Fused heterocyclic compounds as inhibitors of diacylglycerol kinase.

Abstract

Disclosed herein are compounds of Formula (I) that are DGK inhibitors for activating T cells, promoting T cell proliferation, and / or exhibiting anti-tumor activity, methods of using the compounds disclosed herein for treating cancer, and pharmaceutical compositions containing the compounds. The above-mentioned needs have been met by providing the compounds disclosed herein that have a novel core structure and exhibit desired inhibition of DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity against DGKα over DGKζ. TIFF2026504410000333.tif53165

Description

[Technical Field]

[0001] Disclosed herein are compounds of formula (I) that activate T cells, promote T cell proliferation, and / or exhibit anti-tumor activity, methods of using the compounds disclosed herein to treat cancer, and pharmaceutical compositions comprising the compounds. [Background technology]

[0002] Diacylglycerol kinases (DGKs) are a family of lipid kinases that phosphorylate diacylglycerol (DAG) and convert it to phosphatidic acid (PA). As a substrate for DGKs, DAG is generated from inositol phospholipids and other phospholipids in the cell membrane by hydrolysis of phospholipase C (PLC) in response to activation of various cell surface receptors, including G-protein-coupled receptors (GPCRs) and immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors (Rhee, Sue Goo. Annual review of biochemistry. 2001, 70.1:281-312). DAG is one of the important intracellular second messengers that recruit and activate many downstream effectors, including protein kinase C (PKC), protein kinase D (PKD) family members, and Ras guanyl nucleotide-releasing protein (RasGRP), which activate the NF-κB and extracellular-regulated kinase (ERK) pathways (Merida, Isabel, et al. Biochemical Journal. 2008, 409.1:1-18; Joshi, Rohan P., et al. International Journal of Molecular Sciences. 2013, 14.4:6649-6673). By consuming DAG, DGK regulates and adjusts the threshold and duration of DAG-mediated signaling. The mammalian DGK family contains 10 different members, with DGKα, DGKζ, and DGKδ being the three major isoforms abundantly expressed in lymphoid tissues (Joshi, Rohan P., et al. International Journal of Molecular Sciences. 2013, 14.4:6649-6673).

[0003] Cancer immunotherapy is a type of cancer treatment that manipulates and strengthens the host immune system to recognize and attack cancer cells. The majority of research has focused on targeting depleted CD8 +Research is focused on targeting immune checkpoint inhibitors, such as CTLA-4 and PD-1 / PD-L1, to reactivate T cells. It has become clear that peripheral T cell tolerance, which normally prevents harmful autoimmune diseases, can be hijacked by tumors and disrupt antitumor immune responses during carcinogenesis (Nussing, Simone, et al. Frontiers in Immunology. 2020, 11:2461). T cell anergy, one of the most important mechanisms of T cell tolerance, has been reported to occur in tumor-infiltrating T cells and contribute to the immunosuppressive nature of the tumor microenvironment (Abe, Brian T., and Fernando Macian. Oncoimmunology. 2013, 2.2:e22679). The anergy-associated transcription factor early growth response gene 2 (Egr2) directly binds to the Dgka and Dgkz promoters and increases their expression (Zheng, Yan, et al. Journal of Experimental Medicine 2012, 209.12:2157-2163; Zheng, Yan, et al. Molecular Immunology 2013, 55.3-4:283-291). In anergic T cells, DGKα and DGKζ both negatively regulate DAG signaling downstream of the TCR, playing an important role in reducing the intensity of TCR activation (Chen, Shelley S., et al. Frontiers in Cell and Developmental Biology 2016, 4:130). Therefore, we investigated immune cells expressing DGKα and DGKζ as potential targets for reversing the hyporesponsiveness of tumor-infiltrating T cells. It has been demonstrated that genetic deletion of DGKα or DGKζ enhances cytokine production and proliferation of T cells (Olenchock, Benjamin A., et al. Nature immunology. 2006, 7.11:1174-1181; Zhong, Xiao-Ping, et al. Nature immunology. 2003, 4.9:882-890).Single knockout of DGKα or DGKζ in both mouse or human chimeric antigen receptor (CAR)-T cells demonstrated superior effector function as determined by enhanced in vitro cytotoxicity and cytokine secretion when cocultured with antigen-expressing T cells (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577; Jung, In-Young, et al. Cancer Research. 2018, 78.16:4692-4703). MesoCAR-transduced DGKα- or DGKζ-deficient T cells also demonstrated significantly increased in vivo activity against mesothelioma (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577). - / - Mice showed enhanced tumor suppression in both orthotopic and subcutaneous implantation models (Wesley, Erin M., et al. Immunohorizons. 2018, 2.4:107-118; Wee, Susan, et al. AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 936). In addition to their T cell regulatory functions, both DGKα and DGKζ are also involved in regulating NK cell activation at tumor sites (Prinz, Petra U., et al. International Journal of Cancer. 2014, 135.8:1832-1841; Yang, Enjun, et al. The Journal of Immunology. 2016, 197.3:934-941). Furthermore, DGKΚ has been found to play an important role in controlling the activation threshold of mature B cells (Wheeler, Matthew L., et al. Science Signaling. 2013, 6, 297: ra91-ra91). In summary, all of these preclinical data suggest that inhibition of the subject DGKα and DGKΚ may be therapeutically beneficial in promoting immunity against cancer. Although existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated clear clinical benefits in subsets of patients with various tumor types, there remains an unmet medical need for the development of novel immunotherapies to achieve robust and durable clinical antitumor responses. Preclinical data strongly suggest that there is great potential for the development of DGKα- and DGKζ-targeted therapies to improve antitumor immunity. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Rhee, Sue Goo.Annual review of biochemistry.2001,70.1:281-312 [Non-patent document 2] Merida, Isabel, et al.Biochemical Journal.2008,409.1:1-18 [Non-patent document 3] Joshi,Rohan P.,et al.International Journal of Molecular Sciences.2013,14.4:6649-6673 [Non-patent document 4] Nussing,Simone,et al.Frontiers in Immunology.2020,11:2461 [Non-Patent Document 5] Abe,Brian T.,and Fernando Macian.Oncoimmunology.2013,2.2:e22679 [Non-patent document 6] Zheng,Yan,et al.Journal of Experimental Medicine 2012,209.12:2157-2163;Zheng,Yan,et al.Molecular Immunology.2013,55.3-4:283-291 [Non-Patent Document 7] Chen,Shelley S.,et al.Frontiers in Cell and Developmental Biology.2016,4:130 [Non-patent document 8] Olenchock,Benjamin A.,et al.Nature immunology.2006,7.11:1174-1181 [Non-Patent Document 9] Zhong,Xiao-Ping,et al.Nature immunology.2003,4.9:882-890 [Non-Patent Document 10] Riese, Matthew J., et al.Cancer Research.2013,73.12:3566-3577 [Non-Patent Document 11] Jung,In-Young,et al.Cancer Research.2018,78.16:4692-4703 [Non-Patent Document 12] Wesley,Erin M.,et al.Immunohorizons.2018,2.4:107-118 [Non-Patent Document 13] Wee,Susan,et al.AACR;Cancer Res 2019;79(13 Suppl) [Non-Patent Document 14] Prinz,Petra U.,et al.International Journal of Cancer.2014.135.8:1832-1841 [Non-Patent Document 15] Yang,Enjun,et al.The Journal of Immunology.2016,197.3:934-941 [Non-Patent Document 16] Wheeler, Matthew L., et al.Science Signaling.2013,6.297:ra91-ra91 Summary of the Invention [Means for solving the problem]

[0005] The above needs have been met by providing compounds disclosed herein that have novel core structures and exhibit desired inhibition of DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity for DGKα over DGKζ. In some embodiments, the compounds disclosed herein exhibit selective inhibitory activity for DGKζ over DGKα. In some embodiments, the compounds disclosed herein exhibit dual inhibitory activity for both DGKα and DGKζ. In some embodiments, the compounds disclosed herein exhibit equivalent inhibitory activity for DGKα and DGKζ.

[0006] As used herein, compounds of formula (I) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, During the ceremony, X1 is C or N, X2 is selected from -CH- or N; R1 is hydrogen or alkyl optionally substituted with deuterium or halogen; R2 is hydrogen, halogen, alkyl, or cyano, provided that when X1 is N, R2 is absent; R4 is hydrogen, halogen, or alkyl, wherein the alkyl is optionally substituted with deuterium or halogen; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyano, or heterocyclyl, wherein the alkyl or alkenyl is unsubstituted or substituted with halogen, cyano, heterocyclyl, alkoxy, hydroxy, or cycloalkyl; R7, R9, R8, and R 10 are each independently hydrogen, alkyl, or alkoxy, wherein the alkyl is unsubstituted or substituted with halogen, with the proviso that at least one of R7 and R9 is not hydrogen; L1 is a direct bond or -C(R L1 )(R L2 )-, and the R L1 and the R L2 each independently being hydrogen or C optionally substituted with deuterium, halogen, alkyl, alkylene, alkynyl, cyano 1~4 is alkyl, Cy1 is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R 3a and each R 3a is independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cyano, heterocyclyl, or heterocyclyloxy; where: each alkyl portion thereof is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxy, cyano, or heterocyclyl; each of said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; Provided are compounds of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof:

[0007] X 1 , X 2 Definition of

[0008] In some embodiments, X 1 is C. In some embodiments, X 1 is N.

[0009] In some embodiments, X2 is -CH-. In some embodiments, X2 is N.

[0010] R 1 Definition of

[0011] In some embodiments, R is hydrogen or C optionally substituted with deuterium, halogen, hydroxy, alkoxy, or cycloalkyl. 1~4In some embodiments, R is hydrogen or C 1~3 It is alkyl.

[0012] In some embodiments, R1 is hydrogen, methyl, methyl-d3, ethyl, isopropyl, or n-propyl. In some embodiments, R1 is hydrogen, methyl, or ethyl. In some embodiments, R1 is hydrogen or methyl.

[0013] R 2 Definition of

[0014] In some embodiments, R2 is hydrogen, halogen, C 1~4 In some embodiments, R2 is alkyl or cyano. In some embodiments, R2 is hydrogen, F, Br, Cl, CN, cyanomethyl, methyl, or ethyl. In some embodiments, R2 is hydrogen, F, Br, CN, or methyl. In some embodiments, R2 is hydrogen, F, Br, or CN.

[0015] In some embodiments, when X 1 is N, R 2 is absent.

[0016] R 4 Definition of

[0017] In some embodiments, R4 is alkyl optionally substituted with hydrogen, halogen, or deuterium. In some embodiments, R4 is hydrogen, methyl, or methyl-d3.

[0018] R 5 Definition of

[0019] In some embodiments, R5 is hydrogen, alkyl, alkenyl, alkynyl, or cyano, wherein the alkyl is unsubstituted or substituted with cyano, cycloalkyl, or heterocyclyl containing one oxygen atom. 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl, wherein the alkyl is cyano, C3~6 It is substituted with a cycloalkyl or a heterocyclyl containing one oxygen atom.

[0020] In some embodiments, R5 is hydrogen, -CN, -CH2-CN, -CH(CH3)CN, -CH2-CH2-CN, -CH2-CH2-CH2-CN, -CH(CH3)-CH2-CN, -CH2-CH(CH3)-CN, -CH(CH2CH3)-CN, oxiran-2-ylmethyl, oxiran-2-yl, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl , prop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, azetidin-2-yl, azetidin-3-yl, azetidin-3-ylmethyl, azetidin-1-yl, azetidin-1-ylmethyl, aziridin-1-yl, aziridin-1-ylmethyl, aziridin-2-yl, aziridin-2-ylmethyl, 1-cyanocyclopropyl, 2-cyanocyclopropyl or 2-cyanocyclobutyl. In some embodiments, R5 is hydrogen, -CN, -CH2-CN, -CH(CH3)CN, -CH2-CH2-CN, CH2-CH2-CH2-CN, -CH(CH3)-CH2-CN, -CH2-CH(CH3)-CN, -CH(CH2CH3)-CN, prop-2-yn-1-yl, but-3-yn-1-yl, or pent-3-yn-1-yl. In some embodiments, R5 is -CN, -CH 2- CN, -CH2-CH2-CN.

[0021] R 7 / R 9 、 R 8 / R 10 Definition of

[0022] In some embodiments, each of R7 and R9 is independently hydrogen or alkyl, wherein the alkyl is unsubstituted or substituted with halogen, alkoxy, amino, cycloalkyl, or heterocyclyl. Preferably, each of R7 and R9 is independently C substituted with halogen or alkoxy. 1~4 More preferably, each of R7 and R9 is independently a C alkyl group that is unsubstituted or substituted with halogen or alkoxy. 1~2 It is alkyl.

[0023] In some embodiments, R7 and R9 are each independently hydrogen, methyl, ethyl, isopropyl, n-propyl, methoxymethyl, or 2-methoxyethyl, provided that at least one of R7 and R9 is not hydrogen.

[0024] In some embodiments, R7 is methyl and R9 is methyl. In some embodiments, R7 is hydrogen and R9 is methyl. In some embodiments, R7 is methyl and R9 is hydrogen. In some embodiments, R7 is hydrogen and R9 is ethyl. In some embodiments, R7 is ethyl and R9 is hydrogen. In some embodiments, R7 is ethyl and R9 is ethyl. In some embodiments, R7 is methyl and R9 is ethyl.

[0025] In some embodiments, R and R 10 are each hydrogen.

[0026] In some embodiments, the 5-carbon of the piperazine ring is in the R configuration with the proviso that R9 is not hydrogen.

[0027] In some embodiments, the 2-carbon of the piperazine ring is a chiral carbon and the 5-carbon of the piperazine ring is in the R configuration, with the proviso that R7 is hydrogen and R9 is not hydrogen.

[0028] In some embodiments, the carbon at position 2 of the piperazine ring is in the S configuration and the carbon at position 5 of the piperazine ring is in the R configuration, with the proviso that R7 and R9 are not both hydrogen.

[0029] In some embodiments, the 2-carbon and 5-carbon of the piperazine ring are both in the R configuration, with the proviso that R7 is methoxymethyl and R9 is not hydrogen.

[0030] In some embodiments, the 5-carbon of the piperazine ring is in the S configuration with the proviso that R9 is not hydrogen. In some embodiments, the 5-carbon of the piperazine ring is in the S configuration with the proviso that R9 is methoxymethyl.

[0031] In some embodiments, the carbon at position 2 of the piperazine ring is an achiral carbon and the carbon at position 5 of the piperazine ring is in the S configuration, with the proviso that R7 is hydrogen and R9 is not hydrogen.

[0032] In some embodiments, the carbon at position 2 of the piperazine ring is in the S configuration with the proviso that R7 is methoxymethyl.

[0033] L 1 Definition of

[0034] In some embodiments, L is a direct bond, —C(R L1 )(R L2 )-, and the R L1 and the R L2 each independently being hydrogen or C optionally substituted with halogen, deuterium, alkyl, alkylene, alkynyl, or cyano. 1~4 It is alkyl.

[0035] In some embodiments, L is a direct bond, -CH-, -CH(CH)-, -CH(CD)-, -CH(CHCH)-, -CH(CH)-, -CH(CHF)-, or -C(CH)-. More preferably, L is -CH-, -CH(CH)-, or -CH(CD)-.

[0036] As used herein, a compound of formula (II) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, R 11 is methyl or ethyl, and X1, R2, R7, R9, and Cy1 are as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0037] In some embodiments, R 11 is ethyl, R7 is ethyl, and R9 is ethyl.

[0038] In some embodiments, R 11 is ethyl, R7 is methyl, and R9 is methyl.

[0039] In some embodiments, R 11 is ethyl, R7 is methyl, and R9 is ethyl.

[0040] In some embodiments, R 11 is ethyl, R7 is ethyl, and R9 is methyl.

[0041] In some embodiments, R 11 is methyl, R7 is ethyl, and R9 is ethyl.

[0042] In some embodiments, R 11 is methyl, R7 is methyl, and R9 is ethyl.

[0043] In some embodiments, R 11 is methyl, R7 is ethyl, and R9 is methyl.

[0044] In some embodiments, R 11 is methyl, R7 is methyl, and R9 is methyl.

[0045] In some embodiments, R 11 and the carbon attached to Cy1 is in the R configuration.

[0046] In some embodiments, R 11 and the carbon attached to Cy1 is in the S configuration.

[0047] As used herein, a compound of formula (IIa) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, R 11 is methyl or ethyl, and X1, R2, R7, R9, and Cy1 are as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0048] As used herein, a compound of formula (IIb) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, R 11 is methyl or ethyl, and X1, R2, R7, R9, and Cy1 are as defined above, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0049] Cy 1 Definition of

[0050] In some embodiments, Cy 1 is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R 3a and each R 3aare independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cycloalkyl, heterocyclyl, or heterocyclyloxy, each alkyl portion of which is unsubstituted or substituted with halogen, alkoxy, hydroxy, or heterocyclyl, and each of said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy.

[0051] In some embodiments, R 3a is selected from F, Br, Cl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutane, difluoromethyl, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, isopropoxy, cyclopropoxy.

[0052] In some embodiments, Cy1 is selected from the group consisting of one, two, or three substituents R 3a and each R is a heterocyclyl optionally substituted with 3a is independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cycloalkyl, heterocyclyl, or heterocyclyloxy, each alkyl portion of which is unsubstituted or substituted with halogen, alkoxy, hydroxy, or heterocyclyl, and each of the cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy. In some embodiments, R 3a is F, Br, Cl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutane, difluoromethyl, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, isopropoxy, cyclopropoxy.

[0053] In some embodiments, Cy1 is selected from the group consisting of one, two, or three substituents R 3a is phenyl optionally substituted with

[0054] In some embodiments, Cy1 is phenyl, which is substituted with one R as disclosed herein at the 4-position. 3a and in other positions R 3a is optionally replaced by In some embodiments, Cy1 is a monocyclic 5-9 membered heterocyclyl or heteroaryl, or a bicyclic 7-10 membered heterocyclyl or heteroaryl, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0055] In some embodiments, Cy1 is a monocyclic 5-9 membered heterocyclyl or a bicyclic 7-10 membered heterocyclyl, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0056] In some embodiments, Cy1 is a monocyclic 5-9 membered heteroaryl or a bicyclic 7-10 membered heteroaryl, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0057] In some embodiments, the monocyclic 5-9 membered heterocyclyl or heteroaryl is [ka] each of which is unsubstituted or contains one, two or three R 3a wherein each of X4, X5, X6, X7, and X8 is independently selected from N or C; and X9 is selected from C, N, S, or O.

[0058] In some embodiments, the monocyclic 5-9 membered heteroaryl is thiazole, isothiazole, triazole, pyridine, pyrazine, pyrimidine, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0059] In some embodiments, the monocyclic 5-9 membered heteroaryl is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-3-yl, isothiazol-4-yl, pyrazin-1-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0060] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] is.

[0061] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] each of which is unsubstituted or contains one, two or three R 3a wherein ring A is a 6-membered carbocyclic or heterocyclic ring, ring B is selected from a 5- or 6-membered monocyclic carbocyclic or monocyclic heterocyclic ring fused to ring A to form an AB bicyclic ring, and each of Y, Y, and Y is independently N or C.

[0062] In some embodiments, ring B is [ka] is.

[0063] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] is.

[0064] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] is.

[0065] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] is.

[0066] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] wherein each of Z1, Z2, and Z3 is N or CH, with the proviso that at least two of Z1, Z2, and Z3 are N. In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is [ka] wherein each of Z1 and Z3 is N or CH, with the proviso that at least one of Z1 and Z2 is N. In some embodiments, [ka] is.

[0067] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, chroman, isochroman, 2,3-dihydrobenzo[b][1,4]dioxin, thiochroman, isothiochroman, 2,3-dihydrobenzo[b][1,4]dithiin, quinoxalinyl, isoquinoline, quinoxaline, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 2,3-dihydro-[1,4]dioxino ... 4]dioxino[2,3-c]pyridine, 3,4-dihydro-2H-pyrano[3,2-b]pyridine, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3, 4-Tetrahydro-1,7-naphthyridine, 3H-indole, 1H-isoindole, benzofuran, benzo[b]thiophene, 3H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[3,4-b]pyridine, furo[2,3-b]pyridine, thieno[2,3-b]pyridine, benzo[d]thiazole, benzo[d]oxazole, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, oxazolo[4,5-b]pyridine, thiazolo[4,5-b]pyridine, 2,3-dihydro-1H-indene, 2 ,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 1,3-dihydrobenzo[c]thiophene, 2,3-dihydrobenzo[b]thiophene, benzo[b]thiophene, thieno[3,2-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, or pyrrolo[1,2-a]pyrimidine, each of which is unsubstituted or contains one, two, or three R 3a is replaced by .

[0068] In some embodiments, the bicyclic 7-10 membered heteroaryl is selected from the group consisting of 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, chroman, isochroman, 2,3-dihydrobenzo[b][1,4]dioxin, thiochroman, isothiochroman, 2,3-dihydrobenzo[b][1,4]dithiin, quinoxalinyl, isoquinoline, quinoxaline, 2,3-dihydro-[1,4]dioxino[2, 3-b]pyridine, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridine, 3,4-dihydro-2H-pyrano[3,2-b]pyridine, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 5,6,7, 8-Tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydro-1,7-naphthyridine, 3H-indole, 1H-isoindole, benzofuran, benzo[b]thiophene, 3H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[3,4-b]pyridine, furo[2,3-b]pyridine, thieno[2,3-b]pyridine, benzo[d]thiazole, benzo[d]oxazole, benzo[d]oxazole, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, oxazolo[4,5-b]pyridine, thiazolo[4,5-b]pyridine, 2,3-dihydro-1H-indene, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 1,3-dihydrobenzo[c]thiophene or 2,3-dihydrobenzo[b]thiophene, each of which is unsubstituted or substituted by one, two or three R.

[0069] In some embodiments, the bicyclic 7-10 membered heteroaryl is quinoxaline, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d]thiazole, thiazolo[5,4-b]pyridine, benzo[b]thiophene, or thieno[3,2-b]pyridine, each of which is unsubstituted or substituted with 1, 2, or 3 R.

[0070] In some embodiments, the bicyclic 7-10 membered heteroaryl is benzo[b]thiophene, thieno[3,2-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, or pyrrolo[1,2-a]pyrimidine, each of which is unsubstituted or substituted with 1, 2, or 3 R.

[0071] In some embodiments, the bicyclic 7-10 membered heteroaryl is benzo[b]thiophene, thieno[3,2-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[1,5-a]pyridine, each of which is unsubstituted or substituted with 1, 2, or 3 R.

[0072] In some embodiments, the bicyclic 7-10 membered heterocyclyl or heteroaryl is 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, chroman-7-yl, chroman-8-yl, isochroman-7-yl, isochroman-8-yl, 2,3-dihydrobenzo[b][1,4]dioxin-7-yl, 2,3-dihydrobenzo[b ][1,4]dioxin-8-yl, thiochroman-7-yl, thiochroman-8-yl, 2,3-dihydrobenzo[b][1,4]dithiin-7-yl, 2,3-dihydrobenzo[b][1,4]dithiin-8-yl, quinoxalinyl-7-yl, quinoxalinyl-8-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-7-yl, quinoxalin-8-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-di Hydro-[1,4]dioxino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin Lysin-5-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridin-6-yl, 2,3-Dihydro-[1,4]dithiino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-7-yl, 1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl 1,2,3,4-tetrahydro-2,7-naphthyridin-6-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-6-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl, 3H-indol-4-yl , 3H-indol-5-yl, 3H-indol-6-yl, 3H-indol-7-yl, 1H-isoindol-4-yl, 1H-isoindol-5-yl, 1H-isoindol-6-yl, 1H-isoindol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, 3H-pyrrolo[3, 2-b]pyridin-5-yl, 3H-pyrrolo[3,2-b]pyridin-6-yl, 3H-pyrrolo[3,2-b]pyridin-7-yl, 7H-pyrrolo[3,4-b]pyridin-2-yl, 7H-pyrrolo[3,4-b]pyridin-3-yl, 7H-pyrrolo[3,4-b]pyridin-4-yl, furo[2,3-b]pyridin-4-yl, furo[2,3-b]pyridin-5-yl, furo[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, oxazolo[5,4-b]pyridin-5-yl, oxazolo[5,4-b]pyridin-6-yl, oxazolo[5,4-b]pyridin-7-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b ]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, oxazolo[4,5-b]pyridin-5-yl, oxazolo[4,5-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-di 1,3-Dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, 1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl, 1,3-dihydrobenzo[c]thiophen-4-yl, 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-4-yl, 2,3-dihydrobenzo[b]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-6-yl, 2,3-dihydrobenzo[b]thiophen-7-yl, benzo[b]thiophen-6-yl, benzo[ b]thiophen-5-yl, benzo[b]thiophen-7-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-7-yl, imidazo[1,2-b]pyridazin-8-yl, pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[1,5-a]pyrimidin-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrrolo[1,2-b]pyridazin-3-yl, pyrrolo[1,2-b]pyridazin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl -yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl, pyrrolo[1,2-a]pyrimidin-2-yl, pyrrolo[1,2-a]pyrimidin-3-yl, or pyrrolo[1,2-a]pyrimidin-4-yl, each of which is unsubstituted or substituted with one, two, or three R3a.

