixture was heated at 120°C for 1 hour. After cooling, the mixture was filtered through a Celite pad and washed with SiO2 and MeOH. The filtrate was evaporated under reduced pressure, and the residue was ground with SiO2. The solid was filtered off, and the filtrate was evaporated under reduced pressure. The title compound was obtained as a yellow powder (460 mg, 91%), which was used as the crude product. LCMS(ES) + ) Method 2: m / z 334(M+H) + , RT 1.48 minutes.

[0253] Step 6: tert-butyl 8-oxo-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate A solution of tert-butyl 8-hydroxy-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate (460 mg, 1.38 mmol) cooled to 0°C in DCM (6.9 mL) was treated with des-martin periodinane (643.7 mg, 1.52 mmol). The resulting mixture was heated to room temperature and stirred for 90 minutes. The reaction mixture was then cooled to 0°C and treated with Na2S2O3 (1 M aqueous solution) to separate the phases. The aqueous phase was extracted with DCM (60 mL). The combined organic matter was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-70% siRNA in petroleum ether). The title compound was obtained as a white powder (287 mg, 63%). 1 H NMR (400 MHz, DMSO-d6) δ 4.44 (s, 2H), 3.94 (br d, J=12.5 Hz, 2H), 2.96 (br s, 2H), 2.74-2.66 (m, 4H), 2.42-2.35 (m, 2H), 1.68-1.60 (m, 4H), 1.42 (s, 9H). LCMS (ES + ) Method 2: m / z 332 (M+H) + , RT 1.82 minutes.

[0254] Step 7: tert-butyl(S,Z)-8-((tert-butylsulfinyl)imino)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate A solution of tert-butyl 8-oxo-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate (287.0 mg, 0.87 mmol) and (R)-2-methylpropane-2-sulfinamide (315.0 mg, 2.60 mmol) in Ti(OEt)4 (2.18 mL, 10.39 mmol) and THF (2.0 mL) was heated at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with siRNA and H2O. The resulting solid was filtered off and washed with siRNA. The phases were separated, the organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-70% siRNA in petroleum ether). The title compound was obtained as a yellow powder (161 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 4.39 (s, 2H), 4.02-3.95 (m, 2H), 2.91-2.80 (m, 3H), 2.76-2.72 (m, 3H), 2.37-2.32 (m, 2H), 1.78-1.71 (m, 4H), 1.41 (s, 9H), 1.13 (s, 9H).LCMS (ES + ) Method 2: m / z 435 (M+H) + , RT 1.90 minutes.

[0255] Step 8: tert-butyl(S)-8-(((S)-tert-butylsulfinyl)amino)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate A solution of tert-butyl(S,Z)-8-((tert-butylsulfinyl)imino)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate (161.0 mg, 0.37 mmol) cooled to -50°C in THF (2.3 mL) was treated with NaBH4 (21.0 mg, 0.56 mmol), and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with H2O, and the phases were separated. The organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL), and the solution was heated under reflux for 1 hour. After removing volatiles under reduced pressure, the residue was purified by flash chromatography (gradient elution of 0-2.5% MeOH in ethyl acetate). The title compound was obtained as a white powder (65 mg, 24%, diastereomer ratio 90 / 10). LC-MS (ES) + ) Method 2: m / z 437(M+H) + , RT 1.72 minutes.

[0256] Step 9: (S)-2-methyl-N-((S)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)propan-2-sulfinamide bis(2,2,2-trifluoroacetate) (Intermediate 19) A solution of tert-butyl(S)-8-(((S)-tert-butylsulfinyl)amino)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-1'-carboxylate (65.0 mg, 0.15 mmol) in DCM (1.2 mL) was treated with TFA (0.3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was then azeotropically removed with toluene and Et2O to obtain the title compound as a colorless oil (130 mg, purity 50%, 77%, diastereomer ratio 88 / 12), which was used as the crude product in the next step. LCMS (ES + ) Method 2: m / z 337(M+H) + , RT 0.98 min. Intermediate 20: 2-amino-3-chloropyridine-4-thiol

[0257] [ka]

[0258] Step 1: tert-butyl(tert-butoxycarbonyl)(3-chloro-4-iodopyridine-2-yl)carbamate A solution of 3-chloro-4-iodopyridine-2-amine (1.12 g, 4.40 mmol) and Boc2O (5.06 mL, 22.01 mmol) in DCM (44.0 mL) was treated with DMAP (107 mg, 0.88 mmol) and TEA (1.84 mL, 13.2 mmol) and stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM, washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 5-50% siRNA in petroleum ether). The title compound was obtained as a white powder (1.85 g, 92%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J=5.0 Hz, 1H), 7.78 (d, J=5.0 Hz, 1H), 1.43 (s, 18H); LCMS (ES + ) Method 2: m / z 455 (M+H) + , RT 2.28 minutes.

[0259] Step 2: 2-Ethylhexyl 3-((2-(bis(tert-butoxycarbonyl)amino)-3-chloropyridine-4-yl)thio)propanoate A solution of tert-butyl(tert-butoxycarbonyl)(3-chloro-4-iodopyridine-2-yl)carbamate (1.83 g, 4.02 mmol) and 2-ethylhexyl 3-mercaptopropanoate (1.01 mL, 4.43 mmol) in degassed dried 1,4-dioxane (20.0 mL) was treated with Pd2(dba)3 (99.17 mg, 0.11 mmol), Xantphos (125.33 mg, 0.22 mmol), and DIPEA (1.4 mL, 8.05 mmol), and the mixture was stirred at 95°C for 2 hours. After cooling, the reaction mixture was filtered on a solka floc pad, then volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound as an orange oily substance (2.19 g, 99%). 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J=5.0 Hz, 1H), 7.09 (d, J=5.0 Hz, 1H), 4.12-4.04 (m, 2H), 3.28 (t, J=7.3 Hz, 2H), 2.76 (t, J=7.3 Hz, 2H), 1.64-1.55 (m, 1H), 1.42 (s, 18H), 1.39-1.26 (m, 8H), 0.91 (t, J=7.2 Hz, 6H); LCMS (ES + ) Method 2: m / z 545 (M+H) + , RT 2.85 minutes.

[0260] Step 3: 2-amino-3-chloropyridine-4-thiol (intermediate 20) A solution of 2-ethylhexyl 3-((2-(bis(tert-butoxycarbonyl)amino)-3-chloropyridine-4-yl)thio)propanoate (2.51 g, 4.60 mmol) cooled to -78°C in THF (16.0 mL) was treated with t-BuOK (1.0 M solution in THF; 9.21 mL, 9.21 mmol), and the mixture was stirred at -78°C for 1 hour. After adding H2O, the organic solvent was removed under reduced pressure. The aqueous phase was washed with Et2O (3×), and the collected organic matter was concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution of 0-100% MeCN in H2O) to obtain a mixture of mono and bis-Boc products (2 / 1 ratio). The mixture was dissolved in 1,4-dioxane / saturated NaHCO3 aqueous solution (50 mL, 1 / 1 volume / volume) and treated with Boc2O (1.0 g). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was converted to H2O. i The aqueous phase was diluted with a mixture of PrOH / CHCl3 (9 / 1) and washed with HCl (1N). i Extraction was performed with PrOH / CHCl3(9 / 1) solution. The organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% MeCN / H2O + 0.1% TFA). The title compound was obtained as a yellow powder (664 mg, 90%). 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.9 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H). LCMS (ES + ) Method 2: m / z 161 (M+H) + , RT 0.32 minutes. Intermediate 21: 3-Chloro-2-((4-methoxybenzyl)amino)pyridine-4-thiol

[0261] [ka]

[0262] Step 1: 3-Chloro-4-iodo-N-(4-methoxybenzyl)pyridine-2-amine A solution of 3-chloro-2-fluoro-4-iodopyridine (1.0 g, 3.88 mmol) in DMSO (10.0 mL) was treated with 4-methoxybenzylamine (1.02 mL, 7.77 mmol) and stirred at 80°C for 4 hours. After cooling, the mixture was diluted with siRNA and H2O, the two phases were separated, the organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether). The title compound was obtained as a colorless oil (1.35 g, 93%). 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J=5.3 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.06 (d, J=5.3 Hz, 1H), 6.89 (d, J=8.1 Hz, 2H), 5.35 (br s, 1H), 4.58 (d, J=5.5 Hz, 2H), 3.81 (s, 3H). LCMS (ES + ) Method 2: m / z 375 (M+H) + , RT 2.31 minutes.

[0263] Step 2: 2-Ethylhexyl 3-((3-chloro-2-((4-methoxybenzyl)amino)pyridine-4-yl)thio)propanoate In the synthesis of intermediate 20, the procedure described in step 2 was used to obtain the title compound as an orange oily substance (1.61 g, 96%). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=5.5 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.47 (d, J=5.7 Hz, 1H), 5.22 (br s, 1H), 4.61 (d, J=5.5 Hz, 2H), 4.10-4.03 (m, 2H), 3.81 (s, 3H), 3.24 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 1.62-1.55 (m, 1H), 1.40-1.25 (m, 8H), 0.90 (t, J=7.5 Hz, 6H); LCMS (ES + ) Method 2: m / z 465 (M+H) + , RT 2.75 minutes.

[0264] Step 3: 3-Chloro-2-((4-methoxybenzyl)amino)pyridine-4-thiol (intermediate 21) A solution of 2-ethylhexyl 3-((3-chloro-2-((4-methoxybenzyl)amino)pyridine-4-yl)thio)propanoate (1.61 g, 3.46 mmol) in MeOH (34.7 mL, 0.86 mol) was treated with NaOMe (25% by weight in MeOH; 13.23 mL, 14.54 mmol), and the mixture was stirred at room temperature for 18 hours. After adding H2O, the solvent was removed under reduced pressure. The aqueous phase was washed with Et2O (3×), then cooled to 0°C, acidified with HCl (6N aqueous solution), and extracted with a mixture of CHCl3 / iPrOH (9 / 1). The organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (960 mg, 99%), which was used as the crude product. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J=5.3 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.56 (d, J=5.3 Hz, 1H), 5.25 (br s, 1H), 4.61 (d, J=5.0 Hz, 2H), 3.81 (s, 3H). LCMS (ES +) Method 2: m / z 281 (M+H) + , RT 1.11 minutes. Intermediate 22: 3-amino-5-chloropyrazine-2-thiol

[0265] [ka]

[0266] Step 1: Methyl 3-((3-amino-5-chloropyrazine-2-yl)thio)propanoate A solution of 3-bromo-6-chloropyrazine-2-amine (1.0 g, 4.8 mmol) in degassed dried 1,4-dioxane (10 mL) was treated with Pd(OAc)2 (26.93 mg, 0.12 mmol), Xantphos (138.80 mg, 0.24 mmol), methyl 3-mercaptopropionate (0.53 mL, 4.8 mmol), and DIPEA (1.67 mL, 9.6 mmol). The mixture was stirred in a sealed vial at 95°C for 18 hours. After cooling, the reaction mixture was filtered through a solka floc pad. Volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 5-50% siRNA in petroleum ether) to obtain the title compound as a pale yellow powder (1.06 g, 89%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 4.83 (br s, 2H), 3.72 (s, 3H), 3.47 (t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H); LCMS (ES + ) Method 2: m / z 248 (M+H) + , RT 1.53 minutes.

[0267] Step 2: 3-amino-5-chloropyrazine-2-thiol (intermediate 22) A solution of methyl 3-((3-amino-5-chloropyrazine-2-yl)thio)propanoate (1.06 g, 4.28 mmol) cooled to -30°C in THF (8.6 mL) was treated with EtONa (20 wt% solution in EtOH; 9.9 mL, 5.56 mmol). The mixture was gradually warmed to room temperature. After 2 hours, EtOH was removed under reduced pressure, and the residue was diluted with DCM. Precipitation of the product was observed, the solid was filtered, and treated with aqueous NaOH (1N) solution. The aqueous phase was washed with DCM and treated with aqueous HCl (6N) solution. A yellow solid precipitated, which was filtered and dried to obtain the title compound (0.69 g, 99%). 1 H NMR (400 MHz, DMSO-d6) δ 14.07 (br s, 1H), 7.85 (br s, 1H), 7.11 (s, 1H), 6.96 (br s, 1H). LCMS (ES + ) Method 2: m / z 162 (M+H) + , RT 0.68 minutes. Intermediate 23: 1-Acetyl-4-((3-amino-5-chloropyrazine-2-yl)thio)-3,3-difluoroindorin-2-one

[0268] [ka]

[0269] Step 1: 3,3-difluoro-4-iodoindoline-2-one A solution of 4-iodoindoline-2,3-dione (780 mg, 2.86 mmol) cooled to 0°C in DCM (10.6 mL) was treated dropwise with N,N-diethyl-1,1,1-trifluoro-λ-4-sulfanamine (1.13 mL, 8.57 mmol). The resulting mixture was stirred at room temperature for 18 hours, and then added dropwise to an aqueous solution of NaHCO3 (1.95 g in 10.5 mL of H2O) with vigorous stirring. The layers were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic layers were washed with H2O and brine, dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound as a brown powder (425 mg, purity 87%, 44%). 1 H NMR (400 MHz, DMSO-d6) δ 11.3 (br s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H); LCMS (ES + ) Method 1: m / z 296 (M+H) + , RT 1.60 minutes.

[0270] Step 2: 1-acetyl-3,3-difluoro-4-iodoindoline-2-one A solution of 3,3-difluoro-4-iodoindorin-2-one (200 mg, 0.680 mmol) cooled to 0°C in THF (2.6 mL) was treated dropwise with boranedimethyl sulfide complex (2 M in THF; 1.36 mL, 2.71 mmol). The resulting mixture was stirred at room temperature for 2 hours, and then quenched by dropwise addition of 10% aqueous citric acid (1 mL). H₂O (5 mL) was then added, and the mixture was extracted with SiO₂ (2 × 30 mL). The combined organic layer was washed with brine, dehydrated with Na₂SO₄, filtered, and partially concentrated under reduced pressure. DIPEA (0.24 mL, 1.36 mmol) and AcCl (0.1 mL, 1.36 mmol) were added at 0°C, and the mixture was stirred for 2 hours. H₂O was added, and the organic layer was separated. The aqueous phase was extracted with SiO₂. The combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound (70 mg, 32%). LC-MS (ES) + ) Method 1: m / z 323(M+H) + , RT 1.73 minutes.

[0271] Step 3: 1-Acetyl-4-((3-amino-5-chloropyrazine-2-yl)thio)-3,3-difluoroindorin-2-one (intermediate 23) A suspension of degassed Xantphos (25.71 mg, 0.04 mmol), 3-amino-5-chloropyrazine-2-thiol (intermediate 22; 49.52 mg, 0.31 mmol), 1-acetyl-3,3-difluoro-4-iodoindoline-2-one (90.0 mg, 0.28 mmol), DIPEA (0.15 mL, 0.89 mmol), and Pd2(dba)3 (20.34 mg, 0.02 mmol) in 1,4-dioxane (2.0 mL) was heated at 65°C for 1 hour. After cooling, the reaction mixture was filtered through a solka floc pad. Volatiles were removed under reduced pressure, and the title compound was used as the crude product. LCMS (ES) + ) Method 1: m / z 355(MH) - , RT 1.64 minutes. Intermediate 24: 1-benzyl-4,6-dihydro-1H-fl[3,4-c]pyrazole-3-carbaldehyde

[0272] [ka]

[0273] Step 1: Ethyl 2-oxo-2-(4-oxotetrahydrofuran-3-yl) acetate A solution of dihydrofuran-3(2H)-one (2.0 g, 23.23 mmol) cooled to -78°C in THF (120 mL) was treated with LDA (2N in THF; 11.62 mL, 23.23 mmol) and stirred at -78°C for 15 minutes. Diethyl oxalate (3.47 mL, 25.55 mmol) was added, and the reaction mixture was stirred at -78°C for 30 minutes, then stirred at room temperature for 3 hours. The reaction mixture was quenched with 1N aqueous HCl and then partitioned between siRNA and aqueous citric acid. The organic phase was separated, washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (3.5 g, 81%), which was used without further purification.

[0274] Step 2: Ethyl 1-benzyl-4,6-dihydro-1H-fl[3,4-c]pyrazole-3-carboxylate A solution of ethyl 2-oxo-2-(4-oxotetrahydrofuran-3-yl) acetate (3.5 g, 18.8 mmol) in EtOH (25 mL) was treated with sulfuric acid (0.25 mL, 13.55 mmol) and benzylhydrazine dihydrochloride (3.67 g, 18.8 mmol), and the reaction mixture was heated at 85 °C for 30 minutes. After cooling to room temperature, the reaction product was neutralized by the addition of 2N NaOH. The mixture was then concentrated under vacuum, and the residue was partitioned between pharmaceutically acceptable ammonium compounds and H₂O. The organic phase was separated, washed with saturated NaHCO₃ solution and brine, dehydrated with Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-50% pharmaceutically acceptable ammonium compounds in petroleum ether) to obtain the title compound as a yellow oily substance (1.45 g, 28%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 3H), 7.30-7.28 (m, 2H), 5.31 (s, 2H), 4.94-4.92 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.30-4.28 (m, 2H), 1.38 (t, J=7.3 Hz, 3H); LCMS (ES + ) Method 1: m / z 273 (M+H) + , RT 1.59 minutes.

[0275] Step 3: (1-benzyl-4,6-dihydro-1H-fluoro[3,4-c]pyrazole-3-yl)methanol A solution of ethyl 1-benzyl-4,6-dihydro-1H-flu[3,4-c]pyrazole-3-carboxylate (1.7 g, 6.24 mmol) in THF (50 mL) was treated with LiAlH4 (1 M in THF; 7.49 mL, 7.49 mmol) at 0°C, and the mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched at 0°C by adding H2O (1.1 mL) and 15% NaOH in H2O (0.28 mL). Then Na2SO4 was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered through a solka floc pad, and the filtrate was concentrated to dryness to obtain the title compound as a colorless oil (1.33 g, 93%). LCMS (ES) + ) Method 1: m / z 231(M+H) + , RT 1.03 minutes.

[0276] Step 4: 1-benzyl-4,6-dihydro-1H-fl[3,4-c]pyrazole-3-carbaldehyde (intermediate 24) A solution of (1-benzyl-4,6-dihydro-1H-fluoro[3,4-c]pyrazole-3-yl)methanol (1.33 g, 5.78 mmol) in DCM (50 mL) was treated at 0°C with saturated NaHCO3 solution (1.46 g, 17.33 mmol) and Des-Martin periodinane (3.18 g, 7.51 mmol), and the mixture was stirred at this temperature for 2 hours. The reaction product was quenched by adding 1 M Na2S2O3 aqueous solution and extracted by DCM (3×). The combined organic layer was washed with saturated NaHCO3 solution and brine, dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-30% phenylethylamine in petroleum ether) to obtain the title compound as a white powder (1.1 g, 83%). LCMS (ES) + ) Method 1: m / z 229(M+H) + , RT 1.38 minutes. Intermediate 25: (R)-N-((S)-1,8-dihydro-3H,6H-spiro[flo[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide

[0277] [ka]

[0278] (R)-N-((S)-1,8-dihydro-3H,6H-spiro[flo[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide bis(2,2,2-trifluoroacetate) was prepared according to the procedure described for intermediate 19 (using 1-benzyl-4,6-dihydro-1H-flo[3,4-c]pyrazole-3-carbaldehyde intermediate 24 in step 2 and Pd / C (10 wt / wt%) instead of Pd(OH)2 in step 5). Intermediate 25 was obtained as a colorless oil. LCMS(ES + ) Method 1: m / z 339(M+H) + , RT 0.75 min. Intermediate 26: 8-bromo-5-chloroimidazo[1,5-a]pyrazine

[0279] [ka]

[0280] Step 1: 2-Bromo-3-(bromomethyl)-5-chloropyrazine A solution of 2-bromo-5-chloro-3-methylpyrazine (1.0 g, 4.82 mmol) in CCl4 (10 mL) was treated with NBS (1.29 g, 7.23 mmol) and 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (166.6 mg, 0.96 mmol). The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with DCM and H2O. The phases were separated, the organic phase was washed with brine, dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-12% siRNA in petroleum ether) to obtain the title compound as a yellow oily substance (664 mg, purity 75%, 36%).

[0281] Step 2: N-((3-bromo-6-chloropyrazine-2-yl)methyl)formamide A solution of 2-bromo-3-(bromomethyl)-5-chloropyrazine (984 mg, 3.44 mmol) in DMF (5.7 mL) was treated with sodium diformylamide (490 mg, 5.15 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. MeOH (11.4 mL) and H2O (114 μL) were added, and the resulting mixture was stirred at 70°C for 1 hour. Volatile substances were removed under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 0-100% ethyl phosphate in petroleum ether) to obtain the title compound as a yellow solid (325 mg, purity 75%, 28%). LC-MS (ES) + ) Method 1: m / z 248-250(M+H) + , RT 0.90 min.

