PRMT5 inhibitor

Abstract

The present invention relates to substituted nucleoside analogs of formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions for treating diseases, disorders, or conditions associated with overexpression of the PRMT5 enzyme. The present invention also relates to methods for treating diseases, disorders, or conditions associated with overexpression of the PRMT5 enzyme. TIFF2022536337000215.tif57161

Description

[Technical Field]

[0001] The present invention relates to a substituted nucleoside analog of formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions for treating diseases, disorders, or conditions associated with the overexpression of the PRMT5 enzyme. The present invention also relates to a method for treating diseases, disorders, or conditions associated with the overexpression of the PRMT5 enzyme.

[0002] Cross-reference of related applications This application claims the interests of Indian Provisional Patent Application No. IN201921022971 and Indian Provisional Patent Application No. IN201921022972, both filed on June 10, 2019, whose entire disclosures are incorporated herein by reference for all purposes. [Background technology]

[0003] Protein methylation is a common post-translational modification that affects protein activity and interactions with other biomolecules. N-methylation typically occurs on the nitrogen atom of arginine, lysine, and histidine residues, and various enzyme families exist to catalyze the methylation reaction, each specific to the amino acid residue being methylated.

[0004] A family of nine enzymes called protein arginine N-methyltransferases (PRMTs) are responsible for the methylation of the guanidinium group of arginine. The guanidinium group of arginine has two terminal nitrogen atoms that are subject to monomethylation or dimethylation. Depending on the type of dimethylation, the enzymes are further classified as type I or type II. Type I PRMTs catalyze monomethylation or asymmetric dimethylation, while type II enzymes catalyze symmetric dimethylation. Some of the substrates that undergo methylation are histones, Sm ribonucleoprotein, MRE11, and p53-binding protein 1.

[0005] Arginine side chain methylation plays a crucial role in various cellular functions, including transcriptional activation and repression, mRNA translation, premRNA splicing, protein transport, and signal transduction. This also occurs with countless substrates. Therefore, PRMT enzymatic activity influences cellular processes such as cell proliferation, damaged DNA repair, and the cell cycle and cell death. PRMT enzyme-mediated hypermethylation has been shown to be linked to certain disease conditions, including cancer (Nature Reviews Cancer 2013, pp. 13, 37; Cellular and Molecular Life Sciences 2015, pp. 72, 2041; Trends in Biochemical Sciences 2011, pp. 36, 633).

[0006] Currently, the most studied type II enzyme is PRMT5, which is conserved across eukaryotes. Overexpression of PRMT5 is associated with carcinogenesis and reduced patient survival in several human malignancies (Cell Mol Life Sci., 2015, pp. 72, 2041). PRMT5 is a putative oncogene because it directly interacts with proteins that are typically dysregulated or mutated in cancer (Mol Cell Biol, 2008, pp. 6262). Transcriptional repression of tumor suppressor genes such as P53, RB-1, and ST7, or upregulation of cyclins D1, CDK4, CDK6, eLF4E, MITF, and FGFR3, mediated by PRMT5, is associated with carcinogenesis in both solid tumors and hematological malignancies. PRMT5 is located in the nucleus and cytoplasm, and its overexpression is not limited to these, but is associated with glioblastoma multiforme (Oncogene, 2017, 36, p. 263), prostate cancer (Oncogene, 2017, 36, p. 1223), pancreatic cancer (Science, 2016, 351, p. 1214), mantle cell lymphoma (Nature Chemical Biology, 2015, 11, p. 432), non-Hodgkin lymphoma and diffuse large B-cell lymphoma (Journal of Biological Chemistry, 2013, 288, 35534), acute myeloid leukemia (Leukemia, 2018, 32, p. 499), and acute lymphoblastic leukemia (AACR; Cancer Research 2017; 77 (13 supplement): Abstract nr 1128), multiple myeloma (Leukemia, 2018, 32, 996p), non-small cell lung cancer (The Biochemical Journal, 2012, 446, 235p), small cell lung cancer (AACR; Cancer Research 2017; 77(13 supplement): Abstract nr DDT02-04), breast cancer (Cell Reports, 2017, 21, 3498p), triple-negative breast cancer (AACR; Cancer Res 2015;75(15 Supplement): Abstract nr 4786), Gastric cancer (International Journal of Oncology, 2016, 49, p. 1195), Colorectal cancer (Oncotarget, 2015, 6, p. 22799), Ovarian cancer (J Histochem Cytochem 2013, 61, p. 206), Bladder cancer (Clinical Cancer Research, 2018, CCR-18-1270), Hepatocellular carcinoma (Oncology Reports, 2018, 40, p. 536), Melanoma (PLoS One, 2013, 8, e74710; J Clin Invest. 2018, 128, p. 517), Sarcoma (Oncology It is associated with a wide range of cancers, including Letters, 2018, 16, p. 2161; oropharyngeal squamous cell carcinoma (Oncotarget, 2017, 8, p. 14847); chronic myeloid leukemia (J Clin Invest, 2016, 126, p. 3961); epithelial squamous cell carcinoma (Carcinogenesis, 2017, 38, p. 827); nasopharyngeal carcinoma (Oncology Reports, 2016, 35, p. 1703); neuroblastoma (Molecular Oncology, 2015, 9, p. 617); endometrial cancer (Gynecol Oncol., 2016, 140, 145); and cervical cancer (Pharmazie, 2018, 73, p. 269). These findings led to further research demonstrating that inhibition of PRMT5 reduces cell proliferation (Molecular and Cellular Biology 2008, 28, pp. 6262; The Journal of Biological Chemistry 2013, 288, pp. 35534).

[0007] Inhibitors of arginine methyltransferase were first disclosed in 2004 by Cheng et al., Journal of Biological Chemistry, Vol. 279 (23), p. 23892. Since then, various other compounds and substances exhibiting high selectivity for type I or type II arginine methyltransferase have been disclosed. Other publications disclosing small molecules as inhibitors of PRMT5 include International Publication Nos. 2011077133, 2011079236, 2014100695, 2014100716, 2014100719, 2014100730, 2014100734, 2014128465, 2014145214, 2015200677, 2015200680, and 2015198. This refers to publications No. 229, International Publication Nos. 2016022605, 2016034671, 2016034673, 2016034675, 2016038550, 2016135582, 2016145150, 2016178870, 2017032840, 2018160824, 2018152501, 2018085818, 2018065365, and ACS Medicinal Chemistry Letters 2015, 6, p. 408. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2011077133 [Patent Document 2] International Publication No. 2011079236 [Patent Document 3] International Publication No. 2014100695 [Patent Document 4] International Publication No. 2014100716 [Patent Document 5] International Publication No. 2014100719 [Patent Document 6] International Publication No. 2014100730 [Patent Document 7] International Publication No. 2014100734 [Patent Document 8] International Publication No. 2014128465 [Patent Document 9] International Publication No. 2014145214 [Patent Document 10] International Publication No. 2015200677 [Patent Document 11] International Publication No. 2015200680 [Patent Document 12] International Publication No. 2015198229 [Patent Document 13] International Publication No. 2016022605 [Patent Document 14] International Publication No. 2016034671 [Patent Document 15] International Publication No. 2016034673 [Patent Document 16] International Publication No. 2016034675 [Patent Document 17] International Publication No. 2016038550 [Patent Document 18] International Publication No. 2016135582 [Patent Document 19] International Publication No. 2016145150 [Patent Document 20] International Publication No. 2016178870 [Patent Document 21] International Publication No. 2017032840 [Patent Document 22] International Publication No. 2018160824 [Patent Document 23] International Publication No. 2018152501 [Patent Document 24] International Publication No. 2018085818 [Patent Document 25] International Publication No. 2018065365 [Patent Document 26] International Publication No. 2012002577 [Patent Document 27] U.S. Patent Application Publication No. 2009 / 149466 [Patent Document 28] International Publication No. 2012 / 40279 [Patent Document 29] International Publication No. 2015 / 054572 [Patent Document 30] International Publication No. 2012 / 037108 [Patent Document 31] U.S. Patent Application Publication No. 2010 / 125089 [Patent Document 32] International Publication No. 2008 / 75110 [Patent Document 33] International Publication No. 2017 / 46737 [Patent Document 34] U.S. Patent Application Publication No. 2015 / 225407 [Patent Document 35] U.S. Patent Application Publication No. 2019 / 0111060 [Patent Document 36] International Publication No. 2018 / 167800 [Patent Document 37] International Publication No. 2007 / 79162 [Patent Document 38] International Publication No. 2007 / 079162 [Patent Document 39] International Publication No. 2006 / 091905 [Non-patent literature]

[0009] [Non-Patent Document 1] Nature Reviews Cancer 2013, p. 13, 37 [Non-Patent Document 2] Cellular and Molecular Life Sciences 2015, 72, 2041 pages [Non-Patent Document 3] Trends in Biochemical Sciences 2011, 36, 633 pages [Non-licensed Document 4] Cell Mol Life Sci., 2015, 72, 2041 pages [Non-licensed Document 5] Mol Cell Biol, 2008, 28, 6262 pages [Non-licensed Document 6] Oncogene, 2017, 36, 263 pages [Non-licensed Document 7] Oncogene, 2017, 36, 1223 pages [Non-licensed Document 8] Science, 2016, 351, 1214 pages [Non-licensed Document 9] Nature Chemical Biology, 2015, 11, page 432 [Non-licensed Document 10] Journal of Biological Chemistry, 2013, 288, 35534 pages [Non-licensed Document 11] Leukemia, 2018, 32, 499 pages [Non-licensed Document 12] AACR; Cancer Research 2017;77(13 Addendum): Abstract nr 1128 [Non-licensed Document 13] Leukemia, 2018, 32, 996 pages [Non-licensed Document 14] The Biochemical Journal, 2012, page 446, 235 [Non-licensed Document 15] AACR;Cancer Research 2017;77(13 Addendum):Abstract nr DDT02-04 [Non-licensed Document 16] Cell Reports, 2017, 21, 3498 pages [Non-licensed Document 17] AACR;Cancer Res 2015;75(15 addendum):Abstract nr 4786 [Non-licensed Document 18] International Journal of Oncology, 2016, 49, page 1195 [Non-licensed Document 19] Oncotarget, 2015, 6, 22799 pages [Non-licensed Document 20] J Histochem Cytochem 2013, 61, 206 pages [Non-licensed Document 21] Clinical Cancer Research, 2018, CCR-18-1270 [Non-licensed Document 22] Oncology Reports, 2018, 40, 536 pages [Non-licensed Document 23] PLoS One, 2013, 8, e74710 [Non-licensed Document 24] J Clin Invest. 2018, 128, 517 pages. [Non-licensed Document 25] Oncology Letters, 2018, 16, 2161 pages [Non-licensed Document 26] Oncotarget, August 2017, page 14847 [Non-licensed Document 27] J Clin Invest, 2016, 126, 3961 pages [Non-licensed Document 28] Carcinogenesis, 2017, 38, 827 pages [Non-licensed Document 29] Oncology Reports, 2016, 35, 1703 pages [Non-licensed Document 30] Molecular Oncology, 2015, 9, page 617 [Non-licensed Document 31] Gynecol Oncol., 2016, pages 140, 145 [Non-licensed Document 32] Pharmazie, 2018, 73, 269 pages [Non-licensed Document 33] Molecular and Cellular Biology 2008, 28, 6262 pages [Non-licensed Document 34] The Journal of Biological Chemistry 2013, 288, 35534 pages [Non-licensed Document 35] Chengら, Journal of Biological Chemistry-Volume 279 (23), Page 23892 [Non-licensed Document 36] ACS Medicinal Chemistry Letters 2015, 6, 408 pages [Non-licensed Document 37] Purinergic Signalling(2015)11:371~387 [Non-licensed Document 38] J.Med.Chem, 2017, 60(9), 3958~3978 [Non-licensed Document 39] American Chemical Society, 1949, Volume 71, Pages 6~10 [Non-licensed Document 40] ACS Med.Chem.Lett.2015, 6, 1150~1155 [Non-licensed Document 41] Wolfら, JACS, 1949, 71, 6~10 [Non-licensed Document 42] Organic Letters, 2018, Vol. 20, No. 2, pp. 441-444 [Non-licensed Document 43] Kenneth A. Jacobson; Purinergic Signaling(2015)11:371~387 [Non-licensed Document 44] Tetrahedron, 2007, Volume 63, No. 39, Pages 9836~9841 [Non-licensed Document 45] Heterocycles, 2017, Volume 95, No. 1, pp. 445-461 [Non-licensed Document 46] Journal of Medicinal Chemistry, 1992, Vol. 35, No. 2, pp. 324 - 331

Summary of the Invention

Problems to be Solved by the Invention

[0010] According to one aspect, the present invention provides a compound of general formula (I), its stereoisomers, or its pharmaceutically acceptable salts

Chemical Formula

Chemical Formula

Chemical Formula

[0011] Details of one or more embodiments of the present invention shown below are illustrative in nature and are not intended to limit the scope of the invention. Other features, purposes and advantages of the present invention will be apparent from this specification and the claims.

[0012] According to one embodiment, the present invention relates to a compound having the structure of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Ring A, Hy, L1, R 2a , R 2' , R a , R b , R 3 (and n are as defined above in this specification) To provide.

[0013] According to one embodiment, the present invention relates to a compound having the structure of formula (IIa), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, L1, R 2a , R 2' , R a , R b , R 3 , R, R 10and n are as defined above herein) provides

[0014] According to another embodiment, the present invention relates to a compound having the structure of formula (III), its stereoisomers, or its pharmaceutically acceptable salts [Chemical formula] (wherein ring A, Hy, L1, R 2a , R 2' , R a , R b , R 3 and n are as defined above herein) provides

[0015] In any of the above embodiments of the present invention, R 3 is independently selected, at each occurrence, from halogen, substituted or unsubstituted alkyl, and -NR 7 R 8 .

[0016] In certain embodiments, R 3 is independently selected from F, Cl, Br, -NH2, -CH3 and -CH(F)2.

[0017] In any of the above embodiments of the present invention, L1 is selected from -CH2- or -NH-.

[0018] In any of the above embodiments of the present invention, R a , R b , R 2' and R 2a are independently hydrogen or methyl.

[0019] In certain embodiments, R a , R b , R 2' and R 2a are hydrogen.

[0020] According to embodiments of the present invention, ring A is selected from formulas (i), (ii), (iii), and (iv), and substituent R on ring A 3 but, [ka] It may be substituted on any of the ring carbon atoms.

[0021] According to embodiments of the present invention, Hy is selected from formulas (a-1) to (h-1), provided that if Hy is (h-1), then ring A cannot be formula (i). [ka]

[0022] According to embodiments of the present invention, R 10 However, it is selected from hydrogen, -F, and methyl.

[0023] In certain embodiments of the present invention, Hy is [ka] Selected from.

[0024] In any of the above embodiments of the present invention, R a , R b , R 2' and R 2a is independently hydrogen or methyl; L1 is selected from -CH2- or -NH-; ring A is selected from formulas (i), (ii), (iii) and (iv), and substituent R on ring A 3 However, substitution may occur on any of the ring carbon atoms. [ka] R 3 However, in each appearance, halogen, substituted or unsubstituted alkyl, and -NR 7 R 8Hy is selected independently from; Hy is selected from equation (a-1)~(h-1), provided that if Hy is selected from equation (a-1)~(h-1), then ring A cannot be equation (i), [ka] R, -NR 4 R 5 , hydrogen, and selected from substituted or unsubstituted alkyl; Z is CR 10 and selected from N; R 10 However, it is selected from hydrogen, halogens, and substituted or unsubstituted alkyl groups; R 4 and R 5 However, hydrogen and substituted or unsubstituted alkyl are independently selected; R 6 n is selected from hydrogen and substituted or unsubstituted alkyl groups; n is an integer in the range of 0 to 4 (inclusive); and m is an integer in the range of 0 to 1 (inclusive).

[0025] Examples 1 to 30 given herein are representative compounds and represent only illustrative properties; they are not intended to limit the scope of the present invention.

[0026] It should be understood that formulas (I), (II), (IIa), and (III) structurally encompass all stereoisomers and isotopes (where applicable) and pharmaceutically acceptable salts that can be conceived from the chemical structures generally described herein.

[0027] According to one embodiment, compounds of formulas (I), (II), (IIa), and (III) are provided, either in the form of a free base or a pharmaceutically acceptable salt thereof.

[0028] In another aspect of the present invention, compounds of formulas (I), (II), (IIa), and (III), stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided for treating diseases, disorders, symptoms, or conditions related to the PRMT5 enzyme.

[0029] One embodiment of the present invention provides compounds of formulas (I), (II), (IIa), and (III), their stereoisomers, or pharmaceutically acceptable salts thereof for treating a disease, disorder, symptom, or condition by inhibition of the PRMT5 enzyme.

[0030] In another aspect of the present invention, compounds of formulas (I), (II), (IIa), and (III), stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided for use as pharmaceuticals.

[0031] In another aspect of the present invention, compounds of formulas (I), (II), (IIa), and (III), stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided for use in treating diseases, disorders, symptoms, or conditions related to PRMT5.

[0032] One embodiment of the present invention provides compounds of formulas (I), (II), (IIa), and (III), their stereoisomers, or pharmaceutically acceptable salts thereof, for use in treating diseases, disorders, symptoms, or conditions caused by inhibition of the PRMT5 enzyme.

[0033] In another aspect of the present invention, a method for inhibiting PRMT5 is provided by using a compound selected from formulas (I), (II), (IIa), and (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0034] In another aspect of the present invention, a method is provided for treating a disease, disorder, or condition related to PRMT5 by using a compound selected from formulas (I), (II), (IIa), and (III).

[0035] In another aspect of the present invention, a method for treating a disease, disorder, or condition related to PRMT5 is selected from glioblastoma multiforme, prostate cancer, and pancreatic cancer, mantle cell lymphoma, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epithelial squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, and cervical cancer.

[0036] Another aspect of the present invention provides the use of compounds selected from formulas (I), (II), (IIa), and (III), their stereoisomers, or pharmaceutically acceptable salts thereof for the manufacture of a pharmacopoeia for treating a disease, disorder, symptom, or condition associated with PRMT5.

[0037] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I), (II), (IIa), and (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0038] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (IIa), and (III), its stereoisomer, or a pharmaceutically acceptable salt thereof, for use in treating a disease, disorder, symptom, or condition related to PRMT5 by administration to a subject requiring it.

[0039] In another aspect of the present invention, the disease, disorder, symptom, or condition associated with PRMT5 is selected from the group consisting of glioblastoma multiforme, prostate cancer, and pancreatic cancer, mantle cell lymphoma, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epithelial squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, and cervical cancer.

[0040] In another embodiment of the present invention, a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(6-amino-9H-purine-9-yl)cyclopenta-3-en-1,2-diol (compound 1); (1S,2R,5R)-3-(2-(6-amino-7-chloro-1,5-naphthyridine-3-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 2); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(3-aminoquinoxaline-6-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 3); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-1-(2-(3-aminoquinoxaline-6-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 4); (1S,2R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 5); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-1-yl)cyclopenta-3-en-1,2-diol (compound 6); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(((6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)oxy)methyl)cyclopenta-3-en-1,2-diol (compound 7); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 8); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 9); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(5-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 11); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)oxy)methyl)cyclopenta-3-en-1,2-diol (compound 12); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 14); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 15); 4-amino-1-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-4,5-dihydroxycyclopenta-2-en-1-yl)pyrimidine-2(1H)-one (compound 16); 6-amino-3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-4,5-dihydroxycyclopenta-2-en-1-yl)pyrimidine-4(3H)-one (compound 17); 3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-4,5-dihydroxycyclopenta-2-en-1-yl)-6-methylpyrimidine-4(3H)-one (compound 18); 6-amino-3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-4,5-dihydroxycyclopenta-2-en-1-yl)-5-fluoropyrimidine-4(3H)-one (compound 19); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-chloro-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 20); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(5,6-difluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 21); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compounds 22A and B); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-3-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compounds 23A and B); (1R,2R,3S,4R,5S)-1-(2-(6-amino-7-chloro-1,5-naphthyridine-3-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 24); (1S,2R,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 25); (1S,2R,5R)-3-(2-(2-amino-3-bromoquinoline-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 26); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 27); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinoline-7-yl)ethyl)-5-(8H-imidazo[1,2-a]pyrrolo[2,3-d]pyrimidine-8-yl)cyclopenta-3-en-1,2-diol (compound 28); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 29); and (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-(methoxyamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 30) That is the case.

[0041] In another embodiment of the present invention, a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(6-amino-9H-purine-9-yl)cyclopenta-3-en-1,2-diol (compound 1); (1S,2R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 5); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-1-yl)cyclopenta-3-en-1,2-diol (compound 6); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 14); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol (compound 15); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compounds 22A and B); and (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-3-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)cyclopenta-3-en-1,2-diol (compounds 23A and B) That is the case.

[0042] Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below.

[0043] For the purposes of interpreting this specification, the following definitions apply, and wherever used in the singular, the plural form is also included, and vice versa.

[0044] The terms "halogen" or "halo" refer to fluorine, chlorine, bromine, or iodine.

[0045] The term "alkyl" refers to an alkane-derived hydrocarbon group that contains only carbon and hydrogen atoms in its skeleton, is unsaturated, has 1 to 6 carbon atoms, and is bonded to the rest of the molecule by a single bond, such as (C1-C6) alkyl or (C1-C4) alkyl. Representative groups include, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and n-pentyl. Unless otherwise specified or stated otherwise, all alkyl groups described or requested herein may be linear or branched.