[0073] In some embodiments, the bicyclic 7-10 membered heteroaryl is 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, chroman-7-yl, chroman-8-yl, isochroman-7-yl, isochroman-8-yl, 2,3-dihydrobenzo[b][1,4]dioxin-7-yl, 2,3-dihydrobenzo[b][1,4]dioxy. quinoxalinyl-7-yl, quinoxalinyl-8-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-7-yl, quinoxalin-8-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]di Oxino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl, 3 ,4-dihydro-2H-thiopyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-7-yl, 1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 5,6,7 ,8-tetrahydro-1,7-naphthyridin-6-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-8-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-6-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl, 3H-indol-4-yl, 3H-indol-4-yl Indol-5-yl, 3H-indol-6-yl, 3H-indol-7-yl, 1H-isoindol-4-yl, 1H-isoindol-5-yl, 1H-isoindol-6-yl, 1H-isoindol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, 3H-pyrrolo[3,2- b]pyridin-5-yl, 3H-pyrrolo[3,2-b]pyridin-6-yl, 3H-pyrrolo[3,2-b]pyridin-7-yl, 7H-pyrrolo[3,4-b]pyridin-2-yl, 7H-pyrrolo[3,4-b]pyridin-3-yl, 7H-pyrrolo[3,4-b]pyridin-4-yl, furo[2,3-b]pyridin-4-yl, furo[2,3-b]pyridin-5-yl, furo[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, oxazolo[5,4-b]pyridin-5-yl, oxazolo[5,4-b]pyridin-6 -yl, oxazolo[5,4-b]pyridin-7-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, oxazolo[4,5-b]pyridin-5-yl, oxazolo[4,5-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl yl, thiazolo[4,5-b]pyridin-7-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, 1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl, 1, 3-dihydrobenzo[c]thiophen-4-yl, 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-4-yl, 2,3-dihydrobenzo[b]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-6-yl, 2,3-dihydrobenzo[b]thiophen-7-yl, each of which is unsubstituted or substituted with one, two, or three R3a.

[0074] In some embodiments, the bicyclic 7-10 membered heteroaryl is selected from the group consisting of benzo[b]thiophen-6-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-7-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-7-yl, imidazo[1,2-b]pyridazin-8-yl, pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[1,5-a]pyrimidin-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyrid ...ridin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyrazolo[1,5-a]pyrimidin-8-yl, pyr pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrrolo[1,2-b]pyridazin-3-yl, pyrrolo[1,2-b]pyridazin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl, pyrrolo[1,2-a]pyrimidin-2-yl, pyrrolo[1,2-a]pyrimidin-3-yl, or pyrrolo[1,2-a]pyrimidin-4-yl, each of which is unsubstituted or substituted by one, two, or three R3a.

[0075] In some embodiments, Cy1 is quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, 3-chloroquinoxalin-6-yl, 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 4-fluoro-2- (trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 4-cyclopropyl-2-fluorophenyl, 6-cyclopropylpyridin-3-yl, 5-isopropoxypyridin-2-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, or 2-methylbenzo[d]thiazol-6-yl yl, benzo[d]thiazol-5-yl, 2-difluoromethyl-methylthieno[2,3-b]pyridin-6-yl, imidazo[1,2-b]pyridazin-6-yl, 2-methyl-imidazo[1,2-b]pyridazin-6-yl, 2-ethyl-imidazo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 2-methyl-pyrazolo[1,5-a]pyrimidin-5-yl, 2-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-methyl-3-fluoro-pyrazolo [1,5-a]pyrimidin-5-yl, 3-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-cyclopropyl-pyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-pyrazolo[1,5-a]pyrimidin-5-yl, 2,3-difluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-3-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, or 2-methyl-pyrazolo[1,5-a]pyridin-5-yl.

[0076] In some embodiments, Cy1 is [ka] is.

[0077] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] is.

[0078] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] In some embodiments, Cy1 is [ka] is.

[0079] Provided herein are compounds selected from Table 1.

[0080] Provided herein is a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, which is any one of the exemplified compounds.

[0081] Provided herein are pharmaceutical compositions comprising one or more compounds herein, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0082] Provided herein are methods of treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound herein or a pharmaceutical composition herein. DETAILED DESCRIPTION OF THE INVENTION

[0083] definition The following terms have the indicated meanings throughout this specification.

[0084] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0085] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0086] The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups derived from an alkane by removing one hydrogen atom from the same carbon atom, containing 1 to 18, for example, 1 to 12, further for example, 1 to 10, even further for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1~6Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. Alkyl groups may optionally be enriched with deuterium, e.g., -CD3, -CD2CD3, etc. The term "alkylene" refers to a hydrocarbon group selected from straight- and branched-chain saturated hydrocarbon groups derived from an alkane by removing two hydrogen atoms from the same carbon atom, containing from 1 to 6, e.g., 1 to 4 carbon atoms, further e.g., 1 to 3, even further e.g., 1, 2, or 3 carbon atoms, including, but not limited to, methylene (-CH2-), ethylene (-CH2CH2-), 1-methylmethylene (-CH(CH3)-), or trimethylene (-CH2CH2CH2-).

[0087] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0088] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC 1~8 Alkyl, HaloC 1~6 Alkyl or haloC 1~4 Alkyl includes, but is not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, and the like.

[0089] The terms "alkyloxy" or "alkoxy" refer to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Alkyloxy, e.g., C 1~6 Alkyloxy or C 1~4 Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0090] The term "amino" refers to -NH2.

[0091] The term "alkenyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkenyl groups (e.g., C2-6 alkenyl) include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0092] The term "alkynyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkynyl groups (e.g., C2-6 alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0093] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0094] For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even more for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups (e.g., C 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 (Abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0095] The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen atoms have been replaced with one or more deuterium atoms, such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," and the like. For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one carbon-bonded hydrogen atom has been replaced with deuterium. A deuterated alkyl group has at least one carbon atom bonded to deuterium, and a carbon atom can be bonded to two or more deuterium atoms, and it is also possible for two or more carbon atoms in an alkyl group to be bonded to deuterium.

[0096] The term "aryl", used alone or in combination with other terms, refers to a group selected from:

[0097] 5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

[0098] Bicyclic ring systems (e.g., 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and

[0099] Tricyclic ring systems (eg, 10-15 membered tricyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0100] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5~10Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0101] As used herein, the term "heteroaryl" refers to a group selected from:

[0102] a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon;

[0103] a 7-12 membered bicyclic ring containing as ring member(s) at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and

[0104] An 11-14 membered tricyclic ring containing as ring member(s) at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0105] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form an N-oxide.

[0106] As used herein, the term "optionally oxidized sulfur" refers to -S-, SO, or SO2.

[0107] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic heteroaromatic ring has 5, 6, 7, 8, 9, or 10 ring members, containing 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic, 5-6 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0108] Examples of heteroaryl groups or monocyclic or bicyclic heteroaromatic rings include (as numbered from the attachment position assigned priority 1) 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl), pyridyl or pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or 2,4-pyrimidinyl, 3, 5-pyrimidinyl), imidazolyl (e.g., 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, or 2,4-imidazolyl), imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzo furyl, benzimidazolyl, indolyl (e.g., 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, or 1H-indol-7-yl), isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl (e.g., pyrazin-2-yl), pyridazinyl, pyrrolyl, triazolyl (e.g., 1, 2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, or quinolin-7-yl), isoquinolinyl (e.g., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl), pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl aryl, benzoxazolyl (e.g., benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, or benzo[d]oxazol-7-yl), quinazolinyl, quinoxalinyl (e.g., quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, or quinoxalin-8-yl), naphthyridinyl (e.g., 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, or 1,8-naphthyridin-4-yl), 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl (e.g., 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl), furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-8-yl, azol-5-yl, benzo[d]thiazol-6-yl, or benzo[d]thiazol-7-yl), benzo[d]imidazolyl (e.g., 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, or 1H-benzo[d]imidazol-7-yl), [1,2,4]triazolo[1,5-a]pyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,[1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, or [1,2,4]triazolo[1,5-a]pyridin-8-yl), 3H-imidazo[4,5-b]pyridinyl (e.g., 3H-imidazo[4,5-b]pyridin-2 -yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, or 3H-imidazo[4,5-b]pyridin-7-yl), 1H-imidazo[4,5-b]pyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-5-yl, yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-7-yl), [1,2,4]triazolo[1,5-a]pyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[1,5-a]pyridin-5-yl, [1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyridin-7-yl, or [1,2,4]triazolo[1,5-a]pyridin-8-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0109] Additionally, a "heteroaryl" fused with a "heterocyclyl" is defined as a "heteroaryl."

[0110] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and includes monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0111] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0112] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include (as numbered from the attachment position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpho, and morpho. 2-thiaminyl, morpholin-3-yl, oxiranyl, 1-aziridinyl, 2-aziridinyl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, 1-azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, Homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azatianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, and dihydropyranyl , dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0113] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected via a common carbon atom (referred to as a spiro atom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. Depending on the number of common spiro atoms, the spiroheterocyclyl is classified as a monospiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a dispiroheterocyclyl, and more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.

[0114] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent atom pair (carbon atom and carbon atom, or carbon atom and nitrogen atom) with another ring and contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in the fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of membered rings, the fused heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and preferably refers to a bicyclic or tricyclic fused heterocyclyl, and more preferably refers to a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles include, but are not limited to, octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), and octahydro-benzo[b][1,4]dioxine groups.

[0115] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, in which each of two rings in the system shares two non-consecutive atoms and contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings in a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of membered rings, the bridged heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl groups.

[0116] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0117] As used herein, the phrase "substantially pure" means that the title stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, even further such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the phrase "substantially pure" means that the title stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0118] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, it is intended that such double bond include both E and Z geometric isomers.

[0119] When the compounds disclosed herein contain a disubstituted cyclohexyl or disubstituted cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt cis and trans configurations, where cis means that both substituents are found above the two substitution positions on the carbon, while trans means that they are on opposite sides of each other.

[0120] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps may be separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or flash column chromatography. Flash column chromatography can include any method, including, for example, reverse-phase and normal-phase, size-exclusion, ion-exchange, high-, medium-, and low-pressure liquid flash column chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer flash column chromatography, and small-scale thin-layer and flash column techniques. Those skilled in the art will apply the technique most likely to achieve the desired separation.

[0121] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as flash column chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column.

[0122] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Flash column chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302]. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993. The absolute configuration of a chiral center in a compound can be determined using methods known to those skilled in the art, such as single crystal X-ray crystallography or co-crystal formation of the compound of interest with a target protein, optionally in combination with spectroscopic techniques, such as NMR spectroscopy. In some embodiments, the absolute configuration of a chiral center in a compound can be elucidated from the X-ray single crystal structure of the compound. In some embodiments, the absolute configuration of a chiral center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding chiral center in another compound or intermediate obtained from the same or similar synthetic method.

[0123] "Pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base function with a suitable organic acid, or an acidic group with a suitable base.

[0124] "Selective inhibitory activity" or "selectivity" refers to the difference in the degree of inhibition against DGKα and DGKζ; the greater the degree of inhibition against a particular isoform compared to another isoform, the more selective the inhibitor is for that particular isoform. In some embodiments, a "compound that exhibits selective inhibitory activity against DGKα over DGKζ" refers to a compound having an IC50 against DGKα of about 2000 nM or less and a ratio of the IC50 for DGKζ to the IC50 for DGKα of about 20 or more; a "compound that exhibits selective inhibitory activity against DGKζ over DGKα" refers to a compound having an IC50 against DGKζ of about 2000 nM or less and a ratio of the IC50 for DGKα to the IC50 for DGKζ of about 20 or more; and a "compound that exhibits dual inhibitory activity" refers to a compound that exhibits inhibitory activity against both DGKα and DGKζ of about 500 nM or less and a ratio of the two IC50 values ​​of 20 or less.

[0125] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0126] As defined herein, "pharmaceutically acceptable salts thereof" includes salts of at least one compound of formula (I), and salts of stereoisomers of compounds of formula (I), e.g., salts of enantiomers and / or diastereomers.

[0127] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contacting a reagent with the cell and contacting a reagent with a fluid that contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0128] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, that is effective in "treating" a disease or disorder in a subject, as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of a disease, disorder, or condition.

[0129] The pharmaceutical composition comprising the compound disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral or topical administration.For oral administration, the pharmaceutical composition can be a conventional solid formulation such as tablet, powder, granule, capsule, or liquid formulation such as water or oil suspension, or other liquid formulation such as syrup, solution, suspension, etc.For parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oil suspension concentrate, freeze-dried powder, etc.Preferably, the pharmaceutical composition formulation is selected from tablet, coated tablet, capsule, suppository, nasal spray, or injection, more preferably tablet or capsule.The pharmaceutical composition can be a single dose of precise dosage.In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0130] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water, various organic solvents, fillers such as starch, sucrose, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecanol; absorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients, such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, flavoring agents, sweetening agents, and dyes.

[0131] The term "disease" refers to any disease, ailment, illness, symptom or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0132] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" can be substituted with the words "containing," "including," or, in some cases, "having."

[0133] Throughout this specification and the claims that follow, the term "Cn-m" denotes an inclusive range, where n and m are integers and indicate the number of carbons. Examples include C 1~8 , C 1~6 Examples include:

[0134] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0135] [Table 2-1] [Table 2-2]

[0136] General synthetic scheme The compounds disclosed herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0137] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, at temperatures that can vary from room temperature to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0138] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0139] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica flash column chromatography.

[0140] Chiral analytical HPLC was used for retention time analysis of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used. The preparation of homochiral examples can be carried out by techniques known to those skilled in the art. Absolute stereochemistry was not assigned at the newly formed carbon-nitrogen bond.

[0141] The compounds disclosed herein can be prepared according to the following Schemes I-II.

[0142] Scheme I [ka]

[0143] where R 1 ~R 9 and R 8L (L 1 -Cy 1 The substitutions in (corresponding to) are defined as described in formula (I).

[0144] In Scheme I, commercially available compound 1 is reacted with diethyl malonate under heating conditions via a cyclization reaction to give compound 2. Compound 2 is reacted with a chlorinating agent (such as SOCl or POCl) to give compound 3. Compound 3 is reacted with an appropriate chiral secondary amine via a nucleophilic aromatic substitution reaction to give compound 4. Compound 4 is reacted with an appropriate benzyl alcohol under basic conditions (such as NaH) via a nucleophilic aromatic substitution reaction to give compound 5. Compound 5 is deprotected using acid / heat conditions (such as TFA) to give compound 6, and compound 6, containing the secondary amine, is subsequently protected with a protecting group (such as di-tert-butyl dicarbonate) to give compound 7. Compound 7 is then annealed with an appropriate R 1 Reaction of -X with -X under basic conditions (e.g., K2CO3, Cs2CO3) gives compound 8. Compound 8 containing a bromine atom can be converted to the corresponding compound 9, typically by Pd-catalyzed methoxycarbonylation using an appropriate Pd catalyst (e.g., Pd(dppf)Cl2) and a methoxycarbonylating reagent (e.g., CO / MeOH). Compound 9 is reduced using a reducing agent (e.g., NaBH4) to give compound 10 as an alcohol. Compound 10 containing a hydroxyl group can be chlorinated by treatment with a chlorinating agent (e.g., SOCl2 or MsCl) to give compound 11. Compound 11 as a benzyl halide can be converted to the corresponding compound 12 by treatment with a cyanating agent (e.g., TMSCN) under basic conditions (e.g., Cs2CO3 or nBu4NF). Compound 12 is deprotected using acidic conditions (e.g., TFA or 4 M HCl solution in 1,4-dioxane) to give compound 13. Tertiary amine compounds 14 are prepared by reductive alkylation with aldehydes or ketones, the most frequently used procedure being phosphonium salt-mediated alkylation of the amine with the corresponding alcohol (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521).

[0145] Scheme II [ka]

[0146] where R 1 ~R 9 and R 8L (L 1 -Cy 1 The substitutions in (corresponding to) are defined as described in formula (I).

[0147] In Scheme II, compound 2 is prepared by reductive amination with an aldehyde or ketone, the most frequently used procedure being phosphonium salt-mediated alkylation of the amine with the corresponding alcohol (Florencio Zaragoza and Henrik Stephensen, J. Org. Chem. 2001, 66, 2518-2521). Compound 2 is deprotected using acid conditions (such as TFA or a 4M HCl solution in 1,4-dioxane) to give compound 3. Compound 3 is reacted with commercially available compound 4 via a nucleophilic aromatic substitution reaction to give compound 5. Compound 5 is reacted with an appropriate benzyl alcohol under basic conditions (such as NaH) via a nucleophilic aromatic substitution reaction to give compound 6. Compound 6 is deprotected using acid / heat conditions (such as TFA) to give compound 7. Compound 7 is then converted to the appropriate R 1 Reaction of -X with -X under basic conditions (e.g., K2CO3, Cs2CO3) gives compound 8. Compound 8 containing a bromine atom can be converted to the corresponding compound 9, typically by Pd-catalyzed methoxycarbonylation using an appropriate Pd catalyst (e.g., Pd(dppf)Cl2) and a methoxycarbonylating reagent (e.g., CO / MeOH). Compound 9 is reduced using a reducing agent (e.g., NaBH4) to give compound 10 as an alcohol. Compound 10 containing a hydroxyl group can be chlorinated by treatment with a chlorinating agent (e.g., SOCl2 or MsCl) to give compound 11. Compound 11 as a benzyl halide can be converted to the corresponding compound 12 by treatment with a cyanating agent (e.g., TMSCN) under basic conditions (e.g., Cs2CO3 or nBu4NF). [Example]

[0148] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Unless otherwise specified, experimental methods in the examples described below are conventional. Unless otherwise specified, all reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are prepared according to standard or reference methods. Silica gel (100-200 mesh) for flash column chromatography and silica gel (GF254) for thin-layer flash column chromatography (TLC) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China. Unless otherwise specified, all are eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybdophosphate in ethanol. Unless otherwise specified, all extraction solvents are dried over anhydrous Na2SO4. 1 H NMR spectra were recorded on a Bruck-400 nuclear magnetic resonance spectrometer using TMS (tetramethylsilane) as the internal standard. LC / MS data were recorded using an Agilent 1100 high-performance liquid flash column chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) and an ion trap (ESI source) detecting at 214 nm and 254 nm. All compound names, except for reagents, were generated by ChemDraw®.

[0149] synthesis

[0150] [Table 3]

[0151] [Table 4]

[0152] Intermediate 1: 7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carbonitrile [ka]

[0153] Step A: 2-Bromopyrazolo[1,5-a]pyrimidine-5,7-diol [ka]

[0154] To a solution of 5-bromo-1H-pyrazol-3-amine (3.2 g, 20 mmol) in EtOH (50 ml) was added diethyl malonate (6.4 g, 40 mmol) and sodium methanolate (2.1 g, 40 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature and filtered. The filter cake was dissolved in H2O and the pH was adjusted to 2-3. The resulting mixture was filtered. The filter cake was dried to give the title compound (2 g, 44%). MS: m / e 230 (M+1) + .

[0155] Step B: 2-Bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine [ka]

[0156] To a mixture of 2-bromopyrazolo[1,5-a]pyrimidine-5,7-diol (2 g, 0.88 mmol) in POCl3 (10 mL) was added N,N-dimethylaniline (5 mL). The resulting mixture was stirred at 90 °C overnight. The mixture was concentrated in vacuo. The residue was added to ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (1.4 g, 61%). MS: M / e 266 (M+1) + .

[0157] Step C: tert-Butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0158] To a solution of 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1.1 g, 4.2 mmol) in THF (15 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1.06 g, 5 mmol) and DIPEA (1 g, 8 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (1.2 g, 65%). MS: M / e 444 (M+1) + .

[0159] Step D: tert-Butyl (2R,5S)-4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0160] To a solution of phenylmethanol (108 mg, 1 mmol) in THF (15 ml) was added NaH (60% in oil, 80 mg, 2 mmol). The reaction was stirred at room temperature for 0.5 hours. To the mixture was added tert-butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.5 mmol), and the reaction was stirred at 70° C. overnight. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (230 mg, 89%). MS: M / e 516 (M+1) + .

[0161] Step E: 2-Bromo-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0162] A mixture of tert-butyl (2R,5S)-4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (180 mg, 0.35 mmol) in TFA (5 mL) was stirred at 80° C. overnight. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO and extracted with DCM. The organic layer was dried over NaSO, filtered and concentrated. The crude product obtained was used directly in the next step without further purification. MS: M / e 326 (M+1) + .

[0163] Step F: tert-Butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0164] To a solution of 2-bromo-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one in DMF (5 mL) was added di-tert-butyl decarbonate (106 mg, 0.5 mmol) and DIPEA (129 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. H2O was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (120 mg, 81% yield for two steps). MS: M / e 426 (M+1) + .

[0165] Step G: tert-Butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0166] To a solution of tert-butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (120 mg, 0.28 mmol) in 1,4-dioxane (5 mL) was added trimethyl phosphate (197 mg, 1.4 mmol) and K2CO3 (58 mg, 0.42 mmol). The reaction mixture was stirred at 95 °C overnight. H2O was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (122 mg, 100%). MS: M / e 440 (M+1) + .

[0167] Step H: tert-Butyl (2R,5S)-4-(2-cyano-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0168] To a solution of tert-butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 0.11 mmol) in 1,4-dioxane / HO (5 mL / 2.5 mL) was added Zn(CN) (38 mg, 0.33 mmol), t-BuXphos Pd G (39 mg, 0.05 mmol), and t-BuXPhos (47 mg, 0.11 mmol). The reaction mixture was stirred overnight at 95 °C under nitrogen protection. HO was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (40 mg, 95%). MS: M / e 387 (M+1) + .

[0169] Step I: 7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carbonitrile [ka]

[0170] A mixture of tert-butyl (2R,5S)-4-(2-cyano-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (40 mg, 0.1 mmol) in TFA (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was used directly in the next step without further purification. MS: M / e 287 (M+1) + .

[0171] Intermediate 2: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0172] Step A: Methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0173] To a solution of tert-butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (3.4 g, 7.7 mmol) in MeOH (40 mL) was added Pd(dppf)2Cl2 (365 mg, 0.5 mmol) and Et3N (2 g, 20 mmol). The reaction mixture was stirred at 90 °C under a CO atmosphere for 16 hours. The mixture was cooled to room temperature. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title compound (2 g, 59.8%). MS: M / e 420.2 (M+1) + .

[0174] Step B: tert-Butyl (2R,5S)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0175] A mixture of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (1.6 g, 3.8 mmol) in THF (10 mL) was cooled to 0 °C. To the mixture was added LiAlH (175 mg, 4.6 mmol). The resulting mixture was stirred at 0 °C for 30 minutes. To the mixture was added HO (0.2 ml), 15% NaOH solution (0.2 ml), and HO (0.6 ml). The mixture was filtered. The filtrate was concentrated under vacuum. The crude product was purified by column chromatography to give the title compound (1.2 g, 80%). MS: M / e 392.2 (M+1) + .

[0176] Step C: tert-Butyl (2R,5S)-2,5-dimethyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate [ka]

[0177] To a mixture of tert-butyl (2R,5S)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 3.8 mmol) in DCM (15 mL) was added methanesulfonyl chloride (877 mg, 7.7 mmol) and EtN (1.5 g, 15.2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated. The crude product was used directly in the next step. MS: M / e 470.2 (M+1) + .

[0178] Step D: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0179] To a mixture of tert-butyl (2R,5S)-2,5-dimethyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate from the last step in acetonitrile (20 mL) was added TMSCN (1.1 g, 11.4 mmol) and K2CO3 (2.6 g, 19 mmol). The reaction was stirred at 80 °C overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title compound (700 mg, 45.7% for two steps). MS: M / e 401.2 (M+1) + .

[0180] Intermediate 3: 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0181] Step A: tert-Butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0182] To a mixture of 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.03 g, 19 mmol) in THF (50 mL) was added tert-butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate (5.6 g, 24.7 mmol) and DIPEA (4.9 g, 38 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography to give the title compound (7.8 g, 89.6%). MS: M / e 458 (M+1) + .

[0183] Step B: tert-Butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0184] To a mixture of 2-(methylsulfonyl)ethan-1-ol (3.6 g, 29 mmol) in THF (80 mL) was added NaH (60% in oil, 1.71 g, 42.75 mmol). The reaction was stirred at room temperature for 0.5 h. To the mixture was added tert-butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (7.8 g, 17.1 mmol), and the reaction was stirred at 70 °C overnight. The mixture was added to NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (7.83 g, 100%). MS: M / e 440 (M+1) + .

[0185] Step C: tert-Butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0186] To a mixture of tert-butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (7.83 g, 17.8 mmol) in 1,4-dioxane (80 mL) was added trimethyl phosphate (12.5 g, 89 mmol) and K2CO3 (4.95 g, 35.6 mmol). The reaction mixture was sealed and stirred at 95 °C for 4 h. H2O was added to the mixture and filtered. The residue was dissolved in EA and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (7 g, 87.5%). MS: M / e 454 (M+1) + .