[0282] Step 3: 8-bromo-5-chloroimidazo[1,5-a]pyrazine (intermediate 26) A solution of N-((3-bromo-6-chloropyrazine-2-yl)methyl)formamide (160.0 mg, 0.64 mmol) dissolved in POCl3 (1.5 mL, 0.64 mmol) was heated at 90°C for 30 minutes. After the mixture cooled to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and treated with saturated aqueous NaHCO3 solution. The phases were separated, and the organic phase was washed with H2O and brine. The organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with MeOH, the solid was filtered, and washed again with MeOH. The solvent was concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (130 mg, 87%). LCMS (ES) + ) Method 1: m / z 230-232(M+H) + , RT 1.14 minutes. Intermediate 27: 6-Chloro-3-((8-Chloro-2-methylimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-amine

[0283] [ka]

[0284] In Step 2, intermediate 22 was used, and the above intermediate was prepared according to the procedure described for intermediate 41. Intermediate 27 was obtained as an orange solid (52 mg, 46%). LC-MS (ES) + ) Method 1: m / z 326(M+H) + , RT 1.33 minutes. Intermediate 28: (S)-4'-iodo-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]

[0285] [ka]

[0286] Step 1: tert-butyl(S)-6-(((2-fluoropyridine-3-yl)oxy)methyl)-5-azaspiro[2.4]heptane-5-carboxylate 2-Fluoro-3-hydroxypyridine (850 mg, 7.51 mmol) and tert-butyl(6S)-6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate (2.13 g, 9.39 mmol) were dissolved in dry THF (15.0 mL), and then PPh3 (3.94 g, 15.03 mmol) and DIAD (2.95 mL, 15.03 mmol) were added at room temperature under an argon atmosphere. The resulting mixture was stirred for 18 hours. The mixture was concentrated, and the crude product was purified by column chromatography (eluate: 0-50% ethyl acetate in cyclohexane) to obtain the title compound (1.26 g, 52%) as a yellow oil. LCMS (ES) + ) Method 5: m / z 267[M+H-tBu] + .

[0287] Step 2: (S)-6-(((2-fluoropyridine-3-yl)oxy)methyl)-5-azaspiro[2.4]heptane tert-butyl(S)-6-(((2-fluoropyridine-3-yl)oxy)methyl)-5-azaspiro[2.4]heptane-5-carboxylate (1.26 g, 3.92 mmol) was dissolved in DCM (7 mL) and treated with HCl (4 N; 7.0 mL) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 4 hours. After completion, the solvent was evaporated under reduced pressure. The crude product was diluted in DCM and concentrated to obtain the title compound (1.02 g, quantitatively) as a grayish-white solid (2 × HCl salt). LC-MS (ES) + ) Method 6: m / z 223[M+H] + .

[0288] Step 3: (S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (S)-6-(((2-fluoropyridine-3-yl)oxy)methyl)-5-azaspiro[2.4]heptane (1.02 g, 4.58 mmol) was dissolved in EtOH (27.5 mL), and K2CO3 (3.17 g, 22.92 mmol) was added. The mixture was stirred at 65°C for 18 hours, then filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (eluate: 0-40% ethyl ethyl hydroxyl in cyclohexane) to obtain the title compound (448 mg, 51%) as a yellow oil. LCMS (ES + ) Method 5: m / z 203[M+H] + .

[0289] Step 4: (S)-4'-iodine-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (intermediate 28) (S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (285 mg, 1.40 mmol) was dissolved in dry THF (7.0 mL), and then t-BuLi (1.7 M in pentane; 2.90 mL, 4.93 mmol) was added dropwise under an N2 atmosphere at -78°C. The mixture was stirred at this temperature for 1 hour. Then, a solution of I2 (715.3 mg, 2.81 mmol) in dry THF (1.0 mL) was added dropwise at -78°C. The resulting mixture was warmed to room temperature and stirred for 3 hours. At completion, the reaction was quenched with H2O at 0°C and extracted with SiO(3×). The phases were separated, the organic phase was washed with brine, dehydrated with Na2SO4, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (eluent: 0-10% siRNA in cyclohexane) to obtain the title compound (308 mg, 66%) as a white solid. 1H NMR (500 MHz DMSO-d6) δ 7.28 (d, J=5.3 Hz, 1H), 6.85 (d, J=5.3 Hz, 1H), 4.54 (dd, J=10.4, 3.4 Hz, 1H), 3.93-3.84 (m, 1H), 3.56 (d, J=10.5 Hz, 1H), 3.49 (t, J=10.0 Hz, 1H), 3.16 (d, J=10.6 Hz, 1H), 1.83 (t, J=10.9 Hz, 1H), 1.62 (dd, J=11.8, 5.7 Hz, 1H), 0.72-0.55 (m, 4H); LCMS (ES + ) m / z 329 [M+H] + Intermediate 29: 2-Ethylhexyl 3-(((S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)propanoate

[0290] [ka]

[0291] Step 1: 2-Ethylhexyl 3-(((S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)propanoate (intermediate 29) Intermediate 28 (200 mg, 0.61 mmol) was dissolved in dried 1,4-dioxane (2.0 mL), and heptane-3-yl-3-mercaptopropanoate (152.5 μL, 0.67 mmol), Xantphos (35.2 mg, 0.06 mmol), Pd2(dba)3 (33.5 mg, 0.04 mmol), and DIPEA (212.9 μL, 1.22 mmol) were added at 20°C. The mixture was purged with argon and heated in a pressure vessel at reflux temperature for 1 hour. After completion, the mixture was diluted with H2O and extracted with DCM (×3). The combined organic extract was washed with brine (×2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluate: 0-30% siRNA in cyclohexane) to obtain the title compound (245 mg, 96%) as an orange oil. 1 H NMR (500 MHz, CDCl3) δ 7.65 (d, J=5.4 Hz, 1H), 6.41 (d, J=5.4 Hz, 1H), 4.50 (dd, J=10.3, 3.3 Hz, 1H), 4.05-3.94 (m, 3H), 3.72 (d, J=10.0 Hz, 1H), 3.52 (t, J=9.9 Hz, 1H), 3.30 (d, J=10.2 Hz, 1H), 3.18 (t, J=7.5 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.86 (t, J= 0.9 Hz, 1H), 1.70-1.60 (m, 1H), 1.58-1.50 (m, 1H), 1.39-1.31 (m, 2H), 1.27 (s, 6H), 0.88 (t, J=7.3 Hz, 6H), 0.78-0.58 (m, 4H); LCMS (ES + ) Method 9: m / z 419 [M+H] + . Intermediate 30: (S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine

[0292] [ka]

[0293] Step 1: tert-butyl(S)-2-(((2-fluoropyridine-3-yl)oxy)methyl)pyrrolidine-1-carboxylate 2-Fluoro-3-hydroxypyridine (300 mg, 2.65 mmol) and Boc-L-prolinol (640.7 mg, 3.18 mmol) were dissolved in dry THF (5.3 mL), and then PPh3 (1.04 g, 3.98 mmol) and DEAD (624 μL, 3.98 mmol) were added at room temperature under an N2 atmosphere. The resulting mixture was stirred at room temperature for 18 hours, concentrated, and the crude product was purified by column chromatography (eluate: 0-20% RINKAN in cyclohexane) to obtain the title compound (403 mg, 51%) as a pale yellow oil. LCMS (ES) + ) Method 5: m / z 241[M+H-tBu] + .

[0294] Step 2: (S)-2-fluoro-3-(pyrrolidine-2-ylmethoxy)pyridine 353 mg, 1.19 mmol of tert-butyl(S)-2-(((2-fluoropyridine-3-yl)oxy)methyl)pyrrolidine-1-carboxylate was dissolved in 2.1 mL of dichloride (DCM), and 2.1 mL of HCl (4N) in 1,4-dioxane was added. The mixture was stirred at room temperature for 4 hours. After completion, the solvent was evaporated under reduced pressure. The crude product was diluted with DCM and evaporated again. This procedure was repeated three times to obtain the title compound (284 mg, quantitatively) as a white solid (2 × HCl salt). LC-MS (ES) + ) Method 7: m / z 197[M+H] + .

[0295] Step 3: (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (S)-2-fluoro-3-(pyrrolidine-2-ylmethoxy)pyridinebisHCl salt (284 mg, 1.16 mmol) was dissolved in EtOH (6.9 mL), and K2CO3 (800 mg, 5.79 mmol) was added. The mixture was stirred at 65°C for 18 hours. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluate: 0-3% MeOH in CHCl3) to obtain the title compound (191 mg, 93%) as a yellow oil. LCMS (ES) + ) Method 5: m / z 177[M+H] + .

[0296] Step 4: (S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (intermediate 30) (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine (191 mg, 1.08 mmol) was dissolved in dry THF (5.4 mL), and BuLi (2.5 M in hexane; 1.08 mL, 2.71 mmol) was added dropwise under an N2 atmosphere at -78°C. The mixture was heated to 0°C and stirred for 1.5 hours, then cooled again to -78°C, and a solution of I2 (330 mg, 1.30 mmol) in dry THF (650 μL) was added dropwise at -78°C. The resulting mixture was heated to room temperature and stirred for 18 hours, then quenched with saturated NH4Cl aqueous solution and diluted with SiO2. The phases were separated, the organic phase was washed with brine, dehydrated with MgSO4, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (eluent: 0-25% ethyl acetate in cyclohexane) to obtain the title compound (85 mg, 26%) as a beige solid. 1 H NMR (300 MHz DMSO-d6) δ 7.32 (d, J=5.3 Hz, 1H), 6.85 (d, J=5.3 Hz, 1H), 4.58 (dd, J=10.3, 3.5 Hz, 1H), 3.71-3.50 (m, 2H), 3.43 (t, J= 9.8 Hz, 2H), 2.16-1.81 (m, 3H), 1.57-1.39 (m, 1H); LCMS (ES+ ) Method 8: m / z 303 [M+H] + . Intermediate 31: 5-bromo-4-chloro-2-methyl-2H-indazole

[0297] [ka]

[0298] Step 1: 5-bromo-4-chloro-1H-indazole A solution of 4-bromo-3-chloro-2-methylaniline (867 mg, 3.93 mmol) in AcOH (17 mL) was treated with NaNO2 (339.0 mg, 4.91 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, the residue was suspended in H2O, filtered, and washed with H2O and n-heptane. The phases were separated, and the organic phase was concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-30% siRNA in cyclohexane) to obtain the title compound as a pale orange solid (328 mg, 36%). LC-MS (ES) + )m / z 231(M+H) + , RT 1.59 minutes.

[0299] Step 2: 5-bromo-4-chloro-2-methyl-2H-indazole (intermediate 31) A solution of 5-bromo-4-chloro-1H-indazole (1.49 g, 6.45 mmol) in toluene (32 mL) at 0°C was treated with trimethyloxonium tetrafluoroborate (1.43 g, 9.65 mmol). The resulting mixture was heated to room temperature and stirred for 5 hours. After completion, the mixture was quenched with saturated NaHCO3 solution and extracted with toluene. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (gradient elution of 0-30% toluene in n-heptane) to obtain the title compound as an orange solid (900 mg, 57%). 1H NMR (500 MHz, DMSO-d6): 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 + ) m / z 245 (M+H) + , RT 1.69 minutes. Intermediates 32 and 33: 3-chloro-4-iodo-2-(1H-pyrazole-1-yl)pyridine and 2-chloro-5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine

[0300] [ka]

[0301] Step 1: 3-Chloro-4-iodo-2-(1H-pyrazole-1-yl)pyridine (intermediate 32) A solution of 3-chloro-2-fluoro-4-iodopyridine (200 mg, 0.78 mmol), 1H-pyrazole (105.8 mg, 1.55 mmol), and K2CO3 (217.9 mg, 1.55 mmol) in DMF (3 mL) was stirred at 80°C for 3 hours. After cooling, the mixture was treated with 5% citric acid, and the resulting aqueous layer was extracted with DCM (3 × 2 mL). The collected organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound as an amorphous white solid (196 mg, 83%). LCMS (ES) + ) Method 1: m / z 306(M+H) + , RT 1.70 minutes.

[0302] Step 2: 2-Chloro-5-((3-Chloro-2-(1H-Pyrazole-1-yl)pyridine-4-yl)thio)pyrazine (intermediate 33) A solution of sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in the synthesis of steps 1 and 2; 30 mg, 0.18 mmol), 3-chloro-4-iodo-2-(1H-pyrazole-1-yl)pyridine (intermediate 32; 62 mg, 0.20 mmol), Xantphos (10.3 mg, 0.02 mmol), Pd2(dba)3 (16.3 mg, 0.02 mmol), and DIPEA (84 μL, 0.48 mmol) in 1,4-dioxane (0.6 mL) was heated at 110 °C for 1 hour. After cooling, the solvent was removed under reduced pressure to obtain a residue, which was purified by reverse-phase chromatography (15-55% MeCN / H2O + 0.1% TFA). After removing the solvent under reduced pressure, the obtained residue was dissolved in SiO4 and treated with saturated NaHCO3 solution. The organic phase was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure to obtain the title compound as a yellow solid (13 mg, 23%). LCMS(ES + ) Method 1: m / z 324, 26 (M+H) + , RT 1.88 minutes. Intermediates 34 and 35: 3-chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)-4-iodopyridine and 2-chloro-5-((3-chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine

[0303] [ka]

[0304] Step 1: 3-Chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)-4-iodopyridine (intermediate 34) A solution of 3-chloro-2-fluoro-4-iodopyridine (200 mg, 0.78 mmol), 3,5-dimethyl-1H-pyrazole (149.4 mg, 1.55 mmol), and K2CO3 (217.9 mg, 1.55 mmol) in DMF (3 mL) was stirred at 80°C for 8 hours under microwave irradiation. After cooling, the mixture was concentrated under reduced pressure, the residue was dissolved in toluene, and washed with H2O and 5% citric acid. The organic layer was washed with brine, dehydrated with Na2SO4, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of toluene at 0-50% in petroleum ether) to obtain the title compound as a yellowish solid (150 mg, 58%). 1 H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.6 Hz, 2H), 6.07 (s, 1H), 2.18 (s, 3H), 2.12 (s, 3H). LCMS (ES + ) Method 1: m / z 334, 336 (M+H) + , RT 1.79 minutes.

[0305] Step 2: 2-Chloro-5-((3-Chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine (intermediate 35) A solution of sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in the synthesis of steps 1 and 2; 30 mg, 0.18 mmol), intermediate 34 (67 mg, 0.20 mmol), Xantphos (20.5 mg, 0.04 mmol), Pd2(dba)3 (32.5 mg, 0.04 mmol), and DIPEA (92 μL, 0.53 mmol) in 1,4-dioxane (0.6 mL) was heated at 110 °C for 1 hour. After evaporating the solvent under vacuum, the residue was dissolved in DCM (5 mL) and washed with H2O. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel (gradient elution of 25% siRNA in petroleum ether) to obtain the title compound (29 mg, 40%). LCMS (ES) + ) Method 1: m / z 352, 354 (M+H) +, RT 1.95 minutes. Intermediate 36: 3-Chloro-4-((6-chloropyridazine-3-yl)thio)pyridine-2-amine

[0306] [ka]

[0307] Step 1: 3-Chloro-4-((6-chloropyridazine-3-yl)thio)pyridine-2-amine A solution of intermediate 20 (25.1 mg, 0.16 mmol), 3-chloro-6-iodopyridazine (25 mg, 0.10 mmol), Xantphos (12 mg, 0.02 mmol), Pd2(dba)3 (9.5 mg, 0.01 mmol), and DIPEA (54 μL, 0.31 mmol) in 1,4-dioxane (1.0 mL) was heated at 90 °C for 24 hours. After cooling, the solvent was removed under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-70% siRNA + 5% MeOH in petroleum ether) to obtain the title compound as a white powder (12 mg, 42%). LC-MS (ES) + ) Method 1: m / z 273(M+H) + , RT 1.17 minutes. Intermediate 37: tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-1-carboxylate

[0308] [ka]

[0309] Step 1: 1-benzyl-1H-1,2,3-triazole-4-carbaldehyde A suspension of 1H-1,2,3-triazole-5-carbaldehyde (1.0 g, 10.3 mmol), K2CO3 (3.6 g, 25.76 mmol), and benzyl bromide (1.3 mL, 10.96 mmol) in dry MeCN (34 mL) was heated at 70°C for 1 hour. The mixture was diluted with toluene and washed with H2O (×2) and brine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (10% to 30% siRNA in petroleum ether) to obtain the title compound as a white powder (965 mg, 50%). 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.98 (s, 1H), 7.44-7.30 (m, 5H), 5.70 (s, 2H). LCMS (ES + ) Method 1: m / z 188 (M+H) + , RT 1.39 minutes.

[0310] Step 2: 1-(tert-butyl)4-ethyl4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate Starting with 1-benzyl-1H-1,2,3-triazole-4-carbaldehyde (965 mg, 5.15 mmol), the procedure is the same as described in step 2 of the synthesis of intermediate 1. LCMS (ES + ) Method 1: m / z 445(M+H) + , RT 1.94 minutes

[0311] Step 3: tert-butyl 4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate Starting with 1-(tert-butyl)4-ethyl4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (2.0 g, 4.48 mmol), the procedure is the same as that described in step 3 of the synthesis of intermediate 1. LCMS(ES) +)(Method 1)m / z 403(M+H) + , RT 1.65 minutes

[0312] Step 4: tert-butyl 4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate Starting with tert-butyl 4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.74 g, 4.32 mmol), the procedure was carried out in the same manner as described in step 4 of the synthesis of intermediate 1. After purification by flash chromatography on silica gel (20% to 80% phenylethylamine in cyclohexane), a white solid was obtained (838 mg, 40%, 3 steps). 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.40-7.26 (m, 5H), 5.66-5.54 (m, 3H), 4.76 (d, J=4.9 Hz, 1H), 4.38-4.28 (m, 1H), 4.28-4.20 (m, 1H), 3.68-3.47 (m, 2H), 3.19-3.02 (m, 4H), 1.54-1.32 (m, 14H). LCMS (ES + ) Method 1: m / z 481 (M+H) + , RT 1.83 minutes.

[0313] Step 5: tert-butyl4'-hydroxy-4'H,6'H-spiro[cyclohexane-1,5'-pyrrolo[1,2-c][1,2,3]triazole]-4-carboxylate A solution of tert-butyl 4-((1-benzyl-1H-1,2,3-triazole-4-yl)(hydroxy)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (838 mg, 1.74 mmol) in dry MeOH (25 mL) was heated at 90°C for 24 hours in a sealed tube. Volatile substances were removed under reduced pressure. The white powder was dissolved in DME (6 mL), and NaOH (20% in H2O; 2.0 mL, 11.94 mmol) and thiophenol (0.9 mL, 8.74 mmol) were added. The mixture was heated at 90°C for 6 hours. After cooling, the mixture was diluted with ELISA and washed with H2O (×2). The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. After reverse-phase purification (5% to 40% MeCN / H2O + 0.1% TFA), the title compound was obtained as a grayish-white powder (210 mg, 42%, 2 steps). 1 H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 5.79 (d, J=6.9 Hz, 1H), 4.73 (d, J=6.9 Hz, 1H), 4.32-4.21 (m, 2H), 3.66-3.54 (m, 2H), 3.26-3.10 (m, 2H), 1.81-1.69 (m, 1H), 1.57-1.37 (m, 12H). LCMS (ES + ) Method 1: m / z 295 (M+H) + , RT 1.34 minutes

[0314] Step 6: tert-butyl4'-oxo-4'H,6'H-spiro[cyclohexane-1,5'-pyrrolo[1,2-c][1,2,3]triazole]-4-carboxylate Starting with tert-butyl 4'-hydroxy-4'H,6'H-spiro[cyclohexane-1,5'-pyrrolo[1,2-c][1,2,3]triazole]-4-carboxylate (210 mg, 0.713 mmol), the procedure is the same as that described in step 6 of the synthesis of intermediate 1. LCMS (ES + ) method 1m / z 293(M+H) + , RT 1.61 minutes.

[0315] Step 7: tert-butyl(R,Z)-4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-1-carboxylate Starting with tert-butyl4'-oxo-4'H,6'H-spiro[cyclohexane-1,5'-pyrrolo[1,2-c][1,2,3]triazole]-4-carboxylate (208 mg, 0.71 mmol), the same procedure as described in step 7 of the synthesis of intermediate 1 was followed. After purification by flash chromatography on silica gel (0% to 100% ethyl acetate + 5% MeOH in petroleum ether), the title compound was obtained as a white powder (265 mg, 94%, 2 steps). 1 H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 4.75-4.61 (m, 2H), 3.96 (br d, J=13.3 Hz, 2H), 3.09-2.84 (m, 2H), 1.86-1.82 (m, 2H), 1.82-1.62 (m, 2H), 1.42 (s, 9H), 1.22 (s, 9H). LCMS (ES + ) Method 1: m / z 396 (M+H) + , RT 1.87 minutes.