[0046] The term "haloalkyl" refers to an alkyl group defined on which one or more halogen atoms defined on are substituted. For example, there are (C1-C6) haloalkyls or (C1-C4) haloalkyls. Suitablely, a haloalkyl may be a polyhaloalkyl, including a monohaloalkyl, dihaloalkyl, or perhaloalkyl. A monohaloalkyl may have one iodine, bromine, chlorine, or fluorine atom. Dihaloalkyls and polyhaloalkyls may be substituted with two or more of the same halogen atoms or combinations of different halogen atoms. Suitablely, a polyhaloalkyl may be substituted with up to 12 halogen atoms. Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, etc. A perhaloalkyl refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Unless otherwise specified or stated otherwise, all haloalkyl groups described or requested herein may be linear or branched.

[0047] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system having 3 to 12 carbon atoms, for example (C3~C 10 This refers to cycloalkyl groups, (C3-C6) cycloalkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, etc. Examples of polycyclic cycloalkyl groups, though not limited to these, include perhydronaphthyl, adamantyl and norbornyl groups, crosslinked cyclic groups or spirodicyclic groups, such as spiro(4,4)nonal-2-yl.

[0048] The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms, including monocyclic, bicyclic, and tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0049] The terms “heterocyclic ring,” “heterocyclyl ring,” or “heterocyclyl” refer, unless otherwise specified, to substituted or unsubstituted non-aromatic 3- to 15-membered rings consisting of a carbon atom and one or more heteroatoms independently selected from N, O, or S. Heterocyclic rings can be monocyclic, dicyclic, or tricyclic ring systems, which may include condensation, bridging, or spirocyclic systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocyclic ring may be oxidized to various oxidation states. Furthermore, the nitrogen atom may be quaternized, and the heterocyclic ring or heterocyclyl may contain one or more olefinic bonds, and one or two carbon atoms in the heterocyclic ring or heterocyclyl may be suspended by -CF2-, -C(O)-, -S(O)-, S(O)2, etc. Furthermore, the heterocyclic ring may be condensed with an aromatic ring. Non-restrictive examples of heterocyclic rings include azetidinyl, benzopyranil, chromanil, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanil, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, and perhydr Examples include roazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxadinyl, quinuclidinyl, tetrahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfoneindoline, benzodioxole, tetrahydroquinoline, and tetrahydrobenzopyran. Any atom of the heterocyclic ring that results in the formation of a stable structure may be bonded to the heterocyclic ring.

[0050] The term "heteroaryl" refers, unless otherwise specified, to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring having one or more heteroatoms independently selected from N, O, or S. Heteroaryls can be monocyclic, bicyclic, or tricyclic ring systems. Any atom of the heteroaryl ring may be bonded to the heteroaryl ring, resulting in the formation of a stable structure. Non-restrictive examples of heteroaryl rings include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthylidinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolidinyl, acridinyl, phenadinyl, and phthalazinyl.

[0051] The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be "R" or "S". The compounds of the present invention include all diastereomers and enantiomers, as well as mixtures thereof. Unless specifically mentioned, a reference to a stereoisomer applies to any of the possible stereoisomers. Whenever a stereoisomer composition is not specified, it should be understood that all possible stereoisomers are included.

[0052] The term "stereoisomer" refers to a compound that consists of the same atoms bonded together by the same bonds, but has different, non-interchangeable three-dimensional structures. The three-dimensional structure is called the stereoconfiguration. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed. The term "chiral center" refers to a carbon atom to which four different groups are bonded. As used herein, the term "diastereomer" refers to a stereoisomer that is not an enantiomer. The term "racemate" or "racemic mixture" refers to a mixture of enantiomers in equal proportions.

[0053] The terms “to treat” or “to treat” a condition, disorder, or state include (a) preventing or delaying the onset of developing clinical symptoms of a condition, disorder, or state in a subject who is already suffering from or susceptible to the condition, disorder, or state but has not yet experienced or shown any clinical or subclinical symptoms of the condition, disorder, or state; (b) inhibiting the condition, disorder, or state, i.e., cessating or reducing the development of the disease or at least one of its clinical or subclinical symptoms; (c) reducing the disease, disorder, or state or at least one of its clinical or subclinical symptoms; or (d) mitigating the disease, i.e., causing regression of the condition, disorder, or state or at least one of its clinical or subclinical symptoms.

[0054] The term "inhibitor" refers to a molecule that binds to an enzyme and partially or completely inhibits the activity of said enzyme.

[0055] The term "subject" includes mammals (especially humans) and other animals, such as domesticated animals (e.g., household pets including cats and dogs) and non-domesticated animals (wildlife, etc.).

[0056] The "therapeutic dose" refers to the amount of a compound sufficient to produce the intended effect in a subject when administered to treat a disease, disorder, or condition. The therapeutic dose varies depending on the compound, the disease and its severity, and the age, weight, health status, and responsiveness of the subject being treated.

[0057] Pharmaceutically acceptable salts The compounds of the present invention may form salts with acids or bases. The compounds of the present invention may be sufficiently basic or acidic to form stable, non-toxic acid or base salts, and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Non-limiting examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts formed by the addition of acids, including hydrochloride salts. Non-limiting examples of pharmaceutically acceptable salts include inorganic and organic base addition salts formed by the addition of bases. The compounds of the present invention may also form salts with amino acids. Pharmaceutically acceptable salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid using standard procedures well known in the art.

[0058] Screening of the compounds of the present invention for PRMT5 inhibitory activity can be achieved by using various in vitro and in vivo protocols as referred to herein, or by methods known in the art.

[0059] Pharmaceutical composition The present invention relates to a pharmaceutical composition containing a compound of formula (I), (II), (IIa), and (III) disclosed herein, or a pharmaceutically acceptable salt thereof. In particular, a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula (I), (II), (IIa), and (III) described herein, and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the intended pharmaceutical composition contains an amount of the compound described herein sufficient to inhibit PRMT5 and treat the diseases described herein when administered to a subject.

[0060] Target subjects include, for example, living cells and mammals, including humans. The compounds of the present invention may be associated with pharmaceutically acceptable excipients (such as carriers or diluents), diluted by carriers, or encapsulated in carriers, which may be in the form of capsules, sachets, paper, or other containers. Pharmaceutically acceptable excipients include pharmaceutical agents that do not induce the production of antibodies harmful to the organism receiving the composition and can be administered without excessive toxicity.

[0061] Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, lower alkyl ethers of stearic acid or cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0062] The pharmaceutical composition may also contain one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts for affecting osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents, or any combination thereof. The pharmaceutical compositions of the present invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art.

[0063] The pharmaceutical compositions described herein can be prepared by prior art known in the art. For example, an active compound can be mixed with a carrier, diluted with a carrier, or encapsulated in a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier acts as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed onto a granular solid container, such as a sachet.

[0064] The pharmaceutical composition may be in conventional forms, such as capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions, or products for topical administration.

[0065] The route of administration may be any route that effectively delivers the active compound of the present invention to the appropriate or desired site of action. Appropriate routes of administration include, but are not limited to, oral, oral inhalation, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ocular (e.g., using eye drops) or topical (e.g., using topical ointment).

[0066] Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, sugar-coated tablets (containing active ingredients in powder or pellet form), lozenges, and troches. Tablets, sugar-coated tablets, or capsules having talc and / or carbohydrate carriers or binders are particularly suitable for oral administration. Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin, and sterile injection solutions, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral administration, injection solutions or suspensions, preferably aqueous solutions in which the active compound is dissolved in polyhydroxylated castor oil, are particularly suitable.

[0067] Pharmaceutical preparations are preferably in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. Unit dosage forms may be packaged preparations, packages containing isolated amounts of preparations, such as pocketed tablets, capsules, and powders in vials or ampoules. Unit dosage forms may also be capsules, tablets, caplets, cachets or lozenges themselves, or an appropriate number of any of these in a packaged form.

[0068] The total daily dose of the compound of the present invention for administration to target patients naturally depends on the mode of administration. For example, oral administration may require a higher total daily dose than intravenous (directly into the bloodstream) administration. The amount of the active ingredient in a unit dose preparation can be varied or adjusted, depending on the potency of the active ingredient or the mode of administration, ranging from 0.1 mg to 1000 mg for oral administration and from 1 μg to 5000 μg for inhalation.

[0069] Those skilled in the art can determine appropriate doses of compounds for use in the treatment of the diseases and disorders described herein. Therapeutic doses are generally determined through dose-range studies in subjects, based on preliminary evidence derived from animal studies. The dose must be sufficient to produce the desired therapeutic benefit without causing undesirable side effects in the patient. For example, the daily dose of a PRMT5 inhibitor may range from about 0.1 to about 30.0 mg / kg when administered orally. The mode of administration, dosage form, appropriate pharmaceutical excipients, diluents, or carriers can also be readily used and modified by those skilled in the art. All conceivable changes and modifications are within the scope of the present invention.

[0070] Treatment method The present invention provides compounds of formulas (I), (II), (IIa), and (III) as protein arginine methyltransferase-5 (PRMT5) inhibitors, and pharmaceutical compositions thereof, for treating diseases, disorders, or conditions associated with the overexpression of PRMT5. The present invention further provides a method for treating diseases, disorders, or conditions associated with the overexpression of PRMT5 in a subject by administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention to a subject in need.

[0071] In another aspect, the present invention relates to a method for treating a disease, disorder, or condition associated with the overexpression of PRMT5. In this method, a subject requiring such treatment is administered a therapeutically effective amount of a compound of formula (I), (II), (IIa), and (III) described herein, or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment of the present invention, the disease, disorder, or condition associated with the overexpression of PRMT5 is cancer.

[0073] In another embodiment, the present invention provides methods for treating cancer, particularly glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epithelial squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer and cervical cancer.

[0074] It should be understood that the present invention encompasses compounds of formulas (I), (II), (IIa), and (III) or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders referred to herein.

[0075] It should be understood that the present invention encompasses compounds of formulas (I), (II), (IIa), and (III) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating diseases or disorders referred to herein.

[0076] General preparation method The compounds of the formulas described herein can be prepared by techniques known in the art. Furthermore, the compounds of the formulas described herein can be prepared by following the reaction sequence shown in the schemes provided below. Furthermore, where specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned in the schemes below, other bases, acids, reagents, solvents, coupling agents, etc. known in the art may also be used and are therefore understood to be within the scope of the invention. Variations in reaction conditions, such as reaction temperature and / or duration, which may be used as known in the art, are also within the scope of the invention. All isomers of the compounds of the formulas described in these schemes are also included within the scope of the invention unless otherwise specified.

[0077] Scheme-1: [ka]

[0078] Scheme-1 illustrates the synthesis of the compound of formula 9. The compound of formula 3 can be obtained by the Mitsunobu reaction of the compound of formula 1 and the compound of formula 2, prepared by following the procedure described in Purinergic Signaling (2015) 11:371-387, but not limited to the Mitsunobu reaction, in the presence of a phosphine such as PPh3 (triphenylphosphine), and using various azodicarboxylate reagents such as DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate). Typically, these reactions are carried out in an ether solvent such as THF (tetrahydrofuran), MeTHF (methyltetrahydrofuran), dioxane, or similar solvents at a temperature in the range of 0°C to 25°C. The compound of formula 4 can be formed by treating the compound of formula 3 with fluoride ions such as ammonium fluoride or TBAF (tetra-n-butylammonium fluoride), but not limited to the Mitsunobu reaction. Typically, these reactions are carried out in ether solvents such as THF, MeTHF, dioxane, or similar solvents at temperatures ranging from 0°C to 40°C. Compound 6 is obtained by the Mitsunobu reaction of the compound of formula 4 and compound 5 (PG1 is a protecting group such as p-methoxybenzyl, but not limited to this) in the presence of a phosphine such as PPh3, and using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out in ether solvents such as THF, MeTHF, dioxane, or similar solvents at temperatures ranging from 0°C to 25°C. Deprotection of the benzoyl group of compound 6 can be carried out with reagents such as NH3 (ammonia), but not limited to this, yielding compound 7. Typically, these reactions can be carried out in alcohol solvents such as MeOH (methanol), EtOH (ethanol), or similar solvents at temperatures ranging from 0°C to 25°C.While not limited to these, the compound of formula 7 can be obtained by activation with various aryl sulfonyl halides such as 2,4,6-triisopropylbenzenesulfonyl chloride, in the presence of bases such as DMAP (4-dimethylaminopyridine), DIPEA (N,N-diisopropylethylamine), and NEt3 (triethylamine), followed by substitution with NH3. While not limited to these, the compound of formula 9 can be obtained by deprotection of the compound of formula 8 with an acid such as HCl or TFA (trifluoroacetic acid). Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC (high-performance liquid chromatography), or SFC (supercritical fluid chromatography).

[0079] Scheme 2: [ka]

[0080] Scheme-2 illustrates the synthesis of the compound of formula 14. The compound of formula 11 can be obtained by the Mitsunobu reaction of the compound of formula 1 and the compound of formula 10, but not limited to this, in the presence of a phosphine such as PPh3, and not limited to this, using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 25°C. The compound of formula 12 can be formed by treating the compound of formula 11 with fluoride ions such as ammonium fluoride or TBAF. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 40°C. The compound of formula 13 can be obtained by the Mitsunobu reaction of the compound of formula 12 and the compound of formula 5, but not limited to this, in the presence of a phosphine such as PPh3, and not limited to this, using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out at temperatures ranging from 0°C to 25°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. However, the compounds of formula 14 can also be obtained by deprotecting the compounds of formula 13 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures ranging from 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0081] Scheme 3: [ka]

[0082] Scheme 3 illustrates the synthesis of the compound of Formula 21. Among other things, in the presence of a phosphine such as PPh3 and using various azodicarboxylate reagents such as DEAD or DIAD, the compound of Formula 16 is obtained by the Mitsunobu reaction of the compound of Formula 1 and the compound of Formula 15. Typically, these reactions are carried out at a temperature in the range of 0 °C to 25 °C in an ether solvent such as THF, MeTHF, dioxane or a similar solvent. The compound of Formula 17 is formed, among other things, by treatment of the compound of Formula 16 with fluoride ions such as ammonium fluoride, TBAF. Typically, these reactions are carried out at a temperature in the range of 0 °C to 40 °C in an ether solvent such as THF, MeTHF, dioxane or a similar solvent. Among other things, in the presence of a phosphine such as PPh3 and using various azodicarboxylate reagents such as DEAD or DIAD, the compound of Formula 18 is obtained by the Mitsunobu reaction of the compound of Formula 17 and the compound of Formula 5. Typically, these reactions are carried out at a temperature in the range of 0 °C to 25 °C in an ether solvent such as THF, MeTHF, dioxane or a similar solvent. The compound of Formula 18 can give the compound of Formula 20 by treatment with aqueous ammonia. Typically, these reactions are carried out in an ether solvent such as dioxane at a temperature in the range of 120 °C to 170 °C in a steel bomb. Among other things, the compound of Formula 21 is obtained by deprotection of the compound of Formula 20 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25 °C to 50 °C. The compounds of all steps can be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC.

[0083] Scheme 4:

Chemical Structure

[0084] Scheme 4 illustrates the synthesis of the compound of formula 30. While not limited to this, the compound of formula 23 can be obtained by the Mitsunobu reaction of the compound of formula 1 and the compound of formula 22 (X=-Cl, -Br) in the presence of a phosphine such as PPh3, and, while not limited to this, using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 25°C. The compound of formula 24 can be formed by treating the compound of formula 23 with a fluoride ion such as TBAF, while not limited to this. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 40°C. While not limited to this, the compound of formula 25 can be obtained by oxidation of the compound of formula 24 with various oxidizing agents such as Dess-Martin periodinane. Typically, these reactions can be carried out at temperatures ranging from 0°C to 40°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. However, when treating with the compounds of formula 25, KO is not limited to these. t Bu, NaO tIn the presence of a base such as Bu, LiHMDS, NaHMDS or KHMDS, among others, but not limited thereto, the compound of formula 26 is obtained by means of a reagent such as methyltriphenylphosphonium bromide. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane or a similar solvent at a temperature in the range of 0 °C to 25 °C. The compound of formula 28 can be synthesized, among others, by hydroboration of the compound of formula 26 with a suitable borane such as 9-BBN, followed by, among others, addition of the compound of formula 27 (Y = -Br, -I) synthesized according to the procedure reported in WO 2012002577 in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, among others, an inorganic base such as tripotassium phosphate or Cs2CO3, and subsequent N-oxide formation, chlorination with phosphoroxychloride, and nucleophilic substitution with PMB-NH2 or as described in J. Med. Chem., 2017, 60(9), 3958 - 3978. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane or a similar solvent and are carried out at a temperature in the range of 25 °C to 70 °C. The compound of formula 28 (where R 4 and R 5 are as defined above herein) when treated with the compound of formula 19 gives the compound of formula 29. Typically, these reactions are carried out in an ether solvent such as dioxane at a temperature in the range of 120 °C to 170 °C in a steel bomb. The compound of formula 30 is obtained, among others, by acetonide deprotection of the compound of formula 29 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25 °C to 50 °C. The compounds of all steps can be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC.

[0085] Scheme 5:

Chemical Structure

[0086] Scheme 5 illustrates the synthesis of the compound of formula 39. The compound of formula 1 can be obtained by treating it with various sulfonyl chlorides such as MsCl and TsCl, but not limited to, in the presence of a base such as NEt3 or DIPEA, but not limited to, in the presence of a base such as MsCl or TsCl. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in a halogenated solvent such as CH2Cl2, CHCl3, or a similar solvent. The compound of formula 33 can be synthesized by nucleophilic substitution of the compound of formula 31 with the compound of formula 32 in the presence of a base such as NaH or LiH, but not limited to, in the presence of a base such as MsCl or TsCl. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in a solvent such as DMF, DMAc, NMP, or a similar solvent. The compound of formula 34 is prepared by treating it with an anhydride such as (Boc)2O, but not limited to, in the presence of a base such as NEt3, DIPEA, or DMAP, but not limited to, in the presence of a base such as MsCl or TsCl. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. Compounds of formula 35 are formed by treatment of compounds of formula 34 with fluoride ions such as TBAF, but are not limited to these. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 0°C to 25°C. Compounds of formula 36 can be obtained by oxidation of compounds of formula 35 with various oxidizing agents such as Dess-Martin periodinane, but are not limited to these. Typically, these reactions are carried out in a halogenated solvent such as CH2Cl2, CHCl3, or a similar solvent at a temperature in the range of 0°C to 25°C. When treating with compounds of formula 36, ​​but are not limited to these, KO t Bu, NaO tCompounds of formula 37 can be obtained in the presence of a base such as Bu, LiHMDS, NaHMDS, or KHMDS, or, in addition, with a reagent such as methyltriphenylphosphonium bromide. Typically, these reactions are carried out at temperatures ranging from 0°C to 25°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 38 can be synthesized by, but is not limited to, treatment of the compound of formula 37 with a suitable borane such as 9-BBN, followed by, but is not limited to, the addition of the compound of formula 27 (Y=-Br, -I) synthesized by following the procedure reported in International Publication No. 2012002577, in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, but is not limited to, an inorganic base such as tripotassium phosphate or Cs2CO3, followed by N-oxide formation, chlorination with a phosphoroxycyclolide, and nucleophilic substitution with PMB-NH2 or J. Med. Chem, 2017, 60(9), 3958-3978. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. Although not limited to these methods, the compound of formula 39 can be obtained by acetonide deprotection of the compound of formula 38 with an acid such as HCl / MeOH or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. All compounds can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0087] Scheme 6: [ka]

[0088] Scheme 6 illustrates the synthesis of the compound of formula 48. The compound of formula 1 (wherein PG = TBDPS or other protecting group) is prepared by following the procedure described in Purinergic Signalling (2015) 11:371-387. Compound 41 is obtained by the Mitsunobu reaction of compound 1 and compound 40 (X = -Cl, -Br) in the presence of a phosphine such as PPh3, but not limited to, and using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 0°C to 25°C. Compound 42 is formed by treatment of compound 41 with fluoride ions such as TBAF or ammonium fluoride, but not limited to. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 0°C to 40°C. While not limited to this, compounds of formula 43 can be obtained by oxidation of the compounds of formula 42 with various oxidizing agents such as des-martin periodinane. Typically, these reactions can be carried out at temperatures in the range of 0°C to 40°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. When treating with compounds of formula 43, while not limited to this, KO t Bu, NaO tCompounds of formula 44 can be obtained in the presence of a base such as Bu, LiHMDS, NaHMDS, or KHMDS, or, in addition, with a reagent such as methyltriphenylphosphonium bromide. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 45 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of the compound of formula 27 (Y=-Br, -I) synthesized by following the procedure reported in International Publication No. 2012002577, in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, followed by an inorganic base such as tripotassium phosphate or Cs2CO3, followed by N-oxide formation, chlorination with a phosphoroxycyclolide, and nucleophilic substitution with PMB-NH2 or J. Med. Chem, 2017, 60(9), 3958-3978. Typically, these reactions are carried out at temperatures in the range of 25°C to 70°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 45 can be synthesized by the compound of formula 46 (wherein R 4 Treatment with (where is hydrogen) yields the compound of formula 47. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. However, the compound of formula 48 can be obtained by acetonide deprotection of the compound of formula 47 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0089] Scheme 7: [ka]