[0187] Step D: Methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0188] To a solution of tert-butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (7 g, 15.5 mmol) in MeOH (200 mL) was added Pd(dppf)2Cl2 (543 mg, 0.78 mmol) and Et3N (3.13 g, 31 mmol). The reaction mixture was stirred at 90 °C under a CO atmosphere for 16 hours. The mixture was cooled to room temperature. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (4.6 g, 68.6%). MS: M / e 434 (M+1) + .

[0189] Step E: tert-Butyl (2R,5S)-2-ethyl-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-5-methylpiperazine-1-carboxylate [ka]

[0190] A mixture of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (4.6 g, 10.1 mmol) in THF (25 mL) was cooled to 0 °C. LiAlH (304 mg, 8 mmol) was slowly added to the mixture and stirred at 0 °C for 30 min. HO (0.3 mL), 15% NaOH solution (0.3 mL), and HO (0.9 mL) were added to the mixture. The mixture was filtered. The filtrate was concentrated under vacuum. The crude product was purified by column chromatography to give the title product (3.5 g, 87.5%). MS: M / e 406 (M+1)+.

[0191] Step F: tert-Butyl (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate [ka]

[0192] To a mixture of tert-butyl (2R,5S)-2-ethyl-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-5-methylpiperazine-1-carboxylate (3.5 g, 9.2 mmol) in DCM (50 mL) at 0 °C, EtN (1.4 g, 13.8 mmol) and methanesulfonyl chloride (1.26 g, 11 mmol) were added. The resulting mixture was stirred at room temperature for 5 minutes. The mixture was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated to give the crude title compound, which was used directly in the next step. MS: M / e 484 (M+1) + .

[0193] Step G: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0194] To a mixture of tert-butyl (2R,5S)-2-ethyl-5-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate from the last step in MeCN (50 mL) was added TMSCN (4.5 g, 46 mmol) and CsCO (6 g, 18.4 mmol). The reaction was stirred at 80 °C for 2 h. The mixture was concentrated in vacuo. The residue was added to water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography to give the title compound (1.9 g, 50% for two steps). MS: M / e 415 (M+1) + .

[0195] Step H: 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0196] To a mixture of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (1.9 g, 4.6 mmol) in DCM (20 ml) was added TFA (2 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated to give the title product (1.5 g, 100%). MS: M / e 315 (M+1) + .

[0197] Intermediate 4: 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0198] Step A: tert-Butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0199] A solution of 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5 g, 0.019 mol), tert-butyl (2R,5S)-2,5-diethylpiperazine-1-carboxylate (5.93 g, 0.025 mol), and DIPEA (4.87 g, 0.038 mol) in THF (50 ml) was stirred at 80 °C overnight. The solution was diluted with EA (70 ml), washed with brine (40 ml), dried, and evaporated. The residue was purified by flash column chromatography using 0-15% EA in PE to give the title compound (8.4 g, 94%). MS: M / e 472,474 (M+1). + .

[0200] Step B: tert-Butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0201] To a solution of 2-(methylsulfonyl)ethan-1-ol (1.43 g, 0.012 mol) in THF (20 ml), NaH (0.68 g, 60%, 0.017 mol) was added and stirred at room temperature for 10 min. To the above solution, tert-butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate (3.2 g, 6.79 mmol) in THF (15 ml) was added and stirred at 70 °C for 6 h. The reaction was quenched with HO (30 ml) and then extracted with EA (30 ml × 2). The organic layer was washed with brine (10 ml), dried, and evaporated. The residue was purified by flash column chromatography using 40-80% EA in PE to give the title compound (2.4 g, 79%). (Another batch of the title compound (1.8 g, 22%) was obtained using the same procedure as above, giving a total of 4.2 g of the title compound.) MS: M / e 454,456 (M+1) + .

[0202] Step C: tert-Butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0203] A solution of tert-butyl (2R,5S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate (3 g, 6.62 mmol), trimethyl phosphate (4.64 g, 33.14 mmol), and K2CO3 (1.83 g, 13.26 mmol) in dioxane (30 ml) was stirred at 95 °C for 4 h. The reaction was concentrated. The residue was diluted with EA (50 ml), washed with brine (20 ml × 2), dried, and evaporated. The residue was purified by flash column chromatography using 0 to 20% EA in PE to give the title compound (2.6 g, 82%). (Another batch of the title compound (1.0 g, 78%) was obtained using the same procedure as above, giving a total of 3.6 g of the title compound.) MS: M / e 468,470 (M+1) + .

[0204] Step D: Methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0205] A solution of tert-butyl (2R,5S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate (3.6 g, 7.7 mmol), Pd(dppf)Cl2 (0.56 g, 0.77 mmol), and TEA (2.3 g, 23.2 mmol) in MeOH (40 mL) was stirred overnight at 90 °C under a CO atmosphere (2.7 MPa). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using 30-50% EA in PE to give the title compound (2.4 g, 71%). MS: M / e 448 (M+1). + .

[0206] Step E: tert-Butyl (2R,5S)-2,5-diethyl-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate [ka]

[0207] A mixture of methyl 7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (2.2 g, 5 mmol) and LiAlH (0.23 g, 6 mmol) in THF (25 ml) was stirred at 0° C. for 1 h. The reaction was quenched with HO (25 ml) and then extracted with EA (20 ml × 2). The organic layer was dried and evaporated. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound (1.4 g, 67%). MS: M / e 420 (M+1) + .

[0208] Step F: tert-Butyl (2R,5S)-2,5-diethyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate [ka]

[0209] To a solution of tert-butyl (2R,5S)-2,5-diethyl-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.2 g, 2.86 mmol) and TEA (0.87 g, 8.61 mmol) in DCM (15 ml) at 0° C., MsCl (0.41 g, 3.57 mmol) was added and stirred at 0° C. for 30 min. The solution was washed with brine (10 ml×2), dried, and evaporated to dryness to give the title compound (1.4 g, 100%), which was used directly in the next step. MS: M / e 498 (M+1) + .

[0210] Step G: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0211] A mixture of tert-butyl (2R,5S)-2,5-diethyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.4 g, 2.9 mmol), TMSCN (0.85 g, 8.6 mmol), and K2CO3 (1.18 g, 8.55 mmol) in MeCN (15 ml) was stirred at 70 °C for 3.5 h. The solution was poured into water (30 ml) and then extracted with EA (20 ml × 2). The organic layer was washed with brine (10 ml), dried, and evaporated. The residue was purified by flash column chromatography using 40-60% EA in PE to give the title compound (530 mg, 43%). MS: M / e 429 (M+1). + .

[0212] Step H: 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0213] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-diethylpiperazine-1-carboxylate (530 mg, 1.24 mmol) and TFA (2 ml) in DCM (15 ml) was stirred at room temperature for 2 hours. The reaction was washed with aqueous NaHCO (15 ml x 2) and brine (10 ml), dried over NaSO, and then evaporated to dryness to give the title compound (400 mg, 98%), which was used directly in the next step without further purification. MS: M / e 329 (M+1). + .

[0214] Intermediate 5: 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0215] Step A: Ethyl 5-(3-(methoxycarbonyl)ureido)-1H-pyrazole-3-carboxylate [ka]

[0216] A solution of methyl carbamate (2.5 g, 33.33 mmol), oxalyl dichloride (4.66 g, 36.69 mmol), and HCl (4 M in dioxane, 11.67 ml, 46.68 mmol) in toluene (10 mL) was stirred at 120° C. overnight. To the above solution, ethyl 5-amino-1H-pyrazole-3-carboxylate (5.17 g, 33.35 mmol) and DMF (20 mL) were added and stirred at room temperature overnight. The solution was poured into HO (100 mL) and then filtered. The filter cake was dried to give the title compound (7.8 g, 91%). MS: M / e 257 (M+1) + .

[0217] Step B: Ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0218] A solution of ethyl 5-(3-(methoxycarbonyl)ureido)-1H-pyrazole-3-carboxylate (7.8 g, 30.47 mmol) and sodium ethoxide (21%, 19.7 g, 60.84 mmol) in EtOH (100 mL) was stirred at 80° C. for 40 min. The solution was cooled to room temperature and filtered. The filter cake was dissolved in HO (50 mL), adjusted to pH=2, and then filtered. The filtrate was evaporated to dryness to give the title compound (4.7 g, 68%). MS: M / e 225 (M+1) + .

[0219] Step C: Ethyl 2,4-dichloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0220] A solution of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (4.7 g, 20.98 mmol) and DIPEA (5.4 g, 41.86 mmol) in POCl (30 mL) was stirred for 4.5 h at 100° C. The solution was evaporated to dryness to give the title compound (5.46 g, 100%, crude), which was used directly in the next step.

[0221] Step D: Ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-chloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0222] A solution of ethyl 2,4-dichloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (5.46 g, crude), tert-butyl (2R,5S)-2,5-diethylpiperazine-1-carboxylate (5.1 g, 21.07 mmol), and DIEA (13.5 g, 104.65 mmol) in THF (50 mL) was stirred at room temperature overnight. The solution was diluted with EtOAc (100 mL), washed with brine (30 mL x 2), dried, and concentrated. The residue was purified by flash elution with 0-20% EA in PE to give the title compound (1.4 g). MS: M / e 467 (M+1). + .

[0223] Step E: 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid [ka]

[0224] A solution of 2-(methylsulfonyl)ethan-1-ol (480 mg, 3.87 mmol) and NaH (60%, 290 mg, 7.25 mmol) in THF (15 mL) was stirred at room temperature for 30 minutes. To the above solution was added ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-chloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (1.4 g, 3.00 mmol) in THF (5 mL) and stirred at 70 °C overnight. The solution was quenched with HO (10 mL) and then evaporated to dryness to give the product (1.26 g, crude), which was used directly in the next step without further purification. M / e 421 (M+1) + .

[0225] Step F: tert-Butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate [ka]

[0226] A solution of 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid (1.26 g, crude) and CDI (0.61 g, 3.77 mmol) in THF (10 mL) was stirred at room temperature overnight. The above solution was added to a stirred solution of NaBH (0.34 g, 8.95 mmol) in THF (5 mL) and HO (5 mL) at 0 °C and stirred at room temperature overnight. The solution was diluted with EA (20 mL), washed with brine (10 mL × 2), dried, and evaporated. The residue was purified by flash with 0-10% MeOH in DCM to give the title compound (0.4 g). M / e 407 (M+1) + .

[0227] Step G: tert-Butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate [ka]

[0228] A solution of tert-butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate (400 mg, 0.99 mmol) and HMDS (206 mg, 1.28 mmol) in CHCN (10 mL) was stirred at 80 °C for 30 min. Chloro(chloromethyl)dimethylsilane (183 mg, 1.28 mmol) was added to the above solution and stirred at 80 °C for 3 h. The solution was evaporated to dryness and then added to a solution of KF (286 mg, 4.93 mmol) in DMSO (6 mL) and HO (1 mL) and stirred at 100 °C for 1 h. The solution was poured into HO (10 mL) and then extracted with EA (10 mL × 2). The organic layer was washed with brine (10 mL), dried and evaporated. The residue was purified by flash with 0-10% MeOH in DCM to give the title compound (400 mg, 96%). M / e 421 (M+1) + .

[0229] Step H: tert-Butyl (2R,5S)-2,5-diethyl-4-(1-methyl-7-(((methylsulfonyl)oxy)methyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate [ka]

[0230] A solution of tert-butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate (400 mg, 0.95 mmol), MsCl (140 mg, 1.22 mmol) and TEA (290 mg, 2.87 mmol) in DCM (10 mL) was stirred at 0° C. for 30 min. The solution was evaporated to dryness to give the title compound (474 ​​mg, 100%, crude), which was used directly in the next step. M / e 499 (M+1) + .

[0231] Step I: tert-Butyl (2R,5S)-4-(7-(cyanomethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,5-diethylpiperazine-1-carboxylate [ka]

[0232] A solution of tert-butyl (2R,5S)-2,5-diethyl-4-(1-methyl-7-(((methylsulfonyl)oxy)methyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate (474 ​​mg, crude), TMSCN (189 mg, 1.91 mmol), and TBAF (1 M, 1.9 mL, 1.9 mmol) in DCM (10 mL) was stirred at room temperature overnight. The solution was washed with brine (10 mL), dried, and evaporated. The residue was purified by flash with 0-5% MeOH in DCM to give the title compound (230 mg). M / e 430 (M+1) + .

[0233] Step J: 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0234] A solution of tert-butyl (2R,5S)-4-(7-(cyanomethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-2,5-diethylpiperazine-1-carboxylate (230 mg, 0.54 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 3 hours. The solution was evaporated to dryness to give the title compound (170 mg, 100%). M / e 330 (M+1) + .

[0235] The intermediate tert-butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate can also be synthesized by the following procedure. [ka]

[0236] Step A: Ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0237] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-chloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (13 g, 0.028 mol), Pd(dba) (1.28 g, 1.40 mmol), tBuXPhos (1.19 g, 2.8 mmol), and KCO (11.55 g, 0.084 mol) in dioxane (150 ml) and HO (30 ml) was stirred at 60 °C overnight. The reaction solution was poured into water (300 ml) and then extracted with EA (100 ml × 3). The organic layer was washed with brine (50 ml), dried, and concentrated. The resulting residue was purified by flash column chromatography using 30-100% EA in PE to give the title product (11 g, 88%). MS: M / e 449 (M+1) + .

[0238] Step B: Ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0239] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (11 g, 0.025 mol) and HMDS (5.14 g, 0.032 mol) in MeCN (110 ml) was stirred at 80°C for 30 minutes. Chloro(chloromethyl)dimethylsilane (4.56 g, 0.032 mol) was added to the above solution and stirred at 80°C for 3 hours. The reaction solution was evaporated to dryness. A solution of the resulting residue and KF (7.12 g, 0.12 mol) in DMSO (60 ml) and HO (15 ml) was stirred at 100°C for 30 minutes. The reaction solution was poured into water (100 ml) and then extracted with EA (30 ml x 3). The organic layer was washed with brine (30 ml), dried, and concentrated. The residue was purified by flash column chromatography using 25-40% EA in PE to give the title product (10 g, 88%). MS: M / e 463 (M+1) + .

[0240] Step C: 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid [ka]

[0241] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (10 g, 0.022 mol) and LiOH (2.1 g, 0.088 mol) in THF (100 ml) and HO (30 ml) was stirred at 0° C. for 40 min. The reaction solution was diluted with HO (150 ml) and adjusted to pH=4, followed by extraction with EA (30 ml×2). The organic layer was dried over NaSO, filtered, and evaporated to dryness to give the title product (9.4 g, 100%). MS: M / e 435 (M+1) + .

[0242] Step D: tert-Butyl (2R,5S)-2,5-diethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate [ka]

[0243] A solution of 4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid (9.4 g, 0.022 mol) and CDI (5.26 g, 0.032 mol) in THF (100 ml) was stirred at room temperature overnight. The solution was added to a pre-stirred solution of NaBH (2.47 g, 0.065 mol) in THF (30 ml) and HO (30 ml) at 0 °C for 10 min, followed by stirring at 0 °C for 30 min. The resulting solution was poured into water (100 ml) and then extracted with EA (30 ml × 3). The organic layer was dried and concentrated. The residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title product (9 g, 98%). MS: M / e 421 (M+1) + .

[0244] Intermediate 6: 2-(4-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0245] Step A: Ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-2-hydroxypyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0246] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-2-chloropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (7 g, 15.5 mmol), Pd(dba) (710 mg, 0.78 mmol), tBuXPhos (659 mg, 1.55 mmol), and KCO (6.4 g, 46.5 mmol) in dioxane (70 mL) and HO (18 mL) was stirred at 60 °C overnight. The reaction solution was poured into water (100 mL) and then extracted with EA (50 mL × 2). The aqueous layer was adjusted to pH 4-5 with HCl (1 N) and extracted with EA (50 mL × 2). The organic layer was washed with brine (50 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound (3.7 g, 54.8%). MS: M / e 435 (M+1) + .

[0247] Step B: Ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate [ka]

[0248] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-2-hydroxypyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (3.7 g, 8.5 mmol) and HMDS (1.8 g, 11.1 mmol) in MeCN (25 mL) was stirred at 80°C for 1 h. Chloro(chloromethyl)dimethylsilane (1.6 g, 11.1 mmol) was added to the above solution and stirred at 80°C for 4 h. The reaction solution was evaporated to dryness. To the resulting residue was added KF (2.5 g, 42.5 mmol) in DMSO (15 mL) and HO (15 mL) and stirred at 100°C for 1 h. The reaction solution was poured into water (100 mL) and then extracted with EA (30 mL × 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound (3.2 g, 83.5%). MS: M / e 449 (M+1) + .

[0249] Step C: 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid [ka]

[0250] A solution of ethyl 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylate (3.2 g, 0.007 mol) and LiOH (686 mg, 28.58 mmol) in THF (30 mL) and HO (8 mL) was stirred at room temperature for 1 h. The reaction solution was diluted with HO (50 mL), adjusted to pH = 2-3, and then extracted with EA (30 mL × 2). The organic layer was dried over NaSO, filtered, and evaporated to dryness to give the title compound (3 g, crude). MS: M / e 421 (M+1). + .

[0251] Step D: tert-Butyl (2R,5S)-2-ethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-5-methylpiperazine-1-carboxylate [ka]

[0252] A solution of 4-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazine-7-carboxylic acid (3 g, 7.14 mmol) and CDI (1.62 g, 10 mmol) in THF (15 mL) was stirred at room temperature for 2 h. The solution was added to a pre-stirred solution of NaBH (814 mg, 21.42 mmol) in THF (7 mL) and HO (7 mL) at 0 °C, followed by stirring at 0 °C for 1 h. The resulting solution was poured into water (50 mL) and then extracted with EA (20 mL × 3). The organic layer was dried and concentrated. The residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound (1.4 g, 48%). MS: M / e 407 (M+1) + .

[0253] Step E: tert-Butyl (2R,5S)-2-ethyl-5-methyl-4-(1-methyl-7-(((methylsulfonyl)oxy)methyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate [ka]

[0254] A solution of tert-butyl (2R,5S)-2-ethyl-4-(7-(hydroxymethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-5-methylpiperazine-1-carboxylate (1.4 g, 3.45 mmol), MsO (660 mg, 3.79 mmol), and TEA (523 mg, 5.18 mmol) in DCM (20 mL) was stirred at 0° C. for 45 min. The reaction solution was washed with aqueous NaHCO (30 mL) and brine (30 mL), dried over NaSO, filtered, and used directly in the next step. MS: M / e 485 (M+1). + .

[0255] Step F: tert-Butyl (2R,5S)-4-(7-(cyanomethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0256] A solution of tert-butyl (2R,5S)-2-ethyl-5-methyl-4-(1-methyl-7-(((methylsulfonyl)oxy)methyl)-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)piperazine-1-carboxylate (1.67 g, 3.45 mmol), TMSCN (683 mg, 6.9 mmol), and TBAF (1 M in THF, 6.9 mL, 6.9 mmol) in DCM (20 mL) was stirred at room temperature for 1 h. The solution was washed with brine (30 mL x 2), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-10% MeOH in DCM to give the title compound (1 g, 69.9%). MS: M / e 416 (M+1). + .

[0257] Step G: 2-(4-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0258] A solution of tert-butyl (2R,5S)-4-(7-(cyanomethyl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-4-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (1 g, 2.41 mmol) and TMSOTf (642 mg, 2.89 mmol) in DCM (10 mL) was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with aqueous NaHCO (30 mL) and brine (30 mL), dried over NaSO, filtered, and evaporated to dryness to give the title product (610 mg, 80%), which was used directly in the next step without further purification. MS: M / e 316 (M+1) + .

[0259] Compound A1: 7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carbonitrile [ka]

[0260] To a solution of 7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carbonitrile in acetonitrile (5 mL) was added (cyanomethyl)trimethylphosphonium iodide (46 mg, 0.2 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (17.4 mg, 0.2 mmol), and DIPEA (129 mg, 1 mmol). The reaction mixture was sealed and stirred overnight at 105° C. under nitrogen protection. HO was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (6 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.87 (t, J = 4.9 Hz, 2H), 8.13 - 8.00 (m, 3H), 6.62 (d, J = 3.6 Hz, 1H), 5.49 (d, J = 20.0 Hz, 1H), 4.52-4.54(m, 0.5H), 4.04 (d, J = 6.3 Hz, 0.5H), 3.91 (d, J = 6.6 Hz, 0.5H), 3.80 (d, J = 12.2 Hz, 0.5H), 3.69 (s, 1H), 3.64 - 3.55 (m, 1H), 3.48 (s, 3H), 3.23 - 3.17 (m, 0.5H), 2.96 (m, 0.5H), 2.91 (d, J = 10.4 Hz, 1H), 2.20 (d, J = 10.6 Hz, 1H), 1.50 - 1.38 (m, 4.5H), 1.26 (d, J = 6.4 Hz, 1.5H), 1.19 (d, J = 6.6 Hz, 1.5H), 1.11 (d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 443 (M+1) + .

[0261] Compound A2: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0262] To a solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile from the last step in CHCN (5 mL) was added (cyanomethyl)trimethylphosphonium iodide (46 mg, 0.2 mmol), 1-(quinoxalin-6-yl)ethan-1-ol (17.4 mg, 0.2 mmol), and DIPEA (129 mg, 1 mmol). The reaction mixture was sealed and stirred overnight at 105 °C under nitrogen protection. HO was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The resulting crude product was purified by column chromatography to give the title compound A2 (6 mg, 21% for two steps). Another batch of compound A2 (30 mg) was separated into compound A2a (14 mg) and compound A2b (10 mg) by chiral preparative HPLC. The chiral separation conditions are shown below. [Table 5]

[0263] Compound A2: 1 HNMR (400 MHz, CD3OD) δ 8.87 (s, 2H), 8.06 (d, J = 14.0 Hz, 3H), 6.10 (s, 1H), 5.30 (d, J = 14.0 Hz, 1H), 4.62 (s, 0.5H), 4.02 (s, 0.5H), 3.98 (s, 2H), 3.85 (d, J = 23.1 Hz, 1H), 3.73 (d, J = 37.2 Hz, 1H), 3.54 (s, 1H), 3.46 (s, 3H), 3.17 (d, J = 12.3 Hz, 1H), 2.91 (t, J = 15.3 Hz, 2H), 1.44 (d, J = 8.0 Hz, 4H), 1.27 (s, 2H), 1.16 (d, J = 30.5 Hz, 3H) ppm. MS: M / e 457 (M+1) + .

[0264] Compound A2a (earlier peak):1 HNMR (400 MHz, CD3OD) δ 8.92 - 8.81 (m, 2H), 8.08 (d, J = 8.8 Hz, 2H), 8.04 (s, 1H), 6.10 (s, 1H), 5.32 (s, 1H), 4.62 (s, 1H), 3.98 (s, 2H), 3.88 (dd, J = 13.3, 6.8 Hz, 1H), 3.86 - 3.73 (m, 2H), 3.67 (dd, J = 13.1, 10.1 Hz, 1H), 3.46 (s, 3H), 2.94 (dd, J = 12.0, 3.7 Hz, 1H), 2.16-2.21 (m, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.27 (m, 3H), 1.20 (d, J = 6.6 Hz, 3H) ppm. MS: M / e 457 (M+1) + .

[0265] Compound A2b (slower peak): 1 HNMR (400 MHz, CD3OD) δ 8.87 (d, J = 4.3 Hz, 2H), 8.15 - 8.07 (m, 2H), 8.04 (d, J = 8.7 Hz, 1H), 6.11 (s, 1H), 5.28 (s, 1H), 5.02 - 4.86 (m, 1H), 4.02 (d, J = 6.5 Hz, 1H), 3.99 (s, 2H), 3.54 (d, J = 2.0 Hz, 2H), 3.46 (s, 3H), 3.17 (dd, J = 11.8, 3.6 Hz, 1H), 2.89 (d, J = 9.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 6H), 1.12 (d, J = 6.5 Hz, 3H) ppm. MS: M / e 457 (M+1) + .

[0266] Compound A3: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0267] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile from the last step in acetonitrile (8 mL) was added trimethyl(prop-2-yn-1-yl)phosphonium (800 mg, 3.32 mmol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (624 mg, 3.32 mmol), and DIPEA (1.29 g, 10 mmol). The reaction mixture was sealed and stirred overnight at 105 °C under nitrogen protection. The mixture was added HO and extracted with ethyl acetate. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by column chromatography to give the title compound A3, which was separated into compound A3a (85 mg) and compound A3b (105 mg) by preparative HPLC (Method B).

[0268] Compound A3: 11H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 5.4 Hz, 1H), 8.08 - 7.90 (m, 3H), 6.10 (d, J = 1.8 Hz, 1H), 5.30 (d, J = 13.3 Hz, 1H), 4.59 (d, J = 18.2 Hz, 1H), 4.04 - 3.94 (m, 2H), 3.87 - 3.80 (m, 1H), 3.76 (dd, J = 12.2, 3.2 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.46 (s, 3H), 3.17 (dd, J = 11.8, 3.7 Hz, 1H), 2.91 (ddd, J = 11.9, 10.7, 4.7 Hz, 2H), 2.76 (d, J = 2.7 Hz, 3H), 1.43 (dd, J = 7.3, 2.6 Hz, 3H), 1.30 - 1.25 (m, 3H), 1.20 (d, J = 6.6 Hz, 1.5H), 1.11 (d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 471 (M+1) + .