[0316] Step 8: tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-1-carboxylate Starting with tert-butyl(R,Z)-4'-((tert-butylsulfinyl)imino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-1-carboxylate (265 mg, 0.67 mmol), the procedure was carried out in the same manner as described in step 8 of the synthesis of intermediate 1. After purification by flash chromatography on silica gel (0% to 3% MeOH in ethyl acetate), the title compound was obtained as a colorless solid (100 mg, 40%, 2 steps). 1H NMR (300 MHz, DMSO-d6) δ 7.58 (s, 1H), 6.03 (d, J=9.9 Hz, 1H), 4.56 (d, J=10.0 Hz, 1H), 4.35 (dd, J=24.1, 11.8 Hz, 2H), 3.93-3.70 (m, 2H), 3.00 (s, 2H), 1.76-1.58 (m, 3H), 1.41 (s, 10H), 1.15 (s, 9H). LCMS (ES + ) Method 1: m / z 398 (M+H) + , RT 1.53 minutes.

[0317] Step 9: (R)-2-methyl-N-((S)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)propan-2-sulfinamide (intermediate 37) TFA (0.3 mL, 3.92 mmol) was added at room temperature to a solution of tert-butyl(S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-1-carboxylate (100 mg, 0.25 mmol) in DCM. After 2 hours, volatile matter was removed under reduced pressure to obtain a colorless solid (130 mg). LCMS (ES) + ) Method 1: m / z 298(M+H) + . Intermediate 38: (2-(bis(tert-butoxycarbonyl)amino)-3-chloropyridine-4-yl)boronic acid

[0318] [ka]

[0319] Step 1: tert-butyl(4-bromo-3-chloropyridine-2-yl)(tert-butoxycarbonyl)carbamate A solution of 4-bromo-3-chloropyridine-2-amine (106 mg, 0.51 mmol) and Boc2O (558 mg, 2.55 mmol) in DCM (6 mL) was treated with DMAP (12.5 mg, 0.10 mmol) and TEA (0.21 mL, 1.53 mmol). The resulting mixture was stirred at room temperature for 12 hours. H2O (5 mL) was added dropwise, and the mixture was extracted with Et2O (2 × 50 mL). The organic phase was washed with H2O and brine, dehydrated with Na2SO4, concentrated under vacuum, and the residue was purified by flash chromatography (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound as a white solid (184 mg, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 4.0 Hz, 1H), 7.94 (d, J = 4.1 Hz, 1H), 1.36 (s, 18H). LCMS (ES + ) m / z 407, 409 (M+H) + , RT 2.26 minutes.

[0320] Step 2: (2-(bis(tert-butoxycarbonyl)amino)-3-chloropyridine-4-yl)boronic acid (intermediate 38) tert-butyl(4-bromo-3-chloropyridine-2-yl)(tert-butoxycarbonyl)carbamate (100 mg, 0.25 mmol), KOAc (48.2 mg, 0.49 mmol), Pd(dppf)Cl2 · A solution of DCM (20.3 mg, 0.02 mmol) and B2Pin2 (68.5 mg, 0.27 mmol) in 1,4-dioxane (2.5 mL) was stirred at 85°C for 16 hours. After cooling, the mixture was filtered on a solka floc pad, and the filtrate was washed with Â. The organic phase was concentrated under vacuum to obtain the title compound, which was used directly in the next step. LCMS(ES) + )m / z 373(M+H) + , RT 1.55 minutes. Intermediate 39: 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[0321] [ka]

[0322] Step 1: 6-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine 6-Chloro-1H-pyrazolo[3,4-b]pyrazine (850 mg, 5.5 mmol) was suspended in MeCN (7 mL), and then NIS (1.86 g, 8.25 mmol) and HBF4 (48% in H2O; 1.72 mL, 13.14 mmol) were added sequentially. The resulting mixture was refluxed for 3 hours, then cooled in an ice bath and filtered. The yellow precipitate was washed with cold MeCN (×3) to obtain the title compound as a yellow solid (1.25 g, 81%). 1 H NMR (300 MHz, DMSO-d6) δ 14.66 (br s, 1H), 8.70 (s, 1H). LCMS (ES + ) Method 1: m / z 281 (M+H) + , RT 1.65 minutes.

[0323] Step 2: 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (intermediate 39) 6-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (754 mg, 2.69 mmol) was dissolved in DCM (13 mL) and treated with 3,4-dihydro-2H-pyran (0.76 mL, 8.33 mmol) and p-toluenesulfonic acid (155 mg, 0.90 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then poured into saturated NaHCO3 solution (30 mL) and extracted with DCM (×3). The combined organic extract was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (0% to 20% Â in petroleum ether) to obtain the title compound as a pale yellow solid (600 mg, 61%). 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 5.99 (dd, J=10.4 and 2.6 Hz, 1H), 4.14 (m, 1H), 3.82 (m, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H), 1.92-1.74 (m, 2H), 1.67 (m, 1H). LCMS (ES + ) Method 1: m / z 365 (M+H) + , RT 2.16 minutes. Intermediate 40: (R)-2-methyl-N-((S)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-7'-yl)propan-2-sulfinamide

[0324] [ka]

[0325] Step 1: 1-Trityl-1H-1,2,4-triazole-3-carbaldehyde To a solution of 1H-1,2,4-triazole-5-carbaldehyde (257 mg, 2.65 mmol) in dry DMF (6 mL), K₂CO₃ (732 mg, 5.29 mmol) was added at room temperature. After 10 minutes, trityl chloride (1.1 g, 3.97 mmol) was added, and the reaction mixture was stirred at 50°C for 40 minutes. K₂CO₃ (732 mg, 5.29 mmol) was added again, and the reaction mixture was stirred at 50°C for an additional 90 minutes. The reaction mixture was diluted with siRNA, and H₂O was added. The organic layer was separated, washed with H₂O (×2), dehydrated with Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (10% to 30% siRNA in petroleum ether) to obtain the title compound as a grayish-white solid (494 mg, 55%). 1 H NMR (300 MHz, CDCl3) δ 10.07 (d, J=0.6 Hz, 1H), 8.15 (s, 1H), 7.49-7.33 (m, 10H), 7.21-7.10 (m, 5H). LCMS (ES+ ) Method 1: m / z 362 (M+Na) + , RT 2.22 minutes.

[0326] Step 2: 1-(tert-butyl)4-ethyl4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)piperidine-1,4-dicarboxylate LDA (2N in THF; 1.1 mL, 2.12 mmol) was added to a solution of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (0.39 mL, 1.58 mmol) in dry THF (9 mL) at -78°C. After 10 minutes, a solution of 1-trityl-1H-1,2,4-triazole-3-carbaldehyde (589 mg, 1.74 mmol) in dry THF (8 mL) was slowly added. The mixture was warmed to room temperature and stirred for 40 minutes. The reaction product was quenched by the addition of 1N HCl solution and extracted with siRNA. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (30% to 50% siRNA in petroleum ether) to obtain the title compound as a white foam (780 mg, 83%). 1 H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.43-7.30 (m, 9H), 7.21-7.06 (m, 6H), 4.83 (br d, J=7.7 Hz, 1H), 4.19-3.85 (m, 3H), 3.54-3.27 (m, 1H), 3.06-2.87 (m, 1H), 2.87-2.67 (m, 1H), 2.23-2.09 (m, 1H), 2.02-1.90 (m, 1H), 1.72-1.56 (m, 2H), 1.56-1.40 (m, 10H), 1.18 (t, J=7.2 Hz, 3H). LCMS (ES + ) Method 1 m / z 597 (M+H) + , RT 2.50 minutes.

[0327] Step 3: tert-butyl 4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate LiAlH4 (2N solution in THF; 0.11 mL, 0.21 mmol) was added to a solution of 1-(tert-butyl)4-ethyl4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)piperidine-1,4-dicarboxylate (98 mg, 0.16 mmol) in dry THF (1 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then additional LiAlH4 (2N solution in THF; 0.05 mL, 0.095 mmol) was added. After 30 minutes at 0°C, the mixture was quenched by adding Rochelle salt solution and diluted with siRNA and H2O. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the crude title compound as a white foam, which was used in the next step without further purification (84 mg). LCMS (ES + )(Method 1)m / z 555(M+H) + , RT 2.23 minutes.

[0328] Step 4: tert-butyl 4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate Crude tert-butyl 4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)-4-(hydroxymethyl)piperidine-1-carboxylate (84 mg, 0.15 mmol) was stirred in dry DCM (1.5 mL), to which dry DIPEA (0.05 mL, 0.30 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 20 minutes, then diluted in DCM and washed with 5% citric acid solution and H2O. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (30% to 100% siRNA in petroleum ether) to obtain the title compound as a white foam (21 mg, 22% over two steps).1 H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.42-7.31 (m, 9H), 7.18-7.10 (m, 6H), 4.90 (br d, J=5.4 Hz, 1H), 4.32 (dd, J=9.8, 26.3 Hz, 2H), 3.80-3.58 (m, 2H), 3.24-2.98 (m, 3H), 2.87 (s, 3H), 1.82-1.63 (m, 2H), 1.50-1.43 (m, 11H). LCMS (ES + ) Method 1: m / z 633 (M+H) + , RT 2.35 minutes.

[0329] Step 5: tert-butyl7'-hydroxy-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate A solution of tert-butyl 4-(hydroxy(1-trityl-1H-1,2,4-triazole-3-yl)methyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (100 mg, 0.16 mmol) and DIPEA (0.07 mL, 0.40 mmol) in dry DMF (2.7 mL) was heated at 140 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with MeOH, and concentrated. The resulting crude product was purified by preparative HPLC (0% to 40% MeCN / H2O + 0.1% TFA) and lyophilized. The residue was dissolved with ethyl acetate and washed with 1N NaOH aqueous solution. The aqueous layer was extracted with ethyl acetate / MeOH 9:1 (×2), and the combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a colorless oil (42 mg, 90%). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 5.04 (br s, 1H), 4.84 (s, 1H), 3.93 (d, J=10.9 Hz, 1H), 3.75 (d, J=10.9 Hz, 1H), 3.52-3.34 (m, 4H), 2.17-2.02 (m, 1H), 1.68-1.54 (m, 2H), 1.40 (s, 10H). LCMS (ES + ) Method 1: m / z 295 (M+H) + , RT 1.12 minutes.

[0330] Step 6: tert-butyl7'-oxo-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate To a solution of tert-butyl 7'-hydroxy-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate (145 mg, 0.49 mmol) in dry DCM (5.2 mL), des-martin periodinane (231 mg, 0.54 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with DCM and washed with aqueous Na2S2O3. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the crude compound as a brown solid, which was used in the next step without further purification (240 mg). LCMS (ES) + ) Method 1: m / z 293(M+H) + , RT 1.40 minutes.

[0331] Step 7: tert-butyl(R,Z)-7'-((tert-butylsulfinyl)imino)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate A suspension of crude tert-butyl 7'-oxo-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate (theoretically 0.493 mmol) and (R)-(-)-t-butylsulfinamide (179 mg, 1.48 mmol) in Ti(OEt)4 (3 mL, 14.31 mmol) was heated at 100°C for 1 hour. The mixture was cooled to room temperature, diluted with siRNA and H2O, and the solid precipitated and filtered. The filtrate was washed with brine, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0% to 10% MeOH in DCM) to obtain the title compound as a yellow solid (105 mg, 54% in 2 steps). 1 H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 4.35-4.13 (m, 4H), 3.13-2.80 (m, 2H), 2.37-2.17 (m, 1H), 2.15-1.96 (m, 1H), 1.90-1.71 (m, 2H), 1.51 (s, 9H), 1.34 (s, 9H).LCMS (ES + ) Method 1: m / z 396 (M+H) + , RT 1.50 minutes.

[0332] Step 8: tert-butyl(S)-7'-(((R)-tert-butylsulfinyl)amino)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate NaBH4 (18 mg, 0.48 mmol) was added at -50°C to a solution of tert-butyl(R,Z)-7'-((tert-butylsulfinyl)imino)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate (105 mg, 0.27 mmol) in dry THF (2.8 mL). The reaction mixture was stirred at -50°C for 30 minutes, then quenched by adding H2O and ethyl acetate. The phases were separated, and the aqueous layer was extracted with ethyl acetate / MeOH 9:1. The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in EtOH (2.5 mL), and the solution was stirred at 70°C for 9 hours. The solvent was removed under reduced pressure, and the resulting crude product was purified by reverse-phase chromatography (0% to 40% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white solid (90 mg, 85%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 9.65 (s, 1H), 6.24 (d, J=10.0 Hz, 1H), 4.84 (d, J=10.0 Hz, 1H), 4.34 (d, J=11.8 Hz, 1H), 4.19 (d, J=12.0 Hz, 1H), 3.80-3.40 (m, 2H), 3.26-2.92 (m, 2H), 1.75-1.46 (m, 4H), 1.39 (s, 9H), 1.18 (s, 9H). LCMS (ES + ) Method 1: m / z 398 (M+H) + , RT 1.37 minutes.

[0333] Step 9: (R)-2-methyl-N-((S)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-7'-yl)propan-2-sulfinamide (intermediate 40) To a solution of tert-butyl(S)-7'-(((S)-tert-butylsulfinyl)amino)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-1-carboxylate (68 mg, 0.17 mmol) in DCM (3.5 mL), TFA (0.26 mL, 3.42 mmol) was added, and the resulting solution was stirred at room temperature for 1.5 hours. The solvent was removed under vacuum to obtain the crude title compound, which was used in the next step without further purification (88 mg). LCMS (ES) + ) Method 1: m / z 298(M+H) + , RT 0.46 min. Intermediate 41: 8-chloro-7-((5-chloropyrazine-2-yl)thio)-2-methylimidazo[1,2-a]pyridine

[0334] [ka]

[0335] Step 1: 8-Chloro-7-iodo-2-methylimidazo[1,2-a]pyridine A mixture of 3-chloro-4-iodopyridine-2-amine (254 mg, 1 mmol) and chloroacetone (160 μL, 2 mmol) in EtOH (2.5 mL) was heated at 65°C for 3 hours under MW irradiation. Additional chloroacetone (640 μL) was added, and the resulting mixture was stirred at 100°C for 8 hours under MW irradiation. The solvent was removed, the residue was dissolved in DCM (2 mL), and washed with saturated NaHCO3 solution. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-50% ethyl ethyl in petroleum ether). 1 H NMR (DMSO-d6) δ 8.26 (d, J=7.1 Hz, 1H), 7.81 (d, J=0.8 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 2.34 (d, J=0.7 Hz, 3H). LCMS (ES + ) Method 3: m / z 293, 295 (M+H) + , RT 1.62 minutes.

[0336] Step 2: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)-2-methylimidazo[1,2-a]pyridine A solution of sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in the synthesis of steps 1 and 2; 45 mg, 0.27 mmol), 8-chloro-7-iodo-2-methylimidazo[1,2-a]pyridine (89 mg, 0.3 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), and DIPEA (139 μL, 0.8 mmol) in 1,4-dioxane (0.6 mL) was heated at 110 °C for 1 hour. After evaporating the solvent, the residue was dissolved in SiO2 (2 mL) and washed with saturated NaHCO3 solution. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the residue. This residue was purified by flash chromatography on silica gel (gradient elution of 0-50% siRNA in petroleum ether) to obtain the title compound (40 mg, 48%). LC-MS (ES) + ) Method 1: m / z 311, 313 (M+H) + , RT 1.14 minutes. Intermediate 42: Ethyl 6-bromo-3-((S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methylpyrazine-2-carboxylate

[0337] [ka]

[0338] Step 1: Ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate EtOH (19.0 mL) and 1,2-diaminopropane (0.99 mL, 11.48 mmol) were placed in a 50 ml flask, and the resulting colorless, transparent solution was cooled to 0°C. Diethyl 2-oxopropanediol (1.75 mL, 11.48 mmol) was added to the solution, and the reaction mixture was heated to room temperature, stirred for 2 hours, and then heated at 95°C for 24 hours. After cooling, the reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 40-100% ethyl acetate in petroleum ether) to obtain the title compound as a yellow solid (360 mg, 17%). 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (br s, 1H), 7.33 (br s, 1H), 4.26 (q, J=8.0 Hz, 2H), 2.24 (s, 3H), 1.27 (t, J=8.0 Hz, 3H). LCMS (ES + ) Method 1: m / z 183 (M+H) + , RT 0.70 minutes.

[0339] Step 2: Ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate Ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (300 mg, 1.65 mmol) was placed in a flask in DMF (6.6 mL), and the resulting solution was cooled to 0°C. 1-bromopyrrolidine-2,5-dione (307.7 mg, 1.73 mmol) was added, and the reaction mixture was heated to room temperature, stirred for 2 hours, and diluted with H2O and siRNA. The organic phase was washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the title compound as a crude product (430 mg, 100%). LC-MS (ES) + ) Method 1: m / z 261~263(M+H) + , RT 1.22 minutes.

[0340] Step 3: Ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate In a flask, PPh3 (1.3 g, 4.94 mmol) and 1-chloropyrrolidine-2,5-dione (0.67 g, 5.02 mmol) were added in 1,4-dioxane (15.0 mL), and the resulting solution was stirred at room temperature for 30 minutes. Ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (430 mg, 1.65 mmol) was added, and the resulting mixture was heated at 100 °C for 1 hour. After cooling, TEA (4 mL, 1.65 mmol) was added. The volatile matter was concentrated under vacuum, and the residue was purified by flash chromatography (gradient elution of 35% ethyl phosphate in petroleum ether) to obtain the title compound as a yellow oily substance (310 mg, 67%). 1 H NMR (400 MHz, CDCl3) δ 4.49 (q, J=8.0 Hz, 2H), 2.74 (s, 3H), 1.44 (t, J=8.0 Hz, 3H). LCMS (ES + ) Method 1: m / z 279-281 (M+H) + , RT 1.81 minutes.

[0341] Step 4: Ethyl 6-bromo-3-((S)-4'-(((R)-tert-butylsulfinyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methylpyrazine-2-carboxylate (intermediate 42) A solution of intermediate 2 (422.2 mg, 0.64 mmol) in MeCN (7 mL) was treated with K2CO3 (296.7 mg, 2.15 mmol). The reaction mixture was stirred at 55°C for 18 hours. After cooling, the reaction mixture was diluted with siRNA, washed with H2O and brine, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (gradient elution of 0-100% siRNA in petroleum ether) to obtain the title compound as a yellow powder (153 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=1.8 Hz, 1H), 6.08 (d, J=1.5 Hz, 1H), 5.96 (d, J=10.1 Hz, 1H), 4.45 (d, J=9.9 Hz, 1H), 4.32 (q, J=7.0 Hz, 2H), 4.19 (d, J=11.2 Hz, 1H), 4.06 (d, J=11.6 Hz, 1H), 3.82-3.67 (m, 2H), 3.25-3.16 (m, 2H), 1.90-1.83 (m, 1H), 1.77-1.60 (m, 3H), 1.32-1.29 (m, 3H), 1.19-1.15 (m, 3H), 1.13 (s, 9H). LCMS (ES + ) Method 2 m / z 539 (M+H) + , RT 1.81 minutes. Intermediate 43: 6-Chloro-3-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0342] [ka]

[0343] Step 1: 4,6-Dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine A solution of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 6.35 mmol), 3,4-dihydro-2H-pyran (1.68 mL, 18.4 mmol), and p-toluenesulfonic acid monohydrate (241.6 mg, 1.27 mmol) in THF (29 mL) was heated at 70 °C for 1.5 hours. After completion, the solvent was removed under vacuum, and the crude product was purified by flash chromatography (gradient elution of 0-5% MeOH in CHCl3) to obtain the title compound as a white solid (2.23 g, 88%). LC-MS (ES) + )m / z 399(M+H) +

[0344] Step 2: 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one A solution of 4,6-dichloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (2.82 g, 7.0 mmol) in THF (28 mL) was treated with 5 M NaOH aqueous solution (12.7 mL, 63.45 mmol). The mixture was stirred at room temperature for 5 hours, then THF (14 mL) was added. The resulting mixture was stirred at room temperature for 18 hours, then acidified with 6 M HCl aqueous solution and extracted with siRNA. The organic layer was washed with brine, dehydrated with Na₂SO₄, filtered, and concentrated under vacuum. The crude product was ground with n-heptane and dried to obtain the title compound (1.8 g, 67%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 5.66 (dd, J=10.2, 2.2 Hz, 1H), 3.91 (d, J=11.3 Hz, 1H), 3.71-3.59 (m, 1H), 2.35-2.17 (m, 1H), 2.04-1.90 (m, 1H), 1.89-1.78 (m, 1H), 1.77-1.62 (m, 1H), 1.60-1.48 (m, 2H).