[0090] Scheme 7 illustrates the synthesis of the compound of formula 52. The compound of formula 50 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 49 (Y=-Br, -I), although this is not limited to the latter. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 50 can be treated with the compound of formula 19 to give the compound of formula 51. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. Although not limited to these methods, the compound of formula 52 can be obtained by acetonide deprotection of the compound of formula 51 with an acid such as HCl (hydrochloric acid) or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0091] Scheme 8: [ka]

[0092] Scheme 8 illustrates the synthesis of the compound of formula 60. The compound of formula 53 (wherein PG = not limited to, but a protecting group such as TBDPS) is prepared by following the procedure described in Purinergic Signalling (2015) 11:371-387. The compound of formula 54 is obtained by the Mitsunobu reaction of the compound of formula 53 and the compound of formula 40 (X = -Cl, -Br) in the presence of a phosphine such as PPh3, not limited to, but using various azodicarboxylate reagents such as DEAD or DIAD. The compound of formula 55 is formed by treatment of the compound of formula 54 with a fluoride ion such as TBAF, not limited to, but. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 0°C to 25°C. The compound of formula 56 can be obtained by oxidation of the compound of formula 55 with various oxidizing agents such as Dess-Martin periodinane, not limited to, but. When treating with the compound of formula 56, although not limited to that, KO t Bu, NaO t The compound of formula 57 can be obtained in the presence of a base such as Bu, LiHMDS, NaHMDS, or KHMDS, or, not limited to, a reagent such as methyltriphenylphosphonium bromide. The compound of formula 57 is the compound of formula 19 (wherein R 4 and R 5Treatment with (where is hydrogen) yields the compound of formula 58. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. The compound of formula 59 can be synthesized by hydroboration of the compound of formula 58 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or cesium carbonate, and the compound of formula 49 (Y=-Br, -I), although this is not limited to this method. The compound of formula 60 can be obtained by acetonide deprotection of the compound of formula 59 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0093] Scheme 9: [ka]

[0094] Scheme 9 illustrates the synthesis of the compound of formula 68. The compound of formula 62 can be synthesized by nucleophilic substitution of the compound of formula 31 with the compound of formula 61 in the presence of a base such as NaH or LiH. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in a solvent such as DMF, DMAc, NMP, or a similar solvent. The compound of formula 63 is prepared by treating the compound of formula 62 with an anhydride such as (Boc)2O, in the presence of a base such as NET3, DIPEA, or DMAP, at temperatures in the range of 0°C to 25°C. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 64 is formed by treating the compound of formula 63 with a fluoride ion such as TBAF, but is not limited to that. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in ether solvents such as THF, MeTHF, dioxane, or similar solvents. However, the compounds of formula 65 can be obtained by oxidation of the compounds of formula 64 with various oxidizing agents such as Dess-Martin periodinane. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. When treating with the compounds of formula 65, however, KO t Bu, NaO tIn the presence of a base such as Bu, LiHMDS, NaHMDS or KHMDS, among others, and not limited thereto, the compound of formula 66 is obtained by means of a reagent such as methyltriphenylphosphonium bromide. Typically, these reactions are carried out at a temperature in the range of 0 °C to 25 °C in an ether solvent such as THF, MeTHF, dioxane or a similar solvent. The compound of formula 67 can be synthesized, among other things, by treating the compound of formula 66 with a suitable borane such as 9-BBN, followed by, among other things, the addition of the compound of formula 27 (Y = -Br, -I) synthesized according to the procedure reported in WO 2012 / 002577 in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, among other things, an inorganic base such as tripotassium phosphate or Cs2CO3, and subsequent N-oxide formation, chlorination with phosphoroxychloride, and nucleophilic substitution with PMB-NH2 or as described in J. Med. Chem., 2017, 60(9), 3958 - 3978. Typically, these reactions are carried out at a temperature in the range of 25 °C to 70 °C in an ether solvent such as THF, MeTHF, dioxane or a similar solvent. The compound of formula 68 is obtained, among other things, by deprotecting the compound of formula 67 with an acid such as HCl / MeOH or TFA. Typically, these reactions are carried out at a temperature in the range of 25 °C to 50 °C. The compounds of all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC or SFC.

[0095] Scheme 10:

Chemical formula

[0096] Scheme 10 illustrates the synthesis of the compound of formula 73. The compound of formula 70 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of the compound of formula 69 (Y=-Br, -I) by following a similar procedure reported in American Chemical Society, 1949, Vol. 71, pp. 6-10, in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, and a similar procedure. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 70 is treated with NH3 water to give the compound of formula 71. Typically, these reactions are carried out in an ether solvent such as dioxane in a steel cylinder at a temperature in the range of 120°C to 170°C. While not limited to these, the compound of formula 72 can be obtained by cyclization of the compound of formula 71 with a base such as NaHCO3, or by a 2-halo-acetaldehyde such as chloroacetaldehyde. Typically, these reactions are carried out in a protic solvent such as EtOH, MeOH, or H2O at a temperature in the range of 50°C to 80°C. While not limited to these, the compound of formula 73 can be obtained by acetonide deprotection of the compound of formula 72 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0097] Scheme 11: [ka]

[0098] Scheme 11 illustrates the synthesis of the compound of formula 78. The compound of formula 75 can be synthesized by hydroboration of the compound of formula 37 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 74 (Y=Br, -I; PG1 is a protecting group such as p-methoxybenzyl). Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 75 can be treated with NH3 water to give the compound of formula 76. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. While not limited to these, compounds of formula 77 can be obtained by cyclizing the compounds of formula 76 with 2-halo-acetaldehydes such as chloroacetaldehyde. Typically, these reactions are carried out in a protic solvent such as EtOH, MeOH, or H2O at a temperature in the range of 50°C to 80°C. While not limited to these, compounds of formula 78 can be obtained by acetonide deprotection of the compounds of formula 77 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25°C to 50°C. Compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0099] Scheme 12: [ka]

[0100] Scheme 12 illustrates the synthesis of compounds of formulas 88 and 89. Compound 80 can be obtained by the Mitsunobu reaction of compound 1 and compound 79 in the presence of a phosphine such as PPh3, and using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 25°C. Compound 81 can be formed by treatment of compound 80 with a fluoride ion such as TBAF. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or similar solvents at a temperature in the range of 0°C to 40°C. Compound 82 can be obtained by oxidation of compound 81 with various oxidizing agents such as Dess-Martin periodinane. Typically, these reactions can be carried out at temperatures ranging from 0°C to 40°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. However, when treating with the compounds of formula 82, KO is not limited to these. t Bu, NaO tCompounds of formula 83 can be obtained in the presence of a base such as Bu, LiHMDS, NaHMDS, or KHMDS, or, in part, a reagent such as methyltriphenylphosphonium bromide. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 0°C to 25°C. Compounds of formula 84 can be synthesized by hydroboration of the compound of formula 83 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, or, in part, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 74 (Y=Br, -I; PG1 is a protecting group such as p-methoxybenzyl). Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 84 can be treated with NH3 water to give the compound of formula 85. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. However, a mixture of the compounds of formula 86 and 87 can be obtained by cyclization of the compound of formula 85 with a 2-halo-acetaldehyde such as chloroacetaldehyde. Typically, these reactions are carried out in a protic solvent such as EtOH, MeOH, or H2O at a temperature in the range of 50°C to 80°C. However, the compound of formula 88 can be obtained by deprotecting the compound of formula 86 with an acid such as HCl or TFA. Furthermore, the compound of formula 89 can be obtained by deprotecting the compound of formula 87 with an acid such as HCl or TFA. Typically, these reactions are carried out at a temperature in the range of 25°C to 50°C. The compounds from all steps can be purified using standard techniques such as column chromatography, crystallization, reversed-phase HPLC, or SFC.

[0101] Scheme 13: [ka]

[0102] Scheme 13 illustrates the synthesis of the compound of formula 94. While not limited to this, the compound of formula 90 can be obtained by iodination of the compound of formula 42 with a phosphine such as PPh3, or, while not limited to this, with a base such as imidazole. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. While not limited to this, the compound of formula 92 can be obtained by nucleophilic substitution of the compound of formula 90 with the compound of formula 91 in the presence of a base such as Cs2CO3 or K2CO3. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in polar aprotic solvents such as DMF, DMAc, or similar solvents. The compound of formula 92 can be treated with the compound of formula 19 to give the compound of formula 93. Typically, these reactions are carried out in a steel cylinder at temperatures in the range of 120°C to 170°C in an ether solvent such as dioxane. Furthermore, although not limited to these methods, the compound of formula 94 can be obtained by deprotecting the compound of formula 93 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0103] Scheme 14: [ka]

[0104] Scheme 14 illustrates the synthesis of the compound of formula 94. Compound 92 can be obtained by the Mitsunobu reaction of the compound of formula 42 and the compound of formula 91, but not limited to this, in the presence of a phosphine such as PPh3, and not limited to this, using various azodicarboxylate reagents such as DEAD or DIAD. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in an ether solvent such as THF, MeTHF, dioxane, or similar solvents. The compound of formula 92 can be treated with the compound of formula 19 to give compound 93. Typically, these reactions are carried out in a steel cylinder at temperatures in the range of 120°C to 170°C in an ether solvent such as dioxane. Furthermore, compound 94 can be obtained by deprotecting the compound of formula 93 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified using standard techniques such as column chromatography, crystallization, reversed-phase HPLC, or SFC.

[0105] Scheme 15: [ka]

[0106] Scheme 15 illustrates the synthesis of the compound of formula 100. The compound of formula 97 can be synthesized by hydroboration of the compound of formula 95 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 96 (Y=Br, -I), although this is not limited to this method. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 97 can be treated with the compound of formula 19 to give the compound of formula 98. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. Furthermore, although not limited to these, the compound of formula 99 can be obtained by deprotecting the compound of formula 97 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. Furthermore, although not limited to these, the compound of formula 100 can be obtained by deprotecting the compound of formula 98 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0107] Scheme 16: [ka]

[0108] Scheme 16 illustrates the synthesis of the compound of formula 100. The compound of formula 102 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 101 (Y=Br, -I), but not limited to these. Typically, these reactions are carried out at temperatures ranging from 25°C to 70°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 102 can be treated with the compound of formula 19 to give the compound of formula 103. Typically, these reactions are carried out in a steel cylinder at temperatures ranging from 120°C to 170°C in an ether solvent such as dioxane. The compound of formula 103, though not limited to this, can be treated with a reducing agent such as NaBH4 to yield the compound of formula 104. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in an acidic solvent such as acetic acid. Furthermore, although not limited to this, the compound of formula 100 can be obtained by deprotecting the compound of formula 104 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0109] Scheme 17: [ka]

[0110] Scheme 17 illustrates the synthesis of the compound of formula 109. The compound of formula 106 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 105 (Y=Br, -I), although this is not limited to the latter. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent, at a temperature in the range of 25°C to 70°C. The compound of formula 106 can be treated with the compound of formula 19 to give the compound of formula 107. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C, in an ether solvent such as dioxane. The compound of formula 107, though not limited to this, can be treated with a reducing agent such as NaBH4 to yield the compound of formula 108. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in an acidic solvent such as acetic acid. Furthermore, although not limited to these, the compound of formula 109 can be obtained by deprotecting the compound of formula 108 with an acid such as HCl or TFA. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. The compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0111] Scheme 18: [ka]

[0112] Scheme 18 illustrates the synthesis of the compound of formula 114. The compound of formula 111 can be synthesized by hydroboration of the compound of formula 44 with a suitable borane such as 9-BBN, followed by the addition of a Pd catalyst such as Pd(dppf)Cl2 or Pd-118, an inorganic base such as tripotassium phosphate or Cs2CO3, and the compound of formula 110 (Y=Br, -I), although this method does not limit the addition of a Pd catalyst. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of 25°C to 70°C. The compound of formula 111 can be treated with the compound of formula 19 to give the compound of formula 112. Typically, these reactions are carried out in a steel cylinder at a temperature in the range of 120°C to 170°C in an ether solvent such as dioxane. Compounds of formula 112, though not limited to them, can be treated with reducing agents such as NaBH4 to yield compounds of formula 113. Typically, these reactions are carried out at temperatures in the range of 0°C to 25°C in an acidic solvent such as acetic acid. Furthermore, compounds of formula 114 can be obtained by deprotecting compounds of formula 113 with an acid such as HCl or TFA, though not limited to these. Typically, these reactions are carried out at temperatures in the range of 25°C to 50°C. Compounds from all steps can be purified by standard techniques such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0113] Scheme 19: [ka]

[0114] Scheme 19 illustrates the synthesis of the compound of formula 117. While not limited to this, the compound of formula 116 can be obtained by the formylation reaction of the compound of formula 115 with a hindered base such as LDA, or by a formylating agent such as DMF. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent at a temperature in the range of -78°C to 0°C. The compound of formula 116 can be further treated with a nucleophilic fluorinating agent such as DAST to give the compound of formula 117. Typically, these reactions can be carried out in a halogenated solvent such as CH2Cl2, CHCl3, or a similar solvent at a temperature in the range of 0°C to 25°C.

[0115] Scheme 20: [ka]

[0116] Scheme 20 illustrates the synthesis of the compound of formula 124. The compound of formula 118 is not limited to this, but KO t Bu OrNaO t The compound of formula 119 can be obtained by treatment with a reagent such as TosMIC, in the presence of a base such as Bu, or in some other cases. Typically, these reactions are carried out at temperatures ranging from 0°C to 25°C, or in some other cases. tThe reaction can be carried out in a mixture of solvents such as BuOH and DME or a similar solvent. The compound of formula 119 can be converted to the compound of formula 120 by using a borane reagent such as BH3.DMS or BH3.THF, but is not limited to this. Typically, these reactions are carried out at a temperature in the range of 0°C to 70°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent. The compound of formula 121 can be obtained by reacting the compound of formula 120 with a reagent such as ethyl formate, but is not limited to this. Typically, these reactions are carried out at a temperature in the range of 0°C to 60°C. The compound of formula 121 can be converted to the compound of formula 122 by treatment with a reagent such as oxalyl chloride, but is not limited to this, in the presence of a Lewis acid such as FeCl3, but is not limited to this. Typically, these reactions can be carried out at a temperature in the range of 0°C to 25°C in a halogenated solvent such as CH2Cl2, CHCl3, or a similar reagent. Compounds of formula 123 can be obtained by subsequent reactions under acidic conditions at temperatures ranging from 0°C to 65°C. Typically, these reactions can be carried out in protic solvents such as methanol, ethanol, or similar solvents. Compounds of formula 123, but not limited to them, can also be obtained by treatment with reagents such as MnO2 to give compounds of formula 124. Typically, these reactions are carried out at temperatures ranging from 25°C to 100°C in ether solvents such as THF, MeTHF, dioxane, or similar solvents.

[0117] Scheme 21: [ka]

[0118] Scheme 21 illustrates the synthesis of the compound of formula 126. While not limited to this, the compound of formula 126 can also be obtained by the chlorination reaction of the compound of formula 125 in the presence of a hindered base such as LDA, or, while not limited to this, by a chlorinating agent such as perchloroethane. Typically, these reactions are carried out at temperatures in the range of -78°C to 0°C in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent.

[0119] Scheme 22: [ka]

[0120] Scheme 22 illustrates the synthesis of the compound of formula 135. The compound of formula 128 is obtained by treatment of the compound of formula 127 with aminoaldehyde dimethyl acetal. Typically, these reactions can be carried out in hydrocarbon solvents such as toluene, xylene, or similar solvents at temperatures ranging from 25°C to 130°C. However, the compound of formula 129 can be obtained by reduction of the imine of formula 128 with a reducing agent such as NaBH4. Typically, these reactions can be carried out in protic solvents such as methanol, ethanol, or similar solvents at temperatures ranging from 0°C to 25°C. However, the compound of formula 130 can be obtained by tosylation of the compound of formula 129 with a reagent such as tosyl chloride, in the presence of a base such as pyridine. Typically, these reactions can be carried out in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents at temperatures ranging from 0°C to 25°C. While not limited to these, the compound of formula 131 can be obtained by cyclization of the compound of formula 130 with a Lewis acid such as AlCl3. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. While not limited to these, the compound of formula 132 can be obtained by oxidation of the compound of formula 131 with an oxidizing agent such as SeO2. Typically, these reactions can be carried out at temperatures in the range of 150°C to 180°C in hydrocarbon solvents such as o-dichlorobenzene, xylene, or similar solvents. While not limited to the compound of formula 132, the compound of formula 133 can be obtained by treatment with a nucleophilic fluorinating agent such as DAST. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. While not limited to the compound of formula 133, the compound of formula 134 can be obtained by treatment with a reducing agent such as NaBH4. Typically, these reactions are carried out at temperatures ranging from 0°C to 25°C in an acidic solvent, such as acetic acid.The compound of formula 135 is prepared by treating the compound of formula 134 with an anhydride such as (Boc)2O, but not limited to, at a temperature in the range of 0°C to 25°C, in the presence of a base such as NET3, DIPEA, DMAP, etc.

[0121] Scheme 23: [ka]

[0122] Scheme 23 illustrates the synthesis of the compound of formula 138. The compound of formula 136 can be synthesized by treating the compound of formula 135 with a suitable borane such as bispinacolatodiborone, followed by adding an inorganic base such as potassium acetate, in the presence of a Pd catalyst such as Pd(dppf)Cl2 or Pd(PPh3)2Cl2, but not limited to this method. Typically, these reactions are carried out in an ether solvent such as THF, MeTHF, dioxane, or a similar solvent, at a temperature in the range of 25°C to 100°C. The compound of formula 136 can be converted to the compound of formula 137 by using an oxidizing agent such as sodium periodate, but not limited to this method. Typically, these reactions can be carried out in a solvent such as acetone or a similar solvent at a temperature in the range of 0°C to 25°C. The compound of formula 137 can be converted to the compound of formula 138 by treatment with agents such as H2O2 / AcOH, H2O2 / citric acid, etc. Typically, these reactions can be carried out at temperatures ranging from 0°C to 25°C.

[0123] Scheme 24: [ka]

[0124] Scheme 24 illustrates the synthesis of the compound of formula 144. The compound of formula 139 can be converted to the compound of formula 140 by using an oxidizing agent such as PCC, but is not limited to this. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. However, the compound of formula 141 can be obtained by treating the compound of formula 140 with a reagent such as aminoaldehyde dimethyl acetal, but is not limited to this. Typically, these reactions can be carried out at temperatures in the range of 25°C to 130°C in hydrocarbon solvents such as toluene, xylene, or similar solvents. However, the compound of formula 142 can be obtained by reducing the imine of formula 141 with a reducing agent such as NaBH4, but is not limited to this. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in protic solvents such as methanol, ethanol, or similar solvents. Compounds of formula 143 can be obtained by tosylation of the compound of formula 142 with a reagent such as tosyl chloride, in the presence of a base such as pyridine, or in the presence of a base such as tosyl chloride. Typically, these reactions can be carried out at temperatures ranging from 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. Furthermore, compounds of formula 144 can be obtained by cyclization of the compound of formula 143 with a Lewis acid such as AlCl3. Typically, these reactions can be carried out at temperatures ranging from 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents.

[0125] Scheme 25: [ka]

[0126] Scheme 25 illustrates the synthesis of the compound of formula 150. While not limited to this, the compound of formula 146 can be obtained by treating the compound of formula 145 with a reagent such as 1,1-dimethoxypropan-2-one. Typically, these reactions can be carried out in a hydrocarbon solvent such as toluene or xylene, or in a halogenated solvent such as CH2Cl2, CHCl3, or a similar solvent. While not limited to this, the compound of formula 147 can be obtained by reducing the compound of formula 146 with a reducing agent such as NaBH4. Typically, these reactions can be carried out at a temperature in the range of 0°C to 25°C in a protic solvent such as methanol, ethanol, or a similar solvent. While not limited to this, the compound of formula 148 can be obtained by tosyling the compound of formula 147 in the presence of a base such as pyridine, or, while not limited to this, with a reagent such as tosyl chloride. Typically, these reactions can be carried out at a temperature in the range of 0°C to 25°C in a halogenated solvent such as CH2Cl2, CHCl3, or a similar solvent. While not limited to these, the compound of formula 149 can be obtained by cyclizing the compound of formula 148 with a Lewis acid such as AlCl3. Typically, these reactions can be carried out at temperatures in the range of 0°C to 25°C in halogenated solvents such as CH2Cl2, CHCl3, or similar solvents. While not limited to the compound of formula 149, the compound of formula 150 can be obtained by treatment with reagents such as MnO2. Typically, these reactions can be carried out at temperatures in the range of 25°C to 100°C in ether solvents such as THF, MeTHF, dioxane, or similar solvents.

[0127] The following embodiments are provided to further illustrate the present invention and should therefore not be construed as limiting the scope of the invention.