[0269] Compound A3a (earlier peak): 1 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 6.10 (s, 1H), 5.28 (s, 1H), 4.91 (s, 1H), 3.99 (d, J = 5.1 Hz, 3H), 3.54 (s, 2H), 3.45 (s, 3H), 3.16 (d, J = 11.4 Hz, 1H), 2.88 (d, J = 10.9 Hz, 2H), 2.77 (s, 3H), 1.46 - 1.39 (m, 6H), 1.11 (d, J = 6.4 Hz, 3H). MS: M / e 471 (M+1) + .

[0270] Compound A3b (later peak): 1HNMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 6.10 (s, 1H), 5.32 (s, 1H), 4.61 (s, 1H), 3.98 (s, 2H), 3.88 - 3.80 (m, 2H), 3.75 (d, J = 12.2 Hz, 1H), 3.66 (s, 1H), 3.46 (s, 3H), 2.97 - 2.89 (m, 1H), 2.76 (s, 3H), 2.17 (d, J = 12.0 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.29 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H). MS: M / e 471.2 (M+1) + .

[0271] Compound A4: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0272] Step A: tert-Butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0273] A mixture of tert-butyl (2R,5S)-2-ethyl-5-methylpiperazine-1-carboxylate (640 mg, 2.8 mmol), 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.9 mmol), and DIPEA (486 mg, 3.8 mmol) in THF (10 mL) was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The resulting crude product was purified by silica column chromatography (PE: EtOAc = 50:1) to give the title compound (350 mg, 41%). MS: M / e 458 (M+1). + .

[0274] Step B: tert-Butyl (2R,5S)-4-(2-bromo-5-(tert-butoxy)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0275] A mixture of tert-butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (350 mg, 0.77 mmol), t-BuOK (170 mg, 1.54 mmol), and 18-crown-6 (25 mg, 0.1 mmol) in toluene (5 mL) was stirred at 60° C. for 30 minutes under microwave irradiation. The solvent was removed in vacuo. The resulting crude product was purified by silica column chromatography (PE: EtOAc = 50:1) to give the title compound (300 mg, 79%). MS: M / e 496 (M+1). + .

[0276] Step C: Methyl 5-(tert-butoxy)-7-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0277] A mixture of tert-butyl (2R,5S)-4-(2-bromo-5-(tert-butoxy)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (300 mg, 0.61 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), and TEA (310 mg, 3.1 mmol) in MeOH (10 mL) was heated to 90 °C overnight under a CO atmosphere in an autoclave. The solvent was removed under vacuum. The resulting crude product was purified by silica column chromatography (PE: EtOAc = 20:1) to give the desired compound (240 mg, 83% yield) as a yellow oil. MS: M / e 476 (M+1). + .

[0278] Step D: tert-Butyl (2R,5S)-4-(5-(tert-butoxy)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0279] To a solution of methyl 5-(tert-butoxy)-7-((2S,5R)-4-(tert-butoxycarbonyl)-5-ethyl-2-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (220 mg, 0.46 mmol) in THF (10 mL) was added LiAlH solution (0.5 mL, 0.5 mmol, 1 M in THF) at 0 °C. The resulting mixture was stirred at room temperature for an additional 30 min. The reaction was quenched with HO (5 mL) and extracted with EtOAc (50 mL × 3). The organic layer was concentrated to give the crude product, which was further purified by silica column chromatography (PE: EtOAc = 10:1) to give the title compound (170 mg, 82%). MS: M / e 448 (M+1) + .

[0280] Step E: tert-Butyl (2R,5S)-4-(5-(tert-butoxy)-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0281] To a solution of tert-butyl (2R,5S)-4-(5-(tert-butoxy)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (130 mg, 0.29 mmol) and DIPEA (120 mg, 0.6 mmol) in DCM (5 mL) was added MsCl (35 mg, 0.3 mmol) at 0° C. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with HO (5 mL) and extracted with DCM (10 mL × 2). The organic layer was concentrated to give the title compound (130 mg), which was used directly in the next step without further purification. MS: M / e 526 (M+1) + .

[0282] Step F: tert-Butyl (2R,5S)-4-(5-(tert-butoxy)-2-(cyanomethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate [ka]

[0283] To a solution of tert-butyl (2R,5S)-4-(5-(tert-butoxy)-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (130 mg) and TMSCN (90 mg, 0.9 mmol) in DCM (5 mL) was added a TBAF THF solution (0.9 mL, 0.9 mmol, 1 M) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with HO (5 mL) and extracted with DCM (10 mL × 2). The organic layer was concentrated and purified by preparative TLC (PE:EtOAc = 1:1) to give the title compound (60 mg, 49% yield for two steps). MS: M / e 457 (M+1). + .

[0284] Step G: 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0285] To a solution of tert-butyl (2R,5S)-4-(5-(tert-butoxy)-2-(cyanomethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2-ethyl-5-methylpiperazine-1-carboxylate (60 mg, 0.13 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with NH3MeOH solution and adjusted to pH=8. The solvent was concentrated and purified by preparative TLC to give the title compound (50 mg, crude). MS: M / e 301 (M+1) +

[0286] Step H: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0287] A mixture of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (40 mg, 0.13 mmol), 6-(1-chloroethyl)quinoxaline (128 mg, 0.65 mmol), and DIPEA (166 mg, 1.3 mmol) in DMSO (5 mL) was heated to 100° C. overnight. The reaction was diluted with EtOAc (20 mL) and washed with brine (10 mL×2). The organic layer was concentrated and purified by preparative TLC (DCM:MeOH=5:1) to give the title compound A4, which was further purified by preparative HPLC (Method A) to give compound A4a (0.54 mg) and compound A4b (0.63 mg).

[0288] Compound A4a (earlier peak): 1 HNMR (400 MHz, CD3OD) δ 8.88 - 8.87 (m, 2H), 8.13 - 8.02 (m, 3H), 5.93 (s, 1H), 5.22 (s, 1H), 4.11 (d, J = 6.7 Hz, 1H), 3.94 (s, 2H), 3.83 - 3.81 (m, 1H), 3.44 - 3.42 (m, 1H), 3.13 - 3.12 (m, 1H), 2.94 - 2.92 (m, 1H), 2.45 - 2.44 (m, 1H), 2.03 - 2.01 (m 1H), 1.82 - 1.81 (m, 1H), 1.63 - 1.61 (m, 1H), 1.46 - 1.44 (m, 6H), 0.65 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 457 (M+1) + .

[0289] Compound A4b (slower peak): 1HNMR (400 MHz, CD3OD) δ 8.87 - 8.86 (m, 2H), 8.09 - 8.02 (m, 3H), 5.93 (s, 1H), 5.26 (s, 1H), 4.64 - 4.63 (m, 1H), 4.15 - 4.12 (m, 1H), 3.96 - 3.92 (m, 3H), 3.67 - 3.64 (m, 1H), 2.91 - 2.90 (m, 1H), 2.21 - 2.17 (m, 1H), 2.05 - 1.94 (m, 2H), 1.64 - 1.63 (m, 1H), 1.44 (d, J = 6.5 Hz, 3H), 1.20 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 457 (M+1) + .

[0290] Compound A5: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0291] Step A: tert-Butyl (2R,5S)-4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0292] A solution of phenylmethanol (0.88 g, 8.15 mmol) and NaH (60%, 0.41 g, 10.25 mmol) in THF (20 mL) was stirred at room temperature for 30 minutes. To the above solution, a solution of tert-butyl (2R,5S)-4-(2-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (3 g, 6.77 mmol) in THF (10 mL) was added and stirred at 70 °C for 1 hour. The solution was quenched with HO (30 mL) and then extracted with EA (20 mL × 2). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-30% EA in PE to give the title compound (3.4 g, 97%). MS: M / e 516,518 (M+1). + .

[0293] Step B: Methyl 5-(benzyloxy)-7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0294] A solution of tert-butyl (2R,5S)-4-(5-(benzyloxy)-2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 2.91 mmol), Pd(dppf)Cl2 (0.21 g, 0.29 mmol), and TEA (0.88 g, 8.71 mmol) in MeOH was stirred at 90 °C under CO (2.7 MPa) overnight. The reaction was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound (1.4 g, 97%). MS: M / e 496 (M+1). + .

[0295] Step C: tert-Butyl (2R,5S)-4-(5-(benzyloxy)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0296] A solution of methyl 5-(benzyloxy)-7-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.2 g, 2.42 mmol) and LiAlH (1 M in THF, 3.64 mL, 3.64 mmol) in THF (20 mL) was stirred at 0° C. for 30 min. The solution was quenched with HO (30 mL) and then extracted with EA (20 mL × 2). The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound (1.1 g, crude), which was used directly in the next step. MS: M / e 468 (M+1). + .

[0297] Step D: tert-Butyl (2R,5S)-4-(5-(benzyloxy)-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0298] A solution of tert-butyl (2R,5S)-4-(5-(benzyloxy)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (600 mg, 1.28 mmol), MsCl (185 mg, 1.61 mmol), and TEA (389 mg, 3.85 mmol) in DCM (15 ml) was stirred at 0° C. for 30 min. The solution was washed with aqueous NaHCO (10 ml) and brine (10 ml), dried over NaSO, and evaporated to give the title compound (700 mg, 100%).

[0299] Step E: tert-Butyl (2R,5S)-4-(5-(benzyloxy)-2-(cyanomethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0300] A solution of tert-butyl (2R,5S)-4-(5-(benzyloxy)-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (700 mg, 1.28 mmol), TMSCN (381 mg, 3.85 mmol), and K2CO3 (532 mg, 3.86 mmol) in MeCN (15 ml) was stirred at 80 °C for 1 h. The solution was poured into water (20 ml) and then extracted with EA (20 ml × 2). The organic layer was washed with brine (10 ml × 2), dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-30% EA in PE to give the title compound (350 mg, 57%). MS: M / e 477 (M+1). + .

[0301] Step F: 2-(5-(benzyloxy)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0302] A solution of tert-butyl (2R,5S)-4-(5-(benzyloxy)-2-(cyanomethyl)pyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (465 mg, 0.98 mmol) and TFA (2 ml) in DCM (15 ml) was stirred at room temperature for 2.5 hours. The solution was washed with aqueous NaHCO (10 ml) and brine (10 ml), dried over NaSO, and evaporated to give the title compound (360 mg, 98%). MS: M / e 377 (M+1). + .

[0303] Step G: 2-(5-(benzyloxy)-7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0304] A solution of 2-(5-(benzyloxy)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (360 mg, 0.96 mmol), 1-(3-methylquinoxalin-6-yl)ethan-1-ol (270 mg, 1.44 mmol), (cyanomethyl)trimethylphosphonium iodide (698 mg, 2.87 mmol), and DIPEA (1.24 g, 9.61 mmol) in CHCN (6 mL) was stirred at 100 °C for 2 days. The reaction was diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 10–50% EA in PE to give the title compound (400 mg, 77%). MS: M / e 547 (M+1) + .

[0305] Step H: 2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0306] A solution of 2-(5-(benzyloxy)-7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (70 mg, 0.13 mmol) in TFA (2 ml) was stirred at 70° C. overnight. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to give the title compound (3.4 mg). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.82 (d, J = 6.0 Hz, 1H), 8.03 (dd, J = 13.5, 8.6 Hz, 1H), 7.94 (d, J = 12.3 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 5.77 (d, J = 3.3 Hz, 1H), 5.09 (d, J = 16.4 Hz, 1H), 4.82 (s, 0.5H), 4.47 (s, 0.5H), 4.07 (d, J = 7.7 Hz, 2H), 3.94 (q, J = 6.5 Hz, 0.5H), 3.81 (q, J = 6.5 Hz, 0.5H), 3.68 (d, J = 10.8 Hz, 0.5H), 3.63-3.53 (m, 1H), 3.40-3.35 (m, 0.5H), 3.32-3.28 (m, 0.5H), 3.01 (d, J = 7.9 Hz, 0.5H), 2.78 (d, J = 11.4 Hz, 1.5H), 2.70 (d, J = 2.6 Hz, 3H), 2.06 (d, J = 12.2 Hz, 0.5H), 1.36 (t, J = 5.8 Hz, 3H), 1.28 (d, J = 6.7 Hz, 1.5H), 1.17 (d, J = 6.3 Hz, 1.5H), 1.08 (d, J = 6.5 Hz, 1.5H), 1.02 (d, J = 6.4 Hz, 1.5H) ppm. MS: M / e 457 (M+1) + .

[0307] Compound A6: 2-(7-((2S,5R)-4-(1-(3-(difluoromethyl)quinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0308] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (80 mg, 0.267 mmol), 1-(3-(difluoromethyl)quinoxalin-6-yl)ethan-1-ol (90 mg, 0.400 mmol), (cyanomethyl)trimethylphosphonium iodide (130 mg, 0.533 mmol), and DIPEA (103 mg, 0.801 mmol) in CHCN (1 mL) was prepared. The mixture was degassed three times under a N atmosphere. The mixture was then stirred at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH=15:1) and further purified by preparative HPLC (Method B) to give the title compound (25 mg, 19%). 1 H NMR (400 MHz, CD3OD) δ 9.13 (d, J = 4.9 Hz, 1H), 8.24-8.05 (m, 3H), 6.99 (td, J = 54.5, 4.1 Hz, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.30 (d, J = 14.0 Hz, 1H), 4.96-4.92 (m, 0.5H), 4.66-4.61 (m, 0.5H), 4.05 (q, J = 6.4 Hz, 0.5H), 3.98 (d, J = 6.0 Hz, 2H), 3.91 (q, J = 6.5 Hz, 0.5H), 3.87-3.73 (m, 1H), 3.72-3.64 (m, 0.5H), 3.58-3.49 (m, 1H), 3.46 (s, 3H), 3.18 (dd, J = 11.8, 3.5 Hz, 0.5H), 2.99-2.84 (m, 1.5H), 2.16 (d, J = 12.1 Hz, 0.5H), 1.52-1.37 (m, 4H), 1.28 (d, J = 6.5 Hz, 2H), 1.16 (dd, J = 28.1, 6.6 Hz, 3H) ppm. MS: M / e 507 (M+1) + .

[0309] Compound A7: 2-(7-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0310] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (350 mg, 1.167 mmol), 1-(3-methoxyquinoxalin-6-yl)ethan-1-ol (357 mg, 1.750 mmol), (cyanomethyl)trimethylphosphonium iodide (567 mg, 2.334 mmol), and DIPEA (452 ​​mg, 3.501 mmol) in CHCN (2 mL) was prepared. The mixture was degassed three times under a N atmosphere. The mixture was then stirred at 105 °C for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:MeOH=15:1) and further purified by preparative HPLC (Method B) to give the title compound (173 mg, 31%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 6.0 Hz, 1H), 7.95 (dd, J = 12.8, 8.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.5, 1.4 Hz, 1H), 6.10 (d, J = 1.4 Hz, 1H), 5.29 (d, J = 10.9 Hz, 1H), 4.90-4.86 (m, 0.5H), 4.62-4.56 (m, 0.5H), 4.10 (d, J = 5.6 Hz, 3H), 3.99 (d, J = 4.4Hz, 2H), 3.97-3.90 (m, 0.5H), 3.85-3.78 (m, 1H), 3.76-3.70 (m, 0.5H), 3.69-3.62 (m, 0.5H), 3.53 (d, J = 2.0 Hz, 1H), 3.45 (s, 3H), 3.14 (dd, J = 11.8, 3.5 Hz, 0.5H), 2.95-2.85 (m, 1.5H), 2.18 (d, J = 12.2 Hz, 0.5H), 1.42 (dd, J = 10.7, 6.6 Hz, 4H), 1.26 (d, J = 6.5 Hz, 2H), 1.19 (d, J = 6.6 Hz, 2H), 1.10 (d, J = 6.5 Hz, 1H) ppm. MS: M / e 487 (M+1) + .

[0311] Compound A8: 2-(7-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0312] Step A: 2-(7-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0313] To a solution of 2-(7-((2S,5R)-4-(1-(3-methoxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (160 mg, 0.329 mmol) in DCM (5 mL) was added BBr3 (5 mL, 1 M, 4.938 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL), extracted with DCM (30 mL x 2), combined, washed with brine (50 mL x 2), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give the title compound (60 mg, 39%). MS: M / e 473 (M+1) + .

[0314] Step B: 2-(7-((2S,5R)-4-(1-(3-chloroquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0315] A solution of 2-(7-((2S,5R)-4-(1-(3-hydroxyquinoxalin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (60 mg, 0.127 mmol) in POCl (5 mL) was stirred at 80 °C for 2 h. The reaction mixture was poured into HO (30 mL), extracted with DCM (30 mL × 2), combined, washed with brine (50 mL × 2), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative TLC (DCM:MeOH = 15:1) and preparative HPLC (Method B) to give the title compound (2 mg, 3%). 1 H NMR (400 MHz, CD3OD) δ 8.83 (d, J = 4.3 Hz, 1H), 8.11 (dd, J = 11.6, 8.7 Hz, 1H), 8.05-7.95 (m, 2H), 7.78 (s, 1H), 5.62 (s, 1H), 4.76-4.63 (m, 1H), 4.00-3.95 (m, 0.5H), 3.93 (d, J = 2.3 Hz, 2H), 3.82 (q, J = 6.4 Hz, 0.5H), 3.74 (s, 3H), 3.68 (d, J = 9.6 Hz, 1.5H), 3.49-3.42 (m, 0.5H), 3.09 (dd, J = 11.9, 4.0 Hz, 0.5H), 2.95-2.66 (m, 2H), 2.20 (d, J = 12.4 Hz, 0.5H), 1.48-1.38 (m, 4H), 1.22 (dd, J = 12.2, 6.5 Hz, 4H), 1.06 (d, J = 6.5 Hz, 1H) ppm. MS: M / e 491(M+1) + .

[0316] Compound A9: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0317] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (143.5 mg, 0.48 mmol), 1-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)ethan-1-ol (100 mg, 0.48 mmol), (cyanomethyl)trimethylphosphonium iodide (349 mg, 1.44 mmol), and DIPEA (617 mg, 4.78 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography followed by preparative HPLC (Method A) to give the title compound (38 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.30 (dd, J = 8.0, 3.4 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.12 (d, J = 3.6 Hz, 1H), 5.26 (d, J = 6.4 Hz, 1H), 4.48 (s, 1H), 4.13 (d, J = 1.6 Hz, 2H), 3.94 (d, J = 7.0 Hz, 2H), 3.72 (q, J = 6.6 Hz, 0.5H), 3.55 (s, 1H), 3.51-3.37 (m, 2H), 3.34 (s, 3H), 3.14 (d, J = 8.6 Hz, 0.5H), 2.99 (d, J = 8.4 Hz, 0.5H), 2.80-2.70 (m, 1H), 2.10 (d, J = 9.8 Hz, 0.5H), 1.36-1.29 (m, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.17 (d, J = 6.4 Hz, 1.5H), 1.08 (dd, J = 11.1, 6.5 Hz, 3H), 1.01 (d, J = 6.4 Hz, 1.5H) ppm. MS: M / e 492 (M+1) + .

[0318] Compound A10: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0319] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (450 mg, 1.50 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (468 mg, 2.25 mmol), (cyanomethyl)trimethylphosphonium iodide (1.09 g, 4.49 mmol), and DIPEA (1.94 g, 15.04 mmol) in CHCN (8 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A10, which was further separated into compound A10a (56 mg) and compound A10b (61 mg) by preparative HPLC (Method A).

[0320] Compound A10a (earlier peak): 1 H NMR (400 MHz, DMSO-d6) δ 6.88-6.77 (m, 3H), 6.11 (s, 1H), 5.22 (s, 1H), 4.71 (s, 1H), 4.13 (s, 2H), 3.91 (s, 2H), 3.55 (q, J = 6.2 Hz, 1H), 3.39-3.34 (m, 1H), 3.33 (s, 3H), 3.25 (d, J = 11.2 Hz, 1H), 2.91 (dd, J = 11.8, 3.1 Hz, 1H), 2.82-2.73 (m, 1H), 2.64 (d, J = 9.8 Hz, 1H), 1.28 (s, 6H), 1.21 (t, J = 6.7 Hz, 6H), 0.95 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 491 (M+1) + .

[0321] Compound A10b (slower peak): 1H NMR (400 MHz, DMSO-d6) δ 6.82-6.77 (m, 3H), 6.10 (s, 1H), 5.23 (s, 1H), 4.48 (s, 1H), 4.12 (s, 2H), 3.89 (s, 2H), 3.62 (d, J = 12.2 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.46-3.39 (m, 2H), 3.33 (s, 3H), 2.65 (dd, J = 11.6, 3.2 Hz, 1H), 2.09 (d, J = 13.6 Hz, 1H), 1.26 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 6.4 Hz, 3H), 1.07 (t, J = 4.8 Hz, 6H) ppm. MS: M / e 491 (M+1) + .

[0322] Compound A11: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0323] Step A: tert-Butyl (2R,5S)-4-(2-(cyanomethyl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0324] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (700 mg, 1.75 mmol) and select F (774 mg, 2.19 mmol) in MeCN (10 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 35-55% EA in PE to give the title compound (230 mg, 31%). MS: M / e 419 (M+1). + .

[0325] Step B: 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0326] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (230 mg, 0.55 mmol) and TFA (2 ml) in DCM (10 ml) was stirred at room temperature for 30 minutes. The reaction mixture was washed with aqueous NaHCO (10 ml x 2) and brine (10 ml), dried over NaSO, and evaporated to dryness to give the title compound (175 mg, 100%). MS: M / e 319 (M+1). + .

[0327] Step C: 2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0328] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (175 mg, 0.55 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (229 mg, 1.10 mmol), (cyanomethyl)trimethylphosphonium iodide (401 mg, 1.65 mmol), and DIPEA (710 mg, 5.50 mmol) in CHCN (4 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A11, which was further separated by preparative HPLC (Method A) into compound A11a (32 mg) and compound A11b (26 mg).

[0329] Compound A11a (earlier peak): 1H NMR (400 MHz, DMSO-d6) δ 6.89-6.79 (m, 3H), 6.22 (s, 1H), 4.13 (s, 2H), 3.90 (s, 3H), 3.76-3.63 (m, 2H), 3.42 (s, 3H), 3.19 (s, 1H), 3.06 (d, J = 11.7 Hz, 1H), 2.63 (d, J = 8.4 Hz, 1H), 2.08 (dd, J = 10.1, 6.1 Hz, 1H), 1.27 (d, J = 4.0 Hz, 6H), 1.20 (d, J = 6.4 Hz, 3H), 1.03 (dd, J = 12.0, 6.3 Hz, 6H) ppm. MS: M / e 509 (M+1) + .

[0330] Compound A11b (slower peak): 1 H NMR (400 MHz, DMSO-d6) δ 6.87-6.82 (m, 1H), 6.80-6.75 (m, 2H), 6.22 (s, 1H), 4.13 (s, 2H), 4.01 (s, 1H), 3.91 (s, 2H), 3.81 (q, J = 6.9 Hz, 1H), 3.49 (d, J = 11.4 Hz, 1H), 3.41 (s, 3H), 3.02 (d, J = 8.6 Hz, 1H), 2.92-2.86 (m, 1H), 2.56 (s, 1H), 2.25-2.18 (m, 1H), 1.27 (d, J = 7.0 Hz, 9H), 1.12 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.3 Hz, 3H) ppm. MS: M / e 509 (M+1) + .

[0331] Compound A12: 2-(cyanomethyl)-7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka]

[0332] Step A: tert-Butyl (2R,5S)-4-(6-bromo-2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0333] A solution of tert-butyl (2R,5S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (700 mg, 1.75 mmol) and NBS (343 mg, 1.93 mmol) in MeCN (15 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20 ml) and then extracted with EA (10 ml x 2). The organic layer was washed with brine (10 ml), dried, and concentrated. The resulting residue was purified by flash column chromatography using 20-60% EA in PE to give the title compound (520 mg, 62%). MS: M / e 479,481 (M+1). + .

[0334] Step B: tert-Butyl (2R,5S)-4-(6-cyano-2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate [ka]

[0335] A solution of tert-butyl (2R,5S)-4-(6-bromo-2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (520 mg, 1.09 mmol), ZnCN (382 mg, 3.26 mmol), and Pd(PPh) (125.6 mg, 0.11 mmol) in DMF (10 ml) was stirred at 100 °C for 2 days. The reaction mixture was poured into water (20 ml) and then extracted with EA (10 ml × 2). The organic layer was washed with brine (10 ml), dried, and concentrated. The resulting residue was purified by flash column chromatography using 20-60% EA in PE to give the title compound (200 mg, crude). MS: M / e 426 (M+1). + .

[0336] Step C: 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka]

[0337] A solution of tert-butyl (2R,5S)-4-(6-cyano-2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, crude) and TFA (2 ml) in DCM (10 ml) was stirred at room temperature for 30 minutes. The reaction was extracted with HO (10 ml). The aqueous solution was adjusted to pH 8-9 and then extracted with DCM (10 ml x 2). The organic layer was dried over NaSO and then evaporated to dryness to give the title compound (130 mg). MS: M / e 326 (M+1) + .