[0345] Step 3: 6-Chloro-3-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one A solution of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (1.75 g, 4.6 mmol) in DMF (21 mL) was treated with K2CO3 (763 mg, 5.5 mmol), followed by the slow addition of MeI (314.9 μL, 5.0 mmol). The mixture was stirred at room temperature for 18 hours. After completion, the mixture was diluted with H2O, and the solid precipitate was collected by filtration. The crude product was ground with ELISA to obtain the title compound (1.04 g, 57%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 5.73 (dd, J=10.2, 1.5 Hz, 1H), 4.08 (d, J=1.5 Hz, 1H), 3.73 (t, J=11.3 Hz, 1H), 3.68 (s, 3H), 2.54-1.43 (m, 1H), 2.09 (d, J=10.7 Hz, 1H), 1.86 (d, J=13.3 Hz, 1H), 1.82-1.65 (m, 2H), 1.58 (d, J=12.3 Hz, 1H). LCMS (ES + ) m / z 311 (M+H-THP) + Intermediate 44: 3-Chloro-2-(1H-pyrazole-1-yl)pyridine-4-thiol

[0346] [ka]

[0347] Step 1: 2-Ethylhexyl 3-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)propanoate A solution of intermediate 32 (500 mg, 1.64 mmol), 2-ethylhexyl 3-sulfanylpropanoate (0.4 mL, 1.8 mmol), Pd2(dba)3 (40 mg, 0.04 mmol), and Xantphos (51 mg, 0.09 mmol) in 1,4-dioxane (8 mL) was treated with DIPEA (0.57 mL, 3.27 mmol), and the mixture was heated at 100 °C for 2 hours. After cooling, the reaction mixture was filtered on a cellulose pad, and the solvent was concentrated under vacuum. The crude product was purified by flash chromatography (0-100% ethylhexyl in petroleum ether) to obtain the title compound as an orange oil (640 mg, 99%). LC-MS (ES) + ) Method 1: m / z 396 / 398(M+H) + , RT 2.49 minutes.

[0348] Step 2: 3-Chloro-2-(1H-pyrazole-1-yl)pyridine-4-thiol (intermediate 44) A solution of 2-ethylhexyl 3-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)propanoate (390 mg, 0.98 mmol) in MeOH (9.8 mL) was treated with NaOMe (25 wt% in MeOH; 0.9 mL, 0.98 mmol), the mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under vacuum. The resulting residue was dissolved in H2O, washed with Et2O (3×), and then the aqueous phase was diluted with MeCN and lyophilized to obtain the title product as a yellow viscous solid (168 mg, purity 90%, 73%). LCMS(ES) + ) Method 1: m / z 212(M+H) + , RT 1.12 minutes. Intermediate 45: 5-bromo-2-chloro-3-methylpyrimidine-4(3H)-one

[0349] [ka]

[0350] Step 1: 5-Bromo-2-chloropyrimidine-4(3H)-one A solution of 5-bromo-2,4-dichloropyrimidine (2.0 g, 8.78 mmol) in THF (40 mL) was treated with NaOH (1 M aqueous solution; 30.7 mL, 30.72 mmol), stirred at room temperature for 90 minutes, diluted with H2O (100 mL), and acidified to pH 4-5 with HCl (6 N aqueous solution). The mixture was extracted with siRNA (4 × 100 mL), the collected organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was ground with hexane to obtain the title compound as a white solid (1.0 g, 54%). LCMS (ES) + ) method 1m / z 209 / 211(M+H) + , RT 0.72 min.

[0351] Step 2: 5-Bromo-2-chloro-3-methylpyrimidine-4(3H)-one (intermediate 45) A solution of 5-bromo-2-chloropyrimidine-4(3H)-one (1.0 g, 4.77 mmol) cooled to 0°C in DMF (10 mL) was treated with Cs2CO3 (3.1 g, 9.55 mmol) and MeI (0.89 mL, 14.32 mmol), stirred at 0°C for 3 hours and at room temperature for 1.5 hours, then diluted with H2O (20 mL) and extracted with siRNA (5 × 10 mL). The collected organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by flash chromatography (0-80% siRNA in petroleum ether) to obtain the title compound as a yellow powder (220 mg, 21%). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 3.59 (s, 3H). LCMS (ES + ) Method 1: m / z 223 / 225 (M+H) + , RT 0.97 minutes. Intermediate 46: 4-Chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

[0352] [ka]

[0353] Step 1: 5-bromo-4-chloro-1H-indazole A solution of 4-bromo-3-chloro-2-methylaniline (867 mg, 3.93 mmol) in AcOH (17 mL) was treated with NaNO2 (339.0 mg, 4.91 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for 1 hour, then concentrated, the residue was suspended in H2O, filtered, and washed with H2O and n-heptane. The organic phase was concentrated under vacuum to obtain the residue, which was purified by flash chromatography (0-30% siRNA in cyclohexane) to obtain the title compound as a pale orange solid (328 mg, 36%). LC-MS (ES) + ) Method 1: m / z 231(M+H) + , RT 1.59 minutes.

[0354] Step 2: 5-bromo-4-chloro-2-methyl-2H-indazole A solution of 5-bromo-4-chloro-1H-indazole (1.49 g, 6.45 mmol) in toluene (32 mL) at 0°C was treated with trimethyloxonium tetrafluoroborate (1.43 g, 9.65 mmol). The resulting mixture was warmed to room temperature and stirred for 5 hours. After completion, the mixture was quenched with saturated NaHCO3 solution and extracted with toluene. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (0-30% toluene in n-heptane) to obtain the title compound as an orange solid (900 mg, 57%). 1 H NMR (500 MHz, DMSO-d6): 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 minutes.

[0355] Step 3: 4-Chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (intermediate 46) A suspension of 5-bromo-4-chloro-2-methyl-2H-indazole (548.0 mg, 2.23 mmol), B2pin2 (1.36 g, 5.36 mmol), Pd(dppf)Cl2·DCM (163.3 mg, 0.223 mmol), and KOAc (657.2 mg, 6.70 mmol) in 1,4-dioxane (11 mL) was heated at 120 °C for 18 hours. After completion, the mixture was cooled to room temperature, the solid precipitate was filtered off, and washed with ethyl acetate. The filtrate was concentrated under vacuum, and the residue was dissolved in toluene and n-heptane until a precipitate formed. The suspension was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was ground with n-heptane, the solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g, 99%) as a light brown solid. 1H NMR (300 MHz DMSO-d6) δ 8.52 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 4.18 (s, 3H), 1.32 (s, 12H). LCMS (ES+) Method 1: m / z 293 (M+H) + , RT 1.89 minutes. Intermediate 47: 6-Chloropyrido[2,3-b]pyrazine-2-yl-4-nitrobenzenesulfonate

[0356] [ka]

[0357] A solution of 6-chloropyrido[2,3-b]pyrazine-2(1H)-one (1.0 g, 5.5 mmol) in DMF (10 mL) was treated with TEA (0.92 mL, 6.6 mmol) and 4-nitrobenzenesulfonyl chloride (1.22 g, 5.51 mmol). The mixture was stirred at room temperature for 1 hour, then poured into H2O, and the resulting precipitate was filtered off and dried to obtain the title product as a brown solid (1.87 g, 92%). 1 H NMR (400 MHz, DMSO-d6) 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 minutes. Intermediate 48: 6-Chloro-5-((5-chloropyrazine-2-yl)thio)pyrazine-2-amine

[0358] [ka]

[0359] Step 1: 5-Bromo-6-chloropyrazine-2-amine To a suspension of 6-chloranylpyrazine-2-amine (1.2 g, 9.2 mmol) cooled to -20°C in dry DCM (40 mL), NBS (1.64 g, 9.2 mmol) was gradually added, and the reaction mixture was stirred for 3 hours. The mixture was then treated with H2O and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography on silica gel (50% to 100% ethyl ether in petroleum ether) to obtain the title compound as a yellow powder (1 g, 51%). 1 H NMR (300 MHz, DMSO-d6) δ 7.10 (br s, 2H), 7.59-7.72 (m, 1H); LCMS (ES + ) Method 1: m / z 208 (M+H) + , RT 1.53 minutes.

[0360] Step 2: 6-Chloro-5-((5-chloropyrazine-2-yl)thio)pyrazine-2-amine 5-bromanyl-6-chloranylpyrazine-2-amine (56 mg, 0.27 mmol), sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in the synthesis of steps 1 and 2; 30 mg, 0.18 mmol), Xantphos (12.5 mg, 0.022 mmol), and Pd2(dba)3 (20 mg, 0.02 mmol) were mixed in 1.5 ml of degassed dried 1,4-dioxane. Dried DIPEA (0.1 mL, 0.57 mmol) was added under an N2 atmosphere, and the mixture was heated at 100°C for 1 hour. After removing volatiles, the residue was directly purified by reverse-phase chromatography (10% to 55% MeCN / H2O + 0.1% TFA). The collected fractions were combined and extracted with phenylethylamine. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a yellow solid (10 mg, 20%). LC-MS (ES) + ) Method 1: m / z 274(M+H) + , RT 1.72 minutes. Intermediate 49: 8-chloro-7-((5-chloropyrazine-2-yl)thio)-[1,2,4]triazolo[4,3-a]pyridine

[0361] [ka]

[0362] NCS was added to a solution of 8-chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine (14 mg, 0.047 mmol) in dry DMF (0.5 mL), prepared as reported in Step 1 of Example 31. The resulting mixture was heated at 80°C for 15 minutes, then diluted with SiO2 and washed with H2O (×3). The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a yellow solid (15 mg, 96%). 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=1.5 Hz, 1H), 8.57 (d, J=1.4 Hz, 1H), 8.40 (d, J=7.1 Hz, 1H), 7.89 (s, 1H) 7.23 (d, J=7.1 Hz, 1H). LCMS (ES + ) Method 1: m / z 331 (M+H) + , RT 1.88 minutes. Intermediate 50: 8-chloro-7-((5-chloropyrazine-2-yl)thio)-[1,2,4]triazolo[4,3-a]pyridine

[0363] [ka]

[0364] Step 1: 3-Chloro-2-Hydrazinale-4-Iodopyridine A mixture of 3-chloro-2-fluoro-4-iodopyridine (200 mg, 0.78 mmol) and hydrazine hydrate (0.5 mL, 10.2 mmol) in 1-BuOH (0.8 mL) was stirred at room temperature for 3 hours. The solid precipitate was filtered to obtain the title compound as a white solid (200 mg, 95%). LC-MS (ES) + ) Method 1: m / z 270(M+H) + , RT 0.81 min.

[0365] Step 2: 8-Chloro-7-iodo-[1,2,4]triazolo[4,3-a]pyridine 3-chloro-2-hydrazinale-4-iodopyridine (200 mg, 0.74 mmol) and HCO2H (1 mL, 26.4 mmol) were placed in a microwave vial, and the resulting solution was irradiated by MW at 100°C for 15 hours. The solution was diluted with H2O, and the precipitate was filtered to obtain the title compound as a white solid (142 mg, 68%). LC-MS (ES) + ) Method 1: m / z 279(M+H) + , RT 1.15 minutes.

[0366] Step 3: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)-[1,2,4]triazolo[4,3-a]pyridine 8-chloro-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.18 mmol) and 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 23 mg, 0.14 mmol) were used as starting materials, and the above compound was prepared according to the procedure described in step 3A of intermediate 16. Intermediate 50 was obtained as a yellow powder (32 mg, 55%). LCMS (ES) + ) Method 1: m / z 299(M+H) + , RT 1.41 minutes Intermediate 51: 8-chloro-7-((5-chloropyrazine-2-yl)thio)-3-nitroimidazo[1,2-a]pyridine

[0367] [ka]

[0368] Step 1: 8-chloro-7-iodo-3-nitroimidazo[1,2-a]pyridine 65% by weight (0.38 mL, 5.50 mmol) of nitric acid was added at 0°C to a stirred solution of 8-chloro-7-iodoimidazo[1,2-a]pyridine (intermediate 41, prepared as reported in the synthesis of step 1; 383 mg, 1.38 mmol) in sulfuric acid (7 mL). After 1 hour, saturated NaHCO3 solution was slowly added to the mixture at 0°C, and the product was extracted with siRNA. The organic layer was washed with H2O, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a yellow solid (347 mg, 77%), which was used in the next step without further purification. 1 H-NMR (300 MHz DMSO-d6) δ 9.00 (d, J=7.2 Hz, 1H), 8.75 (s, 1H), 7.86 (d, J=7.2 Hz, 1H). LCMS (ES + ) Method 1: m / z 324 (M+H) + , RT 1.75 minutes.

[0369] Step 2: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)-3-nitroimidazo[1,2-a]pyridine The above compound was prepared using 8-chloro-7-iodo-3-nitroimidazo[1,2-a]pyridine (50 mg, 0.15 mmol) and 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 26 mg, 0.15 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. LCMS(ES) + ) Method 1: m / z 342(M+H) + , RT 1.75 minutes. Intermediate 52: N-(8-chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide

[0370] [ka]

[0371] Step 1: N-(3-chloro-4-iodopyridine-2-yl)-4-methylbenzenesulfonamide A mixture of 3-chloro-4-iodopyridine-2-amine (500 mg, 1.96 mmol) and p-toluenesulfonyl chloride (637 mg, 3.34 mmol) in pyridine (0.85 mmol) was stirred at room temperature for 12 hours. The resulting yellow mixture was then diluted with H2O and extracted with siRNA (3×). The organic layer was washed with 1 M HCl solution and evaporated. The residue was dissolved in 1,4-dioxane (1.5 mL), treated with 10% KOH in H2O (600 μL), and then heated at 70°C for 1.5 hours. The resulting solution was acidified with 6N HCl (300 μL) and then extracted with DCM (3×). The collected organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a white solid (370 mg), which was used in the next step without further purification. LCMS(ES) + ) Method 1: m / z 409(M+H) + , RT 2.04 minutes.

[0372] Step 2: 2-(3-chloro-4-iodo-2-(tosylimino)pyridine-1(2H)-yl)acetamide To a solution of N-(3-chloro-4-iodopyridine-2-yl)-4-methylbenzenesulfonamide (370 mg, 0.91 mmol) in DMF (5 mL), DIPEA (173 μL, 1.00 mmol) and iodoacetamide (184 mg, 1.0 mmol) were sequentially added. The resulting mixture was stirred at room temperature for 2 days and then heated at 75°C for 24 hours. Additional DIPEA (173 μL, 1.0 mmol) and iodoacetamide (184 mg, 1.0 mmol) were added, and the reaction was stirred at 75°C for an additional 2 hours. After removing volatiles, the residue was partitioned in siRNA and H2O to separate the phases. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a brownish oily substance (600 mg), which was used in the next step without further purification. LCMS(ES) + ) Method 1: m / z 466(M+H) + , RT 1.81 minutes.

[0373] Step 3: N-(8-chloro-7-iodoimidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide To a solution of 2-(3-chloro-4-iodo-2-(tosylimino)pyridine-1(2H)-yl)acetamide (600 mg, 0.64 mmol) in DCM (1.5 mL), TFAA (0.7 mL, 5.03 mmol) was gradually added at room temperature. The resulting mixture was stirred at 50°C for 2 hours. After removing volatiles, the crude compound was dissolved in DCM and washed with saturated NaHCO3 solution (3 ×). The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting crude compound was purified by flash chromatography on silica gel (0% to 30% ethyl ether in petroleum ether) to obtain the title compound as a yellow solid (170 mg, 50% obtained in 3 steps). LCMS (ES) + ) Method 1: m / z 390(M+H) + , RT 1.48 minutes.

[0374] Step 4: N-(8-chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide N-(8-chloro-7-iodoimidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide (50 mg, 0.13 mmol) and 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 23 mg, 0.14 mmol) were used as starting materials, and the above compound was prepared according to the procedure described in step 3A of intermediate 16. Intermediate 52 was obtained as a brownish powder (32 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=1.4 Hz, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H), 7.81 (s, 1H), 7.19 (d, J = 7.2 Hz, 1H). LCMS (ES + ) Method 1: m / z 408 (M+H) + , RT 1.70 minutes. Intermediate 53: 8-chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-carboxamide

[0375] [ka]

[0376] Step 1: Ethyl 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylate Ethyl bromopirubate (0.05 mL, 0.39 mmol) was added to a solution of 3-chloro-4-iodopyridine-2-amine (100 mg, 0.39 mmol) in IPA (0.7 mL) and H2O (0.7 mL). The resulting mixture was heated to 80°C for 30 minutes under MW irradiation in an oil bath, followed by an additional 6 hours of heating. The precipitate was filtered, and the resulting yellow powder was washed with Et2O and dried under reduced pressure to obtain the title compound (70 mg, 60%). 1 H NMR (300 MHz DMSO-d6) δ 8.66 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.42 (d, J=7.1 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). LCMS (ES + ) Method 1: m / z 351 (M+H) + , RT 1.69 minutes.

[0377] Step 2: 8-Chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxamide A suspension of ethyl 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylate (68 mg, 0.19 mmol) in 1,4-dioxane (1 mL) and 30% NH4OH in H2O (0.8 mL, 5.82 mmol) was refluxed for 10 hours. The resulting mixture was diluted with siRNA and H2O, and K2CO3 was added. The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a pale yellow powder (34 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.65 (br s, 1H), 7.50 (br s, 1H), 7.39 (d, J=7.2 Hz, 1H). LCMS (ES + ) Method 1: m / z 321 (M+H) + , RT 1.35 minutes.

[0378] Step 3: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-carboxamide The above compound was prepared using 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxamide (33 mg, 0.10 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 18 mg, 1.07 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (5% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a brown powder (15 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J=1.4 Hz, 1H), 8.74-8.67 (m, 2H), 8.61 (s, 1H), 7.82 (br s, 1H), 7.65 (br s, 1H), 7.23 (d, J=7.2 Hz, 1H).LCMS (ES + ) Method 1: m / z 340 (M+H) + , RT 1.54 minutes. Intermediate 54: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-carbonitrile

[0379] [ka]

[0380] Step 1: 8-Chloro-7-iodoimidazo[1,2-a]pyridine-2-carbonitri A suspension of 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxamide (82 mg, 0.25 mmol, prepared as described in step 2 of intermediate 53) in POCl3 was stirred at 100°C for 4 hours. The resulting precipitate was filtered, washed with MeCN(3×), and dried under reduced pressure to obtain the title compound as a grayish-white powder (59 mg, 76%). 1 H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.39 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.1 Hz, 1H). LCMS (ES + ) Method 1: m / z 304 (M+H) + , RT 1.68 minutes.

[0381] Step 2: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine-2-carbonil The above compound was prepared using 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carbonitrile (57 mg, 0.19 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 29 mg, 0.172 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (15% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (29 mg, 52%). 1 H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.73 (d, J=1.4 Hz, 1H), 8.64 (d, J=1.4 Hz, 1H), 8.60 (d, J =7.2 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H). LCMS (ES + ) Method 1: m / z 322 (M+H) + , RT 1.86 minutes. Intermediate 55: 6-chloro-5-((5-chloropyrazine-2-yl)thio)pyridine-2-amine

[0382] [ka]

[0383] Step 1: 6-Chloro-5-iodopyridine-2-amine To a solution of 6-chloropyridine-2-amine (500 mg, 3.89 mmol) in dry MeCN (15 mL), NIS (880 mg, 3.9 mmol) was gradually added, and the resulting mixture was stirred at room temperature for 30 minutes. An additional NIS (500 mg, 1.22 mmol) was added, and the mixture was stirred for another 30 minutes. By adding H2O (50 mL), the desired compound precipitated, and the mixture was filtered and dried under reduced pressure to obtain a beige powder (822 mg, 83%). 1 H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=8.4 Hz, 1H), 6.53 (br s, 2H), 6.23 (d, J=8.4 Hz, 1H). LCMS (ES + ) Method 1: m / z 255 (M+H) + , RT 1.69 minutes.