[0128] Abbreviation The following abbreviations may be used herein: Acetic acid (ACOH) Aq. = Water-based AlCl3 = Aluminum Chloride ca = approximately or roughly NH4Cl = Ammonium chloride BH3.DMS = Boranedimethyl sulfide complex BH3.THF = Boranetetrahydrofuran complex 9-BBN=9-borabicyclononane BINAP = 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl Boc=tert-butoxycarbonyl (Boc)2O = di-tert-butyldicarbonate t-Bu or tBu = tert-butyl t-BuOH = tert-butyl alcohol Cs2CO3 = Cesium Carbonate CHCl3 = Chloroform CDCl3 = Deuterated Chloroform DAST = Diethylaminosulfur trifluoride dba = dibenzylideneacetone DBU = 1,8-diazabicyclo[5.4.0]undeca-7-ene CH2Cl2 or DCM = Dichloromethane DMP = Desmartin Periodinaan DEAD = Diethyl azodicarboxylate DIAD = Diisopropyl azodicarboxylate DIPEA = Diisopropylethylamine DMAP = 4-dimethylaminopyridine DMF = N,N-dimethylformamide DMAc = N,N-dimethylacetamide DME = 1,2-dimethoxyethane DMS = Dimethyl sulfide DMSO = Dimethyl sulfoxide DMSO-d6 = Deuterated Dimethyl Sulfoxide Et = ethyl EtOH = Ethanol alkyl = ethyl acetate FeCl3 = iron(III) chloride GCMS = Gas Chromatography-Mass Spectrometry g = grams HPLC = High-Performance Liquid Chromatography HCl = hydrochloric acid H2O = Water H2O2 = Hydrogen peroxide H2SO4 = sulfuric acid K2CO3 = potassium carbonate KOH = potassium hydroxide KO t Bu=potassium tert-butoxide K3PO4 = Potassium Phosphate KHMDS = Potassium bis(trimethylsilyl)amide LiH = Lithium hydride LDA = Lithium diisopropylamide LHMDS = Lithium bis(trimethylsilyl)amide LCMS = Liquid Chromatography Mass Spectrometry m-CPBA = meta-chloroperbenzoic acid mg = milligram Me = methyl MeOH = methanol MeOD = Deuterated methanol MeTHF = 2-methyltetrahydrofuran MS = Molecular Sieve MsCl = Methanesulfonyl Chloride MgSO4 = Magnesium Sulfate MnO2 = Manganese(IV) Oxide m / z=mass-to-charge ratio NaH = Sodium hydride NaBH4 = Sodium borohydride NaO t Bu=sodium tert-butoxide NaHCO3 = Sodium Bicarbonate Na2S2O3 = Sodium Thiosulfate Na2SO3 = Sodium Sulfite NaHMDS = Sodium bis(trimethylsilyl)amide NMP = N-methyl-2-pyrrolidone NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NIS = N-iodosuccinimide NMO = N-methylmorpholine-N-oxide NMR=nuclear magnetic resonance N2 = Nitrogen Ph = Phenyl PPh3 = Triphenylphosphine PDC = Pyridinium Dichlorochromate Pd(OAc)2 = Palladium Acetate Pd / C = Palladium Carbon Pd-118 = [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0) POCl3 = Phosphorus oxychloride PdCl2(dppf)=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 = Bis(triphenylphosphine)palladium(II) dichloride PCC = Pyridinium Chlorochromate PMB = p-methoxybenzyl PTSA = p-toluenesulfonic acid Rt=retention time rt=room temperature Sat.=saturated SFC = Supercritical Fluid Chromatography SeO2 = Selenium dioxide TLC = Thin-Layer Calculation TBAF = Tetrabutylammonium fluoride TsCl=p-toluenesulfonyl chloride TBDMS = tert-butyldimethylsilyl TBDPS = tert-butyldiphenylsilyl Et3N, NET3, or TEA = Triethylamine TFA = Trifluoroacetic Acid p-TsOH = p-toluenesulfonic acid

[0129] experiment intermediate 6-Chloropyrimidine-4(3H)-one [ka]

[0130] The compound in question was prepared by following the same reaction protocol described in U.S. Patent Application Publication No. 2009 / 149466.

[0131] 4,6-Dichloro-5-fluoropyrimidine [ka]

[0132] The indicated compound was prepared by following the same reaction protocol described in International Publication No. 2012 / 40279.

[0133] 6-Chloro-5-fluoropyrimidine-4(3H)-one [ka]

[0134] A mixture of 4,6-dichloro-5-fluoropyrimidine (3.20 g, 19.17 mmol), HCl (14.31 ml, 165 mmol), and water (15 ml) in dioxane (15 ml) was heated at 70°C for 6 hours. The reaction mixture was cooled to rt, and the solvent was evaporated under reduced pressure to obtain 1.5 g of the crude compound. This residue was extracted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (1.2g, 42.2%). GCMS m / z = 148.11 (M+, 70%).

[0135] 3-Benzoylpyrimidine-2,4(1H,3H)-dione [ka]

[0136] The indicated compound was prepared by following the same reaction protocol described in ACS Med.Chem.Lett.2015, 6, 1150-1155.

[0137] 2-amino-4-bromo-6-fluorobenzaldehyde [ka]

[0138] 4-Bromo-2-fluoro-6-nitrobenzaldehyde (prepared according to the same protocol as described in International Publication No. 2015 / 054572; 4.15 g, 16.73 mmol) was stirred in ethanol (20 ml) and acetic acid (20 ml) to which iron powder (2.80 g, 50.2 mmol) was added at 0°C, and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (70 ml) and neutralized with saturated aqueous solution of NaHCO3 (sodium bicarbonate, 100 ml). The resulting emulsion was filtered through celite. The layers were separated, the organic layer was washed with brine (100 ml), and dried on anhydrous Na2SO4 (sodium sulfate). The organic layer was filtered and concentrated under vacuum to obtain the marked compound (3.36 g, 92%) as a pale green solid, which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.78 - 7.54 (m, 2H), 6.84 (t, J = 1.5 Hz, 1H), 6.64 (dd, J = 11.1, 1.8 Hz, 1H).

[0139] 7-Bromo-3-chloro-5-fluoroquinoline-2-amine [ka]

[0140] To a stirred solution of 2-amino-4-bromo-6-fluorobenzaldehyde (9.48 g, 43.5 mmol) in anhydrous acetonitrile (150 ml), DBU (1,8-diazabicyclo[5.4.0]undeca-7-ene) (19.66 ml, 130 mmol) and lithium chloride (3.69 g, 87 mmol) were added at 0°C, followed by the dropwise addition of diethyl (chloro(cyano)methyl)phosphonate (9.2 g, 43.5 mmol) in 50 ml of acetonitrile at the same temperature. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (200 ml). The layers were separated, the organic layer was washed with brine (100 ml), and dried on anhydrous Na2SO4 (sodium sulfate). The organic layer was filtered and concentrated under vacuum to obtain 11.2 g of the crude compound. This residue is processed using gradient elution of ethyl acetate in petroleum ether (0-30%) on a redisep® Rf column using combiflash(R) f When purified using a Teledyne / Isco instrument, the indicated compound (9.48 g, %) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 9.5, 1.9 Hz, 1H), 7.25 (s, 2H); LCMS m / z= 275 (M+1; 100%).

[0141] 3-Bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine [ka]

[0142] The compound in question was prepared by following a reaction protocol similar to that described in International Publication No. 2012 / 037108.

[0143] 7-Bromo-3-chloro-5-fluoro-N-(4-methoxybenzyl)quinoline-2-amine [ka]

[0144] The indicated compound was prepared using appropriate starting materials and following a reaction protocol similar to that described in International Publication No. 2012 / 037108. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 0.8 Hz, 1H), 7.96 (t, J = 6.1 Hz, 1H), 7.58 (dd, J = 1.8, 1.0 Hz, 1H), 7.39 - 7.28 (m, 3H), 6.91 - 6.82 (m, 2H), 4.62 (d, J = 6.1 Hz, 2H), 3.71 (s, 3H); LCMS m / z= 397 (M+1; 100%).

[0145] 7-Bromo-3-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)quinoline-2-amine [ka]

[0146] 7-Bromo-3-chloro-5-fluoroquinoline-2-amine (1.5 g, 5.44 mmol) was added to a stirred suspension in DMF (dimethylformamide, 25 ml) with NaH (sodium hydride, 0.544 g, 13.61 mmol). The resulting mixture was stirred at 0°C for 15 minutes. 4-Methoxybenzyl chloride (1.854 ml, 13.61 mmol) was added dropwise under an N2 atmosphere. The reaction mixture was then stirred at 25°C for 3 hours. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (200 ml). The layers were separated, the organic layer was washed with brine (100 ml), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 2.7 g of the crude compound. This residue was extracted using gradient elution of ethyl acetate in petroleum ether (0-20%) to obtain redisep®® f Column combiflash(R fWhen purified using a Teledyne / Isco instrument, the indicated compound (2.2 g, 78%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 0.9 Hz, 1H), 7.76 (t, J = 1.3 Hz, 1H), 7.52 (dd, J = 9.4, 1.7 Hz, 1H), 7.29 - 7.23 (m, 4H), 6.91 - 6.84 (m, 4H), 4.60 (s, 4H), 3.71 (s, 6H); LCMS m / z= 515.68, 517.68 (M+, M+2; 100%).

[0147] 3-Chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-amine [ka]

[0148] A mixture of 7-bromo-3-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)quinoline-2-amine (2.5 g, 4.85 mmol), bispinacolatodiborone (1.477 g, 5.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.396 g, 0.485 mmol), and potassium acetate (0.809 g, 8.24 mmol) in DMSO (35 ml) was heated at 80°C for 30 minutes in a preheated oil bath. The reaction mixture was cooled to rt. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (100 ml). The layers were separated, the organic layer was washed with brine (30 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 2.3 g of the crude compound. This residue is processed using gradient elution (0-10%) of ethyl acetate in petroleum ether, and redisep®R f Column combi-flash(R fWhen purified using a Teledyne / Isco instrument, the indicated compound (1.5 g, 55%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 0.8 Hz, 1H), 7.81 (d, J = 1.0 Hz, 1H), 7.35 - 7.17 (m, 5H), 6.95 - 6.79 (m, 4H), 4.58 (s, 4H), 3.70 (s, 6H), 1.33 (s, 12H); LCMS m / z= 563.2 (M+, 100%).

[0149] 2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-ol [ka]

[0150] To a stirred solution of 3-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-amine (3 g, 5.33 mmol) in tetrahydrofuran (THF, 40 ml), glacial acetic acid (0.610 ml, 10.66 mmol) was added dropwise at 0°C and the mixture was stirred for 1 hour. Hydrogen peroxide solution (3.27 ml, 32.0 mmol) was slowly added at 0°C. The reaction mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate (25 ml) and water (25 ml). The layers were separated, and the organic layer was stirred with aqueous sodium sulfide solution (25 ml) at 25°C for 15 minutes. The layers were separated, the organic layer was washed with brine (30 ml), and dried on anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 2.1 g of the crude compound. This residue was processed using gradient elution (0-25%) of ethyl acetate in petroleum ether using redisep®®. f Column combi-flash(R f When purified using a Teledyne / Isco instrument, the indicated compound (1.6 g, 66.3%) was obtained as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.21 (s, 1H), 7.25 (d, J = 8.0 Hz, 4H), 6.86 (d, J = 8.1 Hz, 4H), 6.83 - 6.72 (m, 2H), 4.51 (s, 4H), 3.71 (d, J = 3.0 Hz, 6H); LCMS m / z= 453.1 (M+, 100%).

[0151] 3-amino-5-bromopicolinealdehyde [ka]

[0152] 5-bromo-3-nitropicholine aldehyde (prepared by following the same reaction protocol as described in U.S. Patent Application Publication No. 2010 / 125089; 1 g, 4.33 mmol) was stirred in ethanol (5 ml) and acetic acid (5 ml) to which iron powder (0.725 g, 12.99 mmol) was added at 0°C, and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 ml) and neutralized with saturated aqueous NaHCO3 solution (30 ml). The resulting emulsion was filtered through celite. The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain (0.21 g, 24.13%) as a pale green solid, which was used in the next step without purification. 1 LCMS m / z= 201.39, 203.39 (M+, M+2; 100%).

[0153] 7-Bromo-3-chloro-1,5-naphthyridine-2-amine [ka]

[0154] To a stirred solution of 3-amino-5-bromopicoline aldehyde (0.185 g, 0.922 mmol) in acetonitrile (5 ml), DBU (0.096 ml, 0.638 mmol) and lithium chloride (0.060 g, 1.418 mmol) were added at 0°C, followed by the dropwise addition of diethyl (chloro(cyano)methyl)phosphonate (0.150 g, 0.709 mmol) in acetonitrile (3 ml). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.2 g of the crude compound. This residue was extracted using gradient elution (0-50%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.13 g, 70.9%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.88 (m, 2H), 7.34 (d, J = 2.1 Hz, 1H), 6.34 (s, 2H); LCMS m / z= 257.02, 259.52, 261.90 (M-1, M+, M+2; 100%).

[0155] 7-Bromoquinoxaline-2-amine [ka]

[0156] The indicated compound was prepared by following a reaction protocol similar to that described by Wolf et al., JACS, 1949, 71, 6-10.

[0157] 4-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0158] The compound in question was prepared by following the same reaction protocol described in International Publication No. 2008 / 75110.

[0159] 6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine [ka]

[0160] The indicated compound was prepared by following the same reaction protocol described in International Publication No. 2017 / 46737.

[0161] 1H-Pyrazolo[3,4-d]pyrimidine-4-amine [ka]

[0162] The compound in question was prepared by following the same protocol described in U.S. Patent Application Publication No. 2015 / 225407.

[0163] tert-butyl 6-(difluoromethyl)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0164] The compound in question was prepared by following the same reaction protocol described in U.S. Patent Application Publication No. 2019 / 0111060.

[0165] tert-butyl6-(difluoromethyl)-5-fluoro-8-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0166] To a stirred solution of tert-butyl 6-(difluoromethyl)-5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 3.15 mmol) in DCM (40 ml), Et3N (0.879 ml, 6.30 mmol) and trifluoromethanesulfonic anhydride (0.586 ml, 3.47 mmol) were added at 0°C, and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (10 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.2 g of crude compound. This residue was extracted using gradient elution (0-5%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / ISCO instrument yielded the indicated compound (1.079 g, 76%). 1 ¹H NMR (400 MHz, chloroform-d): δ 7.42 (d, J = 5.5 Hz, 1H), 6.89 (t, J = 56 Hz, 1H), 4.69 (s, 2H), 3.72 (t, J = 6.0 Hz, 2H), 2.94 - 2.82 (m, 2H), 1.51 (s, 9H).

[0167] tert-butyl6-(difluoromethyl)-5-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0168] A mixture of tert-butyl 6-(difluoromethyl)-5-fluoro-8-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 2.225 mmol), bispinacolatodiborone (1.695 g, 6.68 mmol), and Et3N (1.861 ml, 13.35 mmol) in dioxane (10 ml) was degassed under nitrogen for 5 minutes in a sealed tube. PdCl2 (dppf) (0.163 g, 0.223 mmol) was added, and the reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (10 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.3 g of the crude compound. When this residue was purified by reverse-phase preparative HPLC under acidic conditions, the indicated compound (0.32 g, 33.7%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.92 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 52 Hz, 1H), 4.90 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 2.96 - 2.73 (m, 2H), 1.52 (s, 9H), 1.37 (s, 12H).

[0169] tert-butyl 8-bromo-6-(difluoromethyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0170] To a stirred solution of tert-butyl 6-(difluoromethyl)-5-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.32 g, 0.749 mmol) dissolved in MeOH (1 ml), copper(II) bromide (0.502 g, 2.247 mmol) was added at rt in water (1 ml). The resulting mixture was stirred at 70°C for 10 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml). The layers were separated, the organic layer was washed with brine (10 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.25 g of crude compound. This residue was extracted using gradient elution (0-5%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.18 g, 63.2%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.66 (d, J = 6.4 Hz, 1H), 6.86 (t, J = 54.8 Hz, 1H), 4.56 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 1.53 (s, 9H).

[0171] 8-Bromo-5-fluoroisoquinoline [ka]

[0172] The compound was prepared by following the same reaction protocol described in International Publication No. 2018 / 167800.

[0173] 8-Bromo-5-fluoroisoquinoline-6-carbaldehyde [ka]

[0174] To a stirred solution of 8-bromo-5-fluoroisoquinoline (1.7 g, 7.52 mmol) in THF (15 ml), LDA (2 M in THF / heptane / ethylbenzene) (5.64 ml, 11.28 mmol) was added at -78°C and stirred for 1 hour. DMF (1.747 ml, 22.56 mmol) was added at -78°C and stirred for 30 minutes. The resulting mixture was quenched in ice water and heated to rt. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1 g of crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (0.467 g, 24.44%). LC-MS m / z = 254.14 (M+; 90%).

[0175] 8-Bromo-6-(difluoromethyl)-5-fluoroisoquinoline [ka]

[0176] To a stirred solution of 8-bromo-5-fluoroisoquinoline-6-carbaldehyde (233 mg, 0.917 mmol) in DCM (6 ml), DAST (0.606 ml, 4.59 mmol) was added at 0°C, and the reaction mixture was stirred for 15 minutes. The resulting mixture was heated to rt and stirred for 16 hours. The resulting mixture was diluted with dichloromethane (10 ml) and quenched with cold saturated NaHCO3 aqueous solution (20 ml). The reaction mixture was stirred to rt for 20 minutes. The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.8 g of crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(Rf Purification using a Teledyne / Isco instrument yielded the indicated compound (0.166 g, 65.6%). LC-MS m / z = 276.02 (M+; 100%).

[0177] 8-Bromo-6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline [ka]

[0178] 8-Bromo-6-(difluoromethyl)-5-fluoroisoquinoline (200 mg, 0.724 mmol) was stirred in acetic acid (4.6 ml), to which NaBH4 (96 mg, 2.54 mmol) was added in fractional amounts at rt. The reaction mixture was stirred at rt for 1.5 hours. The solvent was removed under vacuum at 40°C. The reaction mixture was diluted with dichloromethane (20 ml) and basicized with saturated NaHCO3 aqueous solution (20 ml). The layers were separated, the organic layer was washed with brine (20 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain a sufficiently pure compound (0.2 g, 99%), which was carried over to the next step without further purification. LCMS m / z = 280.0 (M+; 100%).

[0179] tert-butyl 8-bromo-6-(difluoromethyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0180] To a stirred solution of 8-bromo-6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.714 mmol) in DCM (3 ml), Et3N (0.199 ml, 1.428 mmol) and BOC-anhydrous (0.199 ml, 0.857 mmol) were added at 0°C. The resulting mixture was stirred at rt for 2 hours. The reaction mixture was diluted with DCM (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.32 g of crude compound. This residue was extracted using gradient elution (0-9%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / ISCO instrument yielded the indicated compound (0.215 g, 79%). 1 ¹H NMR (400 MHz, chloroform-d): δ 7.66 (d, J = 6.4 Hz, 1H), 6.86 (t, J = 54 Hz, 1H), 4.56 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 1.53 (s, 9H).

[0181] (E)-1-(2-bromo-4-methylphenyl)-N-(2,2-dimethoxyethyl)methanymine [ka]

[0182] A stirred mixture of 2-bromo-4-methylbenzaldehyde (73 g, 367 mmol) and 2,2-dimethoxyethane-1-amine (47.9 ml, 440 mmol) in toluene (450 ml) was heated at 125°C for 4 hours using a Dean-Stark trap. The mixture was cooled to room temperature and concentrated to obtain the crude compound (105 g, 100%) as a pale yellow oil. This crude compound was carried over to the next step without further purification. 1¹H NMR (400 MHz, chloroform-d) δ 8.64 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 1.7, 0.8 Hz, 1H), 7.20 - 7.13 (m, 1H), 4.71 (t, J = 5.3 Hz, 1H), 3.83 (dd, J = 5.3, 1.4 Hz, 2H), 3.45 (s, 6H), 2.37 (s, 3H).

[0183] N-(2-bromo-4-methylbenzyl)-2,2-dimethoxyethane-1-amine [ka]

[0184] (E)-1-(2-bromo-4-methylphenyl)-N-(2,2-dimethoxyethyl)methanymine (105 g, 367 mmol) was dissolved in ethanol (820 ml) and sodium borohydride (20.82 g, 550 mmol) was gradually added at 10°C. The resulting mixture was stirred at rt for 2 hours. The resulting mixture was quenched by slowly adding 100 ml of acetone. Volatile substances were removed under vacuum to obtain 102 g of crude compound. This residue was eluted using gradient elution of methanol in dichloromethane (0-5%) to obtain redisep®R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (83g, 78%). LC-MS m / z = 288.27 (M+).

[0185] N-(2-bromo-4-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide [ka]

[0186] To a solution of N-(2-bromo-4-methylbenzyl)-2,2-dimethoxyethane-1-amine (83 g, 288 mmol) in DCM (1000 ml), pyridine (116 ml, 1440 mmol) was added at rt. A solution of p-toluenesulfonyl chloride (93 g, 490 mmol) in DCM (300 ml) was added dropwise to the above solution. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was diluted with water (1000 ml) and extracted with dichloromethane (500 ml x 2). The layers were separated, the organic layer was washed with brine (500 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 135 g of crude compound. This residue was extracted using gradient elution (0-25%) of ethyl acetate in dichloromethane to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the marked compound (120g, 94%) was obtained as a colorless oil. LCMS m / z = 444.17 (M+2).

[0187] 8-Bromo-6-methylisoquinoline [ka]

[0188] A stirring suspension of aluminum chloride (217 g, 1628 mmol) in DCM (1400 ml) was added dropwise at 0°C to a solution of N-(2-bromo-4-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (120 g, 271 mmol) in DCM (600 ml). The resulting mixture was heated to rt and stirred for 16 hours. The reaction mixture was poured into ice-cold water (2 liters) and DCM (500 ml) and stirred for 1 hour. The layers were separated, the organic layer was washed with brine (500 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 150 g of crude compound. This residue was eluted using gradient elution (0-50%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R fPurification using a Teledyne / Isco instrument yielded the indicated compound (50g, 83%). LCMS m / z = 224.0 (M+2, 100%).