[0338] Step D: 2-(cyanomethyl)-7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka]

[0339] A solution of 2-(cyanomethyl)-7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile (130 mg, 0.40 mmol), 1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (166 mg, 0.80 mmol), (cyanomethyl)trimethylphosphonium iodide (291 mg, 1.20 mmol), and DIPEA (514 mg, 3.98 mmol) in CHCN (3 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A12, which was further separated by preparative HPLC (Method A) into compound A12a (16 mg) and compound A12b (15 mg).

[0340] Compound A12a (earlier peak): 11H NMR (400 MHz, DMSO-d6) δ 6.90 - 6.79 (m, 3H), 6.24 (s, 1H), 4.81 (s, 1H), 4.19 (s, 2H), 3.90 (s, 2H), 3.82 (d, J = 10.0 Hz, 1H), 3.51 (q, J = 6.4 Hz, 1H), 3.35 (s, 3H), 3.28 (d, J = 10.0 Hz, 1H), 3.09 (d, J = 8.6 Hz, 1H), 2.78 (s, 1H), 2.73 (d, J = 11.5 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 3.7 Hz, 6H), 1.19 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H) ppm. MS: M / e 516 (M+1) + .

[0341] Compound A12b (slower peak): 1 1H NMR (400 MHz, DMSO-d6) δ 6.80 (d, J = 8.6 Hz, 3H), 6.23 (s, 1H), 4.64 (s, 1H), 4.17 (s, 2H), 4.05 (d, J = 10.3 Hz, 1H), 3.89 (s, 2H), 3.49 (d, J = 13.8 Hz, 2H), 3.39 (q, J = 6.3 Hz, 1H), 3.35 (s, 3H), 2.87 (d, J = 8.5 Hz, 1H), 2.12 (d, J = 11.4 Hz, 1H), 1.27 (d, J = 3.7 Hz, 6H), 1.22 (d, J = 6.5 Hz, 6H), 0.97 (d, J = 6.2 Hz, 3H) ppm. MS: M / e 516 (M+1) + .

[0342] Compound A13: 2-(7-((2S,5R)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0343] A solution of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (140 mg, 0.47 mmol), 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol (168 mg, 0.93 mmol), (cyanomethyl)trimethylphosphonium iodide (340 mg, 1.40 mmol), and DIPEA (602 mg, 4.67 mmol) in CHCN (4 mL) was stirred at 100° C. for 3 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography and then further purified by preparative HPLC (Method A) to give the title compound (19 mg). 1H NMR (400 MHz, DMSO-d6) δ 6.86-6.76 (m, 3H), 6.11 (d, J = 4.0 Hz, 1H), 5.22 (d, J = 5.9 Hz, 1H), 4.74 (s, 0.5H), 4.48 (s, 0.5H), 4.22 (d, J = 6.9 Hz, 4H), 4.12 (d, J = 5.2 Hz, 2H), 3.64 (d, J = 12.2 Hz, 0.5H), 3.56-3.50 (m, 1H), 3.47-3.38 (m, 1.5H), 3.33 (s, 3H), 3.25 (d, J = 12.2 Hz, 0.5H), 2.91 (d, J = 8.7 Hz, 0.5H), 2.77 (s, 0.5H), 2.66 (d, J = 9.6 Hz, 1H), 2.11 (d, J = 11.0 Hz, 0.5H), 1.24-1.18 (m, 4.5H), 1.10-1.05 (m, 3H), 0.95 (d, J = 6.5 Hz, 1.5H) ppm. MS: M / e 463 (M+1) + .

[0344] Compound A14: 2-(7-((2S,5R)-5-ethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0345] To a mixture of 2-(7-((2S,5R)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (10 mg, 0.03 mmol) from the last step in acetonitrile (5 mL) was added trimethyl(prop-2-yn-1-yl)phosphonium (46 mg, 0.2 mmol), 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (20 mg, 0.1 mmol), and DIPEA (129 mg, 1 mmol). The reaction mixture was sealed and stirred overnight at 105 °C under nitrogen protection. HO was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by preparative TLC (EA) to give the title compound (0.2 mg, 4%). 1 H NMR (400 MHz, CD3OD) δ 8.05 (dd, J = 18.2, 8.8 Hz, 1H), 7.40 (dd, J = 12.4, 9.3 Hz, 2H), 6.12 (s, 1H), 5.33 (s, 1H), 4.68 (s, 1H), 4.03 (s, 1H), 3.98 (d, J = 4.9 Hz, 2H), 3.66 - 3.55 (m, 1H), 3.46 (s, 4H), 3.13 (s, 1H), 2.92 (d, J = 11.6 Hz, 1H), 2.19 (t, J = 7.6 Hz, 1H), 2.03 (d, J = 5.6 Hz, 2H), 1.13 (d, J = 6.7 Hz, 2H), 0.99 (t, J = 7.4 Hz, 2H), 0.90 (t, J = 6.7 Hz, 3H), 0.69 (t, J = 7.4 Hz, 2H) ppm. MS: M / e 505 (M+1) + .

[0346] Compound A15: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0347] Step A: tert-Butyl (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazine-1-carboxylate [ka]

[0348] To a solution of tert-butyl (2S,5R)-2,5-diethylpiperazine-1-carboxylate (726 mg, 3 mmol) in acetonitrile (15 mL) was added 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol (981 mg, 4.5 mmol), (cyanomethyl)trimethylphosphonium (1280 mg, 6 mmol), and DIPEA (1.9 g, 15 mmol). The resulting mixture was sealed and stirred at 100° C. for 24 hours. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (520 mg, 40%). MS: M / e 433 (M+1) + .

[0349] Step B: (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazine [ka]

[0350] To a solution of tert-butyl (2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazine-1-carboxylate (520 mg, 1.2 mmol) in DCM (20 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting crude product (300 mg, 75%) was used directly in the next step without further purification. MS: M / e 333 (M+1) + .

[0351] Step C: 2-Bromo-5-chloro-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine [ka]

[0352] To a mixture of 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (212 mg, 0.8 mmol) in THF (15 mL) was added (2R,5S)-2,5-diethyl-1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazine (0.4 g, 1.2 mmol) and DIPEA (258 mg, 2 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The resulting crude product was purified by column chromatography to give the title compound (400 mg, 89%). MS: M / e 562 (M+1) + .

[0353] Step D: 5-(benzyloxy)-2-bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine [ka]

[0354] To a mixture of phenylmethanol (216 mg, 2 mmol) in THF (15 mL) was added NaH (60% in oil, 160 mg, 4 mmol). The reaction was stirred at room temperature for 0.5 h. To the mixture was added 2-bromo-5-chloro-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (640 mg, 1.13 mmol), and the reaction was stirred at 70° C. overnight. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by column chromatography to give the title compound (600 mg, 84%). MS: M / e 634 (M+1) + .

[0355] Step E: 2-bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0356] A mixture of 5-(benzyloxy)-2-bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (500 mg, 0.78 mmol) in TFA (10 mL) was stirred at 80° C. overnight. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO and extracted with DCM. The organic layer was dried over NaSO, filtered and concentrated. The crude product obtained was used directly in the next step without further purification. MS: M / e 544 (M+1) + .

[0357] Step F: 2-Bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0358] To a mixture of 2-bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (550 mg, 1 mmol) in 1,4-dioxane (5 mL) was added trimethyl phosphate (700 mg, 5 mmol) and K2CO3 (1.39 g, 10 mmol). The reaction mixture was stirred at 95 °C overnight. H2O was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (260 mg, 47%). MS: M / e 558 (M+1) + .

[0359] Step G: Methyl 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0360] To a solution of 2-bromo-7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (130 mg, 0.23 mmol) in MeOH (20 mL) was added Pd(dppf)Cl (7.3 mg, 0.01 mmol) and EtN (101 mg, 1 mmol). The reaction mixture was stirred at 100 °C under a CO atmosphere for 16 h. The mixture was cooled to room temperature. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The resulting crude product was purified by flash column chromatography to give the title compound (100 mg, 80%). MS: M / e 538 (M+1) + .

[0361] Step H: 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-(hydroxymethyl)-4-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0362] To a mixture of methyl 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (80 mg, 0.15 mmol) in THF (10 mL) was added NaBH (37 mg, 1 mmol). The resulting mixture was stirred at 70 °C overnight. The mixture was concentrated in vacuo. The residue was added to ice water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (50 mg, 66%). MS: M / e 510 (M+1) + .

[0363] Step I: (7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)methyl methanesulfonate [ka]

[0364] To a mixture of 7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-(hydroxymethyl)-4-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (50 mg, 0.1 mmol) in DCM (15 mL) was added methanesulfonyl chloride (22.6 mg, 0.2 mmol) and EtN (50 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 30 min. The mixture was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated. The resulting crude product was used directly in the next step without further purification. MS: M / e 470 (M+1) + .

[0365] Step J: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0366] To a mixture of (7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)methyl methanesulfonate (crude from Step I above) in acetonitrile (10 mL) was added TMSCN (19.6 mg, 0.2 mmol) and K2CO3 (55.6 mg, 0.4 mmol). The reaction was stirred at 80 °C overnight. The mixture was added to water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to separate compound A15a (8 mg) and compound A15b (2 mg).

[0367] Compound A15a (earlier peak): 1 HNMR (400 MHz, CD3OD) δ 8.02 (dd, J = 9.4, 5.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 6.12 (s, 1H), 5.30 (s, 1H), 4.45 (s, 1H), 4.06 (s, 2H), 3.98 (s, 1H), 3.58 (d, J = 11.5 Hz, 1H), 3.46 (s, 4H), 2.82 (d, J = 9.1 Hz, 2H), 2.12 (d, J = 12.0 Hz, 1H), 1.88 (dt, J = 17.2, 7.8 Hz, 2H), 1.68 - 1.46 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.51 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 519 (M+1) + .

[0368] Compound A15b (slower peak): 1HNMR (400 MHz, CD3OD) δ 8.12 - 8.02 (m, 1H), 7.42 (t, J = 8.5 Hz, 2H), 6.12 (s, 1H), 5.28 (s, 1H), 4.77 (s, 1H), 4.21 (d, J = 6.2 Hz, 1H), 4.00 (s, 2H), 3.75 (d, J = 10.7 Hz, 1H), 3.46 (s, 4H), 3.38 (s, 1H), 3.06 - 3.02 (m, 1H), 2.31 (d, J = 10.1 Hz, 1H), 2.16 (dd, J = 14.3, 7.0 Hz, 1H), 1.90 - 1.72 (m, 2H), 1.53 (d, J = 7.3 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 519 (M+1) + .

[0369] Compound A16: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(4-fluoro-2-methoxyphenyl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0370] A mixture of 1-(4-fluoro-2-methoxyphenyl)ethan-1-ol (68 mg, 0.4 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (65 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. overnight in a sealed tube. The reaction mixture was diluted with EA (20 mL), washed with brine (10 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (2 mg, 2%). 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (dt, J = 23.2, 7.9 Hz, 1H), 6.87 (t, J = 11.1 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.11 (s, 1H), 5.23 (d, J = 11.7 Hz, 1H), 4.70-4.28 (m, 1H), 4.23 - 3.98 (m, 3H), 3.85 (s, 0.5H), 3.80 (s, 3H), 3.57 - 3.40 (m, 1H), 3.33 (s, 3H), 3.25-2.98 (m, 1H), 2.85 (s, 1H), 2.60 (d, J = 9.1 Hz, 0.5H), 2.36-2.15 (m, 1H), 2.02 - 1.79 (m, 1H), 1.75 - 1.37 (m, 3H), 1.16 (dd, J = 17.3, 6.4 Hz, 3H), 0.80 (dt, J = 29.2, 7.3 Hz, 3H), 0.53 (dt, J = 20.1, 7.3 Hz, 3H) ppm. MS: M / e 481 (M+1) + .

[0371] Compound A17: 2-(7-((2S,5R)-4-(1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0372] A mixture of 1-(2-(difluoromethoxy)-4-fluorophenyl)ethan-1-ol (82 mg, 0.4 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (65 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. overnight in a sealed tube. The reaction mixture was diluted with EA (20 mL), washed with brine (10 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (3 mg, 2%). 1H NMR (400 MHz, DMSO-d6) δ 7.78 - 7.64 (m, 1H), 7.57-7.23 (m, 1H), 7.22 - 7.13 (m, 2H), 6.18 (s, 1H), 5.31 (d, J = 15.5 Hz, 1H), 4.76-4.37 (m, 1H), 4.25-3.99 (m, 3H), 3.95-3.56 (m, 1H), 3.50 (d, J = 11.4 Hz, 0.5H), 3.40 (s, 3H), 3.29 (d, J = 10.5 Hz, 0.5H), 3.10 (d, J = 10.4 Hz, 0.5H), 2.93 (s, 1H), 2.71 (d, J = 9.4 Hz, 0.5H), 2.37-2.17 (m, 1H), 2.08 - 1.83 (m, 1H), 1.81-1.48 (m, 3H), 1.28 (dd, J = 15.4, 6.0 Hz, 3H), 0.94-0.80 (m, 3H), 0.68-0.50 (m, 3H) ppm. MS: M / e 517 (M+1) + .

[0373] Compound A18: 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)-4-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0374] A mixture of 1-(2-(difluoromethyl)-4-fluorophenyl)ethan-1-ol (57 mg, 0.3 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (65 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (103 mg, 0.8 mmol) in MeCN (2 mL) was stirred at 100 °C overnight in a sealed tube. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (10 mL × 3), dried over Na SO , and concentrated to dryness. The resulting residue was purified by preparative TLC (MeOH:DCM = 1:13) to give the title compound (8 mg, 8%). 1 H NMR (400 MHz, CD3OD) δ 7.82-7.62 (m, 1H), 7.59 - 7.15 (m, 3H), 6.12 (s, 1H), 5.30 (d, J = 6.6 Hz, 1H), 4.81-4.38 (m, 1H), 4.16 - 3.74 (m, 4H), 3.61 - 3.35 (m, 4H), 3.21-2.80 (m, 2H), 2.40-2.18 (m, 1H), 2.11 - 1.79 (m, 2H), 1.77 - 1.49 (m, 2H), 1.33 (dd, J = 13.9, 6.5 Hz, 3H), 0.91 (dt, J = 22.4, 7.4 Hz, 3H), 0.62-0.48 (m, 3H) ppm. MS: M / e 501 (M+1) + .

[0375] Compound A19: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0376] Step A: 1-(pyridin-4-yl)ethan-1-ol [ka]

[0377] To a solution of 1-(pyridin-4-yl)ethan-1-one (1.2 g, 10 mmol) in MeOH (10 mL) was added NaBH (190 mg, 5 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was treated with water (50 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography (MeOH:DCM = 0-10%, 25 min) to give the title compound (900 mg, 73%). MS: M / e 124 (M+1) + .

[0378] Step B: 2-(8-((2S,5R)-2,5-diethyl-4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile [ka]

[0379] A mixture of 1-(pyridin-4-yl)ethan-1-ol (37 mg, 0.3 mmol), 2-(8-((2S,5R)-2,5-diethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydroimidazo[1,2-b]pyridazin-2-yl)acetonitrile (65 mg, 0.2 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100 °C overnight in a sealed tube. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (10 mL × 3), dried over Na SO , and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (MeOH:DCM = 0-10%, 30 min) to give the title compound (5 mg, 6%).1 H NMR (400 MHz, CDCl3) δ 8.59 (s, 2H), 7.39 (s, 2H), 5.87 (s, 1H), 5.28 (d, J = 11.8 Hz, 1H), 4.60-4.25 (m, 1H), 3.78 (d, J = 8.5 Hz, 2H), 3.68-3.48 (m, 2H), 3.47-3.28 (m, 4H), 3.11-2.95 (m, 1H), 2.92-2.75 (m, 1H), 2.39-2.17 (m, 1H), 2.07 (s, 1H), 1.87 (s, 1H), 1.73 (s, 1H), 1.52 (d, J = 6.5 Hz, 1H), 1.29 (d, J = 5.7 Hz, 3H), 0.87 (dd, J = 15.8, 8.2 Hz, 3H), 0.67-0.52 (m, 3H) ppm. MS: M / e 434 (M+1) + .

[0380] Compound A20: 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0381] Step A: 1-(4-cyclopropyl-2-fluorophenyl)ethan-1-one [ka]

[0382] To a solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (1.95 g, 9 mol) in toluene (30 mL) were added cyclopropylboronic acid (1.16 g, 13.5 mol), (Cy3P)2PdCl2, K3PO4 (2.86 g, 13.5 mmol), and HO (3 mL). The reaction mixture was protected with a N2 atmosphere and stirred at room temperature overnight. HO (20 mL) was added to the mixture, which was extracted with EA (20 mL x 3), and then concentrated using a rotary evaporator to obtain a residue. The resulting residue was purified by flash column chromatography to obtain the title compound (1.6 g, 100%). MS: M / e 179 (M+1) + .

[0383] Step B: 1-(4-cyclopropyl-2-fluorophenyl)ethan-1-ol [ka]

[0384] To a solution of 1-(4-cyclopropyl-2-fluorophenyl)ethan-1-one (1.6 g, 9 mol) in MeOH was added NaBH (305 mg, 8 mmol). The reaction mixture was stirred at room temperature for 15 minutes. HO (20 ml) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over NaSO and concentrated using a rotary evaporator to obtain a residue. The resulting residue was purified by flash column chromatography to obtain the title compound (1.2 g, 75%). MS: M / e 181 (M+1) + .

[0385] Step A: 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0386] To a solution of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (100 mg, 0.3 mmol), 1-(4-cyclopropyl-2-fluorophenyl)ethan-1-ol (108 mg, 0.6 mmol), and (cyanomethyl)trimethylphosphonium iodide (216 mg, 0.9 mmol) in CHCN (10 mL) was added DIPEA (258 mg, 5 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to give Compound A20a (15 mg) and Compound A20b (17 mg).

[0387] Compound A20a (earlier peak): 1 H NMR (400 MHz, CD3OD) ) δ 7.38 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.76 (dd, J = 11.9, 1.4 Hz, 1H), 6.12 (s, 1H), 5.30 (s, 1H), 4.82 (m, 1H), 4.12 (d, J = 6.6 Hz, 1H), 3.97 (d, J = 5.8 Hz, 1H), 3.75 (d, J = 12.0 Hz, 1H), 3.46 (s, 3H), 3.36 (m, 2H), 3.03 (dd, J = 11.8, 3.7 Hz, 1H), 2.78 (dd, J = 11.7, 2.3 Hz, 1H), 2.46 (d, J = 9.3 Hz, 1H), 1.90 (m, 1H), 1.70 (dd, J = 6.8, 3.4 Hz, 1H), 1.55 (m, 1H), 1.32 (dd, J = 6.5, 1.7 Hz, 6H), 0.98 (m, 2H), 0.68 (t, J = 7.1 Hz, 5H) ppm. MS: M / e 477 (M+1) + .

[0388] Compound A20b (slower peak): 1 H NMR (400 MHz, CD3OD) δ 7.44 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.72 (dd, J = 11.9, 1.4 Hz, 1H), 6.12 (s, 1H), 5.33 (s, 1H), 4.65 (s, 1H), 3.99 (m, 3H), 3.55 (d, J = 12.6 Hz, 1H), 3.46 (s, 3H), 3.33 (s, 1H), 3.13 (d, J = 9.5 Hz, 1H), 2.84 (dd, J = 12.0, 3.6 Hz, 1H), 2.21 (d, J = 11.3 Hz, 1H), 1.87 (m, 2H), 1.56 (dd, J = 13.4, 7.3 Hz, 1H), 1.30 (t, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 0.96 (m, 5H), 0.66 (m, 2H) ppm. MS: M / e 477 (M+1) + .

[0389] Compound A21: 2-(7-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0390] A solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (50 mg, 0.15 mmol), 1-(4-cyclopropyl-2-fluorophenyl)ethan-1-ol (54.9 mg, 0.31 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (196.6 mg, 1.52 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography followed by preparative HPLC (Method A) to give the title compound (21 mg). 1 H NMR (400 MHz, CD3OD) δ 7.40 (dt, J = 22.0, 7.8 Hz, 1H), 6.90 (t, J = 8.1 Hz, 1H), 6.74 (t, J = 11.4 Hz, 1H), 6.12 (s, 1H), 5.28 (d, J = 8.1 Hz, 1H), 4.67 (s, 0.5H), 4.42 (s, 0.5H), 4.15 - 4.03 (m, 1H), 3.99 (d, J = 3.6 Hz, 2.5H), 3.78 (d, J = 12.6 Hz, 0.5H), 3.54 (d, J = 13.1 Hz, 0.5H), 3.46 (s, 3H), 3.37 (d, J = 13.1 Hz, 0.5H), 3.12 (d, J = 9.2 Hz, 0.5H), 2.96 (s, 1H), 2.77 (d, J = 9.1 Hz, 0.5H), 2.45 (d, J = 8.7 Hz, 0.5H), 2.33 (d, J = 12.6 Hz, 0.5H), 2.17 - 1.46 (m, 5H), 1.30 (dd, J = 13.5, 6.5 Hz, 3H), 1.03-0.81 (m, 5H), 0.71-0.51 (m, 5H) ppm. MS: M / e 491 (M+1) + .

[0391] Compound A22: 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0392] To a solution of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (100 mg, 0.5 mmol), 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (200 mg, 1.22 mmol), and (cyanomethyl)trimethylphosphonium iodide (240 mg, 1 mmol) in CHCN (10 mL) was added DIPEA (259 mg, 2 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to give Compound A22a (19 mg) and Compound A22b (22 mg).

[0393] Compound A22a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.1, 2.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.12 (s, 1H), 5.31 (s, 1H), 3.97 (d, J = 5.8 Hz, 1H), 3.83 (d, J = 6.5 Hz, 1H), 3.73 (d, J = 12.3 Hz, 1H), 3.46 (s, 3H), 3.36 (dd, J = 12.7, 2.5 Hz, 1H), 3.05 (dd, J = 11.7, 3.6 Hz, 1H), 2.81 (dd, J = 11.8, 2.2 Hz, 1H), 2.39 (d, J = 9.4 Hz, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.56 (dd, J = 13.5, 7.5 Hz, 1H), 1.34 (d, J = 6.5 Hz, 6H), 1.02 (dt, J = 8.1, 2.9 Hz, 2H), 0.94 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 460 (M+1) + .

[0394] Compound A22b (slower peak): 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.1, 2.0 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.12 (s, 1H), 5.33 (s, 1H), 4.62 (s, 1H), 3.98 (dd, J = 15.8, 9.2 Hz, 2H), 3.69 (q, J = 6.5 Hz, 1H), 3.57 (m, 1H), 3.46 (s, 3H), 3.32 (s, 1H), 3.16 (d, J = 9.8 Hz, 1H), 2.84 (dd, J = 12.0, 3.6 Hz, 1H), 2.15 (m, 1H), 2.07 (m, 1H), 1.87 (ddd, J = 13.5, 10.6, 7.2 Hz, 1H), 1.58 (dd, J = 13.6, 7.3 Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 0.97 (m, 7H) ppm. MS: M / e 460 (M+1) + .

[0395] Compound A23: 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0396] A mixture of 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (33 mg, 0.2 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (52 mg, 0.4 mmol) in MeCN (2 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (5 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (2 mg, 4%). 1 H NMR (400 MHz, CD3OD) δ 8.32 (d, J = 10.2 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.26 - 7.13 (m, 1H), 6.12 (s, 1H), 5.29 (d, J = 8.4 Hz, 1H), 4.75-4.35 (m, 1H), 4.14-3.90 (m, 2.5H), 3.88 - 3.53 (m, 2H), 3.46 (s, 3H), 3.16 (d, J = 9.9 Hz, 1H), 2.98 (s, 1H), 2.80 (d, J = 12.4 Hz, 0.5H), 2.42-2.22 (m, ppm. MS: M / e 474 (M+1) + .

[0397] Compound A24: 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0398] To a solution of 2-(7-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (120 mg, 0.26 mmol) in CHCN (10 mL) was added Select F (101 mg, 0.28 mmol). The reaction mixture was sealed in a bottle and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to give Compound A24a (7 mg) and Compound A24b (15 mg).

[0399] Compound A24a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 1.5 Hz, 1H), 7.72 (dd, J = 8.1, 2.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.16 (s, 1H), 4.31 (s, 1H), 3.99 (q, J = 6.5 Hz, 1H), 3.72 (d, J = 12.1 Hz, 1H), 3.52 (s, 3H), 3.32 (s, 2H), 3.14 (m, 2H), 2.55 (dd, J = 11.5, 4.5 Hz, 1H), 2.35 (d, J = 5.7 Hz, 1H), 2.09 (m, 1H), 1.69 (dd, J = 16.2, 8.5 Hz, 2H), 1.39 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 6.5 Hz, 3H), 1.03 (m, 2H), 0.94 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 478 (M+1) + .