[0384] Step 2: 6-Chloro-5-((5-chloropyrazine-2-yl)thio)pyridine-2-amine The above compound was prepared using 6-chloro-5-iodopyridine-2-amine (70 mg, 0.27 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 49 mg, 0.29 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was purified by reverse-phase chromatography (10% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a brown solid (47 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J =1.4 Hz, 1H), 8.24 (d, J=1.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.97 (br s, 2H), 6.48 (d, J=8.4 Hz, 1H).LCMS (ES + ) Method 1: m / z 273 (M+H) + , RT 1.83 minutes. Intermediate 56: 5-chloro-6-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine

[0385] [ka]

[0386] Step 1: 5-chloro-6-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine Intermediate 55 (25 mg, 0.09 mmol) was used as the starting material, and the above compound was prepared according to the procedure described in step 1 of intermediate 31. The residue was purified by reverse-phase chromatography (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a brown solid (25 mg, 91%). LC-MS (ES) + ) Method 1: m / z 297(M+H) + , RT 1.14 minutes. Intermediate 57: 2-Chloro-5-((3-Chloro-2-(1H-imidazole-1-yl)pyridine-4-yl)thio)pyrazine

[0387] [ka]

[0388] In Step 1, thermal heating was used, 1H-imidazole was used as the starting material, and DMSO was used instead of DMF. The above intermediate was prepared according to the procedure described for Intermediate 33. Intermediate 57 was obtained as a brown solid (34 mg, 97%). LCMS(ES) +) Method 1: m / z 324(M+H) + , RT 1.13 minutes. Intermediate 58: 6-Chloro-3-((3-Chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-amine

[0389] [ka]

[0390] In step 1, thermal heating was used, and in step 2, intermediate 22 was used instead of sodium 5-chloropyrazine-2-thiolate. The above intermediate was prepared according to the procedure described for intermediate 33. Intermediate 58 was obtained as a beige solid (30 mg, 95%). LCMS(ES) + ) Method 1: m / z 339(M+H) + , RT 1.78 minutes. Intermediate 59: 2-chloro-5-((3-chloro-2-(4-fluoro-1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine

[0391] [ka]

[0392] In Step 1, under thermal heating, 1H-imidazole was used as the starting material, and DMSO was used instead of 4-fluoro-1H-pyrazole and DMF, and the above intermediate was prepared according to the procedure described for Intermediate 33. Intermediate 59 was obtained as a beige solid (24 mg, 62%). LC-MS (ES) + ) Method 1: m / z 342(M+H) + , RT 2.03 minutes. Intermediate 60: 6-Chloro-3-((3-Chloro-2-(1H-imidazole-1-yl)pyridine-4-yl)thio)pyrazine-2-amine

[0393] [ka]

[0394] In Step 1, under thermal heating, 1H-imidazole was used as the starting material, and DMSO was used instead of DMF. In Step 2, intermediate 22 was used instead of 5-chloropyrazine-2-thiolate, and the above intermediate was prepared according to the procedure described for intermediate 33. Intermediate 60 was obtained as a beige solid (18 mg, 54%). LCMS(ES) + ) Method 1: m / z 339(M+H) + , RT 1.13 minutes. Intermediate 61: 2-chloro-5-((3-chloro-2-(1H-pyrrole-1-yl)pyridine-4-yl)thio)pyrazine

[0395] [ka]

[0396] In Step 1, under thermal heating, 1H-pyrrole was used as the starting material, and NaH was used as the base instead of K2CO3, and the above intermediate was prepared according to the procedure described for Intermediate 33. Intermediate 61 was obtained as a white solid (6 mg, 31%). LC-MS (ES) + ) Method 1: m / z 323(M+H) + , RT 2.25 minutes. Intermediate 62: 8-Chloro-7-iodoimidazo[1,2-a]pyridine-2(3H)-one

[0397] [ka]

[0398] K2CO3 (60 mg, 0.55 mmol) was added to a solution of bromoacetic acid (110 mg, 0.79 mmol) in H2O (2.5 mL). After 10 minutes, 3-chloro-4-iodopyridine-2-amine (200 mg, 0.79 mmol) was added, and the mixture was heated at 100°C for 5 hours. The brown precipitate was filtered and washed with H2O. This solid was dissolved in MeOH and TFA and purified by reverse-phase chromatography (0% to 25% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow powder (42 mg, 18%). LCMS (ES) + ) Method 1: m / z 295(M+H) + , RT 0.68 min. Intermediate 63: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-1H-pyrrole-3-carboxamide

[0399] [ka]

[0400] Step 1: tert-butyl 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxylate Starting with tert-butyl 1H-pyrrole-3-carboxylate, and using NaH (60% in mineral oil) instead of K2CO3 as the base, the above compound was prepared under thermal heating according to the procedure described in step 1 of intermediate 33. The residue was purified by flash chromatography (gradient elution of 10-100% phenylethylamine in petroleum ether) to obtain the title compound as a colorless solid (240 mg, 70%). 1 H NMR (300 MHz, DMSO-d6) δ 8.13 (dd, J=5.0, 10.9 Hz, 2H), 7.76 (t, J=1.9 Hz, 1H), 7.30 (dd, J=2.2, 3.1 Hz, 1H), 6.55 (dd, J=1.7, 3.1 Hz, 1H), 1.51 (s, 9H).LCMS (ES + ) Method 1: m / z 405 (M+H) + , RT 2.40 minutes.

[0401] Step 2: 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxylic acid To a solution of tert-butyl 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxylate (235 mg, 0.58 mmol) in DCM (2 mL) at room temperature, TFA (0.5 mL, 6.53 mmol) was added, and the resulting mixture was stirred for 3 hours. MeCN was added, and the solid precipitate was filtered off to obtain the title compound as a white solid (171 mg, 84%). 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (br s, 1H), 8.18 (br d, J=12.1 Hz, 2H), 7.87 (br s, 1H), 7.35 (br s, 1H), 6.64 (br s, 1H). LCMS (ES + ) Method 1: m / z 349 (M+H) + , RT 1.72 minutes.

[0402] Step 3: 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxamide To a solution of tert-butyl 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxylate (50 mg, 0.14 mmol) and NH4Cl (9.5 mg, 0.18 mmol) in dry DMF (0.8 mL), dry DIPEA (0.08 mL, 0.43 mmol) and BOP (83 mg, 0.19 mmol) were sequentially added. The resulting mixture was stirred at room temperature for 30 minutes. H2O was added, and the solid precipitate was filtered off to obtain the title compound as a white solid (37 mg, 74%). 1 H NMR (300 MHz, DMSO-d6) δ 8.11 (dd, J =5.0, 16.7 Hz, 2H), 7.82 (s, 1H), 7.52 (br s, 1H), 7.28 (t, J=2.6 Hz, 1H), 6.93 (br s, 1H), 6.70-6.62 (m, 1H).LCMS (ES + ) Method 1: m / z 348 (M+H)+ , RT 1.47 minutes.

[0403] Step 4: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-1H-pyrrole-3-carboxamide The above compound was prepared using 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxamide (36 mg, 0.10 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 22 mg, 0.10 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (5% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale red powder (26 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (d, J=1.3 Hz, 1H), 8.83 (d, J=1.3 Hz, 1H), 8.34 (d, J=5.2 Hz, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.55 (br s, 1H), 7.40-7.30 (m, 2H), 6.95 (br s, 1H), 6.68 (dd, J=1.7, 3.0 Hz, 1H). LCMS (ES + ) Method 1: m / z 366 (M+H) + , RT 1.64 minutes. Intermediate 64: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-N-methyl-1H-pyrrole-3-carboxamide

[0404] [ka]

[0405] Step 1: 1-(3-chloro-4-iodopyridine-2-yl)-N-methyl-1H-pyrrole-3-carboxamide In step 3, a 2M methylamine solution in THF (0.09 mL, 0.18 mmol) was used instead of NH4Cl, and the above compound was prepared according to the procedure described in intermediate 63. The title compound was obtained as a white solid (35 mg, 70%). LC-MS (ES) + ) Method 1: m / z 362(M+H) + , RT 1.58 minutes.

[0406] Step 2: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-N-methyl-1H-pyrrole-3-carboxamide The above compound was prepared using 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrrole-3-carboxamide (36 mg, 0.10 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 30 mg, 0.14 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (5% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (24 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (d, J=1.1 Hz, 1H), 8.83 (d, J=1.1 Hz, 1H), 8.34 (d, J=5.2 Hz, 1H), 8.00 (br d, J=4.4 Hz, 1H), 7.83 (br t, 7.39-7.28 (m, 2H), 6.68 (dd, J=1.6, 2.8 Hz, 1H), 2.74 (d, J=4.3 Hz, 3H). + ) Method 1: m / z 380 (M+H) + , RT 1.73 minutes. Intermediate 65: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-1H-pyrazole-4-carboxamide

[0407] [ka]

[0408] Step 1: Methyl 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxylate Starting with methyl 1H-pyrazole-4-carboxylate, and using NaH (60% in mineral oil) instead of K2CO3 as the base, the above compound was prepared under thermal heating according to the procedure described in step 1 of intermediate 33. The mixture was quenched with a 5% citric acid solution and diluted with RINKAN. The organic layer was washed with H2O, dehydrated with Na2SO4, and filtered to obtain the compound as a beige solid (280 mg, 86%). 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.25-8.18 (m, 3H), 3.81 (s, 3H). LCMS (ES + ) Method 1: m / z 364 (M+H) + , RT 1.81 minutes.

[0409] Step 2: 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxamide In a sealed tube, a solution of methyl 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxylate (280 mg, 0.77 mmol) in 1,4-dioxane (4 mL) and 30% NH4OH in H2O (3.1 mL, 24.3 mmol) was heated at 100°C for 9 hours. H2O was added, the mixture was cooled to 0°C, and the solid precipitate was filtered to obtain the title compound as a white solid (113 mg, 40%). 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.19 (s, 2H), 8.14 (s, 1H), 7.77 (br s, 1H), 7.23 (br s, 1H). LCMS (ES + ) Method 1: m / z 349 (M+H) + , RT 1.28 minutes.

[0410] Step 3: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-1H-pyrazole-4-carboxamide The above compound was prepared using 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxamide (113 mg, 0.32 mmol) and 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 68 mg, 0.32 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (5% to 60% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (10 mg, 8%). 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (d, J=1.3 Hz, 1H), 8.85 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 7.81 (br s, 1H), 7.44 (d, J=5.3 Hz, 1H), 7.24 (br s, 1H).LCMS (ES + ) Method 1: m / z 367 (M+H) + , RT 1.50 minutes. Intermediate 66: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

[0411] [ka]

[0412] Step 1: 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxylic acid To a solution of methyl-1H-pyrazole-4-carboxylate (54 mg, 0.43 mmol) in dry DMF (2 mL) at room temperature, NaH (60% in mineral oil; 18.6 mg, 0.47 mmol) and 3-chloro-2-fluoro-4-iodopyridine (100 mg, 0.39 mmol) were sequentially added. After 30 minutes, the mixture was quenched with H2O. THF (2 mL) and NaOH (4N, 0.5 mL, 2 mmol) were added, and the resulting mixture was stirred for a further 6 hours. Then, the pH was acidified to 1 with 6N HCl at 0°C, and the product was extracted with RINKAN (3×). The organic layer was dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the title compound as a yellow solid (137 mg), which was used in the next step without further purification. LCMS(ES) + ) Method 1: m / z 350(M+H) + , RT 1.50 min.

[0413] Step 2: 1-(3-chloro-4-iodopyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide The above compound was prepared using 1-(3-chloro-4-iodopyridine-2-yl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.17 mmol) and dimethylamine hydrochloride (21 mg, 0.26 mmol) instead of NH4Cl as starting materials, following the procedure described in step 3 of intermediate 63. The crude product was purified by reverse-phase chromatography (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (51 mg, 78%). LC-MS (ES) + ) Method 1: m / z 377(M+H) + , RT 1.42 minutes.

[0414] Step 3: 1-(3-chloro-4-((5-chloropyrazine-2-yl)thio)pyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide The above compound was prepared using 1-(3-chloro-4-iodopyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide (25 mg, 0.07 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 15 mg, 0.07 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified by reverse-phase chromatography (5% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white powder (16 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.86 (d, J=1.1 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.45 (d, J=5.2 Hz, 1H), 3.19 (br s, 3H), 3.00 (br s, 3H). LCMS (ES + ) Method 1: m / z 395 (M+H) + , RT 1.63 minutes. Intermediate 67: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide

[0415] [ka]

[0416] Step 1: 8-Chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylic acid To a suspension of ethyl 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylate (intermediate 53, prepared as reported in the synthesis of step 1, 167 mg, 0.48 mmol) in DME (1.5 mL), NaOH (5N, 2 mL, 10 mmol) was added. The resulting mixture was stirred at room temperature for 48 hours and then cooled to -20°C. The precipitate was filtered to obtain the title compound as a white solid (92 mg, 60%). LCMS (ES) +) Method 1: m / z 323(M+H) + , RT 1.18 minutes.

[0417] Step 2: 8-Chloro-7-iodo-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide The above compound was prepared using 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylic acid (83 mg, 0.26 mmol) and dimethylamine hydrochloride (32 mg, 0.40 mmol) instead of NH4Cl, following the procedure described in intermediate 63 step 3. The compound was purified by reverse-phase chromatography (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white solid (62 mg, 69%). 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 7.38 (d, J=7.1 Hz, 1H), 3.41 (s, 3H), 3.01 (s, 3H).

[0418] Step 3: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide The above compound was prepared using 8-chloro-7-iodo-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide (50 mg, 0.14 mmol) and sodium 5-chloropyrazine-2-thiolate (intermediate 16, prepared as reported in steps 1 and 2 of the synthesis, 31 mg, 0.15 mmol) as starting materials, following the procedure described in step 3A of intermediate 16. The crude compound was directly purified from 0% to 100% (DCM in SiO / 10% MeOH) by flash chromatography to obtain the title compound as a beige solid (40 mg, 75%). 1H NMR (300 MHz, DMSO-d6) δ 8.72-8.67 (m, 1H), 8.63-8.52 (m, 2H), 8.45 (s, 1H), 7.12 (d, J=7.2 Hz, 1H), 3.43 (s, 3H), 3.03 (s, 3H). LCMS (ES + ) Method 1: m / z 368 (M+H) + , RT 1.58 minutes. Intermediates 68a and 68b: 6-chloro-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one

[0419] [ka]

[0420] Step 1: N-(2,3-dichlorophenyl)acetimamide A solution of 2,3-dichloroaniline (1.62 g, 10.0 mmol) in dried DCE (10 mL) and MeCN (0.78 mL) was treated with AlCl3 (1.47 g, 11 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then at 100°C for 18 hours. After cooling, the reaction mixture was treated with ice H2O (30 mL) and extracted with DCM (2×). NaOH (2 M aqueous solution) was added to the mixture to adjust the pH to 10, and the aqueous phase was extracted with DCM. The combined organic layers were dehydrated with Na2SO4 and concentrated under vacuum to obtain the title compound as a brownish oily substance (1.62 g, 80%), which was used as the crude product without further purification. LCMS (ES) + ) Method 1: m / z 203(M+H) + , RT 1.15 minutes.

[0421] Step 2: 3-(2,3-dichlorophenyl)-6-hydroxy-2-methylpyrimidine-4(3H)-one A suspension of N-(2,3-dichlorophenyl)acetimamide (1.61 g, 7.93 mmol) in EtOH (8 mL) was treated with diethylpropanediate (2.42 mL, 15.86 mmol) and EtONa (20% solution in EtOH; 8.88 mL, 23.78 mmol). The resulting mixture was stirred in a sealed tube at 120°C for 18 hours. The reaction mixture was cooled to 25°C, and volatiles were removed under reduced pressure. H2O was added to the residue, the mixture was cooled to 0°C, and the pH was acidified to approximately 2 with HCl (6 M aqueous solution). The mixture was heated to 25°C and stirred for 1 hour. The resulting solid was collected by vacuum filtration, rinsed with Et2O, and dried under reduced pressure to obtain the title compound (955 mg, 44%). LCMS(ES) + ) Method 1: m / z 271(M+H) + , RT 1.08 minutes.

[0422] Step 3: 6-Chloro-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one A solution of 3-(2,3-dichlorophenyl)-6-hydroxy-2-methylpyrimidine-4(3H)-one (950 mg, 3.5 mmol) in POCl3 (10.0 mL) was heated at 100°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ice H2O was added to the mixture and extracted by DCM. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (0-50% ethyl ether in petroleum ether) to obtain the title compound as a beige powder (500 mg, 49%). LCMS (ES) + ) Method 1: m / z 289(M+H) + RT 1.68 min. The above atropisomer mixture was subjected to chiral SFC (flow rate: 10 ml / min, T) on a Berger SFC (trademark) MiniGram-Mettler Toledo AG using a Chiralcel (registered trademark) OD (2 × 25 cm) column. col 40℃, P colSeparation was performed using a supercritical fluid (CO2 used as the eluate): 120 bar, modifier: 5% MeOH (+0.1% TEA) for 3 minutes, 5-15% for 6 minutes, 15% for 10 minutes, 15-5% for 1 minute; intermediate 68a was obtained as the first eluate (RT 10.39 min), and intermediate 68b was obtained as the second eluate (RT 11.21 min). [Examples]

[0423] (Example 1) (S)-1-(5-((2-(trifluoromethyl)pyridine-3-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0424] [ka]

[0425] In a sealed microwave vial, dried DIPEA (0.04 mL, 0.23 mmol) was added to the solutions of intermediate 5 (20 mg, 0.07 mmol) and intermediate 11 (20 mg, 0.06 mmol) in dried DMSO (0.7 mL). The reaction mixture was heated at 120 °C for 3 hours. The residue was directly purified using preparative HPLC-MS (5% to 45% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow powder (12.8 mg, 35%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.62 (dd, J=4.6, 1.0 Hz, 1H), 8.50 (br s, 3H) 8.29 (s, 1H) 7.88 (d, J=8.1 Hz, 1H), 7.67-7.59 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.52 (br d, J=3.8 Hz, 1H), 4.42-4.02 (m, 4H), 3.36-3.71 (m, 2H), 2.03-1.67 (m, 4H); LCMS (ES +) Method 3: m / z 488 (M+H) + , RT 2.08 minutes.

[0426] (Example 2) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0427] [ka]

[0428] In a sealed microwave vial, dried DIPEA (0.06 mL, 0.34 mmol) was added to the solutions of intermediate 12 (27 mg, 0.08 mmol) and intermediate 5 (40.3 mg, 0.15 mmol) in dried 1-BuOH (0.7 mL). The mixture was heated at 120 °C for 10 hours. The crude product was directly purified by preparative HPLC (0% to 30% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white powder (4.5 mg, 10%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.52 (br s, 3H), 8.32 (s, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 6.32 (d, J=1.9 Hz, 1H), 6.26 (d, J=6.9 Hz, 1H), 4.53 (br d, J=4.1 Hz, 1H), 4.44-4.13 (m, 4H), 3.66-3.37 (m, 2H), 2.01-1.71 (m, 4H). LCMS (ES + ) Method 3: m / z 469 (M+H) + , RT 1.93 minutes.

[0429] (Example 3) (S)-1-(6-amino-5-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0430] [ka]

[0431] Using intermediate 5 (14 mg, 0.05 mmol) and intermediate 13 (22 mg, 0.07 mmol) in dried DMSO (0.7 mL) as starting materials, Example 3 was prepared according to the procedure used in Example 1 to obtain a light brown powder (5.3 mg, 16%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.47 (br d, J=4.7 Hz, 4H), 7.73 (s, 1H), 7.62-7.51 (m, 2H), 7.33 (d, J=7.9 Hz, 1H), 6.29 (s, 1H), 4.53-4.43 (m, 1H), 4.43-4.16 (m, 4H), 3.33-3.03 (m, 2H), 1.91-1.58 (m, 4H). LCMS (ES + ) Method 3: m / z 463 (M+H) + , RT 2.15 minutes.

[0432] (Example 4) (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0433] [ka]

[0434] Using intermediate 5 (36.6 mg, 0.14 mmol) and intermediate 14 (20 mg, 0.07 mmol) as starting materials, Example 4 was prepared according to the procedure used in Example 1 to obtain a pale yellow powder (6.8 mg, 18%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.46 (br s, 3H), 7.75 (t, J=3.4 Hz, 2H), 7.57 (d, J=1.7 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 6.10 (d, J=6.9 Hz, 1H), 4.55-4.17 (m, 5H), 3.41-2.96 (m, 1H), 1.99-1.51 (m, 4H). LCMS (ES + ) Method 3: m / z 444 (M+H) + , RT 1.42 minutes.

[0435] (Example 5) (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0436] [ka]

[0437] Using intermediate 6 (25 mg, 0.08 mmol) and intermediate 14 (26 mg, 0.09 mmol) as starting materials, Example 5 was prepared according to the procedure used in Example 1 to obtain a yellow powder (10.5 mg, 20%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.88-8.02 (m, 3H), 7.82-7.71 (m, 2H), 7.67 (s, 1H), 6.10 (d, J=6.9 Hz, 1H), 4.64 (br s, 1H), 4.44-4.14 (m, 4H), 3.39-3.09 (m, 2H), 1.93-1.55 (m, 4H). LCMS (ES +) Method 3: m / z 478 (M+H) + , RT 1.54 minutes.

[0438] (Example 6) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0439] [ka]

[0440] Dried DIPEA (0.050 mL, 0.29 mmol) was added to the solutions of intermediate 16 (26 mg, 0.09 mmol) and intermediate 5 (21 mg, 0.08 mmol) in dried NMP (0.5 mL). The mixture was heated at 115 °C for 10 hours. The residue was purified by preparative HPLC-MS (0% to 35% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow powder (13.6 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ 8.69-8.31 (m, 5H), 7.74 (d, J=6.9 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.32 (d, J=1.8 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 4.57-4.21 (m, 5H), 3.49-3.32 (m, 1H), 3.32-3.17 (m, 1H), 1.95-1.63 (m, 4H). LCMS (ES + ) Method 3: m / z 429 (M+H) + , RT 1.54 minutes.