[0189] 8-Bromoisoquinoline-6-carbaldehyde [ka]

[0190] A suspension of selenium dioxide (28.0 g, 252 mmol) and 8-bromo-6-methylisoquinoline (20 g, 90 mmol) in 1,2-dichlorobenzene (120 ml) was heated at 180°C for 7 hours. The reaction mixture was diluted with 25% MeOH in DCM (500 ml), filtered through a celite bed, and washed with 25% MeOH in DCM (500 ml). The filtrate was concentrated under reduced pressure, and the residue was extracted using gradient elution (0-70%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (5.1g, 23.99%). GC-MS m / z = 235.08 (M+1).

[0191] 8-Bromo-6-(difluoromethyl)isoquinoline [ka]

[0192] To a stirred solution of 8-bromoisoquinoline-6-carbaldehyde (5 g, 21.18 mmol) in DCM (120 ml), DAST (28.0 ml, 212 mmol) was added dropwise at 0°C and stirred for 15 minutes. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM (50 ml), quenched with cold saturated NaHCO3 aqueous solution, and stirred for 20 minutes. The layers were separated, the organic layer was washed with brine (100 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 4.6 g of crude compound. This residue was eluted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (3.3g, 60.4%). GC-MS m / z = 257.08~259.08 (M+, 100%).

[0193] 8-Bromo-6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline [ka]

[0194] 8-Bromo-6-(difluoromethyl)isoquinoline (3 g, 11.62 mmol) was stirred in acetic acid (65 ml), to which NaBH4 (1.539 g, 40.7 mmol) was added in fractional amounts at rt. The reaction mixture was stirred at rt for 1.5 hours. The solvent was removed under vacuum at 40°C. The reaction mixture was diluted with dichloromethane (50 ml) and basicized with saturated NaHCO3 aqueous solution (50 ml). The layers were separated, the organic layer was washed with brine (50 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain a sufficiently pure compound (3.05 g, 100%), which was carried over to the next step without further purification. GCMS m / z = 262.08 (M+; 100%).

[0195] tert-butyl 8-bromo-6-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0196] To a stirred solution of 8-bromo-6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline (3 g, 11.45 mmol) in DCM (70 ml), Et3N (3.19 ml, 22.89 mmol) and BOC-anhydrous (3.19 ml, 13.74 mmol) were added at 0°C. The resulting mixture was stirred at rt for 2 hours. The reaction mixture was diluted with DCM (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 3.2 g of crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / ISCO instrument yielded the indicated compound (2.9 g, 69.9%). 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.59 (s, 1H), 7.26 (s, 1H), 6.59 (t, J = 56.3 Hz, 1H), 4.58 (s, 2H), 3.67 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 1.53 (s, 9H).

[0197] tert-butyl6-(difluoromethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0198] PdCl2(dppf) (0.586 g, 0.801 mmol) was added in one go via rt to a degassed mixture of tert-butyl 8-bromo-6-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.8 g, 16.01 mmol), bispinacolatodiborone (8.13 g, 32.0 mmol), and potassium acetate (6.29 g, 64.1 mmol) in dioxane (60 ml), and stirred at 100°C for 2 hours. The mixture was then cooled to rt, filtered through Celite, and washed with ethyl acetate (50 ml). The filtrate was concentrated under vacuum to obtain 7.2 g of the crude compound. This residue was extracted using gradient elution (0-5%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (6.5g, 99%). LC-MS m / z = 410.23 (M+1, 100%).

[0199] (2-(tert-butoxycarbonyl)-6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)boronic acid [ka]

[0200] Sodium periodate (10.19 g, 47.6 mmol) was added at rt to a solvent mixture of tert-butyl 6-(difluoromethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.50 g, 15.88 mmol), i.e., a solution in water (11.5 ml, ratio 1.000) and acetone (57.5 ml, ratio 5). The resulting mixture was stirred at rt for 1 hour. 1N aqueous HCl (15.88 ml, 15.88 mmol) was added at rt, and the reaction mixture was stirred for a further 4 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The layers were separated, and the combined organic layers were washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 4 g of the crude compound. This residue was then eluted using a gradient elution of methanol in dichloromethane (0-10%) to obtain redisep® R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (2.3g, 44.3%). LC-MS m / z = 328.34 (M+).

[0201] tert-butyl 6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0202] A mixture of (2-(tert-butoxycarbonyl)-6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)boronic acid (0.1 g, 0.306 mmol), hydrogen peroxide (0.031 ml, 0.306 mmol), and a 5% solution of citric acid (2.4 ml, 0.031 mmol) was stirred at rt for 2 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.12 g of crude compound. This residue was extracted using gradient elution of ethyl acetate in petroleum ether (0-15%) to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (0.083 g, 91%). LC-MS m / z = 300.40 (M+).

[0203] 8-Bromo-5-(difluoromethyl)isoquinoline [ka]

[0204] A stirred mixture (88:12) of 5-bromoisoquinoline-8-carbaldehyde and 8-bromoisoquinoline-5-carbaldehyde, synthesized by following the same procedure as reported in International Publication No. 2007 / 79162, 2007, in DCM (20 ml), was mixed with DAST (2.76 ml, 20.86 mmol) at 0°C and stirred for 15 minutes. The reaction mixture was heated to rt and stirred for 16 hours. The reaction mixture was diluted with DCM (50 ml) and basicized with saturated NaHCO3 aqueous solution (50 ml). The layers were separated, the organic layer was washed with brine (20 ml) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.1 g of crude compound. This residue was extracted using gradient elution (0-11%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R fThe mixture was purified using a Teledyne / Isco instrument to obtain 0.717 g of a mixture of 5-bromo-8-(difluoromethyl)isoquinoline and 8-bromo-5-(difluoromethyl)isoquinoline. This mixture was purified by chiral preparative HPLC (Chiralpak IG, flow rate: 1.00 ml / min, mobile phase A: HEX_0.1%DEA, mobile phase B: IPA-MEOH_0.1%DEA, A_B_80_20, 276 nm) to obtain the trace isomer, 8-bromo-5-(difluoromethyl)isoquinoline (0.101 g, Rt=7.14 min), and the major isomer, 5-bromo-8-(difluoromethyl)isoquinoline (0.502 g, Rt=7.98 min). This structural interpretation is based on the information reported in International Publication No. 2007 / 079162. Trace isomers: 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (d, J = 0.9 Hz, 1H), 8.79 (d, J = 6.0 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 8.10 - 8.05 (m, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.63 (t, J = 54.0 Hz, 1H); LCMS m / z = 258.14, 259.96 (M+,M+2, 100%). Major isomer: 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (q, J = 1.4 Hz, 1H), 8.81 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.10 (dd, J = 5.9, 0.9 Hz, 1H), 7.93 - 7.62 (m, 2H); LCMS m / z = 257.06, 259.77 (100%).

[0205] 2-(5-bromo-2-fluorophenyl)propannitrile [ka]

[0206] A stirred suspension of 1-(5-bromo-2-fluorophenyl)ethane-1-one (20 g, 92 mmol) and 1-(isocyanatomethylsulfonyl)-4-methylbenzene (21.59 g, 111 mmol) in DME (94 ml) was prepared using KO. t Bu (20.68 g, 184 mmol) was added at 0°C and the mixture was stirred under an N2 atmosphere for 1 hour. The reaction mixture was heated in rt and stirred for 1 hour. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (200 ml x 2). The layers were separated, the organic layer was washed with brine (200 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 26 g of the crude compound. This residue was purified by silica gel column chromatography (mesh 100-200) using isocratic elution of 10% ethyl acetate in petroleum ether to obtain the marked compound (18 g, 86%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 6.7, 2.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.31 (dd, J = 10.2, 8.8 Hz, 1H), 4.47 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H).

[0207] 2-(5-bromo-2-fluorophenyl)propan-1-amine [ka]

[0208] To a stirred solution of 2-(5-bromo-2-fluorophenyl)propanenitrile (18 g, 79 mmol) in tetrahydrofuran (225 ml), borane-methyl sulfide complex (22.48 ml, 237 mmol) was added at rt. The resulting mixture was stirred at 65°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched with 6M HCl (approx. 50 mL) and refluxed for 2 hours. The reaction mixture was cooled to rt, the pH was made basic with 6M NaOH (approx. 70 mL), and extracted with DCM (500 mL x 3). The combined extracts were dried over sodium sulfate and concentrated under vacuum to obtain 18.2 g of the crude compound. This residue was purified by silica gel column chromatography (mesh 100-200) using isocratic elution with 10% (7N methanolic ammonia) in dichloromethane to obtain the labeled compound (16.3 g, 89%). LCMS: m / z = 232.0 (M+, 100%).

[0209] N-(2-(5-bromo-2-fluorophenyl)propyl)formamide [ka]

[0210] A stirred solution of 2-(5-bromo-2-fluorophenyl)propan-1-amine (14 g, 60.3 mmol) in ethyl formate (24.55 ml, 302 mmol) was stirred at 55°C for 18 hours under an N2 atmosphere. The volatile substances were evaporated under reduced pressure, yielding the crude compound (15.5 g, 99%) as oil, which was used in the next step without further purification. LCMS: m / z = 262.02 (M+2).

[0211] 10-Bromo-7-fluoro-6-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione [ka]

[0212] To a stirred solution of N-(2-(5-bromo-2-fluorophenyl)propyl)formamide (13.6 g, 52.3 mmol) in DCM (460 ml), oxalyl chloride (5.03 ml, 57.5 mmol) was added under nitrogen atmosphere at rt and stirred for 30 minutes. The reaction mixture was then cooled to -10°C, and iron(III) chloride (10.18 g, 62.7 mmol) was added lot-wise. The reaction mixture was heated at rt and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 ml) and basicized with saturated NaHCO3 aqueous solution (150 ml). The layers were separated, the organic layer was washed with brine (100 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain the crude compound (13.9 g, 85%), which was used in the next step without further purification. LCMS: m / z=244.27 (M+2, 100%).

[0213] 8-Bromo-5-fluoro-4-methyl-3,4-dihydroisoquinoline [ka]

[0214] 10-Bromo-7-fluoro-6-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione (8.6 g, 27.4 mmol) was stirred in methanol (310 ml), to which H2SO4 (16 ml, 300 mmol) was added at rt. The resulting mixture was stirred at 65°C for 16 hours under an N2 atmosphere. The solvent was removed under vacuum, and the resulting residue was made basic with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (100 ml x 2). The layers were separated, the organic layer was washed with brine (100 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain the crude compound (6.63 g, 100%), which was used in the next step without further purification. LCMS: m / z = 242.33 (M+, 100%).

[0215] 8-Bromo-5-fluoro-4-methylisoquinoline [ka]

[0216] 8-Bromo-5-fluoro-4-methyl-3,4-dihydroisoquinoline (8 g, 33.0 mmol) was stirred in dioxane (240 ml), to which manganese dioxide (43.1 g, 496 mmol) was added at rt. The resulting mixture was stirred at 101°C for 48 hours under an N2 atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum to obtain 3.7 g of crude compound. This residue was extracted using gradient elution (0-25%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combiflash(R f Upon purification using a Teledyne / Isco instrument (200), the marked compound (3g, 37.8%) was obtained as a pale yellow solid. LC-MS: m / z = 242.27 (M+2, 100%).

[0217] 8-Bromo-5-fluoro-4-methylisoquinoline-6-carbaldehyde [ka]

[0218] To a stirred solution of 8-bromo-5-fluoro-4-methylisoquinoline (4 g, 16.66 mmol) in THF (70 ml), LDA (2 M in THF / heptane / ethylbenzene) (2.7 ml, 24.99 mmol) was added at -78°C and stirred for 1 hour. DMF (3.87 ml, 50.0 mmol) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (50 ml x 2). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 3.5 g of the crude compound. This residue was ground with n-pentane to obtain the labeled compound (3.5 g, 78%). LCMS: m / z = 270.08 (M+2, 100%).

[0219] 8-Bromo-6-(difluoromethyl)-5-fluoro-4-methylisoquinoline [ka]

[0220] To a stirred solution of 8-bromo-5-fluoro-4-methylisoquinoline-6-carbaldehyde (3.5 g, 13.06 mmol) in DCM (100 ml), DAST (8.62 ml, 65.3 mmol) was added dropwise at 0°C and stirred for 15 minutes. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM (50 ml), quenched with cold saturated NaHCO3 aqueous solution (50 ml), and stirred for 20 minutes. The layers were separated, the organic layer was washed with brine (50 ml), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 3.6 g of crude compound. This residue was extracted using gradient elution (0-20%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (2.8 g, 73.9%). LC-MS: m / z = 291.77 (M+1, 100%).

[0221] 8-Bromo-6-chloro-5-fluoroisoquinoline [ka]

[0222] To a stirred solution of 8-bromo-5-fluoroisoquinoline (2 g, 8.85 mmol) in THF (40 ml), LDA (2 M in THF / heptane / ethylbenzene) (8.52 ml, 13.27 mmol) was added at -78°C and stirred for 1 hour. Perchloroethane (2.51 g, 10.62 mmol) was added, and the reaction mixture was stirred at -78°C for 30 minutes. The reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (50 ml x 2). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.22 g of crude compound. This residue was extracted using gradient elution (0-15%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (0.160 g, 7%). LC-MS: m / z = 262.0 (M+2, 100%).

[0223] 2-bromo-4,5-difluorobenzaldehyde [ka]

[0224] A mixture of (2-bromo-4,5-difluorophenyl)methanol (15 g, 67.3 mmol) and PCC (17.40 g, 81 mmol) in DCM (350 ml) was stirred at rt for 2 hours. The solvent was evaporated under vacuum at 35°C, and the resulting residue was purified by silica gel column chromatography (mesh 100-200) using isocratic elution of 10% ethyl acetate in petroleum ether to obtain the marked compound (10 g, 67%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 10.25 (d, J = 3.0 Hz, 1H), 7.79 (dd, J = 10.0, 8.3 Hz, 1H), 7.54 (dd, J = 9.1, 6.7 Hz, 1H).

[0225] (E)-1-(2-bromo-4,5-difluorophenyl)-N-(2,2-dimethoxyethyl)methanymine [ka]

[0226] A stirred mixture of 2-bromo-4,5-difluorobenzaldehyde (10 g, 45.2 mmol) and 2,2-dimethoxyethane-1-amine (5.71 g, 54.3 mmol) in toluene (100 ml) was heated at 130°C for 4 hours using a Dean-Stark trap. The resulting mixture was cooled to rt and concentrated under vacuum to obtain the crude compound (13.94 g, 100%) as a pale yellow oil. This crude compound was carried over to the next step without further purification. LCMS: m / z = 331.40 (M + 23).

[0227] N-(2-bromo-4,5-difluorobenzyl)-2,2-dimethoxyethane-1-amine [ka]

[0228] (E)-1-(2-bromo-4,5-difluorophenyl)-N-(2,2-dimethoxyethyl)methaneimine (13.94 g, 45.2 mmol) was stirred in ethanol (150 ml), and sodium borohydride (2.57 g, 67.9 mmol) was gradually added at rt, stirring for 2 hours. Acetone (30 ml) was slowly added to the reaction mixture at 0°C. Volatile substances were removed under vacuum, and the residue was eluted using a methanol gradient (0-5%) in dichloromethane to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (14g, 99%). LC-MS: m / z = 310.28 (M+, 10%).

[0229] N-(2-bromo-4,5-difluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide [ka]

[0230] A stirring solution of N-(2-bromo-4,5-difluorobenzyl)-2,2-dimethoxyethane-1-amine (14 g, 45.1 mmol) in DCM (180 ml) was mixed with pyridine (18.26 ml, 226 mmol) at rt. A solution of p-toluenesulfonyl chloride (14.63 g, 77 mmol) in DCM (71 ml) was added dropwise to the above solution. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (200 ml x 2). The layers were separated, the organic layer was washed with brine (200 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 20.5 g of crude compound. This residue was extracted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (18g, 86%). LC-MS: m / z = 488.0 (M+23, 100%).

[0231] 8-Bromo-5,6-difluoroisoquinoline [ka]

[0232] To a stirred suspension of aluminum chloride (17.23 g, 129 mmol) in DCM (110 ml), a solution of N-(2-bromo-4,5-difluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (10 g, 21.54 mmol) in DCM (40 ml) was added dropwise at 0°C. The resulting mixture was heated to rt and stirred for 16 hours. The reaction mixture was poured into ice-cold water (500 ml) and DCM (250 ml) and stirred for 1 hour. The layers were separated, the organic layer was washed with brine (500 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 4 g of crude compound. This residue was eluted using gradient elution (0-40%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Upon purification using a Teledyne / Isco instrument (200), the indicated compound (1.5 g, 28.5%) was obtained as a grayish-white solid. LC-MS: m / z = 244.14 (M+, 100%).

[0233] (2-bromo-5-fluorophenyl)methanamine [ka]

[0234] The compound was prepared by following the same reaction protocol described in Organic Letters, 2018, Vol. 20, No. 2, pp. 441-444.

[0235] (E)-N-(2-bromo-5-fluorobenzyl)-1,1-dimethoxypropane-2-imine [ka]

[0236] A mixture of (2-bromo-5-fluorophenyl)methaneamine (29 g, 142 mmol), 1,1-dimethoxypropan-2-one (19.78 ml, 163 mmol), and magnesium sulfate (17.11 g, 142 mmol) in DCM (150 ml) was stirred at rt for 15 hours. The resulting mixture was filtered through celite, and the filtrate was evaporated under vacuum to obtain the marked compound (41 g, 95%), which was used directly in the next step without further purification.

[0237] N-(2-bromo-5-fluorobenzyl)-1,1-dimethoxypropane-2amine [ka]

[0238] (E)-N-(2-bromo-5-fluorobenzyl)-1,1-dimethoxypropane-2-imine (41 g, 135 mmol) was stirred in methanol (700 ml), and NaBH4 (6.12 g, 162 mmol) was gradually added at 0°C. The reaction mixture was stirred for 20 minutes. The resulting mixture was heated to rt and stirred for 2 hours. Acetone (250 mL) was slowly added to the flask, and the reaction was quenched at 0°C. The solvent was evaporated under vacuum to obtain 43 g of crude compound. This residue was eluted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the marked compound (39 g, 94%) was obtained as a pale yellow oil. LC-MS: m / z = 306.28 (M+, 15%).

[0239] 8-Bromo-5-fluoro-3-methyl-3,4-dihydroisoquinoline [ka]

[0240] Chlorosulfonic acid (43.5 ml, 653 mmol) was slowly added to N-(2-bromo-5-fluorobenzyl)-1,1-dimethoxypropan-2-amine (20 g, 65.3 mmol) at -10°C, and the reaction mixture was stirred in rt for 15 hours. The resulting mixture was basicized with cold saturated NaHCO3 aqueous solution and extracted with ethyl acetate (200 ml x 2). The layers were separated, the organic layer was washed with brine (200 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 11.3 g of crude compound. This residue was extracted using gradient elution of ethyl acetate in petroleum ether (0-10%) to obtain redisep®R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (9g, 56.9%). LC-MS: m / z = 242.02 (M+, 100%).

[0241] 8-Bromo-5-fluoro-3-methylisoquinoline [ka]

[0242] 8-bromo-5-fluoro-3-methyl-3,4-dihydroisoquinoline (9 g, 37.2 mmol) was stirred in dioxane (350 ml) in a sealed tube, to which manganese dioxide (48.5 g, 558 mmol) was added at rt. The resulting mixture was stirred at 101°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum to obtain 4.1 g of crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (3.6 g, 40.3%). LC-MS: m / z = 240.02 (M+, 100%).

[0243] 8-Bromo-5-fluoro-3-methylisoquinoline-6-carbaldehyde [ka]

[0244] To a stirred solution of 8-bromo-5-fluoro-3-methylisoquinoline (3.60 g, 15 mmol) in THF (80 ml), LDA (11.25 ml, 22.49 mmol) was added at -78°C and stirred for 1 hour. DMF (3.48 ml, 45.0 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The resulting mixture was quenched with saturated NH4Cl aqueous solution (100 ml) and extracted with ethyl acetate (50 ml x 2). The layers were separated, the organic layer was washed with brine (50 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.7 g of crude compound. This residue was extracted using gradient elution of ethyl acetate in petroleum ether (0-15%) to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (1.3g, 32.3%). LC-MS: m / z = 268.08 (M+, 100%).

[0245] 8-Bromo-6-(difluoromethyl)-5-fluoro-3-methylisoquinoline [ka]

[0246] To a stirred solution of 8-bromo-5-fluoro-3-methylisoquinoline-6-carbaldehyde (0.800 g, 2.98 mmol) in DCM (50 ml), DAST (1.971 ml, 14.92 mmol) was added at 0°C, and the reaction mixture was stirred for 15 minutes. The resulting mixture was heated to rt and stirred for 3 hours. The resulting mixture was diluted with dichloromethane (20 ml) and quenched with cold saturated NaHCO3 aqueous solution (20 ml). The reaction mixture was stirred to rt for 20 minutes. The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.82 g of crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (0.65 g, 75%). LC-MS: m / z = 290.14 (M+, 100%).

[0247] ((3aR,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [ka]

[0248] The indicated compound was prepared by following the same reaction protocol described by Kenneth A. Jacobson et al.; Purinergic Signalling (2015) 11:371-387.