[0400] Compound A24b (slower peak):1 H NMR (400 MHz, CD3OD) δ 8.37 (d, J = 1.6 Hz, 1H), 7.75 (dd, J = 8.1, 2.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.17 (s, 1H), 4.14 (d, J = 6.0 Hz, 1H), 3.98 (d, J = 5.8 Hz, 1H), 3.89 (dd, J = 13.6, 9.6 Hz, 2H), 3.53 (s, 3H), 3.35 (d, J = 3.3 Hz, 2H), 3.07 (m, 1H), 2.84 (dd, J = 11.7, 3.5 Hz, 1H), 2.16 (dd, J = 11.7, 4.1 Hz, 1H), 2.07 (m, 1H), 1.83 (m, 1H), 1.62 (dd, J = 13.7, 6.9 Hz, 1H), 1.33 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.01 (m, 2H), 0.91 (m, 5H) ppm. MS: M / e 478 (M+1) + .

[0401] Compound A25: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(5-isopropoxypyridin-2-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0402] A mixture of 1-(5-isopropoxypyridin-2-yl)ethan-1-ol (33 mg, 0.2 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (52 mg, 0.4 mmol) in MeCN (2 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (5 mL × 3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (5 mg, 10%). 1 H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.51 (t, J = 8.8 Hz, 1H), 7.43 (s, 1H), 6.12 (s, 1H), 5.30 (d, J = 8.7 Hz, 1H), 4.74-4.40 (m, 2H), 4.13 - 3.87 (m, 3H), 3.78 (s, 1H), 3.63 - 3.38 (m, 4H), 3.20 - 2.82 (m, 2H), 2.42-2.17 (m, 1H), 2.16 - 1.79 (m, 2H), 1.74 - 1.48 (m, 2H), 1.33 (d, J = 5.5 Hz, 9H), 0.98-0.81 (m, 3H), 0.67-0.52 (m, 3H) ppm. MS: M / e 492 (M+1) + .

[0403] Compound A26: 2-(7-((2S,5R)-4-(1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0404] A mixture of 1-(6-cyclopropyl-2-fluoropyridin-3-yl)ethan-1-ol (36 mg, 0.2 mmol), 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (33 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol), and DIPEA (52 mg, 0.4 mmol) in MeCN (5 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (10 mL×3), dried over NaSO, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (9 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 18.1, 10.3 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 6.10 (s, 1H), 5.23 (d, J = 13.9 Hz, 1H), 4.67-4.26 (m, 1H), 4.10 (d, J = 6.5 Hz, 2H), 4.01 - 3.90 (m, 0.5H), 3.87-3.74 (m, 1H), 3.58-3.38 (m, 1H), 3.32 - 3.28 (m, 2H), 3.27 - 2.97 (m, 1H), 2.90-2.73 (m, 1H), 2.70 - 2.51 (m, 1H), 2.30 (d, J = 10.1 Hz, 0.5H), 2.18-1.86 (m, 2H), 1.83 - 1.35 (m, 4H), 1.24 (dd, J = 18.4, 6.5 Hz, 3H), 0.94 (dd, J = 7.9, 3.0 Hz, 2H), 0.89 - 0.69 (m, 5H), 0.61-0.43 (m, 3H) ppm. MS: M / e 492 (M+1) + .

[0405] Compound A27: 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0406] A solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (200 mg, 0.61 mmol), 1-(benzo[d]thiazol-6-yl)ethan-1-ol (218 mg, 1.22 mmol), (cyanomethyl)trimethylphosphonium iodide (445 mg, 1.83 mmol), and DIPEA (787 mg, 6.10 mmol) in CHCN (6 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A27, which was further separated by preparative HPLC (Method A) into compound A27a (22 mg) and compound A27b (48 mg, crude).

[0407] Compound A27a (earlier peak): 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.13 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 6.10 (s, 1H), 5.20 (s, 1H), 4.66 (s, 1H), 4.10 (s, 2H), 3.89 (q, J = 6.2 Hz, 1H), 3.46 (d, J = 11.3 Hz, 1H), 3.24 (d, J = 9.8 Hz, 1H), 2.90 (q, J = 7.8 Hz, 2H), 2.55 (s, 3H), 2.31 (d, J = 8.4 Hz, 1H), 2.09-1.94 (m, 1H), 1.72-1.60 (m, 1H), 1.60-1.42 (m, 2H), 1.31 (d, J = 6.3 Hz, 3H), 0.78 (t, J = 7.5 Hz, 3H), 0.49 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 490 (M+1) + .

[0408] Compound A27b (slower peak): Purity 68.2% (214 nm), MS: M / e 490 (M+1) + .

[0409] Compound A28: 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0410] To a mixture of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 25.2 mmol) in acetonitrile (2 mL) was added (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), 1-(benzo[d]thiazol-6-yl)ethan-1-ol (50 mg, 0.28 mmol), and DIPEA (129 mg, 1 mmol). The reaction mixture was sealed and stirred overnight at 105 °C under nitrogen protection. HO was added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to separate into Compound A28a (3 mg) and Compound A28b (3 mg).

[0411] Compound A28a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 9.21 (s, 1H), 8.09 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 6.12 (s, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 3.98 (d, J = 5.0 Hz, 3H), 3.71 (d, J = 12.6 Hz, 1H), 3.46 (s, 3H), 3.39 (d, J = 9.9 Hz, 1H), 3.09 (dd, J = 11.8, 3.6 Hz, 1H), 2.89 (d, J = 9.9 Hz, 1H), 2.45 (d, J = 9.0 Hz, 1H), 1.76 (m, 1H), 1.62 (dd, J = 13.4, 7.2 Hz, 1H), 1.40 (t, J = 6.0 Hz, 6H), 0.63 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 476 (M+1) + .

[0412] Compound A28b (slower peak): 1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.11 (s, 1H), 5.34 (s, 1H), 4.62 (s, 1H), 4.03 (d, J = 12.6 Hz, 1H), 3.96 (s, 2H), 3.84 (d, J = 6.5 Hz, 1H), 3.62 (d, J = 11.4 Hz, 1H), 3.46 (s, 3H), 3.22 (d, J = 10.6 Hz, 1H), 2.87 (m, 1H), 2.19 (d, J = 12.1 Hz, 1H), 1.90 (d, J = 4.2 Hz, 1H), 1.63 (dd, J = 13.4, 7.0 Hz, 1H), 1.39 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 476 (M+1) + .

[0413] Compound A29: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0414] To a solution of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (150 mg, 0.5 mmol), 1-(thiazolo[5,4-b]pyridin-5-yl)ethan-1-ol (180 mg, 1 mmol), and (cyanomethyl)trimethylphosphonium iodide (361 mg, 1.5 mmol) in CHCN (10 mL) was added DIPEA (387 mg, 3 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to separate into Compound A29a (34 mg) and Compound A29b (35 mg).

[0415] Compound A29a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 9.34 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 4.84 (s, 1H), 4.17 (t, J = 6.6 Hz, 1H), 3.71 (d, J = 12.3 Hz, 1H), 3.44 (m, 4H), 3.32 (s, 2H), 3.15 (dd, J = 11.8, 3.6 Hz, 1H), 2.85 (dd, J = 11.8, 2.6 Hz, 1H), 2.41 (d, J = 8.0 Hz, 1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.44 (d, J = 6.7 Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H), 0.67 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 477 (M+1) + .

[0416] Compound A29b (slower peak): 1H NMR (400 MHz, CD3OD) δ 9.33 (s, 1H), 8.40 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 6.12 (s, 1H), 5.35 (s, 1H), 4.63 (s, 1H), 3.99 (m, 3H), 3.64 (d, J = 10.4 Hz, 1H), 3.46 (s, 3H), 3.32 (s, 1H), 3.21 (d, J = 10.2 Hz, 1H), 2.96 (dd, J = 12.1, 3.7 Hz, 1H), 2.11 (m, 1H), 1.91 (m, 1H), 1.59 (dd, J = 13.5, 7.3 Hz, 1H), 1.42 (d, J = 6.7 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 477 (M+1) + .

[0417] Compound A30: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0418] To a solution of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (100 mg, 0.3 mmol), 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-ol (100 mg, 0.5 mmol), and (cyanomethyl)trimethylphosphonium iodide (241 mg, 1 mmol) in CHCN (5 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method B) to separate into Compound A30a (3 mg) and Compound A30b (5 mg).

[0419] Compound A30a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.55 (m, 1H), 6.12 (s, 1H), 5.30 (s, 1H), 4.85 (s, 1H), 3.97 (s, 2H), 3.93 (d, J = 6.5 Hz, 1H), 3.71 (d, J = 12.5 Hz, 1H), 3.46 (d, J = 6.7 Hz, 3H), 3.38 (d, J = 12.2 Hz, 1H), 3.07 (dd, J = 11.8, 3.6 Hz, 1H), 2.87 (d, J = 11.7 Hz, 1H), 2.83 (s, 3H), 2.45 (d, J = 9.8 Hz, 1H), 1.74 (m, 1H), 1.60 (dd, J = 13.1, 7.5 Hz, 1H), 1.38 (d, J = 6.5 Hz, 6H), 0.63 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 490 (M+1) + .

[0420] Compound A30b (slower peak): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 5.34 (s, 1H), 4.62 (s, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.96 (s, 2H), 3.79 (q, J = 6.4 Hz, 1H), 3.61 (d, J = 10.4 Hz, 1H), 3.46 (s, 3H), 3.21 (d, J = 10.0 Hz, 1H), 2.86 (dd, J = 12.1, 3.7 Hz, 1H), 2.81 (s, 3H), 2.18 (d, J = 11.5 Hz, 1H), 1.89 (m, 1H), 1.61 (dd, J = 13.5, 7.2 Hz, 1H), 1.37 (d, J = 6.5 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 490 (M+1) + .

[0421] Compound A31: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0422] A solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (50 mg, 0.15 mmol), 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-ol (58.8 mg, 0.30 mmol), (cyanomethyl)trimethylphosphonium iodide (111.1 mg, 0.46 mmol), and DIPEA (196.6 mg, 1.52 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography and then further purified by preparative HPLC (Method A) to give the title compound (16 mg). 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J = 10.0 Hz, 1H), 7.89-7.80 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.12 (s, 1H), 5.29 (d, J = 9.2 Hz, 1H), 4.72 (s, 0.5H), 4.40 (s, 0.5H), 4.07 (d, J = 8.6 Hz, 0.5H), 3.98 (d, J = 7.3 Hz, 2H), 3.92 (q, J = 6.6 Hz, 0.5H), 3.77 (q, J = 6.6 Hz, 1H), 3.60 (d, J = 11.7 Hz, 0.5H), 3.46 (s, 3H), 3.39 (d, J = 11.8 Hz, 1H), 3.22 (d, J = 11.8 Hz, 0.5H), 3.03 (s, 0.5H), 2.82 (d, J = 3.3 Hz, 3H), 2.78 (s, 0.5H), 2.43 (d, J = 8.9 Hz, 0.5H), 2.31 (d, J = 12.1 Hz, 0.5H), 2.20-1.92 (m, 1H), 1.90-1.78 (m, 1H), 1.70-1.55 (m, 2H), 1.37 (dd, J = 10.4, 6.5 Hz, 3H), 0.92 (dt, J = 23.7, 7.3 Hz, 3H), 0.53 (dt, J = 35.2, 7.4 Hz, 3H) ppm. MS: M / e 504 (M+1) + .

[0423] Compound A32: 2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0424] A solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (200 mg, 0.61 mmol), 1-(benzo[d]thiazol-5-yl)ethan-1-ol (218 mg, 1.22 mmol), (cyanomethyl)trimethylphosphonium iodide (445 mg, 1.83 mmol), and DIPEA (787 mg, 6.10 mmol) in CHCN (6 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound A32, which was further separated by preparative HPLC (Method A) into compound A32a (15 mg) and compound A32b (32 mg, crude).

[0425] Compound A32a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.12-8.02 (m, 2H), 7.58 (d, J = 8.3 Hz, 1H), 6.11 (s, 1H), 5.28 (s, 1H), 4.73 (s, 1H), 3.99 (s, 2H), 3.98-3.93 (m, 1H), 3.76 (d, J = 11.8 Hz, 1H), 3.45 (s, 3H), 3.39 (d, J = 11.8 Hz, 1H), 3.10-3.00 (m, 2H), 2.45 (d, J = 9.1 Hz, 1H), 2.23-2.09 (m, 1H), 1.91-1.79 (m, 1H), 1.77-1.55 (m, 2H), 1.41 (d, J = 6.3 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.58 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 490 (M+1) + .

[0426] Compound A32b (slower peak): 70% purity (214 nm), MS: M / e 490 (M+1) + .

[0427] Compound A33: 2-(4-methyl-7-((2R)-2-methyl-1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0428] Step A: tert-Butyl (2R)-4-cyano-2-methylpiperidine-1-carboxylate [ka]

[0429] To a solution of tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (5 g, 23 mmol) in THF (12 mL) was added Tosmic (1.17 g, 6 mmol) and t-BuOK (672 mg, 6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours. H2O was added to the mixture, which was then extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (2.5 g, 49%). MS: M / e 225 (M+1) + .

[0430] Step B: (2R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid [ka]

[0431] To a solution of tert-butyl (2R)-4-cyano-2-methylpiperidine-1-carboxylate (2.5 g, 10 mmol) in EtOH (80 mL) was added NaOH (1 M, 80 ml). The resulting mixture was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo. H2O was added to the residue to adjust the pH to 1-2. The mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step (1 g, 41%). MS: M / e 244 (M+1) + .

[0432] Step C: tert-Butyl (2R)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-2-methylpiperidine-1-carboxylate [ka]

[0433] To a solution of (2R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (1 g, 4 mmol) in DCM (20 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (864 mg, 6 mol), EDCI (1.3 g, 7 mmol), and DMAP (1.39 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (700 mg, 47.6%). MS: M / e 370 (M+1) + .

[0434] Step D: tert-Butyl (2R)-4-(3-((3-bromo-1H-pyrazol-5-yl)amino)-3-oxopropanoyl)-2-methylpiperidine-1-carboxylate [ka]

[0435] To a mixture of tert-butyl (2R)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-2-methylpiperidine-1-carboxylate (700 mg, 1.89 mmol) in THF (15 mL) was added 3-bromo-1H-pyrazol-5-amine (370 mg, 2 mmol). The resulting mixture was stirred at 70° C. overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography to give the title product (660 g, 80.4%). MS: M / e 429 (M+1) + .

[0436] Step E: tert-Butyl (2R)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0437] To a mixture of tert-butyl (2R)-4-(3-((3-bromo-1H-pyrazol-5-yl)amino)-3-oxopropanoyl)-2-methylpiperidine-1-carboxylate (640 mg, 1.5 mmol) in dioxane (5 mL) was added KPO (424 mg, 2 mmol). The reaction was sealed and stirred at 110 °C for 16 h. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered and concentrated. The crude product was purified by column chromatography to give the title product (350 mg, 56.9%). MS: M / e 411 (M+1) + .

[0438] Step F: tert-Butyl (2R)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0439] To a mixture of tert-butyl (2R)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (350 mg, 0.85 mmol) in dioxane (5 mL) was added trimethyl phosphate (595 mg, 4.25 mmol) and K2CO3 (1.18 g, 8.5 mmol). The reaction mixture was stirred at 95 °C overnight. H2O was added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (400 mg, 100%). MS: M / e 425 (M+1) + .

[0440] Step G: Methyl 7-((2R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0441] To a solution of tert-butyl (2R)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (400 mg, 0.85 mmol) in MeOH (20 mL) was added Pd(dppf)Cl (140 mg, 0.2 mmol) and EtN (404 mg, 4 mmol). The reaction mixture was stirred at 90 °C under a CO atmosphere for 16 hours. The mixture was cooled to room temperature. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (380 mg, 100%). MS: M / e 405 (M+1) + .

[0442] Step H: tert-Butyl (2R)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0443] To a mixture of methyl 7-((2R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (380 mg, 1 mmol) in THF (10 mL) was added NaBH (76 mg, 2 mmol). The resulting mixture was stirred at 70° C. overnight. The mixture was concentrated under vacuum. The residue was added to ice water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (200 mg, 56.1%). MS: M / e 377 (M+1) + .

[0444] Step I: tert-Butyl (2R)-2-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate [ka]

[0445] To a mixture of tert-butyl (2R)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (200 mg, 0.5 mmol) in DCM (15 mL) was added methanesulfonyl chloride (114 mg, 1 mmol) and EtN (202 mg, 2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was used directly in the next step. MS: M / e 455 (M+1) + .

[0446] Step J: tert-Butyl (2R)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0447] To a mixture of tert-butyl (2R)-2-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate from the last step in acetonitrile (10 mL) was added TMSCN (160 mg, 1.6 mmol) and K2CO3 (359 mg, 2.6 mmol). The reaction was stirred at 80 °C overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (60 mg). MS: M / e 386 (M+1) + .

[0448] Step K: 2-(4-methyl-7-((2R)-2-methylpiperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0449] A mixture of tert-butyl (2R)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (60 mg, 0.16 mmol) in TFA (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The resulting residue was used directly in the next step. MS: M / e 286 (M+1) + .

[0450] Step L: 2-(4-methyl-7-((2R)-2-methyl-1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0451] To a solution of 2-(4-methyl-7-((2R)-2-methylpiperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile from the last step in acetonitrile (5 mL) was added 1-(quinoxalin-6-yl)ethan-1-ol (17.4 mg, 0.1 mmol), (cyanomethyl)trimethylphosphonium (125 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol). The reaction mixture was sealed and stirred at 105 °C under nitrogen protection for 16 h. HO was added to the mixture, which was then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A33a (1.48 mg) and compound A33b (1.75 mg).

[0452] Compound A33a (earlier peak):1 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J = 7.1, 1.8 Hz, 2H), 8.09 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 10.4 Hz, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 4.06 - 3.97 (m, 2H), 3.66 (d, J = 8.5 Hz, 1H), 3.49 (s, 3H), 3.13 (s, 2H), 2.80 (d, J = 12.4 Hz, 2H), 2.15 (d, J = 11.2 Hz, 1H), 1.87 (d, J = 8.2 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.34 (s, 1H), 1.16 (d, J = 6.7 Hz, 3H). MS: M / e 442 (M+1) + .

[0453] Compound A33b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J = 7.6, 1.7 Hz, 2H), 8.08 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 10.1 Hz, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 4.00 (s, 1H), 3.94 (d, J = 6.4 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.50 (s, 3H), 2.78 (s, 2H), 2.66 (t, J = 11.4 Hz, 1H), 2.53 (d, J = 12.1 Hz, 1H), 2.07 (dd, J = 11.0, 4.0 Hz, 2H), 1.91 (s, 1H), 1.45 (d, J = 6.6 Hz, 3H), 1.34 (s, 1H), 1.29 (d, J = 6.6 Hz, 3H). MS: M / e 442 (M+1) + .

[0454] Compound A34: 2-(4-methyl-7-((2S)-2-methyl-1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0455] Step A: tert-Butyl (2S)-4-cyano-2-methylpiperidine-1-carboxylate [ka]

[0456] To a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (4.26 g, 20 mmol) in DME (12 mL) was added EtOH (1.84 g, 40 mmol), Tosmic (5.85 g, 30 mmol), and t-BuOK (6.72 g, 60 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. H2O was added to the mixture, which was then extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (3 g, 66.9%). MS: M / e 225 (M+1) + .

[0457] Step B: (2S)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid [ka]

[0458] To a solution of tert-butyl (2S)-4-cyano-2-methylpiperidine-1-carboxylate (3 g, 13.3 mmol) in EtOH (50 mL) was added NaOH (2 M, 50 ml). The resulting mixture was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo. H2O was added to the residue to adjust the pH to 1-2. The mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was used directly in the next step (3 g, 100%). MS: M / e 244 (M+1) + .

[0459] Step C: tert-Butyl (2S)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-2-methylpiperidine-1-carboxylate [ka]

[0460] To a solution of (2S)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (10 g, 16.5 mmol) in DCM (20 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 g, 19.8 mol), EDCI (4.7 g, 24.8 mmol), and DMAP (3.5 g, 24.8 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (3.9 g, 65%). MS: M / e 370 (M+1) + .

[0461] Step D: tert-Butyl (2s)-4-(3-((3-bromo-1H-pyrazol-5-yl)amino)-3-oxopropanoyl)-2-methylpiperidine-1-carboxylate [ka]

[0462] To a mixture of tert-butyl (2s)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-2-methylpiperidine-1-carboxylate (3.9 g, 10.5 mmol) in THF (15 mL) was added 3-bromo-1H-pyrazol-5-amine (1.69 g, 10.5 mmol). The resulting mixture was stirred at 70° C. overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (3 g, 66.8%). MS: M / e 429 (M+1) + .

[0463] Step E: tert-Butyl (2s)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0464] To a mixture of tert-butyl (2S)-4-(3-((3-bromo-1H-pyrazol-5-yl)amino)-3-oxopropanoyl)-2-methylpiperidine-1-carboxylate (1.5 g, 3.5 mmol) in dioxane (5 mL) was added KPO (3 g, 14 mmol). The reaction was sealed and stirred at 110 °C for 16 h. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (900 mg, 64.2%). MS: M / e 411 (M+1) + .

[0465] Step F: tert-Butyl (2S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0466] To a mixture of tert-butyl (2S)-4-(2-bromo-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (430 mg, 1 mmol) in dioxane (5 mL) was added trimethyl phosphate (700 mg, 5 mmol) and K2CO3 (1.39 g, 10 mmol). The reaction mixture was stirred at 95 °C overnight. H2O was added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title product (500 mg, 100%). MS: M / e 425 (M+1) + .

[0467] Step G: Methyl 7-((2S)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate [ka]

[0468] To a solution of tert-butyl (2S)-4-(2-bromo-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (500 mg, 1 mmol) in MeOH (20 mL) was added Pd(dppf)2Cl2 (140 mg, 0.2 mmol) and Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 90 °C under a CO atmosphere for 16 hours. The mixture was cooled to room temperature. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (240 mg, 59.4%). MS: M / e 405 (M+1) + .

[0469] Step H: tert-Butyl (2S)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0470] To a mixture of methyl 7-((2S)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (240 mg, 0.59 mmol) in THF (10 mL) was added NaBH (76 mg, 2 mmol). The resulting mixture was stirred at 70° C. overnight. The mixture was concentrated under vacuum. The residue was added to ice water and extracted with ethyl acetate. The organic phase was dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title compound (130 mg, 54.1%). MS: M / e 377 (M+1) + .

[0471] Step I: tert-Butyl (2S)-2-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate [ka]

[0472] To a mixture of tert-butyl (2S)-4-(2-(hydroxymethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (130 mg, 0.35 mmol) in DCM (15 mL) was added methanesulfonyl chloride (114 mg, 1 mmol) and EtN (202 mg, 2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was used directly in the next step. MS: M / e 455 (M+1) + .

[0473] Step J: tert-Butyl (2S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate [ka]

[0474] To a mixture of tert-butyl (2S)-2-methyl-4-(4-methyl-2-(((methylsulfonyl)oxy)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate from the last step in acetonitrile (10 mL) was added TMSCN (160 mg, 1.6 mmol) and K2CO3 (359 mg, 2.6 mmol). The reaction was stirred at 80 °C overnight. The mixture was added to water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by column chromatography to give the title product (120 mg). MS: M / e 386 (M+1) + .

[0475] Step K: 2-(4-methyl-7-((2S)-2-methylpiperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0476] A mixture of tert-butyl (2S)-4-(2-(cyanomethyl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)-2-methylpiperidine-1-carboxylate (120 mg, 0.3 mmol) in TFA (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The resulting residue was used directly in the next step. MS: M / e 286 (M+1) + .

[0477] Step L: 2-(4-methyl-7-((2S)-2-methyl-1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0478] To a solution of 2-(4-methyl-7-((2R)-2-methylpiperidin-4-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile from the last step in acetonitrile (5 mL) was added 1-(quinoxalin-6-yl)ethan-1-ol (174 mg, 1 mmol), (cyanomethyl)trimethylphosphonium (241 mg, 1 mmol), and DIPEA (258 mg, 2 mmol). The reaction mixture was sealed and stirred at 105 °C under nitrogen protection for 16 h. HO was added to the mixture, which was then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound A34a 1 (0.88 mg) and compound A34b (1.36 mg).

[0479] Compound A34a (earlier peak):1 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J = 7.2, 1.8 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 8.02 (dd, J = 8.8, 1.6 Hz, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 4.57 (s, 1H), 4.08 - 3.97 (m, 2H), 3.71 - 3.61 (m, 1H), 3.49 (s, 3H), 3.20 - 3.07 (m, 1H), 2.83 (t, J = 11.0 Hz, 1H), 2.18 (dd, J = 17.6, 9.9 Hz, 1H), 1.88 (dd, J = 9.0, 3.4 Hz, 2H), 1.46 (d, J = 6.5 Hz, 3H), 1.30 (s, 2H), 1.17 (d, J = 6.7 Hz, 3H) ppm. MS: M / e 442 (M+1) + 。

[0480] Compound A34b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J = 7.7, 1.9 Hz, 2H), 8.11 - 8.06 (m, 2H), 8.02 (d, J = 1.6 Hz, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 4.57 (s, 1H), 4.01 - 3.91 (m, 2H), 3.77 - 3.70 (m, 1H), 3.50 (s, 3H), 2.65 (d, J = 12.1 Hz, 1H), 2.54 (d, J = 12.6 Hz, 1H), 2.09 (d, J = 3.7 Hz, 1H), 1.90 (d, J = 10.4 Hz, 1H), 1.65 (dd, J = 12.2, 4.2 Hz, 1H), 1.45 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.6 Hz, 5H) ppm. MS: M / e 442 (M+1) + 。

[0481] Compound A35: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0482] Step A: 1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethan-1-one [ka]

[0483] A mixture of 5-chloro-2-methylthiazolo[5,4-b]pyridine (250 mg, 1.35 mmol), tributyl(1-ethoxyvinyl)stannane (738 mg, 2.04 mmol), and Pd(PPh3)2Cl2 (95 mg, 0.14 mmol) in DMF (3 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was purified by flash column chromatography. The product was diluted with ethyl acetate, HCl (3 mL, 3 M in dioxane) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated, adjusted to pH = 8-9 with saturated NaHCO3 solution, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The resulting residue was purified by flash column chromatography to give the title compound (200 mg, 77%). MS: M / e 193 (M+1) +

[0484] Step B: 1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethan-1-ol [ka]

[0485] To a solution of 1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethan-1-one (200 mg, 1.04 mmol) in MeOH (3 mL) was added NaBH (39 mg, 1.04 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, and dried over NaSO. The resulting residue was purified by flash column chromatography to give the title compound (180 mg, 90%). MS: M / e 195 (M+1) + .