[0441] (Example 7) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0442] [ka]

[0443] Using intermediate 6 (25.5 mg, 0.08 mmol) and intermediate 16 (25 mg, 0.09 mmol) as starting materials, Example 7 was prepared according to the procedure used in Example 6 to obtain a grayish-white powder (12 mg, 25%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.75-8.48 (m, 4H), 8.39 (d, J=1.0 Hz, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.67 (s, 1H), 6.20 (d, J=6.9 Hz, 1H), 4.66 (br s, 1H), 4.46-4.22 (m, 4H), 3.48-3.19 (m, 2H), 1.94-1.60 (m, 4H). LCMS (ES + ) Method 3: m / z 463 (M+H) + , RT 1.66 minutes.

[0444] (Example 8) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-bromo-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0445] [ka]

[0446] Using intermediate 7 (12 mg, 0.03 mmol) and intermediate 16 (10.5 mg, 0.04 mmol) as starting materials, Example 8 was prepared according to the procedure used in Example 6 to obtain a pale yellow solid (3.6 mg, 17%). 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.79-8.62 (m, 4H), 8.50 (d, J=1.2 Hz, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.77 (s, 1H), 6.31 (d, J=6.9 Hz, 1H), 4.74 (br s, 1H), 4.59-4.31 (m, 4H), 3.61-3.29 (m, 2H), 2.08-1.69 (m, 4H). LCMS (ES + ) Method 3: m / z 507 (M+H) + , RT 1.70 minutes.

[0447] (Example 9) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-fluoro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0448] [ka]

[0449] Using intermediate 8 (5 mg, 0.02 mmol) and intermediate 16 (7.5 mg, 0.03 mmol) as starting materials, Example 9 was prepared according to the procedure used in Example 6 to obtain a yellow powder (2.7 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ 8.84-8.61 (m, 4H), 8.49 (d, J=1.1 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.67 (d, J=4.0 Hz, 1H), 6.31 (d, J=6.9 Hz, 1H), 4.77 (br s, 1H), 4.55-4.31 (m, 4H), 3.65-3.47 (m, 1H), 3.45-3.27 (m, 1H), 2.09-1.69 (m, 4H). LCMS (ES + ) Method 3: m / z 447 (M+H) + , RT 1.59 minutes.

[0450] (Example 10) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0451] [ka]

[0452] Using intermediate 9 (8 mg, 0.03 mmol) and intermediate 16 (11 mg, 0.04 mmol) as starting materials, Example 10 was prepared according to the procedure used in Example 6 to obtain a white solid (4.8 mg, 20%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.67 (d, J=1.1 Hz, 1H), 8.60-8.43 (m, 4H), 7.84 (d, J=6.9 Hz, 1H), 7.46 (s, 1H), 6.31 (d, J=6.9 Hz, 1H), 4.62 (br s, 1H), 4.54-4.28 (m, 4H), 3.64-3.48 (m, 1H), 3.47-3.30 (m, 1H), 2.20 (s, 3H), 2.06-1.92 (m, 2H), 1.90-1.77 (m, 1H), 1.76-1.66 (m, 1H).LCMS (ES + ) Method 3: m / z 443 (M+H) + , RT 1.64 minutes.

[0453] (Example 11) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0454] [ka]

[0455] Step 1: (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 16 (9.2 mg, 0.03 mmol) and intermediate 3 (10 mg, 0.03 mmol) as starting materials, according to the procedure used in Example 6, to obtain a crude compound (17 mg), which was used without purification. LCMS(ES + ) Method 1: m / z 547(M+H) + , RT 1.40 minutes.

[0456] Step 2: (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (Example 11) HCl (4N in 1,4-dioxane; 0.10 mL, 0.40 mmol) was added to the solution of the substance from the previous step (17 mg, 0.03 mmol) in DCM (0.5 mL). The crude product was directly purified by flash chromatography on a C18 cartridge (0% to 35% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale beige powder (8.3 mg, 49% obtained in two steps). 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=1.1 Hz, 1H), 8.53-8.26 (m, 4H), 7.74 (d, J=7.0 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 6.10 (s, 1H), 4.52-4.12 (m, 5H), 3.46-3.30 (m, 1H), 3.30-3.15 (m, 1H), 2.20 (s, 3H), 1.90-1.63 (m, 4H). LCMS (ES + ) Method 3: m / z 443 (M+H) + , RT 1.62 minutes.

[0457] (Example 12) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0458] [ka]

[0459] Step 1: (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 16 (13 mg, 0.05 mmol) and intermediate 4 (15 mg, 0.04 mmol) as starting materials, following the procedure used in Example 6, to obtain a crude compound (25 mg), which was used without purification. LCMS(ES + ) Method 1: m / z 563(M+H)+ , RT 1.38 minutes.

[0460] Step 2: (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Using the material from the previous step as a starting material, Example 12 was obtained as a light beige powder (6.7 mg, 26% over two steps) according to the procedure of Example 11. 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.57 (br s, 1H), 8.52-8.36 (m, 4H), 7.74 (d, J=6.9 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 5.72 (s, 1H), 4.50-4.29 (m, 3H), 4.28-4.09 (m, 2H), 3.78 (s, 3H), 3.42-3.13 (m, 2H), 1.90-1.63 (m, 4H). LCMS (ES + ) Method 3: m / z 459 (M+H) + , RT 1.64 minutes.

[0461] (Example 13) (S)-1-(5-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0462] [ka]

[0463] K2CO3 (26.6 mg, 0.19 mmol) was added to the solutions of intermediate 17 (20 mg, 0.07 mmol) and intermediate 5 (65 mg, 0.16 mmol) in dried MeCN (0.5 mL). The mixture was heated at 110 °C for 18 hours. The crude product was directly purified by flash chromatography on a C18 cartridge (0% to 35% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (21 mg, 56%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.59-8.43 (m, 4H), 8.35 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=7.0 Hz, 1H), 6.32 (s, 1H), 6.17 (d, J=6.9 Hz, 1H), 4.81 (dd, J=10.4, 3.6 Hz, 1H), 4.54-4.22 (m, 5H), 3.93-3.80 (m, 1H), 3.80-3.65 (m, 2H), 3.55-3.33 (m, 2H), 3.29- 3.15 (m, 1H), 2.25-1.97 (m, 3H), 1.93-1.65 (m, 4H), 1.64-1.47 (m, 1H). LCMS (ES + ) Method 3: m / z 477 (M+H) + , RT 1.68 minutes.

[0464] (Example 14) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0465] [ka]

[0466] Using intermediate 10 (19 mg, 0.06 mmol) and intermediate 16 (19 mg, 0.07 mmol) as starting materials, Example 14 was prepared according to the procedure used in Example 6 to obtain a pale yellow solid (12 mg, 32%). 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (br s, 4H), 8.39 (d, J=0.8 Hz, 1H), 7.74 (d, J=6.9 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 4.62 (br s, 1H), 4.47-4.22 (m, 4H), 3.49-3.19 (m, 2H), 2.17 (s, 3H), 1.96-1.58 (m, 4H). LCMS (ES + ) Method 3: m / z 477 (M+H) + , RT 1.76 minutes.

[0467] (Example 15) (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0468] [ka]

[0469] Step 1: (R)-N-((S)-1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 18 (17 mg, 0.07 mmol) and intermediate 2 (26 mg, 0.06 mmol) as starting materials for 3 hours according to the procedure used in Example 6 to obtain the crude compound as a brown solid (45 mg), which was used without purification. LCMS(ES) + ) Method 1: m / z 492(M+H) + , RT 1.25 minutes.

[0470] Step 2: (R)-N-((S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide, (R)-N-((S)-1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl Starting with (L)-2-methylpropane-2-sulfinamide (45 mg, 0.06 mmol) and sodium 2-amino-3-chloropyridine-4-thiolate (prepared according to the procedure used in intermediate 14 step 3; 20 mg, 0.10 mmol), the compound was prepared according to the procedure used in intermediate 13 step 1 and purified by preparative HPLC-MS (0% to 45% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (10 mg, 27% over 2 steps). LC-MS (ES) + ) Method 1: m / z 572(M+H) + , RT 1.19 minutes.

[0471] Step 3: (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (Example 15) Using the substance from the previous step (10 mg, 0.02 mmol) as a starting material, Example 15 was prepared according to the procedure in Step 2 of Example 11, and purified by preparative HPLC-MS (0% to 35% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white solid (3.9 mg, 45%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 1.85-1.72 (m, 1H), 2.07-1.89 (m, 2H), 2.24-2.07 (m, 1H), 3.59-3.42 (m, 1H), 3.69 (br t, J=11.3 Hz, 1H), 4.36-4.04 (m, 3H), 4.60-4.37 (m, 2H), 6.32 (d, J=1.7 Hz, 1H), 6.52-6.44 (m, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.72 (d, J=6.9 Hz, 1H), 8.16 (br s, 2H), 8.50 (br s, 4H). LCMS (ES + ) Method 3: m / z 468 (M+H) + , RT 1.36 minutes.

[0472] (Example 16) (S)-1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0473] [ka]

[0474] Step 1: tert-butyl(S)-(1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate Dried DIPEA (0.1 mL, 0.57 mmol) was added to the solutions of intermediate 18 (40 mg, 0.17 mmol) and intermediate 5 (48 mg, 0.18 mmol) in dried NMP (0.9 mL). The mixture was heated at 120 °C for 1.5 hours, then cooled to room temperature, and Boc₂O (113 mg, 0.52 mmol) was added. After 1 hour, the mixture was diluted with SiO₂ and washed with H₂O (×2). The organic layer was dehydrated with Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a C₁₄ cartridge (5% to 45% MeCN / H₂O + 0.1% TFA) to obtain the title compound as a yellow solid (21 mg, 24% as a 2-step process). LC-MS (ES) + ) Method 1: m / z 488(M+H) + , RT 1.49 minutes.

[0475] Step 2: Methyl(S)-3-((5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-yl)thio)propanoate Methyl(S)-3-((5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-yl)thio)propanoate is converted to tert-butyl(S)-(1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5 Starting with '-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (20 mg, 0.04 mmol) and methyl 3-mercaptopropionate (5.3 mg, 0.04 mmol), the intermediate was prepared according to the procedure used in step 2 of intermediate 14. It was purified by preparative HPLC-MS (5% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white solid (18 mg, 83%). LC-MS (ES) + ) Method 1: m / z 528(M+H) + , RT 1.45 minutes.

[0476] Step 3: Sodium (S)-5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-thiolate Sodium (S)-5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-thioate was prepared using methyl (S)-3-((5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-yl)thio)propanoate as a starting material, according to the procedure used in Step 3 of Example 14, and obtained as a pale yellow solid (15 mg, 94%). LCMS(ES) + ) Method 1: m / z 464(M+H) + , RT 1.34 minutes.

[0477] Step 4: tert-butyl(S)-(1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate Under an N2 atmosphere, a mixture of intermediate 31 (9.5 mg, 0.03 mmol), sodium (S)-5-(4'-((tert-butoxycarbonyl)amino)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)imidazo[1,2-c]pyrimidine-8-thiolate (15 mg, 0.03 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), Xantphos (1.9 mg, 0.003 mmol), and DIPEA (0.02 mL, 0.115 mmol) in degassed dried 1,4-dioxane (7 mL) was stirred at 110 °C for 4 hours. After removing volatile matter, the crude product was purified by preparative HPLC-MS (10% to 55% MeCN / H2O + 0.1% TFA) to obtain a white solid (2 mg, 10%). LC-MS (ES) + ) Method 1: m / z 606(M+H) + , RT 1.65 minutes.

[0478] Step 5: (S)-1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Using tert-butyl(S)-(1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate as a starting material, Example 16 was prepared according to the procedure used in the synthesis of Step 2 of Example 11, and the title compound was obtained as a white powder (0.6 mg, 54%). LCMS(ES) + ) Method 3: m / z 506(M+H) + , RT 1.82 minutes.

[0479] (Example 17) (S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0480] [ka]

[0481] Step 1: tert-butyl((S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate tert-butyl((S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate, using the procedure in the preparation of intermediate 14, ter t-butyl(S)-(1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate (prepared as Example 16, Step 1; 26 mg, 0.053 mmol) and intermediate 15 (15 mg, 0.06 mmol) were used as starting materials, and the preparation was carried out according to the procedure described for intermediate 13 (Step 1). After evaporation of volatile matter, the crude product obtained was purified by flash chromatography on silica gel (10% to 100% (siRNA + 3% MeOH) in petroleum ether) to obtain the title compound as a pale yellow solid (15 mg, 45%). LCMS (ES +) Method 1: m / z 616(M+H) + , RT 1.36 minutes.

[0482] Step 2: (S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine was prepared using the substance from the previous step (15 mg, 0.02 mmol) as a starting material, following the procedure in Example 11 (Step 2), to obtain a white powder (8.1 mg, 54%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.77-8.36 (m, 4H), 8.15 (d, J=3.6 Hz, 2H), 7.59 (d, J=1.8 Hz, 1H), 7.41 (d, J=6.9 Hz, 1H), 6.42-6.31 (m, 2H), 4.89 (dd, J=10.6, 3.5 Hz, 1H), 4.55 (br d, J=3.2 Hz, 1H), 4.50-4.39 (m, 1H), 4.36-4.26 (m, 1H), 4.25-4.01 (m, 2H), 3.96-3.83 (m, 1H), 3.83-3.58 (m, 3H), 3.58-3.41 (m, 2H), 2.26-1.91 (m, 6H), 1.87-1.75 (m, 1H), 1.68-1.50 (m, 1H). LCMS (ES + ) Method 3: m / z 516 (M+H) + , RT 1.46 minutes.

[0483] (Example 18) (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0484] [ka]

[0485] Step 1: tert-butyl(S)-(1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate The tert-butyl(S)-(1-(8-bromoimidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate was prepared using intermediate 18 (40 mg, 0.17 mmol) and intermediate 6 (57 mg, 0.19 mmol) as starting materials, following the procedure used in Step 1 of Example 16. The mixture was purified by preparative HPLC (10% to 65% MeCN / H2O, +0.1% TFA), diluted with ethyl acetate, and evaporated to dryness to obtain the title compound as a yellow solid (32 mg, 35%). LC-MS (ES) + ) Method 1: m / z 522(M+H) + , RT 1.66 minutes.

[0486] Step 2: tert-butyl(S)-(1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate tert-butyl(S)-(1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)carbamate was prepared using the substance from the previous step and sodium 2-amino-3-chloropyridine-4-thiolate (intermediate 14, prepared according to the procedure used in step 3; 16 mg, 0.08 mmol) as starting materials, according to the procedure used in intermediate 13 (step 1), and purified by preparative HPLC (10% to 55% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow solid (25 mg, 68%); LCMS (ES) + ) Method 1: m / z 602(M+H) + , RT 1.49 minutes.

[0487] Step 3: (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine Using the material from the previous step as a starting material, Example 18 was obtained by following the procedures in Example 11 and Step 2, and the title compound was obtained as a white powder (16 mg, 65%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.68 (br s, 3H), 8.51-8.44 (m, 1H), 8.18-8.05 (m, 2H), 7.74 (d, J=6.9 Hz, 1H), 7.69 (br s, 1H), 6.48-6.39 (m, 1H), 4.73 (br s, 1H), 4.41 (dd, J=11.7, 9.0 Hz, 2H), 4.22-4.00 (m, 2H), 3.74-3.59 (m, 1H), 3.59-3.43 (m, 1H), 2.23-2.07 (m, 1H), 2.05-1.89 (m, 2H), 1.85-1.71 (m, 1H). LCMS (ES + ) Method 3 m / z 502 (M+H) + , RT 1.49 minutes.

[0488] (Example 19) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0489] [ka]

[0490] Step 1: (R)-N-((S)-1-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide A solution of intermediate 2 (103.4 mg, 0.25 mmol) in DMSO (1.0 mL) was treated with 5-bromo-8-chloroimidazo[1,5-a]pyrazine (58.6 mg, 0.25 mmol) and DIPEA (0.16 mL, 0.88 mmol), and the mixture was heated at 100°C for 40 minutes. After cooling, the reaction mixture was diluted with siRNA and H2O. The organic phase was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% siRNA (+20% MeOH) in petroleum ether). The title compound was obtained as a pale pink powder (77 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.05 (s, 1H), 7.47 (s, 1H), 7.31 (s, 1H), 6.10 (m, 1H), 5.95 (d, J=9.9 Hz, 1H), 4.47 (d, J=9.3 Hz, 1H), 4.42-4.33 (m, 2H), 4.26 (d, J=11.4 Hz, 1H), 4.13 (d, J=11.0 Hz, 1H), 3.45-3.36 (m, 2H), 1.95-1.66 (m, 4H), 1.13 (s, 9H).LCMS (ES + ) Method 1: m / z 492 (M+H) + , RT 1.15 minutes.

[0491] Step 2: (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide A suspension of Pd2(dba)3 (14.32 mg, 0.02 mmol), (S)-N-((S)-1-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (77.0 mg, 0.16 mmol), intermediate 20 (0.01 mL, 0.23 mmol), Xantphos (90.48 mg, 0.16 mmol), and DIPEA (0.058 mL, 0.63 mmol) in dried 1,4-dioxane (1.0 mL) was heated at 110 °C for 18 hours. After cooling, the mixture was filtered on a solka floc pad, the solid was washed with siRNA, and the solvent was removed under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% siRNA in petroleum ether to 0-20% MeOH in DCM). The title compound was obtained as a yellow powder (29 mg, 27%). LC-MS (ES) + ) Method 1: m / z 572(M+H) + , RT 1.17 minutes.

[0492] Step 3: (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (trifluoroacetate) A solution of (S)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (29.0 mg, 0.05 mmol) in DCM (1.0 mL) was treated with HCl (4N in 1,4-dioxane; 0.05 mL, 0.10 mmol), the reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (40% to 100% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white powder (10.6 mg, 44%). 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br s, 3H), 8.30 (s, 1H), 8.12 (s, 1H), 7.65-7.60 (m, 3H), 6.68 (br s, 2H), 6.33 (s, 1H), 5.78 (d, LCMS (ES) + ) Method 1: m / z 468 (M+H) + , RT 0.80 minutes.

[0493] (Example 20) (S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine(trifluoroacetate)

[0494] [ka]

[0495] Step 1: (R)-N-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide A solution of (R)-2-methyl-N-((S)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)propan-2-sulfinamide bis(2,2,2-trifluoroacetate) (intermediate 19; 29.0 mg, 0.04 mmol), 3-((2-amino-3-chloropyridine-4-yl)thio)-6-chloropyrazine-2-amine (intermediate 14; 10.0 mg, 0.03 mmol), and K2CO3 (28.8 mg, 0.21 mmol) in MeCN (0.4 mL) was heated at 85°C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ELISA and H2O. The organic phase was washed with brine, dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and used as the crude product for the next step. LCMS(ES + ) Method 1: m / z 588(M+H) + , RT 1.35 minutes.

[0496] Step 2: (S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine(trifluoroacetate) (R)-N-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide (25.0 mg, 0.02 mmol) was dissolved in HCl (1.25 N in MeOH; 0.27 mL, 0.34 mmol) and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (10% to 100% MeCN / H2O + 0.1% TFA) to obtain the title compound as a yellow powder (3.8 mg, 46%). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (br s, 3H), 7.72 (s, 1H), 7.68 (d, J=5.5 Hz, 1H), 6.89 (br s, 2H), 6.28 (br s, 2H), 5.85 (d, J=5.5 Hz, 1H), 4.38-4.14 (m, 5H), 3.16-3.08 (m, 2H), 2.78-2.56 (m, 4H), 2.35-2.30 (m, 2H), 1.85-1.60 (m, 4H). LCMS (ES + ) Method 1: m / z 484 (M+H) + , RT 0.89 minutes.

[0497] (Examples 21 and 22) (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine (trifluoroacetate) and 1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-ol (trifluoroacetate)

[0498] [ka]

[0499] Step 1: (R)-N-((S)-1'-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide In the synthesis of Example 19 using intermediate 19, the title compound was obtained as a pale pink solid (27 mg, 59%) using the procedure described in Step 1. LCMS(ES) + ) Method 1: m / z 532(M+H) + , RT 1.41 minutes.