[0249] 4-Chloro-7-((3aS,4R,6aR)-6-(iodomethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0250] Iodine (2.051 g, 8.08 mmol) was slowly added to a stirred solution of imidazole (0.931 g, 13.67 mmol) and triphenylphosphine (2.119 g, 8.08 mmol) in DCM (40 ml) at 0°C. A solution of ((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (2 g, 6.22 mmol) in DCM (40 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was heated in rt and stirred for 3 hours. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 2.3 g of crude compound. This residue was extracted using gradient elution (0-7%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (1.91 g, 71.2%). LC-MS m / z = 432.04 (M+).

[0251] (3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde [ka]

[0252] To a stirred solution of ((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (2.50 g, 7.77 mmol) in CH2Cl2 (40 ml) at 0°C, Des-Martin periodinane (3.95 g, 9.32 mmol) was gradually added and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum to obtain 2.71 g of crude compound. This residue was extracted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (2.32 g, 93%) was obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 10.00 (s, 1H), 8.67 (s, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.78 (dd, J = 2.6, 0.9 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 5.97 (dt, J = 2.8, 1.4 Hz, 1H), 5.76 (dd, J = 5.9, 1.5 Hz, 1H), 4.88 (dt, J = 5.9, 1.1 Hz, 1H), 1.54 (s, 3H), 1.40 (s, 3H); LCMS m / z = 320.2 (M+1, 100%).

[0253] 4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0254] To a chilled suspension of methyl(triphenyl)phosphonium bromide (5.03 g, 14.07 mmol) in THF (30 mL) at 0°C, 1M KHMDS (14.07 mL, 14.07 mmol) in THF was slowly added and the mixture was stirred for 5 minutes. The reaction mixture was heated to 25°C and stirred for 10 minutes. The reaction mixture was cooled to 0°C, and a solution of (3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde (1.8 g, 5.63 mmol) in THF (1 ml) was slowly added. The reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 2.1 g of the crude compound. This residue was extracted using gradient elution of ethyl acetate in petroleum ether (0-7%) to obtain redisep® R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.81 g, 45.3%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.72 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.66 - 6.57 (m, 2H), 5.94 (d, J = 2.6 Hz, 1H), 5.81 - 5.75 (m, 2H), 5.57 (dd, J = 6.0, 1.5 Hz, 1H), 5.49 (d, J = 10.9 Hz, 1H), 4.66 (dt, J = 6.0, 1.0 Hz, 1H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS m / z =318.09 (M+1, 100%).

[0255] 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (A). 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(B). [ka]

[0256] To a degassed solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 8.93 mmol) in dioxane (80 ml) and water (10 ml), tripotassium phosphate (4.66 g, 26.8 mmol), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.582 g, 0.893 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (12.48 ml, 89 mmol) were added at 25°C. The reaction mixture was heated at 80°C for 8 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The layers were separated, the organic layer was washed with brine (50 ml), and dried on anhydrous sodium sulfate. The organic layer was filtered and concentrated under vacuum to obtain 4.3 g of the crude compound. This residue was purified using a combiflash (Rf200, Teledyne / Isco) instrument on a redisep® Rf column with gradient elution (0-20%) of ethyl acetate in petroleum ether, yielding the marked compounds A (3.2 g, 66%) and B (0.75 g, 15.98%) as grayish-white solids. 1H NMR (400 MHz, chloroform-d) δ 8.83 (s, 1H), 7.71 (tt, J = 6.6, 1.5 Hz, 4H), 7.48 - 7.37 (m, 6H), 6.91 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.88 (s, 2H), 5.25 (d, J = 5.7 Hz, 1H), 4.60 (d, J = 5.7 Hz, 1H), 4.55 - 4.45 (m, 2H), 2.77 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H), 1.11 (s, 9H); LCMS m / z = 540.4 (M+1; 100%); B 1 H NMR(400 MHz, chloroform-d) δ 7.71 (tt, J = 6.6, 1.5 Hz, 4H), 7.53 - 7.35 (m, 6H), 6.98 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.90 (d, J = 14.5 Hz, 2H), 5.26 (d, J = 5.7 Hz, 1H), 4.61 (d, J = 5.7 Hz, 1H), 4.51 (d, J = 9.3 Hz, 2H), 1.46 (s, 3H), 1.33 (s, 3H), 1.28 (s, 2H), 1.11 (s, 9H); LCMS m / z = 526.44 (M+1; 100%).

[0257] ((3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [ka]

[0258] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (3.20 g, 5.93 mmol) in THF (20 ml), TBAF (8.89 ml, 8.89 mmol) was slowly added at 25°C, and the reaction mixture was stirred at 25°C for 15 hours. Volatile substances were removed under vacuum, and the crude residue was eluted using gradient elution (0-100%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (1.5 g, 84%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 5.90 - 5.78 (m, 2H), 5.41 (ddd, J = 5.8, 1.7, 0.9 Hz, 1H), 4.65 (dt, J = 5.8, 0.9 Hz, 1H), 4.56 - 4.42 (m, 2H), 3.35 (d, J = 8.2 Hz, 1H), 2.74 (s, 3H), 1.53 (s, 3H), 1.37 (s, 3H); LCMS m / z = 302.21 (M+1; 100%).

[0259] (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde. [ka]

[0260] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.50 g, 4.98 mmol) in dichloromethane (100 ml) at 0°C, des-martin periodinane (2.53 g, 5.97 mmol) was gradually added and the mixture was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (50 ml). The layers were separated, the organic layer was washed with brine (50 ml) and dried on anhydrous sodium sulfate. The organic layer was filtered and concentrated under vacuum to obtain the crude compound. This crude residue was purified using a combiflash (Rf200, Teledyne / Isco) instrument on a redisep® Rf column with gradient elution (0-30%) of ethyl acetate in petroleum ether, yielding the marked compound (0.95 g, 63.8%) as a grayish-white solid. 1 H NMR (400 MHz, chloroform-d) δ 10.00 (s, 1H), 8.80 (s, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.82 - 6.76 (m, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.00 (dt, LCMS m / z = 300.15 (M+1; 100%)

[0261] 7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. [ka]

[0262] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1 H NMR (400 MHz, chloroform-d) δ 8.83 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.68 - 6.53 (m, 2H), 5.95 (d, J = 2.5 Hz, 1H), 5.80 - 5.71 (m, 2H), 5.56 (dd, J = 6.0, 1.4 Hz, 1H), 5.47 (d, J = 10.8 Hz, 1H), 4.65 (d, J = 5.8 Hz, 1H), 2.75 (s, 3H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS m / z = 298.5 (M+1; 100%).

[0263] 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0264] To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (synthesized according to Tetrahedron, 2007, Vol. 63, No. 39, pp. 9836-9841, 1.2 g, 2.83 mmol) in THF (15 ml), 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.738 g, 4.80 mmol), triphenylphosphine (2.59 g, 9.89 mmol), and DIAD (1.923 ml, 9.89 mmol) were slowly added at 0°C and the mixture was stirred for 5 minutes. The reaction mixture was then brought to 25°C and stirred for 1 hour. Volatile substances are removed in a vacuum, and the crude residue is used for gradient elution (0-15%) of ethyl acetate in petroleum ether on a redisep® Rf column using combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (1.1 g, 69.5%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.84 (s, 1H), 7.70 (ddt, J = 6.6, 5.0, 1.5 Hz, 4H), 7.50 - 7.34 (m, 6H), 6.94 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 5.84 (dt, J = 19.8, 2.2 Hz, 2H), 5.30 (d, J = 5.7 Hz, 1H), 4.63 (d, J = 5.6 Hz, 1H), 4.57 - 4.42 (m, 2H), 1.43 (s, 3H), 1.33 (s, 3H), 1.10 (s, 9H); LCMS m / z = 560.3 (M+; 100%).

[0265] (3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [ka]

[0266] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 0.893 mmol) in THF (5 ml) at 0°C, TBAF (1.250 ml, 1.250 mmol) was slowly added, and the reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was then brought to 25°C and stirred for 30 minutes. After removing volatile substances in a vacuum, the crude residue was purified using a combiflash instrument (Rf200, Teledyne / Isco) on a redisep® Rf column with gradient elution of ethyl acetate in petroleum ether (0-40%), yielding the marked compound (0.27 g, 94%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 7.28 (s, 1H), 7.08 (d, J = 3.7 Hz, 1H), 6.57 (d, J = 3.7 Hz, 1H), 5.92 - 5.62 (m, 2H), 5.47 (d, J = LCMS m / z = 321.09 (M+; 100%).

[0267] (3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-carbaldehyde [ka]

[0268] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde. 1 H NMR (400 MHz, chloroform-d) δ 9.99 (s, 1H), 8.86 (s, 1H), 7.04 (d, J = 3.7 Hz, 1H), 6.75 (dd, J = 2.6, 0.9 Hz, 1H), 6.65 (d, J = 3.7 Hz, 1H), 6.00 (dt, J = 2.7, 1.4 Hz, 1H), 5.77 (dd, J = 5.9, 1.5 Hz, 1H), 4.88 (dd, J = 5.9, 1.2 Hz, 1H), 1.53 (s, 3H), 1.40 (s, 3H); LCMS m / z = 319.90 (M+; 100).

[0269] 2-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0270] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.64 - 6.53 (m, 2H), 5.93 (d, J = 2.6 Hz, 1H), 5.81 - 5.69 (m, 2H), LCMS m / z = 318.15 (M+; 100).

[0271] 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0272] To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (5.0 g, 11.78 mmol) in THF (5 ml) at 0°C, triphenylphosphine (9.27 g, 35.3 mmol) was added, followed by the slow addition of DIAD (6.87 ml, 35.3 mmol), and the mixture was stirred for 30 minutes. The reaction mixture was heated to rt and stirred for 16 hours. The reaction mixture was diluted with MTBE (300 mL) and filtered. The filtrate was evaporated under vacuum to obtain 4.6 g of crude compound. This residue was extracted using gradient elution (0-5%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combi-flash(R f When purified using a Teledyne / Isco instrument, the indicated compound (4g, 59.2%) was obtained as a colorless oil. LCMS: m / z = 374.17 (M+, 100%).

[0273] ((3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [ka]

[0274] 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (4 g, 6.97 mmol) was stirred in THF (50 ml), to which TBAF (8.36 ml, 8.36 mmol) was slowly added at 0°C, and the reaction mixture was stirred for 30 minutes. The reaction mixture was heated to rt and stirred for 16 hours. The volatile substances were evaporated under vacuum to obtain 2.7 g of the crude compound. This residue was extracted using gradient elution (0-70%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combi-flash(R f When purified using a Teledyne / Isco instrument, the marked compound (2.1g, 90%) was obtained as a colorless oil. LCMS: m / z = 336.1 (M+1, 100%).

[0275] (3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[a][1,3]dioxol-6-carbaldehyde [ka]

[0276] ((3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (2.1 g, 6.25 mmol) was stirred in 30 ml of DCM, and des-martin periodinane (3.18 g, 7.50 mmol) was gradually added at rt and stirred for 2 hours. The reaction mixture was diluted in 50 ml of DCM and filtered through celite. The filtrate was washed with a 1:1 saturated mixture of NaHCO3 and sodium thiosulfate (100 mL x 2). The layers were separated, the organic layer was washed with brine (50 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.8 g of the crude compound. This residue is processed using gradient elution (0-40%) of ethyl acetate in petroleum ether, and redisep®R f Column combi-flash(R f When purified using a Teledyne / Isco instrument, the indicated compound (1.5 g, 71.9%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.61 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.11 - 7.02 (m, 1H), 5.97-5.96 (m, 1H), 5.59 (dd, J = 6.0, 1.4 Hz, 1H), 4.77-4.75 (m, 1H), 2.41 (d, J = 1.2 Hz, 3H), 1.40 (s, 3H), 1.29 (s, 3H).

[0277] 4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0278] To a stirred suspension of methyltriphenylphosphonium bromide (1.712 g, 4.79 mmol) in THF (50 ml), KHMDS (4.79 ml, 4.79 mmol) was gradually added at 0°C, and the reaction mixture was stirred for 10 minutes. A solution of (3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde (1.0 g, 3.00 mmol) in THF (10 ml) was slowly added, and the mixture was stirred at 0°C for 10 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 ml) and extracted with ethyl acetate (20 ml x 2). The layers were separated, the organic layer was washed with brine (50 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 1.3 g of the crude compound. This residue was then eluted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep®. f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.7 g, 70.4%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.31 (d, J = 1.3 Hz, 1H), 6.60 (dd, J = 17.6, 10.8 Hz, 1H), 5.87 (d, J = 2.7 Hz, 1H), 5.77 (d, J = 2.7 Hz, 1H), 5.66 - 5.55 (m, 2H), 5.42 (dd, J = 10.8, 1.6 Hz, 1H), 4.65 (d, J = 5.9 Hz, 1H), 2.40 (d, J = 1.2 Hz, 3H), 1.39 (s, 3H), 1.31 (s, 3H)

[0279] (3aR,4S,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate [ka]

[0280] The indicated compound was prepared by following the same reaction protocol described in Heterocycles, 2017, Vol. 95, No. 1, pp. 445-461.

[0281] 1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine [ka]

[0282] To a stirred suspension of 1H-pyrazolo[3,4-d]pyrimidine-4-amine (1.785 g, 13.21 mmol) in DMF (50 ml), NaH (0.581 g, 14.53 mmol) was added at 0°C, and the reaction mixture was stirred for 30 minutes. A solution of (3aR,4S,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (5.00 g, 13.21 mmol) in DMF (25 mL) was slowly added at 0°C, and the mixture was stirred for 5 minutes. The reaction mixture was brought to 25°C and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 ml) and extracted with ethyl CH2Cl2 (50 ml). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3.5 g of the crude compound. This residue was purified using a combiflash (Rf200, Teledyne / Isco) instrument on a redisep® Rf column with gradient elution (0-60%) of ethyl acetate in petroleum ether to obtain the marked compound (2.1 g, 38.1%) as a grayish-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.40 (s, 1H), 7.99 (d, J = 3.4 Hz, 1H), 5.96 (s, 1H), 5.74 (d, J = 2.4 Hz, 1H), 5.38 (d, J = 5.8 Hz, 1H), 4.-91-4.89 (m, 1H), 4.43 (d, J = 2.3 Hz, 2H), 1.51 (s, 3H), 1.38 (s, 3H), 0.92 (s, 9H), 0.10 (d, J = 3.6 Hz, 6H); LCMS m / z = 417.23 (M+; 100%).

[0283] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0284] To a stirred solution of 1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (2.1 g, 5.03 mmol) in THF (30 ml), triethylamine (2.103 ml, 15.09 mmol) and DMAP (0.061 g, 0.503 mmol) were added at 25°C, and the reaction mixture was stirred for 10 minutes. BOC-anhydrous (2.452 ml, 10.56 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. Volatile substances are removed in a vacuum, and the crude residue is used for gradient elution (0-15%) of ethyl acetate in petroleum ether on a redisep® Rf column using combiflash(R fWhen purified using a Teledyne / Isco instrument, the indicated compound (1.85 g, 59.5%) was obtained as a colorless oil. LCMS m / z = 618.32 (M+; 100%).

[0285] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0286] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of ((3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol. LCMS m / z = 504.2 (M+; 100).

[0287] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-formyl-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0288] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of (3aS,4R,6aR)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde. LCMS m / z = 502.44 (M+; 20%).

[0289] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0290] The indicated compound was synthesized by following the same protocol as described for the preparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine. LCMS m / z = 500.49 (M+; 20%).

[0291] 1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine [ka]

[0292] A stirring solution of 6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (0.788 g, 5.28 mmol) in DMF (20 ml) was mixed with NaH (0.317 g, 7.92 mmol) at 0°C and stirred for 15 minutes. A solution of (3aR,4S,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (2.00 g, 5.28 mmol) in DMF (5 mL) was slowly added and stirred at rt for 15 hours. The reaction mixture was diluted with diethyl ether (50 ml x 2) and washed with water (25 ml). The layers were separated, the organic layer was washed with brine (50 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain the crude compound (1.6 g, 70.2%), which was used directly in the next step without purification. LCMS m / z = 432.30 (M+1).

[0293] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0294] To a stirred solution of 1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (1.60 g, 3.71 mmol) in THF (20 ml), TEA (2.067 ml, 14.83 mmol) and DMAP (0.045 g, 0.371 mmol) were added at rt and stirred for 10 minutes. BOC-anhydrous (3.44 ml, 14.83 mmol) was added and stirred for 15 hours. The volatile substances were evaporated under vacuum to obtain 2 g of crude compound, which was used directly in the next step without purification. LCMS m / z = 632.09 (M+).

[0295] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0296] To a stirred solution of tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate (2.0 g) in THF (20 ml), TBAF (4.43 ml, 4.43 mmol) was slowly added, and the mixture was stirred at rt for 15 hours. The volatile substances were evaporated under vacuum to obtain 1.5 g of the crude compound. This residue was extracted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combi-flash(R fWhen purified using a Teledyne / Isco instrument, the indicated compound (1.1 g, 67.1%) was obtained as a colorless oil. LCMS m / z = 518.07 (M+1).

[0297] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-formyl-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0298] To a stirred solution of tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate (1.10 g) in 25 ml of DCM, des-martin periodinane (3.61 g, 8.50 mmol) was gradually added at rt and stirred for 10 minutes. The reaction mixture was heated at rt and stirred for 3 hours. The volatile substances were evaporated under vacuum to obtain 1.2 g of the crude compound. This residue was extracted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combi-flash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.9 g, 82%) was obtained as a colorless oil. LCMS m / z = 515.57 (M+).

[0299] tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate [ka]

[0300] To a stirred solution of methyltriphenylphosphonium bromide (1.039 g, 2.91 mmol) in THF (3 ml), KHMDS (2.91 ml, 2.91 mmol) was slowly added at 0°C and stirred for 3 minutes. A solution of tert-butyl(tert-butoxycarbonyl)(1-((3aS,4R,6aR)-6-formyl-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)carbamate (0.75 g) in THF (3 ml) was slowly added at 0°C. The reaction mixture was stirred for 5 minutes. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.6 g of the crude compound. This residue was extracted using gradient elution (0-10%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.47 g, 62.9%) was obtained as a colorless oil. LCMS m / z = 514.30 (M+1).

[0301] ((3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [ka]

[0302] The compound was prepared by following the same reaction protocol described in Journal of Medicinal Chemistry, 1992, Vol. 35, No. 2, pp. 324-331.

[0303] (3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde [ka]

[0304] To a stirred solution of ((3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (2.1 g, 6.51 mmol) at 0°C in CH2Cl2 (5 ml), des-martin periodinane (3.31 g, 7.81 mmol) was gradually added and the mixture was stirred for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and water (50 mL) and filtered through celite. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum to obtain 1.93 g of the crude compound. This residue was purified by combiflash using gradient elution (0-70%) of ethyl acetate in petroleum ether to obtain the marked compound (1.79 g, 86%) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ 10.00 (s, 1H), 8.76 (s, 1H), 8.11 (s, 1H), 6.83 - 6.52 (m, 1H), 5.84-5.82 (m, 2H), 5.13 - 4.86 (m, 1H), 1.54 (s, 3H), 1.42 (s, 3H); LCMS m / z = 320.47 (M+, 100%).

[0305] 6-Chloro-9-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-9H-purine. [ka]

[0306] To a stirred suspension of methyltriphenylphosphonium bromide (0.278 g, 0.779 mmol) in THF (3 mL) at 0°C, 1 M KHMDS (0.779 ml, 0.779 mmol) was added dropwise, and the reaction mixture was stirred at 25°C for 20 minutes. The reaction mixture was cooled to -10°C to -15°C, and a solution of (3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde (0.1 g, 0.312 mmol) in THF (3 ml) was slowly added. The reaction mixture was stirred at -10°C for 10 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 0.31 g of the crude compound. This residue was purified by combiflash using gradient elution (0-15%) of ethyl acetate in petroleum ether to obtain the marked compound (0.021 g, 21.13%) as a grayish-white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 8.03 (s, 1H), 6.62 (dd, J = 17.6, 10.8 Hz, 1H), 5.82 (dd, J = 17.5, 1.1 Hz, 1H), 5.78 (d, J = 2.7 Hz, 1H), 5.75 (s, 1H), 5.65 - 5.62 (m, 1H), 5.54 (d, J = 10.9 Hz, 1H), 4.78 (dd, J = 5.9, 1.1 Hz, 1H), 1.52 (s, 3H), 1.42 (s, 3H); LCMS m / z =319.4 (M+1, 20%)

[0307] 3-Benzoyl-1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione [ka]

[0308] (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (1 g, 2.355 mmol), triphenylphosphine (1.544 g, 5.89 mmol), and 3-benzoylpyrimidine-2,4(1H,3H)-dione (1.018 g, 4.71 mmol) were stirred in 20 ml of dehydrated THF. A solution of DEAD (0.932 ml, 5.89 mmol) in 5 ml of dehydrated THF was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16 hours, and then the solvent was removed under vacuum. This residue was extracted using gradient elution (0-40%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.6 g, 40.9%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 8.4, 1.3 Hz, 2H), 7.84 - 7.77 (m, 1H), 7.73 - 7.57 (m, 6H), 7.56 - 7.38 (m, 7H), 5.88 (d, J = 8.0 Hz, 1H), 5.83 - 5.73 (m, 1H), 5.30 (d, J = 2.6 Hz, 1H), 5.18 (d, J = 5.8 Hz, 1H), 4.81 - 4.72 (m, 1H), 4.49-4.43 (m, 1H), 4.34-4.29 (m, 1H), 1.27 (s, 3H), 1.23 (s, 3H), 1.04 (s, 9H). LCMS m / z = 623.09(M+1; 50%).