[0486] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0487] A mixture of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (160 mg, 0.5 mmol), 1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethan-1-ol (194 mg, 1 mmol), (cyanomethyl)trimethylphosphonium iodide (361 mg, 1.5 mmol), and DIPEA (387 mg, 3 mmol) in CHCN (8 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (200 mg, 80%), which was further separated by preparative HPLC (Method A) into Compound A35a (19 mg, 76%) and Compound A35b (20 mg, 80%).

[0488] Compound A35a (earlier peak). 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 5.31 (s, 1H), 4.45 (s, 1H), 4.08 (m, 1H), 3.93 (m, 3H), 3.62 (m, 1H), 3.46 (s, 3H), 3.20 (m, 1H), 2.89 (m, 4H), 2.21 (m, 1H), 1.90 (m, 2H), 1.68 (m, 1H), 1.57 (m, 1H), 1.39 (d, J = 6.6 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H), 0.53 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 505 (M+1) + .

[0489] Compound A35b (later peak)). 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 5.30 (d, J = 9.8 Hz, 1H), 4.68 (s, 1H), 4.08 (m, 1H), 3.99 (s, 2H), 3.79 (m, 1H), 3.44 (m, 4H), 3.04 (m, 2H), 2.86 (s, 3H), 2.38 (m, 1H), 2.09 (m, 1H), 1.75 (m, 3H), 1.41 (t, J = 9.8 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.58 (m, 3H) ppm. MS: M / e 505 (M+1) + .

[0490] Compound A36: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-6-fluoro-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0491] To a solution of 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (25 mg, 0.05 mmol) in MeCN (5 mL) was added Selectfluor (21 mg, 0.06 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (3 mg, 11.5%). 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(m, 1H), 7.76 (m, 1H), 6.16 (s, 1H), 4.14-3.75 (m, 1H), 3.98 (m, 4H), 3.52 (m, 4H), 3.08 (m, 2H), 2.85 (s, 3H), 2.16 (m, 1H), 1.95 (m, 2H), 1.66 (m, 2H), 1.41 (dd, J = 19.3, 6.6 Hz, 3H), 0.85 (q, J = 7.3 Hz, 3H), 0.58 (dt, J = 22.0, 7.4 Hz, 3H) ppm. MS: M / e 523 (M+1) + .

[0492] Compound A37: 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0493] Step A: Methyl thieno[2,3-b]pyridine-2-carboxylate [ka]

[0494] To a solution of 2-chloronicotinaldehyde (2.8 g, 20 mmol) in DMF (10 mL) was added methyl 2-mercaptoacetate (2.3 g, 22 mmol) and K2CO3 (4.2 g, 30 mmol) at room temperature, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (3 g, 78.9%). MS: M / e 194 (M+1) + .

[0495] Step B: Thieno[2,3-b]pyridin-2-ylmethanol [ka]

[0496] To a solution of methyl thieno[2,3-b]pyridine-2-carboxylate (2.6 g, 13.8 mmol) in THF (10 mL) was slowly added LiAlH (576 mg, 15.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. To the reaction mixture were slowly added HO (0.6 mL), 15% aqueous NaOH (0.6 mL), and HO (1.8 mL). The mixture was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (2.2 g, 100%). MS: M / e 166 (M+1) + .

[0497] Step C: Thieno[2,3-b]pyridine-2-carbaldehyde [ka]

[0498] To a solution of thieno[2,3-b]pyridin-2-ylmethanol (1.8 g, 11 mmol) in DCM was added Dess-Martin reagent (6 g, 14.2 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (1.45 g, 80.5%). MS: M / e 164 (M+1) + .

[0499] Step D: 2-(Difluoromethyl)thieno[2,3-b]pyridine [ka]

[0500] To a solution of thieno[2,3-b]pyridine-2-carbaldehyde (1.45 g, 8.9 mmol) in DCM was added DAST (7.2 g, 44.5 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (1 g, 60.9%). MS: M / e 186 (M+1) + .

[0501] Step E: 2-(Difluoromethyl)thieno[2,3-b]pyridine 7-oxide [ka]

[0502] To a solution of 2-(difluoromethyl)thieno[2,3-b]pyridine (1 g, 5.3 mmol) in DCM was added m-CPBA (1.38 g, 8 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous K2O3 solution (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was used directly in the next step. MS: M / e 202 (M+1) + .

[0503] Step F: 2-(Difluoromethyl)thieno[2,3-b]pyridine-6-carbonitrile [ka]

[0504] To a solution of 2-(difluoromethyl)thieno[2,3-b]pyridine 7-oxide from the last step in DCM was added EtN (1.5 g, 15 mmol) and TMSCN (1.5 g, 15 mmol). The reaction mixture was stirred at 90 °C overnight. HO (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (700 mg, 63.6% for two steps). MS: M / e 211 (M+1) + .

[0505] Step G: 2-(Difluoromethyl)thieno[2,3-b]pyridine-6-carbaldehyde [ka]

[0506] To a solution of 2-(difluoromethyl)thieno[2,3-b]pyridine-6-carbonitrile (416 mg, 1.98 mmol) in THF was added DABIL-H (1 M, 4 mmol, 4 mL), and the mixture was stirred at room temperature for 1 hour. 2N HCl solution (2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Saturated aqueous NaHCO3 solution (30 mL) was added to the resulting solution, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (220 mg, 52.2%). MS: M / e 214 (M+1) + .

[0507] Step H: 1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethan-1-ol [ka]

[0508] To a solution of 2-(difluoromethyl)thieno[2,3-b]pyridine-6-carbaldehyde (300 mg, 1.4 mmol) in THF, CHMgBr (3 M, 1.69 mmol, 0.56 ml) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. HO (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (290 mg, 90%). MS: M / e 230 (M+1) + .

[0509] Step I: 2-(7-((2S,5R)-4-(1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0510] A mixture of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-(difluoromethyl)thieno[2,3-b]pyridin-6-yl)ethan-1-ol (34 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol) and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 hours. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL×3), dried and concentrated. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method A) into Compound A37a (3 mg, 1.1%) and Compound A37b (4 mg, 1.5%).

[0511] Compound A37a (earlier peak). 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.14 (t, J = 55.1 Hz, 1H), 6.12 (s, 1H), 5.31 (s, 1H), 4.44 (s, 1H), 4.09 (m, 1H), 3.97 (s, 2H), 3.92 (q, J = 6.6 Hz, 1H), 3.63 (m, 1H), 3.46 (s, 3H), 3.20 (m, 1H), 2.92 (m, 1H), 2.21 (m, 1H), 1.90 (m, 2H), 1.64 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 0.54 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 540 (M+1) + .

[0512] Compound A37b (later peak)). 1 H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 8.3 Hz, 1H), 7.69 (m, 2H), 7.14 (t, J = 55.1 Hz, 1H), 6.12 (s, 1H), 5.29 (s, 1H), 4.69 (s, 1H), 4.09 (q, J = 6.6 Hz, 1H), 3.99 (s, 2H), 3.79 (m, 1H), 3.44 (m, 4H), 3.07 (m, 2H), 2.38 (m, 1H), 2.11 (m, 1H), 1.76 (m, 3H), 1.44 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H), 0.62 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 540 (M+1) + .

[0513] Compound A38: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0514] Step A: 1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one [ka]

[0515] To a solution of 6-bromo-2-methylimidazo[1,2-b]pyridazine (212 mg, 1 mmol) in DMF (10 mL) were added tributyl(1-ethoxyvinyl)stannane (470 mg, 1.3 mmol) and Pd(PPh)Cl (70 mg, 0.1 mmol). The reaction mixture was protected with a N atmosphere and stirred at 100 °C overnight. The mixture was cooled to room temperature, and 4 M HCl in EA (2 mL) was added, and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated NaHCO solution until pH = 8, diluted with H0, extracted with EA (60 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (145 mg, containing a small amount of triphenylphosphine oxide, 82%). MS: M / e 176 (M+1) + .

[0516] Step B: 1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol [ka]

[0517] To a solution of 1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one (140 mg, 0.8 mmol) in MeOH (5 mL) was added NaBH (30 mg, 0.8 mmol). The resulting mixture was stirred in an ice bath for 30 minutes. The reaction mixture was quenched with HO (20 mL), extracted with EA (80 mL), washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (130 mg, 91%). MS: M / e 178 (M+1) + .

[0518] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0519] To a solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.087 mmol), 1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol (35 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol) in CHCN (3 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to separate compound A38a (5.6 mg, 23.1%) and compound A38b (4.2 mg, 17.2%).

[0520] Compound A38a (earlier peak): 1 H NMR (400 MHz, CD3OD, 1st peak) δ 7.85 (m, 2H), 7.45 (d, J = 9.4 Hz, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 4.45 (s, 1H), 4.06 (m, 1H), 3.98 (s, 2H), 3.85 (m, 1H), 3.60 (m, 1H), 3.46 (s, 3H), 3.15 (m, 1H), 2.93 (m, 1H), 2.44 (s, 3H), 2.24 (m, 1H), 1.85 (m, 2H), 1.71 (m, 1H), 1.55 (m, 1H), 1.41 (d, J = 6.7 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.56 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0521] Compound A38b (slower peak):1 H NMR (400 MHz, CD3OD, 2nd peak) δ 7.86 (m, 2H), 7.41 (d, J = 9.4 Hz, 1H), 6.12 (s, 1H), 5.29 (s, 1H), 4.68 (s, 1H), 4.03 (m, 3H), 3.81 (m, 1H), 3.46 (s, 4H), 3.08 (m, 1H), 2.94 (m, 1H), 2.45 (m, 4H), 2.03 (m, 1H), 1.78 (m, 2H), 1.67 (d, J = 7.9 Hz, 1H), 1.43 (t, J = 9.9 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H), 0.68 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0522] Compound A39: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0523] Step A: 1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one. [ka]

[0524] A mixture of 5-bromopyrazolo[1,5-a]pyrimidine (0.5 g, 2.5 mmol), tributyl(1-ethoxyvinyl)stannane (1.38 g, 3.8 mmol), and Pd(PPh3)2Cl2 (178 mg, 0.25 mmol) in DMF (20 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was purified by flash column chromatography to give 5-(1-ethoxyvinyl)pyrazolo[1,5-a]pyrimidine, which was then diluted with DCM, HCl (5 mL, 4 M in dioxane) was added dropwise, and the mixture was stirred at room temperature for 3 h. The reaction was concentrated, adjusted to pH 8–9 with saturated NaHCO3 solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and the resulting residue was purified by flash column chromatography to give the title compound (0.17 g, 41%). MS: M / e 162(M+1) +

[0525] Step B: 1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0526] To a solution of 1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (170 mg, 1.06 mmol) in MeOH (5 mL) was added NaBH (32 mg, 0.84 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (70 mg). MS: M / e 164 (M+1) + .

[0527] Step C: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0528] To a solution of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (32 mg, 0.2 mmol), and (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol) in CHCN (3 mL) was added DIPEA (258 mg, 2 mmol). The reaction mixture was sealed in a bottle and heated at 105 °C for 16 h, then cooled to room temperature, diluted with water, and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to separate compound A39a (3.2 mg, 13.5%) and compound A39b (2.3 mg, 9.7%).

[0529] Compound A39a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 8.87 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 6.61 (m, 1H), 6.13 (s, 1H), 5.33 (s, 1H), 4.49 (s, 1H), 4.09 (m, 1H), 3.98 (s, 2H), 3.80 (q, J = 6.5 Hz, 1H), 3.64 (m, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 2.96 (m, 1H), 2.25 (m, 1H), 1.85 (m, 3H), 1.55 (m, 1H), 1.39 (d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.61 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0530] Compound A39b (slower peak): 1 H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.62 (m, 1H), 6.13 (s, 1H), 5.30 (s, 1H), 4.71 (s, 1H), 3.99 (m, 3H), 3.81 (m, 1H), 3.47 (m, 4H), 3.26 (m, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.47 (m, 1H), 2.07 (m, 1H), 1.80 (m, 2H), 1.67 (m, 1H), 1.42 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H), 0.68 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0531] Compound A40: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0532] Step A: 5-Chloro-2-methylpyrazolo[1,5-a]pyrimidine [ka]

[0533] To a solution of 2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.5 g, 3.36 mmol) in CHCN (6 mL) was added POCl (1 g, 6.7 mmol). The mixture was stirred at 100 °C for 3 h. The reaction was concentrated, poured into saturated aqueous NaHCO and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO and concentrated to give the title compound (0.33 g, 56%). MS: M / e 168 (M+1) + .

[0534] Step B: 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0535] A mixture of 5-chloro-2-methylpyrazolo[1,5-a]pyrimidine (0.33 g, 1.9 mmol), tributyl(1-ethoxyvinyl)stannane (0.86 g, 2.4 mmol), and Pd(PPh3)2Cl2 (139 mg, 0.19 mmol) in DMF (5 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was purified by flash column chromatography to give 5-(1-ethoxyvinyl)-2-methylpyrazolo[1,5-a]pyrimidine, which was then diluted with DCM. HCl (5 mL, 4 M in dioxane) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated, adjusted to pH 8–9 with saturated NaHCO3 solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.22 g, 76%). MS: M / e 176 (M+1) +

[0536] Step C: 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0537] To a solution of 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.18 g, 0.73 mmol) in MeOH (5 mL) was added NaBH (23 mg, 0.56 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (170 mg, 85%). MS: M / e 178 (M+1). + .

[0538] Step D: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0539] A mixture of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (60 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method A) into Compound A40a (1.9 mg, 7.9%) and Compound A40b (2.2 mg, 9.1%).

[0540] Compound A40a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.40 (s, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 4.48 (s, 1H), 4.07 (m, 1H), 3.98 (s, 2H), 3.75 (m, 1H), 3.62 (m, 1H), 3.46 (s, 3H), 3.15 (m, 1H), 2.95 (m, 1H), 2.47 (s, 3H), 2.25 (m, 1H), 1.82 (m, 3H), 1.56 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H), 0.61 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0541] Compound A40b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 7.1 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.41 (s, 1H), 6.12 (s, 1H), 5.30 (s, 1H), 4.70 (s, 1H), 3.95 (m, 3H), 3.81 (m, 1H), 3.46 (m, 4H), 3.07 (m, 1H), 2.96 (m, 1H), 2.47 (m, 4H), 2.07 (m, 1H), 1.80 (m, 2H), 1.66 (d, J = 7.4 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H), 0.68 (d, J = 7.3 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0542] Compound A41: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0543] Step A: 2-Fluoropyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0544] A mixture of 3-fluoro-1H-pyrazol-5-amine (0.25 g, 2.47 mmol), ethyl (E)-3-ethoxyacrylate (0.7 g, 4.9 mmol), and CsCO (1.6 g, 4.9 mmol) in DMF (10 mL) was stirred at 110° C. under N for 16 h. The solution was collected by filtration, and then acetic acid (5 mL) was added. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.46 g). MS: M / e 154 (M+1) +

[0545] Step B: 5-Chloro-2-fluoropyrazolo[1,5-a]pyrimidine [ka]

[0546] To a solution of 2-fluoropyrazolo[1,5-a]pyrimidin-5(4H)-one (0.46 g, 3 mmol) in CHCN (8 mL) was added POCl (0.92 g, 6 mmol). The mixture was stirred at 90 °C for 3 h. The reaction was concentrated, poured into saturated NaHCO solution, and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.27 g, 52%). MS: M / e 172 (M+1) + .

[0547] Step C: 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0548] A mixture of 5-chloro-2-fluoropyrazolo[1,5-a]pyrimidine (0.27 g, 1.58 mmol), tributyl(1-ethoxyvinyl)stannane (0.68 g, 1.89 mmol), and Pd(PPh3)2Cl2 (110 mg, 0.27 mmol) in DMF (5 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was purified by flash column chromatography to give 5-(1-ethoxyvinyl)-2-fluoropyrazolo[1,5-a]pyrimidine, which was then diluted with DCM. HCl (5 mL, 4 M in dioxane) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated, adjusted to pH 8–9 with saturated NaHCO3 solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.18 g, 63%). MS: M / e 180 (M+1) +

[0549] Step D: 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0550] To a solution of 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.17 g, 0.95 mmol) in MeOH (5 mL) was added NaBH (22 mg, 0.57 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (150 mg). MS: M / e 182 (M+1) + .

[0551] Step E: 2-(7-((2S,5R)-2,5-diethyl-4-(1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0552] A mixture of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (60 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL×3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method A) into Compound A41a (0.69 mg, 2.8%) and Compound A41b (0.85 mg, 3.5%).

[0553] Compound A41a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 6.18 (d, J = 4.9 Hz, 1H), 6.12 (s, 1H), 5.33 (s, 1H), 4.48 (s, 1H), 4.07 (m, 1H), 3.98 (s, 2H), 3.78 (m, 1H), 3.64 (m, 1H), 3.46 (s, 3H), 3.13 (m, 1H), 2.95 (m, 1H), 2.27 (m, 1H), 1.81 (m, 3H), 1.55 (m, 1H), 1.38 (d, J = 6.7 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.63 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 492 (M+1) + .

[0554] Compound A41b (later peak): 1 H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 7.1 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.18 (d, J = 4.9 Hz, 1H), 6.12 (s, 1H), 5.30 (s, 1H), 4.68 (m, 1H), 3.98 (m 3H), 3.82 (m, 1H), 3.46 (m, 4H), 3.07 (m, 1H), 2.96 (m, 1H), 2.48 (m, 1H), 2.14 (m, 1H), 1.81 (m, 2H), 1.65 (m, 1H), 1.40 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 7.5 Hz, 3H), 0.69 (m, 3H) ppm. MS: M / e 492 (M+1) + .

[0555] Compound A42: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0556] A mixture of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (60 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method A) into Compound A42a (0.69 mg, 2.76%) and Compound A42b (0.87 mg, 3.48%).

[0557] Compound A42a (earlier peak): 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.40 (s, 1H), 6.12 (s, 1H), 5.35 (s, 1H), 4.64 (s, 1H), 3.99 (d, J = 15.1 Hz, 3H), 3.78 (m, 1H), 3.64 (m, 1H), 3.46 (s, 3H), 3.16 (m, 1H), 2.97 (m, 1H), 2.46 (s, 3H), 2.15 (m, 1H), 1.91 (m, 1H), 1.56 m, 1H), 1.39 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0558] Compound A42b (slower peak): 1 H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 7.1 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.41 (s, 1H), 6.12 (s, 1H), 5.33 (s, 1H), 3.96 (m, 3H), 3.74 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.82 (m, 1H), 2.47 (m, 4H), 1.79 (m, 1H), 1.67 (m, 1H), 1.40 (d, J = 6.6 Hz, 3H), 1.35 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 7.3 Hz, 3H) ppm. MS: M / e 474 (M+1) + .

[0559] Compound A43: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0560] Step A: 2-Methylpyrazolo[1,5-a]pyrimidine-5-carbonitrile [ka]

[0561] To a stirred solution of 5-chloro-2-methylpyrazolo[1,5-a]pyrimidine (1 g, 6 mmol) in DMF (15 mL) was added ZnCN (2.1 g, 18 mmol), followed by Pd(PPh) (0.7 g, 0.6 mmol). After the addition, the reaction mixture was stirred overnight at 100° C. under N. The reaction mixture was poured into H0 (20 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (650 mg, 68.5%). MS: M / e 159 (M+1) + .

[0562] Step B: 2-Methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid [ka]

[0563] To a stirred solution of 2-methylpyrazolo[1,5-a]pyrimidine-5-carbonitrile (650 mg, 4.11 mmol) in EtOH / HO (20 mL / 5 mL) was added NaOH (658 mg, 16.4 mmol). After the addition, the reaction mixture was stirred at 80 °C overnight. The reaction mixture was acidified with aqueous HCl to pH = 5-6 and then concentrated to give the title compound (crude, 100%), which was used directly in the next step. MS: M / e 178 (M+1) + .

[0564] Step C: N-Methoxy-N,2-dimethylpyrazolo[1,5-a]pyrimidine-5-carboxamide [ka]

[0565] A mixture of 2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid (crude, 4.11 mmol), N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.93 mmol), HATU (1.88 g, 4.93 mmol), and DIPEA (1.06 g, 8.22 mmol) in CHCl (40 mL) was stirred overnight. The reaction mixture was poured into HO (40 mL) and then extracted with CHCl (40 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (690 mg, 76.3%). MS: M / e 221 (M+1) + .

[0566] Step D: 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propan-1-one [ka]

[0567] To a stirred solution of N-methoxy-N,2-dimethylpyrazolo[1,5-a]pyrimidine-5-carboxamide (690 mg, 3.14 mmol) in THF (10 mL) was added EtMgBr (3.0 M, 1.56 mL, 4.7 mL) dropwise at 0 °C. The mixture was then stirred for 20 min. The reaction was quenched with aqueous NH4Cl and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (26 mg, 4.38%). MS: M / e 190 (M+1) + .

[0568] Step E: 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol [ka]

[0569] To a stirred solution of 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propan-1-one (60 mg, 0.32 mol) in MeOH (5 mL) was added NaBH (12 mg, 0.32 mmol). The reaction mixture was then stirred for 10 min. The reaction mixture was treated with HO (10 mL), then concentrated to remove MeOH, and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (60 mg, 98%). MS: M / e 192 (M+1) + .

[0570] Step F: 2-(7-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0571] A mixture of 2-(7-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol (60 mg, 0.3 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 hours. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL×3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound (1.39 mg, 2.8%). 1 H NMR (400 MHz, CD3OD) δ 8.73 (m, 1H), 7.13 (m, 1H), 6.42 (d, J = 7.8 Hz, 1H), 6.11 (s, 1H), 5.33 (d, J = 5.5 Hz, 1H), 4.66 (m, 1H), 3.98 (s, 2H), 3.77 (m, 1H), 3.59 (m, 1H), 3.46 (m, 4H), 3.14 (m, 1H), 3.2-2.85 (m, 1H), 2.47 (s, 3H), 2.02 (m, 1H), 1.90 (m, 1H), 1.77 (m, 2H), 1.54 (m, 1H), 1.34 - 1.18 (m, 3H), 0.97-0.79 (m, 3H), 0.71 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0572] Compound A44: 2-(7-((2S,5R)-4-(1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0573] Step A: 2-Chlorothieno[3,2-b]pyridine [ka]

[0574] A solution of thieno[3,2-b]pyridine (3.15 g, 23.3 mmol) in THF (30 mL) was cooled to -70 °C under N protection, and n-BuLi (1.6 M, 35 mmol, 21.8 mL) was added. The reaction mixture was stirred at -70 °C for 0.5 h. NCS (6.2 g, 46.6 mmol) was added, and the reaction was allowed to warm slowly to room temperature. HO was added to the mixture, which was then extracted with EtOAc. The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EtOAc in PE to give the title compound (3.2 g, 82.5%). MS: M / e 170 (M+1) + .

[0575] Step B: 2-chlorothieno[3,2-b]pyridine 4-oxide [ka]

[0576] To a solution of 2-chlorothieno[3,2-b]pyridine (1.4 g, 8.3 mmol) in DCM (30 mL) was added m-CPBA (2.1 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 2M K2CO3 solution (30 mL) and then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated to give the title compound, which was used directly in the next step. MS: M / e 186 (M+1) + .

[0577] Step C: 2-chlorothieno[3,2-b]pyridine-5-carbonitrile [ka]

[0578] To a solution of 2-chlorothieno[3,2-b]pyridine 4-oxide from the last step in MeCN (15 mL) was added EtN (2 g, 20 mmol) and TMSCN (1.9 g, 19.4 mmol). The reaction was stirred at 90 °C for 3 h. HO (30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (0.8 g, 50% for two steps). MS: M / e 195 (M+1) + .

[0579] Step D: 1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethan-1-one [ka]

[0580] A solution of 2-chlorothieno[3,2-b]pyridine-5-carbonitrile (420 mg, 2 mmol) in THF was cooled to 0°C. To this mixture, CHMgBr (1 M, 2 mmol, 2 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. HO (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (45 mg, 10.6%). MS: M / e 212 (M+1) + .