[0500] Step 2: (R)-N-((S)-1'-(5-((3-chloro-2-((4-methoxybenzylamino)pyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide Suspensions of intermediate 21 (21.3 mg, 0.08 mmol), Ruphos-PdG4 (8.62 mg, 0.01 mmol), NaOtBu (24.3 mg, 0.25 mmol), and (R)-N-((S)-1'-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide (27.0 mg, 0.05 mmol) in a mixture of 1,4-dioxane (1.0 mL) and H2O (0.2 mL) were heated at 100°C for 16 hours. After cooling, the solvent was removed under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% siRNA in petroleum ether to 0-20% MeOH in DCM). The title compound was obtained as an orange powder (27 mg, purity 68%, 38%, diastereomer ratio 8 / 2). LCMS (ES)+ ) Method 1: m / z 732(M+H) + , RT 2.05 minutes.

[0501] Step 3: (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine (trifluoroacetate) and 1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-ol (trifluoroacetate) A solution of (R)-N-((S)-1'-(5-((3-chloro-2-((4-methoxybenzyl)amino)pyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-yl)-2-methylpropane-2-sulfinamide (21 mg, 0.02 mmol) in TFA (1.0 mL) was stirred at room temperature for 20 hours. The resulting mixture was diluted with toluene and concentrated under reduced pressure. The residue was treated with HCl (3.0 M in MeOH; 1.0 mL, 3 mmol) and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (15% to 100% MeCN / H2O + 0.1% TFA) to obtain Example 21 as a white powder (TFA salt; 0.7 mg, 7%). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (br s, 3H), 8.29 (s, 1H), 8.11 (s, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.61 (s, 1H), 6.66 (br s, 2H), 5.77 (d, J=5.3 Hz, 1H), 4.65-4.52 (m, 2H), 4.44-4.39 (m, 1H), 4.34 (d, J=10.7 Hz, 1H), 4.20 (d, J=10.7 Hz, 1H), 3.70-3.61 (m, 1H), 2.76-2.55 (m, 5H), 2.36-2.28 (m, 2H), 1.98-1.67 (m, 4H). LCMS (ES + ) (Method 2) m / z 508 (M+H) + , RT 1.09 minutes. Example 22 was obtained as a white powder (TFA salt; 0.4 mg, 4%). 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.11 (s, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.58 (s, 1H), 6.72 (br s, 2H), 5.82 (d, J=5.5 Hz, 1H), 4.64 (s, 1H), 4.25-4.17 (m, 2H), 4.03-3.98 (m, 2H), 3.88-3.75 (m, 2H), 2.65-2.51 (m, 5H), 2.35-2.28 (m, 2H), 2.03-1.98 (m, 1H), 1.75-1.67 (m, 3H).LCMS (ES + ) Method 1: m / z 509 (M+H) + , RT 1.30 minutes.

[0502] (Example 23) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0503] [ka]

[0504] Example 23 was prepared in the same manner as reported in Example 19 (using intermediate 3 in step 1, intermediate 21 in step 2, and TFA without solvent in step 3), and obtained as a white powder (3 mg, 16%). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (br s, 3H), 8.30 (s, 1H), 8.12 (s, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.61 (s, 1H), 6.70 (br s, 2H), 6.10 (s, 1H), 5.78 (d, J=5.5 Hz, 1H), 4.68-4.55 (m, 2H), 4.43 (d, J=3.3 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.20 (d, J=11.2 Hz, 1H), 3.39-3.65 (m, 2H), 2.22 (s, 3H), 1.96-1.82 (m, 4H). LCMS (ES + ) Method 1: m / z 482 (M+H) + , RT 0.95 minutes.

[0505] (Example 24) (S)-1-(5-(((R)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)imidazo[1,5a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0506] [ka]

[0507] Example 24 was prepared according to the procedure described in the synthesis of Example 19 (using intermediate 29 and t-BuOK in step 2 and HCl (1.0 M in MeOH) in step 3), and obtained as a white powder (1.57 mg, 54%). 1 H NMR (400 MHz, DMSO-d6+TFA) δ 8.79 (s, 1H), 8.54 (br s, 3H), 8.45 (s, 1H), 7.76 (s, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 6.34 (d, J=2.0 Hz, 1H), 6.21 (d, J=6.8 Hz, 1H), 4.86 (dd, J1=10.5 Hz, J2=3.7 Hz, 1H), 4.62-4.43 (m, 4H), 4.31 (d, J=11.4 Hz, 1H), 4.19-4.12 (m, 1H), 3.87-3.82 (m, 1H), 3.72 (br d, J=11.0 Hz, 1H), 3.58-3.50 (m, 1H), 3.38 (d, J=11.0 Hz, 1H), 2.01-1.87 (m, 4H), 1.81-1.74 (m, 2H), 1.40-1.23 (m, 5H).LCMS (ES + ) Method 1: m / z 542 (M+H) + , RT 1.02 minutes.

[0508] (Example 25) (S)-1-(5-(((S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0509] [ka]

[0510] Example 25 was prepared according to the procedure described in the synthesis of Example 13, which uses (S)-4'-((5-chloropyrazine-2-yl)thio)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]2-ethylhexyl (prepared as described in the synthesis of intermediate 17 using intermediate 28 in step 3) and intermediate 5. Example 25 was obtained as a pale yellow powder (4.0 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.44 (br s, 3H), 8.31 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.46 (d, J=5.9 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 5.97 (br d, J=5.9 Hz, 1H), 4.65 (br d, J=7.7 Hz, 1H), 4.50-4.46 (m, 1H), 4.43-4.36 (m, 2H), 4.35-4.24 (m, 2H), 4.02-3.94 (m, 1H), 3.65-3.60 (m, 2H), 3.38-3.17 (m, 3H), 1.92-1.66 (m, 6H), 0.76-0.63 (m, 4H). LCMS (ES + ) Method 1: m / z 503 (M+H) + , RT 0.96 minutes.

[0511] (Example 26) (S)-1-(4-((3-amino-5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-yl)thio)-3,3-difluoroindoline-1-yl)ethane-1-one (trifluoroacetate)

[0512] [ka]

[0513] Using intermediates 5 and 23 as starting materials, Example 26 was prepared according to the procedure used in Example 13, and obtained as a pale yellow powder (2.0 mg, 6%). 1 H NMR (400 MHz DMSO-d6) δ 8.39 (br s, 3H), 8.00 (br d, J=9.0 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.38 (t, J=8.1 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 6.09 (br s, 2H), 4.62 (br t, J=17.2 Hz, 2H), 4.48-4.44 (m, 1H), 4.38-4.27 (m, 2H), 4.23 (br d, J=11.4 Hz, 2H), 3.27-3.20 (m, 1H), 3.14-3.06 (m, 1H), 2.22 (s, 3H), 1.83-1.71 (m, 3H), 1.65-1.61 (m, 1H). LCMS (ES + ) Method 1: m / z 513 (M+H) + , RT 1.06 minutes

[0514] (Example 27) (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,8-dihydro-3H,6H-spiro[fl[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine(trifluoroacetate)

[0515] [ka]

[0516] Using intermediates 25 and 16 (using 1-BuOH as the solvent) as starting materials, Example 27 was prepared according to the procedure used in Example 6, and obtained as a white powder (13.0 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.45 (br s, 3H), 8.36 (s, 1H), 7.69 (d, J=5.7 Hz, 1H), 6.77 (br s, 2H), 5.90 (d, J=5.7 Hz, 1H), 4.87-4.76 (m, 2H), 4.73 (s, 2H), 4.45-4.24 (m, 5H), 3.41-3.36 (m, 1H), 3.27-3.20 (m, 1H), 1.89-1.78 (m, 3H), 1.77-1.70 (m, 1H).LCMS (ES + ) Method 1: m / z 471 (M+H) + , RT 0.84 minutes.

[0517] (Example 28) (S)-(4'-amino-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-2',3'-diyl)dimethanol(trifluoroacetate)

[0518] [ka]

[0519] Example 28 was prepared using intermediate 25 (83 mg, 0.32 mmol) and 5-bromo-8-chloroimidazo[1,5-a]pyrazine (50 mg, 0.22 mmol) (using DMSO as the solvent) in Step 1, and intermediate 21 (51 mg, 0.18 mmol) in Step 2, following the procedure used in Example 15. After removing volatiles under reduced pressure, Step 3 was carried out in two steps: using HCl (3.0 M in MeOH; 1.0 mL, 0.08 mmol), followed by the addition of TFA (2.0 mL). After preparative HPLC (10% to 45% MeCN / H2O + 0.1% TFA), the title compound was obtained as a white solid (17 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.27 (br s, 3H), 8.12 (s, 1H), 7.64 (d, J=5.5 Hz, 1H), 7.61 (s, 1H), 6.81 (br s, 2H), 5.81 (d, J=5.7 Hz, 1H), 4.64-4.50 (m, 6H), 4.42 (br s, 3H), 4.35 (d, J=11.2 Hz, 1H), 4.22 (d, J=11.0 Hz, 1H), 3.67-3.61 (m, 1H), 3.51-3.43 (m, 1H), 2.02-1.81 (m, 3H), 1.73-1.65 (m, 1H).LCMS (ES + ) Method 1: m / z 528 (M+H) + , RT 0.70 minutes.

[0520] (Example 29) (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,8-dihydro-3H,6H-spiro[flo[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine(trifluoroacetate)

[0521] [ka]

[0522] Example 29 was prepared according to the procedure used in Example 28, by performing Step 3 in two steps: using TFA (2.0 mL), removing the solvent, and then adding HCl (1.25 M in MeOH; 1.0 mL). After preparative HPLC (10% to 100% MeCN / H2O + 0.1% TFA), the title compound was obtained as a white solid (3.5 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 3H), 8.31 (s, 1H), 8.12 (s, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.61 (s, 1H), 6.77 (br s, 2H), 5.79 (d, J=5.5 Hz, 1H), 4.86-4.76 (m, 2H), 4.73 (s, 2H), 4.66-4.55 (m, 2H), 4.43 (br d, J=11.0 Hz, 2H), 4.28 (br d, J=11.4 Hz, 1H), 3.78-3.71 (m, 1H), 3.60-3.54 (m, 1H), 1.99-1.75 (m, 4H).LCMS (ES + ) Method 1: m / z 510 (M+H) + , RT 0.86 minutes.

[0523] (Example 30) (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0524] [ka]

[0525] Step 1: 4-((5-bromoimidazo[1,5-a]pyrazine-8-yl)thio)-3-chloro-N-(4-methoxybenzyl)pyridine-2-amine A mixture of 5-bromo-8-chloroimidazo[1,5-a]pyrazine (200 mg, 0.86 mmol) and intermediate 21 (330 mg, 0.88 mmol) in 1,4-dioxane (8.6 mL) was stirred at room temperature for 72 hours. The reaction mixture was diluted with siRNA and H2O was added. The organic phase was separated, washed with H2O and brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the residue. This residue was purified by flash chromatography (gradient elution of 10-100% siRNA in petroleum ether) to obtain the title compound as a pale yellow solid (170 mg, 41%). 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.04 (d, J=5.3 Hz, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 6.80 (d, J=5.0 Hz, 1H), 5.37 (br s, 1H), 4.63 (d, J=5.5 Hz, 2H), 3.82 (s, 3H); LCMS (ES + ) Method 1: m / z 476-478 (M+H) + , RT 2.13 minutes.

[0526] Step 2: (S)-1-(8-((3-chloro-2-((4-methoxybenzyl)amino)pyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine A mixture of 4-((5-bromoimidazo[1,5-a]pyrazine-8-yl)thio)-3-chloro-N-(4-methoxybenzyl)pyridine-2-amine (50 mg, 0.10 mmol), intermediate 2 (47 mg, 0.21 mmol), CuBr (0.38 mg, 0.03 mmol), 1-(2-hydroxy-1-naphthyl)naphthalen-2-ol (1.5 mg, 0.01 mmol), and Cs2CO3 (205 mg, 0.63 mmol) in DMF (1.0 mL) was heated at 100 °C for 4 hours. After cooling, the reaction mixture was partitioned between siRNA and H2O. The organic phase was separated, washed with H2O and brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain the residue, which was treated with HCl (1.0 M) in MeOH and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by flash chromatography (gradient elution of 10-100% siRNA in petroleum ether and 0-20% MeOH in DCM) to obtain the title compound as a yellow solid (9.6 mg, 16%). LC-MS (ES) + ) Method 1: m / z 588(M+H) + , RT 1.55 minutes.

[0527] Step 3: (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (Example 30) The solution of the substance from the previous step (9 mg, 0.02 mmol) in TFA (0.5 mL) was stirred at room temperature until the starting material was completely consumed, and then diluted with toluene. After removing volatiles under vacuum, the residue was purified by preparative HPLC (10% to 100% MeCN / H2O + 0.1% TFA) to obtain the title compound as a pale yellow solid (TFA salt; 5.9 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (br s, 4H), 7.77 (s, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.59 (br d, J=2.0 Hz, 1H), 7.27 (s, 1H), 6.66 (br s, 2H), 6.42 (d, J=5.5 Hz, 1H), 6.33 (d, J=1.8 Hz, 1H), 4.54 (br d, J=4.2 Hz, 1H), 4.36 (d, J=11.4 Hz, 1H), 4.23 (d, J=11.5 Hz, 1H), 3.53-3.48 (m, 2H), 3.14-3.05 (m, 2H), 2.12-2.01 (m, 2H), 1.95-1.92 (m, 1H), 1.76-1.73 (m, 1H); LCMS (ES + ) Method 1: m / z 468 (M+H) + , RT 0.88 minutes.

[0528] (Example 31) (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0529] [ka]

[0530] Step 1: 8-Chloro-7-((5-chloropyrazine-2-yl)thio)imidazo[1,2-a]pyridine Chloroacetaldehyde (50 wt / wt%; 0.08 mL, 0.63 mmol) in H2O was added to a suspension of intermediate 16 (57 mg, 0.21 mmol) in H2O (1.5 mL), and the suspension was heated at 100°C for 4 hours under MW irradiation. The mixture was cooled to 0°C, diluted with H2O, the pH was adjusted to 10 with K2CO3, and the product was extracted with DCM (3×). The organic layers were combined, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the title compound as a brown powder (50 mg, 81%). 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J=1.4 Hz, 1H), 8.62 (d, J=7.2 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.18 (d, J=1.3 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.12 (d, J=7.1 Hz, 1H).LCMS (ES + ) Method 1: m / z 297 (M+H) + , RT 1.11 minutes.

[0531] Step 2: (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (trifluoroacetate) Dried DIPEA (0.04 mL, 0.23 mmol) was added to a solution of intermediate 2 (15 mg, 0.05 mmol) in dried NMP (0.5 mL). The mixture was heated at 110°C for 6 hours. HCl (4N in 1,4-dioxane; 0.13 mL, 0.51 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The product was purified by preparative HPLC-MS (0% to 35% MeCN / H2O + 0.1% TFA), lyophilized, and the title compound was obtained as a yellow powder (8.2 mg, 29%). 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.66 (d, J=7.2 Hz, 1H), 8.62- 8.37 (m, 5H), 8.37-8.30 (m, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.37-6.28 (m, 1H), 4.55-4.22 (m, 5H), 3.48-3.33 (m, 1H), 3.32-3.16 (m, 1H), 1.98-1.64 (m, 4H). LCMS (ES + ) Method 3: m / z 453 (M+H) + , RT 1.53 minutes.

[0532] (Example 32) (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0533] [ka]

[0534] Step 1: 8-Chloro-7-iodoimidazo[1,2-a]pyridine Chloroacetaldehyde (50 wt / wt%; 0.30 mL, 2.36 mmol) in H2O was added to a suspension of 3-chloro-2-fluoro-4-iodopyridine (200 mg, 0.79 mmol) in H2O (2 mL), and the mixture was heated at 100°C for 4 hours under MW irradiation. The mixture was cooled to 0°C, diluted with H2O, basicized to pH=10 with K2CO3, and the product was extracted with DCM (×3). The organic layers were combined, dehydrated with Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the title compound as a brown powder (218 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=7.1 Hz, 1H), 8.13 (d, J=1.1 Hz, 1H), 7.63 (d, J=1.1 Hz, 1H), 7.35 (d, J=7.1 Hz, 1H). LCMS (ES + ) Method 1: m / z 279 (M+H) + , RT 0.81 minutes.

[0535] Step 2: Methyl 3-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)propanoate In a sealed microwave vial, 8-chloro-7-iodoimidazo[1,2-a]pyridine (52 mg, 0.19 mmol), methyl 3-mercaptopropionate (0.02 mL, 0.20 mmol), Pd2(dba)3 (17.1 mg, 0.02 mmol), and Xantphos (11 mg, 0.02 mmol) were dissolved in 1.5 mL of dried 1,4-dioxane (degassed under N2). Dried DIPEA (0.08 mL, 0.47 mmol) was added, and the mixture was heated at 90°C for 1 hour. After cooling, the mixture was evaporated under reduced pressure, and the residue was purified by flash chromatography (gradient elution of 10-100% siRNA in petroleum ether) to obtain the title compound as a pale yellow solid (40 mg, 79%). 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (d, J=7.2 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 3.41-3.27 (m, 5H), 2.71 (t, J=7.0 Hz, 2H). LCMS (ES + ) Method 1: m / z 271 (M+H) + , RT 0.96 minutes.

[0536] Step 3: Sodium 8-chloroimidazo[1,2-a]pyridine-7-thiolate To a solution of methyl 3-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)propanoate (40 mg, 0.15 mmol) in ethanol (1.2 mL), NaOEt (20 wt / wt% solution in EtOH; 0.06 mL, 0.16 mmol) was added at 0°C. The mixture was warmed to room temperature. After 30 minutes, the mixture was evaporated under reduced pressure, and the product was precipitated from DCM. The orange powder was filtered, washed with DCM, and dried under reduced pressure to obtain the title compound (25 mg, 82%). LCMS(ES) + ) Method 1: m / z 185(M+H) + , RT 0.62 min.

[0537] Step 4: (R)-N-((S)-1-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide Dried DIPEA (0.08 mL, 0.46 mmol) was added to a solution of 5-bromo-8-chloroimidazo[1,5-a]pyrazine (25 mg, 0.11 mmol) and intermediate 2 (51 mg, 0.12 mmol) in dried DMSO (0.7 mL). The mixture was heated at 85°C for 10 hours. After preparative HPLC (0% to 35% MeCN / H2O + 0.1% TFA), the title compound was obtained as a yellow solid (31 mg, 58%). 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.05 (s, 1H), 7.48 (d, J =1.8 Hz, 1H), 7.31 (s, 1H), 6.10 (d, J=1.6 Hz, 1H), 5.96 (d, J=9.9 Hz, 1H), 4.53-4.21 (m, 4H), 4.18-4.07 (m, 1H), 3.50-3.36 (m, 2H), 1.95-1.59 (m, 4H), 1.13 (s, 9H). LCMS (ES + ) Method 1: m / z 492 (M+H) + , RT 1.15 minutes.

[0538] Step 5: (R)-N-((S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide In a sealed microwave vial, (R)-N-((S)-1-(5-bromoimidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-yl)-2-methylpropane-2-sulfinamide (30 mg, 0.06 mmol), sodium 8-chloroimidazo[1,2-a]pyridine-7-thiolate (from step 3; 25 mg, 0.12 mmol), Pd2(dba)3 (7 mg, 0.01 mmol), and Xantphos (4.5 mg, 0.01 mmol) were dissolved in 0.5 mL of degassed dried 1,4-dioxane under N2. Dried DIPEA (0.03 mL, 0.18 mmol) was added, and the mixture was heated at 100°C for 1 hour. After preparative HPLC (0% to 30% MeCN / H2O + 0.1% TFA), the title compound was obtained as a yellow solid (22 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ 8.34 (d, J=7.2 Hz, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J=1.1 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 6.33 (d, J=7.2 Hz, 1H), 6.11 (d, J=1.7 Hz, 1H), 6.01 (d, J=9.9 Hz, 1H), 4.66-4.46 (m, 3H), 4.30 (d, J=11.2 Hz, 1H), 4.16 (d, J =11.0 Hz, 1H), 3.61-3.41 (m, 2H), 1.98-1.87 (m, 2H), 1.87-1.66 (m, 2H), 1.19-1.06 (m, 9H). + ) Method 1: m / z 596 (M+H) +, RT 1.15 minutes.

[0539] Step 6: (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (trifluoroacetate) HCl (4N in 1,4-dioxane; 0.05 mL, 0.20 mmol) was added to the solution of the substance from the previous step (21 mg, 0.04 mmol) in DCM (0.5 mL). After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. After preparative HPLC (0% to 30% MeCN / H2O + 0.1% TFA), the title compound was obtained as a yellow powder (11 mg, 50%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 9.02 (s, 1H), 8.76-8.45 (m, 5H), 8.34 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 4.79-4.23 (m, 5H), 3.90-3.70 (m, 1H), 3.69-3.48 (m, 1H), 2.16-1.72 (m, 4H).LCMS (ES + ) (Method 3: m / z 492 (M+H) + , RT 1.39 minutes.