[0309] 3-Benzoyl-1-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione [ka]

[0310] 3-Benzoyl-1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (0.250 g, 0.401 mmol) was stirred in methanol (3 ml), to which ammonium fluoride (0.074 g, 2.007 mmol) was added. The resulting mixture was stirred at rt for 16 hours. After the reaction was complete, methanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude compound. This residue was eluted using gradient elution of methanol in DCM (0-2%) to obtain redisep®R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.13 g, 84%) was obtained as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.00 (m, 2H), 7.85 - 7.76 (m, 1H), 7.70 - 7.58 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 5.86 (d, J = 8.1 Hz, 1H), 5.63 - 5.56 (m, 1H), 5.26 (d, J = 2.9 Hz, 1H), 5.20 (d, J = 5.8 Hz, 1H), 5.11 (t, J = 5.5 Hz, 1H), 4.73 (d, J = 5.8 Hz, 1H), 4.13 (dd, J = 5.1, 2.5 Hz, 2H), 1.33 (s, 3H), 1.27 (s, 3H). LCMS m / z = 385.2 (M+1; 70%).

[0311] 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloropyrimidine-4(3H)-one [ka]

[0312] (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (5.0 g, 11.78 mmol), triphenylphosphine (9.27 g, 35.3 mmol), and 6-chloropyrimidine-4(3H)-one (2.61 g, 20.02 mmol) were stirred in anhydrous THF (180 ml) to which DIAD (6.87 ml, 35.3 mmol) was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at rt for 4 hours, and then the solvent was removed under vacuum. This residue was extracted using gradient elution (0-20%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (5.22 g, 83%). LC-MS m / z = 539.20 (M+2).

[0313] 6-Chloro-3-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-4(3H)-one [ka]

[0314] To a solution of 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloropyrimidine-4(3H)-one (5.2 g, 9.68 mmol) in THF (50 ml), TBAF (13.55 ml, 13.55 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent, the crude product was eluted using gradient elution (0-55%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (2.3g, 80%). LC-MS m / z = 299.27 (M+1).

[0315] 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methylpyrimidine-4(3H)-one [ka]

[0316] (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (2.00 g, 4.71 mmol) was stirred in toluene (50 ml), to which 6-methylpyrimidine-4(3H)-one (0.545 g, 4.95 mmol) and triphenylphosphine (3.09 g, 11.78 mmol) were added. DEAD (1.864 ml, 11.78 mmol) was slowly added at 0°C and stirred for 15 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. Volatile substances were removed under vacuum, and the crude residue was eluted using gradient elution (0-30%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R fPurification using a Teledyne / Isco instrument yielded the indicated compound (1.48 g, 60.8%). LC-MS 517.2(M+)

[0317] 3-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methylpyrimidine-4(3H)-one [ka]

[0318] To a stirred solution of 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-methylpyrimidine-4(3H)-one (1.42 g, 2.75 mmol) in THF (15 ml), TBAF (4.40 ml, 4.40 mmol) was slowly added, and the mixture was stirred at rt for 3 hours. Volatile substances were removed under vacuum to obtain 0.82 g of the crude compound. This residue was extracted using gradient elution (0-15%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combi-flash(R f Upon purification using a Teledyne / Isco instrument, the indicated compound (0.61 g, 80%) was obtained as a grayish-white solid. LC-MS m / z = 279.27 M+1.

[0319] 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-5-fluoropyrimidine-4(3H)-one [ka]

[0320] To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (2.00 g, 4.71 mmol) in toluene (50 ml) at 0°C, 6-chloro-5-fluoropyrimidine-4(3H)-one (0.735 g, 4.95 mmol) and triphenylphosphine (3.09 g, 11.78 mmol) were added, followed by the slow addition of DEAD (1.864 ml, 11.78 mmol), and the mixture was stirred for 30 minutes. The resulting mixture was heated to rt and stirred for 2.5 hours. Volatile substances were removed under vacuum to obtain 2.5 g of the crude compound. This residue was extracted using gradient elution (0-15%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combi-flash(R f Purification using a Teledyne / ISCO instrument yielded the indicated compound (2.1 g, 80%). 1 ¹H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 7.72 - 7.66 (m, 4H), 7.44 - 7.36 (m, 6H), 6.04 - 5.97 (m, 2H), 5.16 (dd, J = 5.8, 1.4 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.48 - 4.35 (m, 2H), 1.37 (d, J = 15.4 Hz, 6H), 1.10 (s, 9H).

[0321] 6-Chloro-5-fluoro-3-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-4(3H)-one [ka]

[0322] To a stirred solution of 3-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-5-fluoropyrimidine-4(3H)-one (2.10 g, 3.78 mmol) in THF (15 ml), TBAF (6.05 ml, 6.05 mmol) was slowly added, and the reaction mixture was stirred at rt for 3 hours. Volatile substances were removed under vacuum to obtain 1.2 g of crude compound. This residue was extracted using gradient elution (0-15%) of ethyl acetate in petroleum ether to obtain redisep®R f Column combi-flash(R f When purified using a Teledyne / ISCO instrument, the indicated compound (1g, 83%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 6.00 (dd, J = 2.5, 1.3 Hz, 1H), 5.97-5.93 (m, 1H), 5.32-5.29 (m, 1H), 4.83-4.80 (m, 1H), 4.49-4.36 (m, 3H), 1.48 (s, 3H), 1.41-1.40 (m, 3H).

[0323] ((3aR,3bR,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b-yl)methanol [ka]

[0324] The compound in question was prepared using a reaction protocol similar to that described in International Publication No. 2006 / 091905.

[0325] (3aR,3bS,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b-carbaldehyde [ka]

[0326] The indicated compound was synthesized by following a reaction protocol similar to that described for the preparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-carbaldehyde. 1 H NMR (400 MHz, chloroform-d) δ 9.34 (s, 1H), 8.63 (s, 1H), 7.18 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.91 (dd, J = 7.1, 1.2 Hz, 1H), 5.11 (s, 1H), 4.82 (dd, J = 7.1, 1.6 Hz, 1H), 2.34 (ddd, J = 9.4, 6.1, 1.6 Hz, 1H), 1.89 - 1.77 (m, 2H), 1.58 (s, 3H), 1.30 (s, 3H); LCMS m / z =333.9 (M+, 100%).

[0327] 4-Chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine. [ka]

[0328] To a stirred suspension of methyltriphenylphosphonium bromide (24.62 g, 68.9 mmol) in THF (200 ml), 1 M KHMDS (68.9 ml, 68.9 mmol) in THF was added at 25°C and stirred for 10 minutes. The resulting yellow suspension was cooled to 0°C, and a solution of (3aR,3bS,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b-carbaldehyde (9.2 g, 27.6 mmol) in THF (80 ml) was slowly added. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution (200 ml) and extracted with ethyl acetate (200 ml). The layers were separated, the organic layer was washed with brine (250 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 11 g of crude compound. This residue was extracted using gradient elution (0-20%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (7g, 77%) was obtained as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.68 (s, 1H), 7.23 (d, J = 3.7 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 5.86 (dd, J = 17.3, 10.6 Hz, 1H), 5.39 - 5.32 (m, 2H), 5.29 (s, 1H), 5.18 (dd, J = 10.6, 0.9 Hz, 1H), 4.59 (dd, J = 7.1, 1.6 Hz, 1H), 1.77 (ddd, J = 9.3, 4.9, 1.6 Hz, 1H), 1.63 (s, 3H), 1.49 (t, J = 5.3 Hz, 1H), 1.27 (s, 3H), 1.18 (ddd, J = 9.3, 5.6, 1.6 Hz, 1H); LCMS m / z =332.28 (M+, 50%).

[0329] 7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. [ka]

[0330] A mixture of 4-chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 9.04 mmol) and aqueous ammonia (19.57 ml, 904 mmol) in dioxane (6 ml) was stirred in a steel cylinder at 130°C for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 4.1 g of crude compound. This residue was extracted using gradient elution of methanol in dichloromethane (0-3%) to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (2.45 g, 87%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.02 (s, 2H), 6.96 (d, J = 3.5 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 5.86 (dd, J = 17.4, 10.7 Hz, 1H), 5.33 (dd, J = 7.2, 1.3 Hz, 1H), 5.23 (dd, J = 17.4, 1.3 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.50 (dd, J = 7.1, 1.6 Hz, 1H), 1.70 (ddd, J = 9.3, 4.8, 1.6 Hz, 1H), 1.46 (s, 3H), 1.29 - 1.22 (m, 1H), 1.19 (s, 3H), 1.10 (ddd, J = 9.1, 5.1, 1.5 Hz, 1H); LCMS m / z =313 (M+1, 100%).

[0331] 3-Chloro-7-(2-((3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine [ka]

[0332] 6-chloro-9-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-9H-purine (0.11 g, 0.345 mmol) in 9-BBN (0.5 molar concentration, 3.45 ml, 1.725 mmol) was heated at 60°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C, and then tripotassium phosphate (0.366 g, 1.725 mmol) in water (0.5 ml) was added and the mixture was stirred for 20 minutes. A solution of 7-bromo-3-chloro-5-fluoroquinoline-2-amine (0.086 g, 0.311 mmol) in THF (1 ml) was added, followed by the addition of PdCl2 (dppf) (0.025 g, 0.035 mmol). The resulting mixture was stirred at 55°C for 2 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml). The layers were separated, the organic layer was washed with brine (10 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.15 g of the crude compound. This residue was subjected to gradient elution of methanol in dichloromethane (0-2.7%) to obtain redisep® R f Column combiflash(R f Upon purification using a Teledyne / Isco instrument, the indicated compound (0.077g) was obtained as a colorless semi-solid. LC-MS m / z = 514.8 (M+, 100%).

[0333] The intermediates in Table 1 were synthesized using appropriate starting materials and at appropriate temperatures, following a reaction protocol similar to that used for the preparation of 3-chloro-7-(2-((3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine.

[0334] [Table 1A]

[0335] [Table 1B]

[0336] [Table 1C]

[0337] [Table 1D]

[0338] [Table 1E]

[0339] [Table 1F]

[0340] [Table 1G]

[0341] [Table 1H]

[0342] 3-Chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine [ka]

[0343] 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.242 g, 0.762 mmol) in 9-BBN (0.5 molar concentration, 4.36 ml, 2.178 mmol) was heated at 50°C for 1 hour under an N2 atmosphere. The reaction mixture was cooled to 25°C, and then tripotassium phosphate (0.578 g, 2.72 mmol) in water (0.5 ml) was added and the mixture was stirred for 20 minutes. A solution of 7-bromo-3-chloro-5-fluoroquinoline-2-amine (0.150 g, 0.544 mmol) in THF (0.5 ml) was added, followed by the addition of dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.035 g, 0.054 mmol). The resulting mixture was stirred at 50°C for 6 hours. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The layers were separated, the organic layer was washed with brine (10 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.345 g of the crude compound. This residue was extracted using gradient elution (0-35%) of ethyl acetate in petroleum ether to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.16 g, 57.5%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.18 (s, 1H), 7.25 (s, 1H), 7.09 - 6.96 (m, 4H), 6.44 (d, J = 3.6 Hz, 1H), 5.67 (s, 1H), 5.56 - 5.51 (m, 1H), 5.35 (d, J = 5.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 1H), 3.05 - 2.98 (m, 2H), 2.74 - 2.56 (m, 2H), 1.38 (s, 3H), 1.28 (s, 3H); LCMS m / z = 514.2 (M+, 100%).

[0344] The intermediates in Table 2 were synthesized using appropriate starting materials and at appropriate temperatures, following a reaction protocol similar to that used for the preparation of 3-chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine.

[0345] [Table 2A]

[0346] [Table 2B]

[0347] [Table 2C]

[0348] [Table 2D]

[0349] 3-Benzoyl-1-(6-(((2-(bis(4-methoxybenzyl)amino)-3-chloroquinoline-7-yl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione [ka]

[0350] 3-Benzoyl-1-((3aS,4R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (0.080 g, 0.208 mmol), 2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-ol (0.151 g, 0.333 mmol), and triphenylphosphine (0.164 g, 0.624 mmol) were stirred in THF (2.5 ml), to which DIAD (0.121 ml, 0.624 mmol) was added dropwise at 0°C. The resulting mixture was stirred at rt for 14 hours. The solvent was evaporated under reduced pressure to obtain 0.21 g of the crude compound. This residue was processed using gradient elution of methanol in dichloromethane (0-1%), and redisep®R f Column combi-flash(R f Purification using a Teledyne / Isco instrument yielded the indicated compound (0.14 g, 82%). LC-MS m / z = 819.05 (M+; 100%).

[0351] The intermediates in Table 4 (Table 3) were synthesized using appropriate starting materials by a reaction protocol similar to that used for the preparation of 3-benzoyl-1-(6-(((2-bis(4-methoxybenzyl)amino)-3-chloroquinoline-7-yl)oxy)methyl)2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione. In some examples, DEAD can be used instead of DIAD.

[0352] [Table 3A]

[0353] [Table 3B]

[0354] tert-butyl8-(((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methoxy)-6-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0355] To a stirred solution of tert-butyl 6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (250 mg, 0.834 mmol) in DMF (volume: 5 ml), Cs2CO3 (306 mg, 0.938 mmol) was added and the mixture was stirred at rt for 30 minutes. The reaction mixture was then cooled to 0°C, and 4-chloro-7-((3aS,4R,6aR)-6-(iodomethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (450 mg, 1.042 mmol) in DMF (1 ml) was added and the mixture was stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated, the organic layer was washed with brine (20 ml), and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.52 g of crude compound. This residue was extracted using gradient elution (0-20%) of ethyl acetate in petroleum ether to obtain redisep® R f Column combiflash(R f Upon purification using a Teledyne / Isco instrument, the indicated compound (0.4 g, 63.6%) was obtained as a grayish-white solid. LC-MS m / z = 603.4 (M+).

[0356] 7-(2-((3aS,4R,6aR)-4-(6-amino-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-chloro-5-fluoroquinoline-2-amine [ka]

[0357] A mixture of 3-chloro-7-(2-((3aS,4R,6aR)-4-(6-chloro-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine (0.300 g, 0.473 mmol), 25% aqueous ammonia (4.09 ml, 47.3 mmol), and dioxane (4 ml) was heated in a steel cylinder at 120°C for 18 hours. The solvent was evaporated under vacuum, and the residue was extracted using gradient elution of methanol in dichloromethane (0-5%) to obtain redisep®® f Column combiflash(R f Upon purification using a Teledyne / Isco instrument (200), the indicated compound (0.24 g, 83%) was obtained as a grayish-white solid. LCMS m / z = 496.42 (M+, 20%).

[0358] The intermediates in Table 5 (Table 4) were synthesized using appropriate starting materials by a reaction protocol similar to that used for the preparation of 7-(2-((3aS,4R,6aR)-4-(6-amino-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-chloro-5-fluoroquinoline-2-amine. In some cases, the reaction was carried out at 80°C or 100°C.

[0359] [Table 4A]

[0360] [Table 4B]

[0361] [Table 4C]

[0362] [Table 4D]

[0363] [Table 4E]

[0364] [Table 4F]

[0365] [Table 4G]

[0366] [Table 4H]

[0367] [Table 4I]

[0368] [Table 4J]

[0369] 1-((3aS,4R,6aR)-6-(((2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione [ka]

[0370] 3-Benzoyl-1-((3aS,4R,6aR)-6-(((2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (1 g, 1.221 mmol) was dissolved in 7N methanolic ammonia (52.3 ml, 366 mmol). The resulting mixture was stirred at 25°C for 3 hours. The solvent was evaporated under vacuum to obtain 0.85 g of the crude compound. This residue was eluted using a gradient elution of methanol in DCM (0-12%) to obtain redisep®R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (0.5 g, 57.3%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (d, J = 2.3 Hz, 1H), 8.29 (s, 1H), 7.65 (d, J = 1.3 Hz, 2H), 7.28- 7.23 (m, 4H), 7.07-7.05 (m, 1H), 6.89 - 6.83 (m, 4H), 5.71 (s, 1H), 5.45 (dd, J = 8.0, 2.3 Hz, 1H), 5.34 - 5.25 (m, 2H), 4.99 - 4.83 (m, 2H), 4.65 (d, J = 5.8 Hz, 1H), 4.55 (s, 4H), 3.71 (s, 6H), 1.38 (s, 3H), 1.30 (s, 3H). LCMS m / z = 715.21 (M+; 100%).

[0371] 4-amino-1-((3aS,4R,6aR)-6-(((2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2(1H)-one [ka]

[0372] A mixture of 1-((3aS,4R,6aR)-6-(((2-(bis(4-methoxybenzyl)amino)-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (0.500 g, 0.699 mmol), DMAP (0.171 g, 1.398 mmol), triethylamine (0.195 ml, 1.398 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (0.423 g, 1.398 mmol) in 50 ml of dehydrated acetonitrile was stirred at 25°C for 20 hours, and then at 80°C for 2 hours. After adding 30% aqueous ammonia (12.10 ml, 559 mmol), the mixture was stirred for a further 5 hours. Dichloromethane (200 mL) and water (100 mL) were added, and the precipitated solid was filtered and dried under vacuum to obtain the marked compound (0.25 g, 50.1%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.38 - 7.18 (m, 5H), 7.19 - 6.97 (m, 4H), 6.86 (d, J = 8.5 Hz, 4H), 5.68 (s, 1H), 5.60 (d, J = LCMS m / z = 714.2 (M+; 100%).

[0373] 7-((3aS,4R,6aR)-6-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine [ka]

[0374] To a stirred solution of 7-((3aS,4R,6aR)-6-(2-(6-(difluoromethyl)-5-fluoroisoquinoline-8-yl)ethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (1.33 g, 2.68 mmol) in acetic acid (28 ml), NaBH4 (0.355 g, 9.39 mmol) was added in fractions at rt, and the mixture was stirred for 1.5 hours. The solvent was evaporated under vacuum at 40°C. The residue was diluted with DCM (30 ml) and basicized with cold saturated NaHCO3 aqueous solution (50 ml). The layers were separated. The organic layer was washed with brine, dried on sodium sulfate, and concentrated to obtain 1.23 g of crude compound, which was carried over to the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.35 - 7.26 (m, 1H), 7.14 (d, J = 3.7 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.73 (d, J = 3.5 Hz, 1H), 6.53 (d, J = 3.5 Hz, 1H), 5.58 (d, J = 11.6 Hz, 2H), 5.33 (t, J = 6.3 Hz, 1H), 4.42 (d, J = 5.7 Hz, 1H), 3.89 (s, 2H), 2.93 (t, J = 5.9 Hz, 2H), 2.89 - 2.74 (m, 3H), 2.65 (d, J = 5.4 Hz, 2H), 1.39 (s, 3H), 1.29 (s, 4H); LCMS: m / z = 499.54 (M+).

[0375] The intermediates in Table 6 (Table 5) were synthesized using appropriate starting materials by a reaction protocol similar to that used for the preparation of 7-((3aS,4R,6aR)-6-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline-8-yl)ethyl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine.

[0376] [Table 5A]

[0377] [Table 5B]

[0378] [Table 5C]

[0379] [Table 5D]

[0380] [Table 5E]

[0381] [Table 5F]

[0382] 7-(2-((3aS,4R,6aR)-4-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine [ka]

[0383] A mixture of 7-(2-((3aS,4R,6aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine (0.050 g, 0.078 mmol), 2-chloroacetaldehyde (0.033 ml, 0.234 mmol), EtOH (0.5 ml, ratio: 1.000), and water (0.500 ml, ratio: 1.000) was heated at 60°C for 6 hours. Water and aqueous NaHCO3 solution were added to the reaction mixture and extracted with ELISA (50 ml x 2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 0.065 g of the crude compound. The resulting residue was subjected to combiflash(R) on a redisep(registered trademark) Rf column using a methanol gradient elution (0-3%) in dichloromethane. f When purified using a Teledyne / Isco instrument, the indicated compound (0.038 g, 73.3%) was obtained as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.37 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.46 (dd, J = 5.5, 1.5 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.23 - 7.17 (m, 2H), 6.86 - 6.77 (m, 2H), 6.60 (d, J = 3.4 Hz, 1H), 6.45 (d, J = 3.3 Hz, 1H), 5.67 (s, 1H), 5.54 (s, 1H), 5.34 (d, J = 5.6 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.43 (d, J = 5.6 Hz, 1H), 3.66 (s, 3H), 3.03 (tq, J = 14.3, 7.4 Hz, 2H), 2.77 - 2.59 (m, 2H), 1.40 (s, 3H), 1.29 (s, 3H); LCMS m / z= 665.3 (M+; 60%).

[0384] The intermediates in Table 7 (Table 6) were synthesized using appropriate starting materials via a reaction protocol similar to that used for the preparation of 7-(2-((3aS,4R,6aR)-4-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine.

[0385] [Table 6A]

[0386] [Table 6B]

[0387] [Table 6C] [Examples]

[0388] (Example 1) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(6-amino-9H-purine-9-yl)cyclopenta-3-en-1,2-diol (compound 1) [ka]

[0389] A mixture of 7-(2-((3aS,4R,6aR)-4-(6-amino-9H-purine-9-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-chloro-5-fluoroquinoline-2-amine (0.05 g, 0.101 mmol) in TFA (1.5 ml) was stirred at 0°C for 2 hours under an N2 atmosphere. The reaction mixture was basicized with ice-cold saturated NaHCO3 aqueous solution (20 ml) and extracted with ethyl acetate (20 ml). The layers were separated, the organic layer was washed with brine (20 ml) and dried on anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum to obtain 0.12 g of the crude compound. This residue was extracted using gradient elution of methanol in dichloromethane (0-15%) to obtain redisep®R f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (19 mg, 41.3%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 7.8 Hz, 2H), 7.91 (s, 1H), 7.47 (s, 2H), 7.23 (s, 1H), 7.09 - 6.92 (m, 3H), 5.62- 5.58 (m, LCMS m / z= 456.23 (M+, 50%).