[0540] (Example 33) (S)-1-(5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0541] [ka]

[0542] A solution of 2-chloro-5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine (intermediate 33; 15 mg, 0.06 mmol), intermediate 5 (15 mg, 0.06 mmol), and DIPEA (28 μL, 0.16 mmol) in NMP (0.4 mL) was heated under MW at 120 °C for 3 hours. After cooling, the reaction product was diluted with ethyl acetate and extracted with 6N HCl. The aqueous layer was washed with DCM, basicized with 2N NaOH aqueous solution, and then extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the residue, which was purified by flash chromatography (gradient elution of 0-100% in ethyl acetate (10% MeOH + 1 / 100 NH4OH aqueous solution in ethyl acetate)). The fraction containing the product was evaporated, and the residue was dissolved in a mixture of MeCN (2 mL), H2O (1 mL), and TFA (a few drops), and lyophilized to obtain the title compound as a yellow solid (4.5 mg, 23%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.61 (d, J=1.1 Hz, 1H), 8.47 (br s, 3H), 8.42 (d, J=1.2 Hz, 1H), 8.18-8.27 (m, 2H), 7.80 (d, J=1.2 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.82 (d, J=5.3 Hz, 1H) 6.54 (t, J=1.9 Hz, 1H), 6.32 (d, J=1.8 Hz, 1H), 4.18-4.59 (m, 5H), 3.18-3.46 (m, 2H), 1.67-1.96 (m, 4H). LCMS (ES + ) Method 3: m / z 480 (M+H) + , RT 2.23 minutes.

[0543] (Example 34) (S)-1-(5-((3-chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine (trifluoroacetate)

[0544] [ka]

[0545] Solutions of intermediate 35 (29 mg, 0.08 mmol), intermediate 5 (31 mg, 0.12 mmol), and DIPEA (243 μL, 1.4 mmol) in NMP (0.8 mL) were heated at 100 °C for 3 hours. After cooling, the reaction mixture was diluted with H₂O (2 mL) and extracted with SiO₂. The organic layer was dehydrated with Na₂SO₄, filtered, and the solvent was removed under reduced pressure to obtain the residue, which was purified by reverse-phase chromatography (gradient elution: 0-30% MeCN / H₂O + 0.1% TFA) to obtain the title compound (30 mg, 69%). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.59-8.63 (m, 1H), 8.43-8.52 (m, 3H), 8.43 (d, J=1.3 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.32 (d, J=1.8 Hz, 1H), 6.02-6.12 (m, 1H), 4.25-4.53 (m, 5H), 3.33-3.48 (m, 1H), 3.16-3.32 (m, 1H), 2.16-2.22 (m, 3H), 2.10-2.15 (m, 3H), 1.68-1.94 (m, 4H). LCMS (ES + ) Method 3: m / z 508 (M+H) + , RT 2.36 minutes.

[0546] (Example 35) (S)-1-(6-((2-amino-3-chloropyridine-4-yl)thio)pyridazin-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine(trifluoroacetate)

[0547] [ka]

[0548] Solutions of intermediate 2 (28.8 mg, 0.05 mmol), intermediate 36 (10.0 mg, 0.04 mmol), and DIPEA (31.9 uL, 0.18 mmol) in 1-BuOH (1.0 mL) were stirred at 100°C for 24 hours. After removing volatile matter, the residue was treated with HCl (1.25 M in MeOH; 3 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-MS (5% to 100% MeCN / H2O + 0.1% TFA) to obtain the title compound as a white powder (3.5 mg, 22%). 1 H NMR (400 MHz, DMSO-d6+TFA) δ 8.46 (br s, 3H), 7.72 (d, J=5.5 Hz, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J=9.2 Hz, 1H), 6.76 (br s, 2H), 6.32 (s, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.47-4.38 (m, 3H), 4.30-4.25 (m, 1H), 3.38-3.34 (m, 1H), 3.26-3.18 (m, 1H), 1.87-1.75 (m, 3H), 1.70-1.65 (m, 1H), 1.27-1.24 (m, 1H). LCMS (ES + ) Method 1: m / z 429 (M+H) + , RT 0.69 minutes.

[0549] (Example 36) (S)-1-(6-amino-5-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine(trifluoroacetate)

[0550] [ka]

[0551] Step 1: (R)-N-((S)-1-(6-amino-5-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(6-amino-5-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 37 (15 mg, 0.04 mmol) and intermediate 13 (14 mg, 0.05 mmol) in dry DMSO (0.7 mL) as starting materials, following the procedure used in Example 6 to obtain a crude compound (28 mg), which was used in the next step without purification. LCMS(ES + ) Method 1: m / z 568(M+H) + , RT 1.72 minutes.

[0552] Step 2: (S)-1-(6-amino-5-((2-(trifluoromethyl)pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine (Example 36) Using the material from the previous step as a starting material, Example 36 was prepared according to the procedure described in Example 11. After purification by preparative HPLC (5% to 45% MeCN / H2O + 0.1% TFA), the title compound was obtained as a brownish powder (3.1 mg, 15%, 2 steps). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.82-8.42 (m, 4H), 7.75 (d, J=10.0 Hz, 2H), 7.54 (dd, J=8.1, 4.6 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 4.76-4.44 (m, 3H), 4.40-4.19 (m, 2H), 3.37-3.06 (m, 2H), 1.91-1.66 (m, 4H). LCMS (ES+ ) Method 3: m / z 464 (M+H) + , RT 2.09 minutes.

[0553] (Example 37) (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine(trifluoroacetate)

[0554] [ka]

[0555] Step 1: (R)-N-((S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 37 (25 mg, 0.06 mmol) and intermediate 14 (21 mg, 0.07 mmol) in dry DMSO (0.7 mL) as starting materials, following the procedure used in Example 6 to obtain a crude compound (37 mg), which was used in the next step without purification. LCMS(ES + ) Method 1: m / z 549(M+H) + , RT 1.13 minutes.

[0556] Step 2: (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine (Example 37) Using the material from the previous step as a starting material, Example 37 was prepared according to the procedure described in Example 11. After purification by preparative HPLC (0% to 35% MeCN / H2O + 0.1% TFA), the title compound was obtained as a brownish powder (6.5 mg, 22%, 2 steps). 1 H NMR (300 MHz, DMSO-d6+TFA) δ 8.55 (br s, 3H), 8.27 (br s, 2H), 7.80-7.71 (m, 3H), 6.10 (d, J=6.8 Hz, 1H), 4.74-4.64 (m, 1H), 4.58 (br s, 1H), 4.53-4.43 (m, 1H), 4.41-4.18 (m, 2H), 3.37-3.07 (m, 2H), 1.94-1.63 (m, 4H). LCMS (ES + ) Method 3: m / z 445 (M+H) + , RT 1.36 minutes.

[0557] (Example 38) (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine(trifluoroacetate)

[0558] [ka]

[0559] Step 1: (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-yl)-2-methylpropane-2-sulfinamide was prepared using intermediate 37 (16 mg, 0.04 mmol) and intermediate 16 (14 mg, 0.05 mmol) in dried NMP (0.5 mL) as starting materials, according to the procedure used in Exa...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, X 1 CR 1 or N, X 2 CR 2 or N, X 3 CR 3 or N, R 1 、 R 2 and R 3 each independently represents H, halogen, OC 1～3 alkyl, or NH 2 , OH or C 1～3 alkyl optionally substituted with halogen, or is optionally selected from R 1 and R 2 These, together with the carbon atoms to which they are bonded, form condensed 5, 6, or 7-membered saturated or partially unsaturated rings containing one or two heteroatoms selected from O, S, and N, each containing a halogen, OH, or NH at the time of appearance. 2 OCH 3 , C 1～3 It is optionally substituted with one or more substituents selected from alkyl groups, or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form condensed 5, 6, or 7-membered saturated or partially unsaturated rings containing one or two heteroatoms selected from O, S, and N, each containing a halogen, OH, or NH at the time of appearance. 2 OCH 3、 C 1～3 It is optionally substituted with one or more substituents selected from alkyl groups, or X 4 CR 5 R 6 , O, S, or X 4 It is a combination, R 4 The rings are aryl, heteroaryl, partially unsaturated aryl, and partially unsaturated heteroaryl rings, and each of these aryl, heteroaryl, partially unsaturated aryl, and partially unsaturated heteroaryl rings is 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, C(=O)NR'R'', NR'C(=O)C 1-6 Alkyl, NR'C(=O)C 1-6 Haloalkyl, CN, HaloC 1～6 Alkoxy, C 1～6 The molecule is optionally substituted with one or more substituents independently selected from alkoxy, saturated 5- or 6-membered heterocyclic rings, aryl, or heteroaryl groups, wherein each saturated 5- or 6-membered heterocyclic ring, aryl, or heteroaryl group is one or more CH groups. 3 NH 2 , optionally substituted with halogen or OH, and R' and R'' are each independently H or C 1～6 It is alkyl, R 5 and R 6 H and C are independent of each other. 1～6 Selected from alkyl, OH, and halogen, Cy-X 4 -R 4 The following are general formulas (A) to (M) 【Chemistry 2】 (In the formula, - R 7 H, C 1～3 Alkyl and NH 2 Selected from, - R 8 H, halogen, C 1～3 Alkyl, and the C 1～3 The alkyl group is optionally substituted with one or more halogens or OH groups. - R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 18 , R 21 and R 26 Each instance of appearance independently produces H, halogen, and C. 1～6 Alkyl or Halo C 1～6 Selected from alkyl groups, - R 12 , R 17 , R 19 and R 20 H and CH 3 Selected from, - R 23 and R 27 H and C are independent of each other. 1～6 Alkyl and hydroxy C 1～6 Selected from alkyl groups, - R 24 H, C 1～6 Alkyl, Halo C 1～6 It is an alkyl or halogen, - R 25 H, halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl or hydroxy C 1～6 It is alkyl, - Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 and Y 8 are each independently selected from N and C) Corresponds to one of the following: X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and Cy-X 4 -R 4 corresponds to the general formula (A), R 4 is s 【Transformation 3】 (In the formula, R 28 is H, halogen or C 1～3 It is alkyl, R 29 (It is a heteroaryl) is Compounds thereof, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

2. The compound of formula (I) according to claim 1, wherein R' and R'' are each independently H or CH3.

3. A compound of formula (I) according to claim 1, wherein R7 is selected from H, CH3 and NH2.

4. General formula (IA), (IB), (IC), or (ID) 【Chemistry 4】 A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the above.

5. R 1 , R 2 and R 3 Each of these independently comprises H, Br, Cl, F, and OCH. 3 CH 3 and CH 2 Selected from OH, or R 2 and R 3 The compound of formula (I) according to claim 1, wherein the elements combine to form a condensed ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, and tetrahydropyrrole.

6. Cy-X 4 -R 4 but, 【Transformation 5】 A compound of formula (I) according to claim 1, selected from the following.

7. X 4 Is S, O, or X? 4 A compound of formula (I) according to claim 1, wherein the bond is a linkage.

8. R 4 The ring is selected from phenyl, pyridine, pyrimidine, pyrazine, 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, and triazolo[4,3-a]pyridine, and the ring is each C(=O)CH 3 , C(=O)OCH 3 OH, halogen, NH 2 , CF 3 , C(=O)CH 3 , 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 The molecule is optionally substituted with one or more substituents independently selected from cycloalkyl, aryl, or heteroaryl groups, wherein each aryl or heteroaryl group is substituted with one or more halogens and C 1～3 A compound of formula (I) according to claim 1, which is optionally substituted with an alkyl group.

9. R 4 ga 2-(trifluoromethyl)pyridine-3-yl, 2-amino-3-chloropyridine-4-yl, (S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine-4-yl, 4-chloro-2-methyl-2H-indazole-5-yl, (R)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl, 3, 3-Difluoroindoline-1-ylethane-1-one, 8-chloroimidazo[1,2-a]pyridine-7-yl, 3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl, 3-chloro-2-(3,5-dimethyl-1H-pyrazole-1-yl)pyridine-4-yl, 2,3-dichlorophenyl, 8-chloro-2-methylimidazo[1,2-a]pyridine-7-yl, 8-chloro-2-cyanoimidazo[1,2-a]pyridine-7-yl, 5-chloroimidazo Dazo[1,2-a]pyridine-6-yl, 6-amino-2-chloropyridine-3-yl, 3-chloro-2-(1H-pyrrole-1-yl)pyridine-4-yl, 3-chloro-2-(4-fluoro-1H-pyrazole-1-yl)pyridine-4-yl, 3-chloro-2-(1H-imidazole-1-yl)pyridine-4-yl, 5-amino-3-chloropyrazine-2-yl, 3,8-dichloroimidazo[1,2-a]pyridine-7-yl, 8-chloro-[1,2,4]tri A compound of formula (I) according to claim 8, selected from the group consisting of zolo[4,3-a]pyridine-7-yl, 8-chloroimidazo[1,2-a]pyridine-2-yl)-2,2,2-trifluoroacetamide, 8-chloroimidazo[1,2-a]pyridine-2-carboxamide, 8-chloroimidazo[1,2-a]pyridine-2-carbonilicate, 8-chloro-N,N-dimethylimidazo[1,2-a]pyridine-2-carboxamide, and 8-fluoroquinoline-4-yl.

10. - (S)-1-(5-((2-((trifluoromethyl))pyridine-3-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((2-((trifluoromethyl))pyridine-3-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-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-chloropyridine-4-yl)thio)pyrazine-2-yl)-2'-methoxy-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-3'-chloro-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((4-chloro-2-methyl-2H-indazole-5-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-(((S)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-3'-chloro-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - 1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,2,3,8-tetrahydro-6H-spiro[cyclopenta[d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-ol; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-2'-methyl-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((R)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)imidazo[1,5a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-(((S)-6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine]-4'-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(4-((3-amino-5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-yl)thio)-3,3-difluoroindoline-1-yl)ethane-1-one; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,8-dihydro-3H,6H-spiro[fl[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-(4'-amino-1-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-2',3'-diyl)dimethanol; - (S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-1,8-dihydro-3H,6H-spiro[flo[3,4-d]pyrrolo[1,2-b]pyrazole-7,4'-piperidine]-8-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2-amino-3-chloropyridine-4-yl)thio)pyridazin-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((2-((trifluoromethyl))pyridine-3-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(3-(2-amino-3-chloropyridine-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-c][1,2,3]triazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-5'H,7'H-spiro[piperidine-4,6'-pyrrolo[2,1-c][1,2,4]triazole]-7'-amine; - (S)-1-(5-((8-chloro-2-methylimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-amino-5-((8-chloroimidazo[1,2-a]pyridine-7-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-(6-((2-amino-3-chloropyridine-4-yl)thio)-3-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methylpyrazine-2-yl)methanol; - (S)-3-(2-amino-3-chloropyridine-4-yl)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-methyl-1,5-dihydro-4H-pyrzolo[3,4-d]pyrimidine-4-one; - (S)-1-(5-((5-amino-3-chloropyrazine-2-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxamide; - (S)-1-(5-((6-amino-2-chloropyridine-3-yl)thio)pyrazine-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]pyridine-6-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carbonitride; - (S)-7-((5-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)pyrazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2(3H)-one; - (S)-1-(5-((3-chloro-2-(1H-imidazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-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-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrrole-1-yl)pyridine-4-yl)thio)pyrazine-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-imidazole-1-yl)pyridine-4-yl)thio)pyrazine-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]pyridine-7-yl)thio)pyrazine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-2-yl)thio)-3-chloropyridine-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)pyrazine-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)pyrazine-2-yl)thio)-3-chloropyridine-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide; - (S)-1-(3-(4-chloro-2-methyl-2H-indazole-5-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrido[2,3-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2-amino-3-chloropyridine-4-yl)thio)pyrido[2,3-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((2-amino-3-chloropyridine-4-yl)thio)-1-methyl-1H-imidazo[4,5-b]pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(8-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)imidazo[1,5-a]pyrazine-5-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-5-((2-amino-3-chloropyridine-4-yl)thio)-2-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-methylpyrimidine-4(3H)-one; - (S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (S)-6-(4'-amino-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-1-yl)-5-chloro-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (S)-1-(5-((8-fluoroquinoline-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloropyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-fluoro-2-methylpyridine-4-yl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(5-((3-chloro-2-(1H-pyrazole-1-yl)pyridine-4-yl)thio)pyrazine-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1'-amine; - (S)-1-(5-((2,3-dichlorophenyl)thio)pyrazine-2-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-((2,3-dichlorophenyl)thio)pyridine-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(3-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-6-(1'-amino-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one; - (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-dimethylpyrimidine-4(3H)-one; - (S)-1-(3-(3-fluoro-2-methylpyridine-4-yl)imidazo[1,5-a]pyrazine-8-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; - (S)-1-(6-(2,3-dichlorophenoxy)pyridine-3-yl)-4'H,6'H-spiro[piperidine-4,5'-pyrrolo[1,2-b]pyrazole]-4'-amine; Compounds selected from, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

11. A compound of formula (I) which is (S)-1-(5-((3-fluoro-2-methylpyridine-4-yl)thio)pyrazine-2-yl)-1'H,3'H-spiro[piperidine-4,2'-pyrrolidine]-1'-amine, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

12. A composition for medical use comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

13. A composition for use in the treatment and / or prevention of diseases or disorders mediated by the activity of SHP2, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

14. A composition for use in the treatment and / or prevention of a disease or disorder selected from the group consisting of cancer, cardiovascular disease, immunological disorders, autoimmune disorders, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, neutropenia, and combinations thereof, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. The composition according to claim 13, wherein the disease or disorder is selected from the group consisting of Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combinations thereof.

16. The composition according to claim 14, wherein any one of the aforementioned cancers is a primary cancer or a metastatic cancer.

17. The composition according to claim 12, used in radiotherapy or in combination with at least one further therapeutic agent.

18. The further therapeutic agent is (a) Alkylating agents including, but not limited to, 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 including, but not limited to, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (Cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and larcitrexed; (c) Taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); mitotic inhibitors, including but not limited to vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunin, which are often plant alkaloids and terpenoids or derivatives thereof; (d) Anti-PD-1 or PD-L1 antibodies such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); and checkpoint inhibitors such as 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, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN); (f) Cytotoxic antibiotics including, but not limited to, actinomycin D (dactinomycin, cosmegene), bleomycin (blenoxane), doxorubicin (adriamycin), daunorubicin (cerubidine), epirubicin (ellence), fludarabine (fludarabine), idarubicin, mitomycin (mitosol), mitoxantrone (novantronone), and plicamycin; aromatase inhibitors including, but not limited to, aminoglutethimide, anastrozole (arimidex), letrozole (femara), borozole (rivizor), and exemestane (aromasin); (g) Angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); (h) Antisteroids and antiandrogens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), and nilutamide (NILANDRON); (i) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) Amsacrin; Calmette-Guéran bacillus (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, Pamidronate and other bisphosphonates; Colchicine; Demethoxypyridine; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Lebamisol; Ronidamine; Mesna; Metformin; Mitotane (o,p'-DDD, LYSODREN); No Codazole; octreotide (SANDOSTATIN); perifosine; porfimer (specifically 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; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione, and other agents such as combinations thereof. A composition according to claim 17, selected from the group consisting of the following.

19. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, alone or in combination with at least one further therapeutic agent and at least one pharmaceutically acceptable excipient.

20. The further therapeutic agent is (a) Alkylating agents including, but not limited to, 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 including, but not limited to, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (Cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and larcitrexed; (c) Taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); mitotic inhibitors, including but not limited to vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, vinorelbine (NAVELBINE), and vinflunin, which are often plant alkaloids and terpenoids or derivatives thereof; (d) Anti-PD-1 or PD-L1 antibodies such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); and checkpoint inhibitors such as 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, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN); (f) Cytotoxic antibiotics including, but not limited to, actinomycin D (dactinomycin, cosmegene), bleomycin (blenoxane), doxorubicin (adriamycin), daunorubicin (cerubidine), epirubicin (ellence), fludarabine (fludarabine), idarubicin, mitomycin (mitosol), mitoxantrone (novantronone), and plicamycin; aromatase inhibitors including, but not limited to, aminoglutethimide, anastrozole (arimidex), letrozole (femara), borozole (rivizor), and exemestane (aromasin); (g) Angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); (h) Antisteroids and antiandrogens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), and nilutamide (NILANDRON); (i) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (j) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (k) Amsacrin; Calmette-Guéran bacillus (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, Pamidronate and other bisphosphonates; Colchicine; Demethoxypyridine; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Lebamisol; Ronidamine; Mesna; Metformin; Mitotane (o,p'-DDD, LYSODREN); No Codazole; octreotide (SANDOSTATIN); perifosine; porfimer (specifically 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; progestins such as medroxyprogesterone acetate (MPA) and megestrol; testosterone; 5-fluoro-2-4(1H,3H)-pyrimidinedione, and other agents such as combinations thereof. A pharmaceutical composition according to claim 19, selected from the group consisting of the following.

21. The pharmaceutical composition according to claim 19 or 20 for use as prescribed in any one of claims 13 to 18.

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