[0390] The examples in Table 8 (Table 7) were synthesized using appropriate starting materials, following a reaction protocol similar to that used for the preparation of (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(6-amino-9H-purine-9-yl)cyclopenta-3-en-1,2-diol) (instead of TFA; TFA / 50°C, HCl / MeOH, aqueous TFA solution, or FeCl3.DCM could also be used at an appropriate temperature). Some of the compounds mentioned below were purified directly by reverse-phase preparative HPLC after basicizing the reaction mixture with 7N methanolic ammonia. Of the compounds purified by reverse-phase preparative HPLC, only Example 21 was purified under acidic conditions; the other compounds were purified under basic conditions. Details of the reverse-phase preparative HPLC conditions are as follows:

[0391] Acidic conditions: YMC ODS-A, 50 × 250 mm, 10 μm; flow rate: 117 ml / min; gradient: linear gradient from aqueous to organic; aqueous: 0.1% formic acid in water:CH3CN(95:5); organic: 0.1% formic acid in water:CH3CN(5:95); 220 nm. Basic conditions: YMC Triart, 50 × 250 mm, 10 μm; flow rate: 117 ml / min; gradient: linear gradient from aqueous to organic; aqueous: 0.1% ammonia in water:CH3CN(95:5); organic: 0.1% ammonia in water:CH3CN(5:95), 220 nm.

[0392] Table 7A

[0393] Table 7B

[0394] Table 7C

[0395] Table 7D

[0396] Table 7E

[0397] Table 7F

[0398]

Table 7G

[0399]

Table 7H

[0400] Table 7I

[0401]

Table 7J

[0402]

Table 7K

[0403] [Table 7L]

[0404] [Table 7M]

[0405] [Table 7N]

[0406] [Table 7O]

[0407] [Table 7P]

[0408] (Example 30) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-(methoxyamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopenta-3-en-1,2-diol [ka]

[0409] A mixture of 3-chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinoline-2-amine (100 mg, 0.194 mmol) and N-methylhydroxylamine hydrochloride (130 mg, 1.555 mmol) in t-butanol (4 ml) was heated in a sealed tube at 50°C for 12 hours. The volatile substances were evaporated under vacuum to obtain 135 g of the crude compound. This residue was extracted using gradient elution of methanol in dichloromethane (0-20%) to obtain redisep®® f Column combiflash(R f When purified using a Teledyne / Isco instrument, the indicated compound (35 mg, 37.1%) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.31 (s, 1H), 7.39 (s, 1H), 7.27 (d, J = 10.7 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 5.58 (d, J = 4.6 Hz, 1H), 5.48 (d, J= 1.8 Hz, 1H), 4.46 (d, J = 5.6 Hz, 1H), 4.06 (t, J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.12 - 2.93 (m, 2H), 2.57 (d, J = 6.7 Hz, 2H); LCMS m / z= 485.05 (M+, 50%).

[0410] Biological examples Biochemical assay protocol 1 The inhibitory effect of the compound on PRMT5 was evaluated using biochemical assays with HTRF detection technology. Biotinylated H4R3 (residues 1-21) was used as the substrate. The compound was pre-incubated for 30 minutes at room temperature in an assay buffer containing 20 mM bicin, pH 7.6, 25 mM NaCl, 2 mM DTT, 0.01% chicken realbumin, and 0.01% Tween-20, with 15-25 ng of PRMT5:MEP50 per well in a 384-well plate. The reaction was initiated by adding 1 μM SAM and 50 nM biotinylated H4R3. The total assay volume was 15 μL. The reaction was continued at room temperature for 120 minutes. Next, a detection solution containing streptavidin-Eu cryptate, anti-rabbit IgG-XL-665, and Histone H4R3 Dimethyl Symmetric (H4R3me2s) polyclonal antibody, all prepared in HTRF detection buffer, was added and incubated at room temperature for a further 30 minutes. The HTRF signal was recorded using a PHERAStar microplate reader. The inhibition percentage of the compound was calculated using the ratio of the signals obtained at 665 nm and 620 nm, as follows: Inhibition % = 100 - ((Test ratio - Negative control ratio) / (Positive control ratio - Negative control ratio) * 100) During the ceremony, Positive control = PRMT5 + SAM + H4R3 Negative control = PRMT5 + H4R3

[0411] Biochemical assay protocol 2 The inhibitory effect of the compound on PRMT5 was evaluated using biochemical assays with HTRF detection technology. Biotinylated H4R3 (residues 1-21) was used as the substrate. The compound was pre-incubated for 30 minutes at room temperature in an assay buffer containing 20 mM bicin, pH 7.6, 25 mM NaCl, 2 mM DTT, 0.01% chicken realbumin, and 0.01% Tween-20, with 2.5 ng of PRMT5:MEP50 per well in a 384-well plate. The reaction was initiated by adding 1 μM SAM and 50 nM biotinylated H4R3. The total assay volume was 15 μL. The reaction was continued at room temperature for 4 hours. Next, a detection solution containing streptavidin-Eu cryptate, anti-rabbit IgG-XL-665, and Histone H4R3 Dimethyl Symmetric (H4R3me2s) polyclonal antibody, all prepared in HTRF detection buffer, was added and incubated at room temperature for a further 30 minutes. The HTRF signal was recorded using a PHERAStar microplate reader. The inhibition percentage of the compound was calculated using the ratio of the signals obtained at 665 nm and 620 nm, as follows: Inhibition % = 100 - ((Test ratio - Negative control ratio) / (Positive control ratio - Negative control ratio) * 100) During the ceremony, Positive control = PRMT5 + SAM + H4R3 Negative control = PRMT5 + H4R3

[0412] [Table 8]

[0413] SDMA Inhibition Assay protocol Z-138 cells (ATCC, CRL-3001™) were seeded at a density of 1 million cells / well in clear, flat-bottomed, tissue culture-grade 48-well plates. Cells were treated with various concentrations of test compounds for 48 hours. Cell lysates were prepared using 1× CST lysis buffer (Cell Signaling Technology, USA), and 500 ng / well / 50 μL of lysate in pH 9.6 carbonate buffer was coated onto 96-well Maxisorb plates and incubated overnight at 4°C. The plates were washed twice in 1× PBS containing 0.05% Tween 20 and blocked in 1% BSA at room temperature for 1 hour. The plates were then incubated with a primary antibody (anti-SDMA antibody; CST number 13222s) at room temperature for 2 hours, followed by two intermittent washing steps, and then with an HRP-conjugated secondary antibody at room temperature for 1 hour.

[0414] For luminescence-based detection, an HRP substrate (substrate A + substrate B in a 1:1 ratio) was added, and the luminescence was read 30 minutes later using a Synergy® 2 reader (Biotek, USA).

[0415] For absorbance-based detection, a TMB substrate was added, followed by color development, and then STOP solution (2N H2SO4) was added. The absorbance (excitation at 450 nm and emission at 540 nm) was measured using a Synergy™ 2 reader (Biotek, USA).

[0416] The percentage of SDMA inhibition was calculated using the following formula against a vehicle control sample containing only 0.1% DMSO in a culture medium. (Mean of untreated controls - mean of the test) ×100 Mean of untreated control

[0417] Using Graph Pad Prism (Graph Pad Software, USA), the ICs of individual compounds 50 The values ​​were calculated using nonlinear regression analysis.

[0418] [Table 9]

[0419] Anticancer activity assay Z-138 cells were seeded in culture medium (IMDM + 10% FBS) at a density of 2000-3000 cells per well. PANC-1 (ATCC, CRL-1469®) and MIA PaCa-2 (ATCC, CRL-1420®) cells were seeded in culture medium (DMEM + 10% FBS) at a density of 200-300 cells per well. Cells were seeded in opaque flat-bottom tissue culture grade 96-well plates, and Z-138 cells (suspended) were seeded and treated with various concentrations of the test compound on the same day. The attached PANC-1 and MIA PaCa-2 cells were allowed to settle overnight under standard cell culture conditions (37°C, 5% CO2). The following day, the cells were treated with various concentrations of the test compound. Z-138 cells, PANC-1 cells, and MIA PaCa-2 cells were treated with the test compound for 96 hours, 7 days, and 10 days, respectively. Cell viability was assessed using CellTiterGlo® (Promega, USA) as directed by the manufacturer. Relative luminescence (RLU) was read using a Synergy® 2 reader (Biotek, USA). This assay measures cell ATP as an indicator of cell viability. RLU is proportional to the number of viable cells in each well.

[0420] The percentage of cell viability inhibition was calculated using the following formula against a vehicle control sample containing only 0.1% DMSO in a culture medium. (Mean of untreated controls - mean of the test) ×100 Mean of untreated control

[0421] Using Graph Pad Prism (Graph Pad Software, USA), the ICs of individual compounds 50 The values ​​were calculated using nonlinear regression analysis.

[0422] Anti-cancer assay (Z-138) [Table 10]

[0423] Anti-cancer assay (MiaPaCa-2) [Table 11]

[0424] In vivo efficacy experiment The Jackson Laboratory, USA, purchased female NOD.CB17-Prkdc between 7 and 11 weeks of age. <scid>Mantle cell lymphoma tumor xenografts were established by injecting cells into the right flank of / J mice. All animal study proposals were reviewed and approved by the Animal Experimentation Committee (IAEC) before the start of experiments.

[0425] Z-138 xenograft For the Z-138 xenograft mouse model, Z-138 cells (ATCC® CRL-3001®) were grown in IMDM medium supplemented with 10% FBS. The cells were incubated under standard conditions at 37°C and 5% CO2. To induce tumor formation, Z-138 cells in IMDM medium were mixed with 200 μL of Matrigel (Corning® Matrigel® Basement Membrane Matrix) in a 1:1.10 × 10⁶ ratio. 6 The cells were mixed according to a specific ratio and subcutaneously injected into each mouse to establish tumors. The tumors were 100-120 mm in size. 3 Once the average volume was reached, the mice were randomized into treatment groups of 8-10 mice. Treatment was started on the day of randomization and continued until the end of the study. The vehicle treatment group and the test compound treatment group received their respective treatments orally twice daily at a dose of 10 mL / kg per mouse via enteral nutrition.

[0426] Mice were housed in individual ventilation cages (IVCs) at a temperature of 22+3°C, humidity of 50+20%, and a 12 / 12-hour light / dark cycle. All experimental activities were conducted in a safety cabinet to ensure sterility.

[0427] Once the tumor became palpable, its size was measured using a digital caliper (Mitutoyo, Japan). The tumor volume (TV) was calculated using the following formula: Tumor volume (mm³) = (L × W²) / 2 In the formula, L: tumor length, W: tumor width (millimeters)

[0428] Use the following formula to calculate the tumor growth inhibition percentage (TGI%): TGI% = [1 - (Tf - Ti) / (Cf - Ci)] × 100 In the formula, Tf and Ti are the final tumor volume and initial tumor volume (test compound), respectively, and Cf and Ci are the final mean tumor volume and initial mean tumor volume (vehicle group), respectively.

[0429] The tumor regression percentage is calculated as follows: TR%:(Ti-Tf) / (Ti)×100 In the formula, Tf and Ti are the final tumor volume and the initial tumor volume, respectively.

[0430] In vivo efficacy experiment The Jackson Laboratory purchased a 10-11 week old female thymus-deficient nude foxn1 from the United States. <nu> Pancreatic cancer tumor fragment xenografts were established by subcutaneous transplantation of 30-45 mm³ tumor fragments into the right flank of / J / mice (Mus musculus). All animal study proposals were reviewed and approved by the Animal Experimentation Committee (IAEC) before the start of experiments.< / nu> < / scid>

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, L 1 is a bond, -CR a R b -, -NR a -, S and O; R a and R b is, at each occurrence, independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Ring A is selected from formulas (i), (ii), (iii) and (iv), and the substituent R on ring A is 3 may be substituted on any of the ring carbon atoms; 【Chemistry 2】 Hy is selected from formulas (a-1) to (h-1), provided that when Hy is (h-1), ring A cannot be formula (i); 【Transformation 3】 R is -NR 4 R 5 , hydrogen, substituted or unsubstituted alkyl, and cycloalkyl; Z is CR 10 and N; R 1 and R 2 together with the carbon atom to which they are attached form a bond to form -C=C-; or R 1 and R 2 together with the carbon atoms to which they are attached form a cyclopropane ring; R 2' and R 2a may be the same or different and are independently selected from hydrogen, and substituted or unsubstituted alkyl; R 3 is, at each occurrence, halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, —C(O)OH, —C(O)O-alkyl, —C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer ranging from 0 to 4 (inclusive); "m" is an integer ranging from 0 to 1 (inclusive); When an alkyl group is substituted, it can be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When a heteroaryl group is substituted, the heteroaryl group may be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the heterocyclyl group is substituted, the heterocyclyl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the aryl group is substituted, the aryl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the cycloalkyl group is substituted, the cycloalkyl group can be selected from halogen, cyano, alkyl, haloalkyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: R 7a is selected from hydrogen, alkyl, haloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl).

2. 10. The compound according to claim 1, having the structure of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 (In the formula, L 1 is a bond, -CR a R b -, -NR a -, S and O; R a and R b is, at each occurrence, independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Ring A is selected from formulas (i), (ii), (iii) and (iv), and the substituent R on ring A is 3 may be substituted on any of the ring carbon atoms; 【Transformation 5】 Hy is selected from formulas (a-1) to (h-1), provided that when Hy is (h-1), ring A cannot be formula (i); 【Transformation 6】 R is -NR 4 R 5 , hydrogen, substituted or unsubstituted alkyl, and cycloalkyl; Z is CR 10 and N; R 2' and R 2a may be the same or different and are independently selected from hydrogen, and substituted or unsubstituted alkyl; R 3 is, at each occurrence, halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, —C(O)OH, —C(O)O-alkyl, —C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer ranging from 0 to 4 (inclusive); "m" is an integer ranging from 0 to 1 (inclusive); When an alkyl group is substituted, it can be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When a heteroaryl group is substituted, the heteroaryl group may be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the heterocyclyl group is substituted, the heterocyclyl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the aryl group is substituted, the aryl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the cycloalkyl group is substituted, the cycloalkyl group can be selected from halogen, cyano, alkyl, haloalkyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: R 7a is selected from hydrogen, alkyl, haloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl).

3. 10. The compound according to claim 1, having the structure of formula (IIa), its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Transformation 7】 (In the formula, L 1 is a bond, -CR a R b -, -NR a -, S and O; R a and R b is, at each occurrence, independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R is -NR 4 R 5 , hydrogen, substituted or unsubstituted alkyl, and cycloalkyl; R 2' and R 2a may be the same or different and are independently selected from hydrogen, and substituted or unsubstituted alkyl; R 3 is, at each occurrence, halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, —C(O)OH, —C(O)O-alkyl, —C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer ranging from 0 to 4 (inclusive); When an alkyl group is substituted, it can be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When a heteroaryl group is substituted, the heteroaryl group may be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the heterocyclyl group is substituted, the heterocyclyl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the aryl group is substituted, the aryl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the cycloalkyl group is substituted, the cycloalkyl group can be selected from halogen, cyano, alkyl, haloalkyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: R 7a is selected from hydrogen, alkyl, haloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl).

4. 10. The compound according to claim 1, having the structure of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 (In the formula, L 1 is a bond, -CR a R b -, -NR a -, S and O; R a and R b is, at each occurrence, independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Ring A is selected from formulas (i), (ii), (iii) and (iv), and the substituent R on ring A is 3 may be substituted on any of the ring carbon atoms; 【Chemistry 9】 Hy is selected from formulas (a-1) to (h-1), provided that when Hy is (h-1), ring A cannot be formula (i); 【Chemistry 10】 R is -NR 4 R 5 , hydrogen, substituted or unsubstituted alkyl, and cycloalkyl; Z is CR 10 and N; R 2' and R 2a may be the same or different and are independently selected from hydrogen, and substituted or unsubstituted alkyl; R 3 is, at each occurrence, halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, —C(O)OH, —C(O)O-alkyl, —C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer ranging from 0 to 4 (inclusive); "m" is an integer ranging from 0 to 1 (inclusive); When an alkyl group is substituted, it can be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When a heteroaryl group is substituted, the heteroaryl group may be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the heterocyclyl group is substituted, the heterocyclyl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the aryl group is substituted, the aryl group can be substituted with halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: When the cycloalkyl group is substituted, the cycloalkyl group can be selected from halogen, cyano, alkyl, haloalkyl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: R 7a is selected from hydrogen, alkyl, haloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl).

5. L 1 But -CH 2 5. The compound according to claim 1, wherein the aryl group is selected from - and -NH-.

6. R 3 is halogen, substituted or unsubstituted alkyl, and -NR 7 R 8 5. The compound of any one of claims 1 to 4, independently selected from:

7. R 3 F, Cl, Br, -NH 2 , -CH 3 and -CH(F) 2 7. The compound of claim 6, independently selected from:

8. R a , R b , R 2' and R 2a 5. The compound of claim 1, wherein is independently selected from hydrogen and methyl.

9. R a , R b , R 2' and R 2a are independently hydrogen or methyl; L 1 But -CH 2 - and -NH-; ring A is selected from formula (i), (ii), (iii) and (iv), and the substituent R on ring A is 3 may be substituted on any of the ring carbon atoms; 【Chemistry 11】 R 3 which, in each occurrence, is selected from halogen, substituted or unsubstituted alkyl, and —NR 7 R 8 are independently selected from R 7 and R 8 is independently selected from hydrogen, and substituted or unsubstituted alkyl; Hy is selected from formulas (a-1) to (h-1), with the proviso that when Hy is (h-1), ring A cannot be formula (i); 【Chemistry 12】 R is -NR 4 R 5 , hydrogen, and substituted or unsubstituted alkyl; Z is CR 10 and N; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R 4 and R 5 are independently selected from hydrogen and substituted or unsubstituted alkyl; R 6 is selected from hydrogen, and substituted or unsubstituted alkyl; "n" is an integer ranging from 0 to 4, inclusive; and "m" is an integer ranging from 0 to 1, inclusive.

10. (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(6-amino-9H-purin-9-yl)cyclopent-3-ene-1,2-diol (Compound 1); (1S,2R,5R)-3-(2-(6-amino-7-chloro-1,5-naphthyridin-3-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 2); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(3-aminoquinoxalin-6-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 3); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(3-aminoquinoxalin-6-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 4); (1S,2R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 5); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-3-ene-1,2-diol (compound 6); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)methyl)cyclopent-3-ene-1,2-diol (compound 7); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 8); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 9); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(5-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 11); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)methyl)cyclopent-3-ene-1,2-diol (compound 12); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 14); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 15); 4-amino-1-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-4,5-dihydroxycyclopent-2-en-1-yl)pyrimidin-2(1H)-one (compound 16); 6-amino-3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-4,5-dihydroxycyclopent-2-en-1-yl)pyrimidin-4(3H)-one (compound 17); 3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-4,5-dihydroxycyclopent-2-en-1-yl)-6-methylpyrimidin-4(3H)-one (compound 18); 6-amino-3-((1R,4R,5S)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-4,5-dihydroxycyclopent-2-en-1-yl)-5-fluoropyrimidin-4(3H)-one (compound 19); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-chloro-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 20); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(5,6-difluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 21); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol ((Compounds 22A and B); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-3-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compounds 23A and B); (1R,2R,3S,4R,5S)-1-(2-(6-amino-7-chloro-1,5-naphthyridin-3-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 24); (1S,2R,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 25); (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 26); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 27); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(8H-imidazo[1,2-a]pyrrolo[2,3-d]pyrimidin-8-yl)cyclopent-3-ene-1,2-diol (compound 28); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 29); and (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-(methoxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 30) 2. The compound of formula (I) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from:

11. (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(6-amino-9H-purin-9-yl)cyclopent-3-ene-1,2-diol (Compound 1); (1S,2R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 5); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-3-ene-1,2-diol (compound 6); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 14); (1S,2R,5R)-3-(2-(6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 15); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-4-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (Compounds 22A and B); and (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(6-(difluoromethyl)-5-fluoro-3-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)ethyl)cyclopent-3-ene-1,2-diol (Compounds 23A and B) 2. The compound of formula (I) according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from:

12. 12. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 11, its stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. 12. A method for treating a disease, disorder, symptom or condition associated with the PRMT5 enzyme, comprising administering to a subject in need thereof an effective amount of a compound described in any one of claims 1 to 11.

14. 14. The method of claim 13, wherein the disease, disorder, symptom or condition associated with the PRMT5 enzyme is glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epithelial squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, and cervical cancer.

15. The method of claim 13, wherein the disease, disorder, symptom or condition associated with the PRMT5 enzyme is cancer.

16. 12. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease, disorder, symptom or condition associated with PRMT5.

17. 17. The use of claim 16, wherein the disease, disorder, symptom or condition associated with PRMT5 is selected from the group consisting of glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epithelial squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, and cervical cancer.

18. 17. The use according to claim 16, wherein the PRMT5-associated disease, disorder, symptom or condition is cancer.