[0581] Step E: 1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethan-1-ol [ka]

[0582] To a solution of 1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethan-1-one (45 mg, 0.2 mmol) in MeOH was added NaBH (9 mg, 0.25 mmol), and the reaction mixture was stirred at room temperature for 15 minutes. H2O (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (30 mg, 67%). MS: M / e 214 (M+1) + .

[0583] Step F: 2-(7-((2S,5R)-4-(1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile [ka]

[0584] A mixture of 2-(7-((2S,5R)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-chlorothieno[3,2-b]pyridin-5-yl)ethan-1-ol (30 mg, 0.15 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in CHCN (3 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL × 3), dried, and concentrated. The resulting residue was purified by flash column chromatography to give the title compound, which was further separated by preparative HPLC (Method A) into Compound A44a (2.5 mg, 9.5%) and Compound A44b (3.5 mg, 13.4%).

[0585] Compound A44a (earlier peak): 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 4.45 (s, 1H), 4.08 (m, 1H), 3.97 (s, 2H), 3.87 (m, 1H), 3.64 (m, 1H), 3.46 (s, 3H), 3.20 (m, 1H), 2.91 (m, 1H), 2.20 (m, 1H), 1.90 (m, 2H), 1.70 (m, 1H), 1.58 (m, 1H), 1.39 (d, J = 6.7 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 0.54 (t, J = 7.5 Hz, 3H) ppm. MS: M / e 524 (M+1) + .

[0586] Compound A44b (slower peak): 1 H NMR (400 MHz, CD3OD) δ 8.28 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 6.12 (s, 1H), 5.29 (s, 1H), 4.71 (m, 1H), 4.05 (m, 1H), 3.99 (s, 2H), 3.79 (m, 1H), 3.45 (m, 4H), 3.06 (m, 2H), 2.38 (m, 1H), 2.12 (m, 1H), 1.77 (m, 3H), 1.41 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H), 0.60 (t, J = 7.4 Hz, 3H) ppm. MS: M / e 524 (M+1) + .

[0587] Compound A45: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0588] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (50 mg, 0.15 mmol), 1-(2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol (54 mg, 0.31 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (196 mg, 1.52 mmol) in CHCN (2 mL) was stirred at 100° C. overnight. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-10% MeOH in DCM, which was then further separated by preparative HPLC (Method A) into Compound A45a (3.1 mg, 4%) and Compound A45b (3.6 mg, 5%).

[0589] Compound A45a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 7.89 - 7.79 (m, 2H), 7.44 (d, J = 9.1 Hz, 1H), 6.43 - 6.12 (m, 0.5H), 6.03 (s, 1H), 5.95 - 5.65 (m, 0.5H), 5.09 - 4.88 (m, 1H), 4.02 - 3.95 (m, 1H), 3.86 - 3.74 (m, 1H), 3.41 (s, 3H), 3.36 - 3.31 (m, 2H), 3.20 - 3.10 (m, 1H), 2.85 - 2.73 (m, 1H), 2.44 (s, 3H), 2.28 (d, J = 11.9 Hz, 1H), 2.00 - 1.75 (m, 2H), 1.64 - 1.46 (m, 2H), 1.40 (d, J = 5.3 Hz, 3H), 1.09 - 0.95 (m, 3H), 0.74 - 0.63 (m, 3H) ppm. MS: M / e 489 (M+1) +

[0590] Compound A45b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 7.90 - 7.80 (m, 2H), 7.39 (d, J = 9.0 Hz, 1H), 6.25 - 5.85 (m, 2H), 5.03 - 4.88 (m, 1H), 4.02 - 3.95 (m, 2H), 3.41 (s, 3H), 3.34 - 3.31 (m, 2H), 3.00 - 2.87 (m, 2H), 2.52 - 2.37 (m, 4H), 2.10 - 1.93 (m, 2H), 1.69 - 1.48 (m, 2H), 1.42 (d, J = 6.3 Hz, 3H), 0.97 - 0.86 (m, 3H), 0.83 - 0.68 (m, 3H) ppm. MS: M / e 489 (M+1) +

[0591] Compound A46: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0592] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (250 mg, 0.76 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (269 mg, 1.52 mmol), (cyanomethyl)trimethylphosphonium iodide (554 mg, 2.28 mmol), and DIPEA (980 mg, 7.60 mmol) in CHCN (6 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (15 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A46a (40.7 mg, 11.0%) and compound A46b (40.0 mg, 10.8%).

[0593] Compound A46a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.40 (s, 1H), 6.04 (s, 1H), 4.91 - 4.85 (m, 2H), 3.99 (s, 2H), 3.72 (q, J = 6.6 Hz, 1H), 3.42 (s, 3H), 3.35 - 3.31 (m, 1H), 3.21 - 3.11 (m, 1H), 2.79 (d, J = 11.7 Hz, 1H), 2.47 (s, 3H), 2.29 (d, J = 11.7 Hz, 1H), 2.04 - 1.83 (m, 2H), 1.65 - 1.45 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 6.8 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 489 (M+1) + .

[0594] Compound A46b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), 6.41 (s, 1H), 6.04 (s, 1H), 5.04 - 4.87 (m, 2H), 4.06 - 3.86 (m, 2H), 3.42 (s, 3H), 3.36 - 3.32 (m, 2H), 3.02 - 2.87 (m, 2H), 2.54 - 2.40 (m, 4H), 2.12 - 2.00 (m, 2H), 1.68 - 1.50 (m, 2H), 1.39 (d, J = 6.5 Hz, 3H), 0.95 (t, J = 6.8 Hz, 3H), 0.76 (s, 3H) ppm. MS: M / e 489 (M+1) + .

[0595] Compound A47: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0596] Step A: 4-Fluoro-3-methyl-1H-pyrazol-5-amine [ka]

[0597] To a solution of 3-methyl-1H-pyrazol-5-amine (0.5 g, 5.1 mmol) in CHCN (20 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.6 g, 4.6 mmol) and stirred at room temperature under N for 16 hours. The solution was purified by flash column chromatography to give the title compound (0.41 g). MS: M / e 116 (M+1). +

[0598] Step B: 3-Fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0599] A mixture of 4-fluoro-3-methyl-1H-pyrazol-5-amine (0.41 g, 3.5 mmol), ethyl (E)-3-ethoxyacrylate (1 g, 7.1 mmol), and CsCO (2.3 g, 7.1 mmol) in DMF (15 mL) was stirred at 110° C. under N for 16 h. The solution was collected by filtration, and then acetic acid (5 mL) was added. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.09 g, 15%). MS: M / e 168 (M+1) +

[0600] Step C: 5-Chloro-3-fluoro-2-methylpyrazolo[1,5-a]pyrimidine [ka]

[0601] To a solution of 3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.09 g, 0.54 mmol) in CHCN (3 mL) was added POCl (0.16 g, 1 mmol). The mixture was stirred at 90 °C for 3 hours. The reaction was concentrated, poured into saturated NaHCO solution, and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.07 g, 70%). MS: M / e 186 (M+1) + .

[0602] Step D: 1-(3-Fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0603] A mixture of 5-chloro-3-fluoro-2-methylpyrazolo[1,5-a]pyrimidine (0.07 g, 0.38 mmol), tributyl(1-ethoxyvinyl)stannane (0.16 g, 0.45 mmol), and Pd(PPh3)2Cl2 (27 mg, 0.038 mmol) in DMF (2 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.06 g, 82%). MS: M / e 194 (M+1) +

[0604] Step E: 1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0605] To a solution of 1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.06 g, 0.31 mmol) in MeOH (5 mL) was added NaBH (7 mg, 0.18 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (150 mg). MS: M / e 196 (M+1) + .

[0606] Step F: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0607] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (100 mg, 0.30 mmol), 1-(3-fluoro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (118.5 mg, 0.61 mmol), (cyanomethyl)trimethylphosphonium iodide (222 mg, 0.91 mmol), and DIPEA (392 mg, 3.04 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A47a (21.9 mg, 14.2%) and compound A47b (20.5 mg, 13.3%).

[0608] Compound A47a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.04 (s, 1H), 4.94 - 4.87 (m, 2H), 3.99 (s, 2H), 3.75 (q, J = 6.6 Hz, 1H), 3.42 (s, 3H), 3.35 - 3.32 (m, 1H), 3.21 - 3.10 (m, 1H), 2.86 - 2.76 (m, 1H), 2.45 (s, 3H), 2.32 (d, J = 12.9 Hz, 1H), 2.04 - 1.82 (m, 2H), 1.67 - 1.47 (m, 2H), 1.38 (d, J = 6.7 Hz, 3H), 1.02 (t, J = 6.9 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H) ppm. MS: M / e 507 (M+1) + .

[0609] Compound A47b (slower peak): 1H NMR (400 MHz, CD3OD) δ 8.62 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.04 (s, 1H), 4.96 - 4.87 (m, 2H), 4.02 - 3.89 (m, 2H), 3.60 - 3.44 (m, 1H), 3.42 (s, 3H), 3.37 - 3.32 (m, 1H), 3.01 - 2.89 (m, 2H), 2.54 - 2.42 (m, 4H), 2.12 - 1.98 (m, 2H), 1.70 - 1.50 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H), 0.94 (t, J = 6.8 Hz, 3H), 0.79 (s, 3H) ppm. MS: M / e 507 (M+1) + .

[0610] Compound A48: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0611] Step A: 6-chloro-3-fluoro-2-methylimidazo[1,2-b]pyridazine [ka]

[0612] To a solution of 6-chloro-2-methylimidazo[1,2-b]pyridazine (501 mg, 3 mmol) in CHCN (10 mL) was added Selectfluor (1.06 g, 3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with HO (60 mL), basified to pH 8 with saturated NaHCO solution, extracted with EA (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography to give the title compound (50 mg, 9%). MS: M / e 186 (M+1) + .

[0613] Step B: 1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one [ka]

[0614] To a solution of 6-chloro-3-fluoro-2-methylimidazo[1,2-b]pyridazine (50 mg, 0.27 mmol) in DMF (5 mL) were added tributyl(1-ethoxyvinyl)stannane (117 mg, 0.32 mmol) and Pd(PPh)Cl (20 mg, 0.027 mmol). The reaction mixture was protected with a N atmosphere and stirred at 100 °C overnight. The mixture was cooled to room temperature, and 4 M HCl in EA (1 mL) was added. The resulting mixture was stirred for 2 h. The reaction was quenched with saturated NaHCO solution until pH 8, diluted with H0, extracted with EA (70 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (20 mg, 38%). MS: M / e 194 (M+1) + .

[0615] Step C: 1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol [ka]

[0616] To a solution of 1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one (20 mg, 0.1 mmol) in MeOH (4 mL) was added NaBH (4 mg, 0.1 mmol). The resulting mixture was stirred in an ice bath for 30 minutes. The reaction mixture was quenched with HO (15 mL), extracted with EA (30 mL x 3), washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (20 mg, 100%). MS: M / e 196 (M+1) + .

[0617] Step D: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0618] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (92.8 mg, 0.28 mmol), 1-(3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol (55 mg, 0.28 mmol), (cyanomethyl)trimethylphosphonium iodide (206 mg, 0.85 mmol), and DIPEA (364 mg, 2.82 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compounds A48a (2.5 mg, 1.8%) and A48b (3.4 mg, 2.4%).

[0619] Compound A48a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 7.84 (d, J = 9.8 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H), 6.45 - 5.73 (m, 2H), 5.10 - 4.87 (m, 2H), 3.99 (s, 1H), 3.87 (q, J = 6.6 Hz, 1H), 3.42 (s, 3H), 3.37 - 3.33 (m, 1H), 3.25 - 3.11 (m, 1H), 2.79 (d, J = 11.7 Hz, 1H), 2.41 (s, 3H), 2.29 (d, J = 12.3 Hz, 1H), 2.05 - 1.77 (m, 2H), 1.66 - 1.50 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H), 1.03 (t, J = 6.8 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 507 (M+1) + .

[0620] Compound A48b (later peak): 1 H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 9.5 Hz, 1H), 7.40 (d, J = 9.4 Hz, 1H), 6.35 - 5.75 (m, 2H), 5.16 - 4.88 (m, 1H), 4.06 (q, J = 6.6 Hz, 1H), 3.98 (s, 1H), 3.42 (s, 3H), 3.36 - 3.33 (m, 2H), 3.00 - 2.90 (m, 2H), 2.53 - 2.37 (m, 4H), 2.08 - 1.95 (m, 2H), 1.70 - 1.54 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H), 0.92 (t, J = 6.8 Hz, 3H), 0.82 - 0.77 (m, 3H) ppm. MS: M / e 507 (M+1) + .

[0621] Compound A49: 2-(4-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0622] Step A: 1-(6-cyclopropylpyridin-3-yl)ethan-1-one [ka]

[0623] A mixture of 1-(6-bromopyridin-3-yl)ethan-1-one (1 g, 5 mmol), cyclopropylboronic acid (473 mg, 5.5 mmol), tricyclohexylphosphane (140 mg, 0.5 mmol), potassium phosphate (1.6 g, 7.5 mmol), and Pd(OAc) (112 mg, 0.5 mmol) in toluene (15 mL) and water (1.5 mL) was stirred overnight at 100 °C under N. The mixture was treated with water (50 mL), extracted with EtOAc (20 mL × 3), washed with brine (50 mL), dried, and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-50% EtOAc in PE, 25 min) to give the title compound (620 mg, 77%). MS: M / e 162 (M+1). + .

[0624] Step B: 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol [ka]

[0625] To a solution of 1-(6-cyclopropylpyridin-3-yl)ethan-1-one (620 mg, 3.8 mmol) in MeOH (10 mL) was added NaBH (117 mg, 3.1 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The resulting mixture was treated with water (100 ml) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and concentrated to dryness. The resulting residue was purified by flash column chromatography (0-100% EtOAc in PE, 25 min) to give the title compound (420 mg, 68%). MS: M / e 164 (M+1) + .

[0626] Step C: 2-(4-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0627] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (50 mg, 0.15 mmol), 1-(6-cyclopropylpyridin-3-yl)ethan-1-ol (49.5 mg, 0.30 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (196 mg, 1.52 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A49a (1.73 mg, 2.4%) and compound A49b (2.45 mg, 3.4%).

[0628] Compound A49a (earlier peak): 1 H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.19 - 5.89 (m, 2H), 5.00 - 4.88 (m, 2H), 4.02 - 3.94 (m, 1H), 3.77 (q, J = 6.4 Hz, 1H), 3.41 (s, 3H), 3.35 - 3.33 (m, 1H), 2.99 (d, J = 10.9 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.44 - 2.31 (m, 1H), 2.15 - 1.97 (m, 3H), 1.58 - 1.45 (m, 2H), 1.34 (d, J = 6.5 Hz, 3H), 1.05 - 1.01 (m, 2H), 0.98 - 0.93 (m, 5H), 0.72 (s, 3H) ppm. MS: M / e 475 (M+1) + .

[0629] Compound A49b (slower peak): 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.35 - 5.73 (m, 2H), 5.00 - 4.88 (m, 1H), 4.02 - 3.95 (m, 1H), 3.61 (q, J = 6.5 Hz, 1H), 3.42 (s, 3H), 3.36 - 3.32 (m, 2H), 3.22 - 3.12 (m, 1H), 2.71 - 2.59 (m, 1H), 2.30 (d, J = 12.8Hz, 1H), 2.09 - 2.04 (m, 1H), 1.93 - 1.83 (m, 2H), 1.59 - 1.53 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H), 1.05 - 0.99 (m, 5H), 0.94 - 0.90 (m, 2H), 0.68 (t, J = 6.9 Hz, 3H) ppm. MS: M / e 475 (M+1) + .

[0630] Compound A50: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0631] Step A: 3-Fluoropyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0632] A mixture of 4-fluoro-1H-pyrazol-5-amine (0.5 g, 5.1 mmol), ethyl (E)-3-ethoxyacrylate (1.4 g, 10 mmol), and CsCO (3.2 g, 10 mmol) in DMF (20 mL) was stirred at 110° C. under N for 16 h. The solution was collected by filtration, and then acetic acid (5 mL) was added. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.7 g, 93%). MS: M / e 154 (M+1) +

[0633] Step B: 5-Chloro-3-fluoropyrazolo[1,5-a]pyrimidine [ka]

[0634] To a solution of 3-fluoropyrazolo[1,5-a]pyrimidin-5(4H)-one (0.7 g, 4.5 mmol) in CHCN (10 mL) was added POCl (1.4 g, 9.1 mmol). The mixture was stirred at 90 °C for 3 h. The reaction was concentrated, poured into saturated NaHCO solution, and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.3 g, 38%). MS: M / e 172 (M+1) + .

[0635] Step C: 1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0636] A mixture of 5-chloro-3-fluoropyrazolo[1,5-a]pyrimidine (0.3 g, 1.75 mmol), tributyl(1-ethoxyvinyl)stannane (0.76 g, 2.1 mmol), and Pd(PPh3)2Cl2 (123 mg, 0.17 mmol) in DMF (5 mL) was stirred at 100 °C under N2 for 16 h. The solution was diluted with EA and washed with water. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.21 g, 66%). MS: M / e 180 (M+1) +

[0637] Step D: 1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0638] To a solution of 1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.21 g, 1.17 mmol) in MeOH (5 mL) was added NaBH (27 mg, 0.7 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (150 mg). MS: M / e 182 (M+1) + .

[0639] Step E: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0640] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (50 mg, 0.15 mmol), 1-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (55 mg, 0.30 mmol), (cyanomethyl)trimethylphosphonium iodide (111 mg, 0.46 mmol), and DIPEA (196 mg, 1.52 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM and then further purified by preparative HPLC (Method A) to give the title compound (4.5 mg, 6.0%). 1 H NMR (400 MHz, CD3OD) δ 8.76 - 8.69 (m, 1H), 8.09 (d, J = 3.1 Hz, 1H), 7.22 (dd, J = 19.7, 7.3 Hz, 1H), 6.35 - 5.75 (m, 2H), 5.10 - 4.88 (m, 1H), 4.84 - 4.65 (m, 1H), 3.98 (q, J = 6.6 Hz, 1H), 3.79 (q, J = 6.6 Hz, 0.5H), 3.42 (s, 3H), 3.36 - 3.32 (m, 1.5H), 3.23 - 3.12 (m, 0.5H), 3.01 - 2.90 (m, 1H), 2.88 - 2.77 (m, 0.5H), 2.55 - 2.43 (m, 0.5H), 2.31 (d, J = 13.2 Hz, 0.5H), 2.13 - 1.83 (m, 2H), 1.69 - 1.51 (m, 2H), 1.43 - 1.37 (m, 3H), 1.06 - 1.00 (m, 1.5H), 0.96 - 0.92(m, 1.5H), 0.78- 0.71 (m, 3H) ppm. MS: M / e 493 (M+1) + .

[0641] Compound A51: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0642] Step A: 6-chloro-2-ethylimidazo[1,2-b]pyridazine [ka]

[0643] To a solution of 6-chloropyridazin-3-amine (0.65 g, 5 mmol) in EtOH (10 mL) was added 1-bromobutan-2-one (0.83 g, 5.5 mmol). The mixture was stirred at 85° C. for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with H2O (50 ml), basified with saturated NaHCO3 solution to pH = 8, extracted with EtOAc (70 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to give the title compound (605 mg, 66%). MS: M / e 182 (M+1) + .

[0644] Step B: 1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one [ka]

[0645] To a solution of 6-chloro-2-ethylimidazo[1,2-b]pyridazine (605 mg, 3.34 mmol) in DMF (15 mL) were added tributyl(1-ethoxyvinyl)stannane (1.33 g, 3.67 mmol) and Pd(PPh)Cl. The reaction mixture was protected with a N atmosphere and stirred at 100 °C overnight. The mixture was cooled to room temperature, and 4 M HCl in EA (10 mL) was added. The resulting mixture was stirred for 5 h. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (70 mL × 2). The aqueous layer was basified to pH = 8 with saturated NaHCO solution, extracted with EtOAc (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (560 mg, 88%). MS: M / e 190 (M+1) + .

[0646] Step C: 1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol [ka]

[0647] To a solution of 1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one (560 mg, 2.97 mmol) in MeOH (10 mL) was added NaBH (112 mg, 2.97 mmol). The resulting mixture was stirred in an ice bath for 30 minutes. The reaction mixture was quenched with HO (60 mL), extracted with EtOAc (70 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the desired product (500 mg, 87%). MS: M / e 192 (M+1) + .

[0648] Step D: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0649] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.20 mmol), 1-(2-ethylimidazo[1,2-b]pyridazin-6-yl)ethan-1-ol (76.6 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (146.2 mg, 0.60 mmol), and DIPEA (258.8 mg, 2.01 mmol) in CHCN (2 mL) was stirred at 100 °C for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A51a (12.6 mg, 12.5%) and compound A51b (15.2 mg, 15.1%).

[0650] Compound A51a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 9.4 Hz, 1H), 7.83 (s, 1H), 7.45 (d, J = 9.4 Hz, 1H), 6.40 - 5.70 (m, 2H), 5.11 - 4.88 (m, 1H), 4.85 - 4.62 (m, 1H), 4.05 - 3.93 (m, 1H), 3.81 (q, J = 6.6 Hz, 1H), 3.42 (s, 3H), 3.37 - 3.32 (m, 1H), 3.22 - 3.10 (m, 1H), 2.87 - 2.73 (m, 3H), 2.29 (d, J = 12.1 Hz, 1H), 2.00 - 1.78 (m, 2H), 1.70 - 1.48 (m, 2H), 1.41 (d, J = 6.5 Hz, 3H), 1.34 (t, J = 7.5 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.1 Hz, 3H) ppm. MS: M / e 503 (M+1) + .

[0651] Compound A51b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 9.5 Hz, 1H), 7.85 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 6.22 - 5.85 (m, 2H), 5.13 - 4.89 (m, 1H), 4.06 - 3.92 (m, 2H), 3.46 - 3.34 (m, 5H), 3.00 - 2.88 (m, 2H), 2.82 (q, J = 7.4 Hz, 2H), 2.52 - 2.38 (m, 1H), 2.10 - 1.94 (m, 2H), 1.70 - 1.53 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.34 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H), 0.77 (s, 3H) ppm. MS: M / e 503 (M+1) + .

[0652] Compound A52: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0653] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.20 mmol), 1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethan-1-ol (77.8 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (146.2 mg, 0.60 mmol), and DIPEA (258.8 mg, 2.01 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A52a (10.2 mg, 10%) and compound A52b (17.5 mg, 17%).

[0654] Compound A52a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 6.40 - 5.70 (m, 2H), 5.14 - 4.88 (m, 1H), 4.86 - 4.62 (m, 1H), 3.98 (s, 1H), 3.86 (q, J = 6.5 Hz, 1H), 3.42 (s, 3H), 3.38 - 3.32 (m, 1H), 3.26 - 3.11 (m, 1H), 2.85 (s, 3H), 2.74 (d, J = 6.5 Hz, 1H), 2.25 (d, J= 12.5 Hz, 1H), 2.00 - 1.85 (m, 2H), 1.64 - 1.50 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 6.8 Hz, 3H), 0.67 (t, J = 6.8 Hz, 3H) ppm. MS: M / e 506 (M+1) + .

[0655] Compound A52b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.23 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.20 - 5.80 (m, 2H), 5.07 - 4.88 (m, 1H), 4.05 (q, J = 6.7 Hz, 1H), 3.98 (s, 1H), 3.45 - 3.32 (m, 5H), 3.06 - 2.89 (m, 2H), 2.86 (s, 3H), 2.44 - 2.33 (m, 1H), 2.14 - 1.98 (m, 2H), 1.69 - 1.46 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H) ppm. MS: M / e 506 (M+1) + .

[0656] Compound A53: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylbenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0657] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.20 mmol), 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-ol (77.4 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (146.2 mg, 0.60 mmol), and DIPEA (258.8 mg, 2.01 mmol) in CHCN (2 mL) was stirred at 100 °C for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A53a (8.1 mg, 8.0%) and compound A53b (10.3 mg, 10.2%).

[0658] Compound A53a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.16 - 5.90 (m, 2H), 5.05 - 4.88 (m, 1H), 4.85 - 4.61 (m, 1H), 4.04 - 3.92 (m, 1H), 3.87 (q, J = 6.0 Hz, 1H), 3.50 - 3.32 (m, 4H), 3.05 (d, J = 12.2 Hz, 1H), 2.93 - 2.78 (m, 4H), 2.50 - 2.34 (m, 1H), 2.18 - 1.99 (m, 2H), 1.62 - 1.41 (m, 2H), 1.38 (d, J = 6.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.66 (s, 3H) ppm. MS: M / e 505 (M+1) + .

[0659] Compound A53b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 6.40 - 5.67 (m, 2H), 5.05 - 4.88 (m, 1H), 4.85 - 4.62 (m, 1H), 4.02 - 3.90 (m, 1H), 3.72 (q, J = 6.6 Hz, 1H), 3.41 (s, 3H), 3.25 - 3.15 (m, 1H), 2.82 (s, 3H), 2.70 - 2.58 (m, 1H), 2.36 (d, J = 12.0 Hz, 1H), 1.98 - 1.83 (m, 3H), 1.64 - 1.53 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 1.03 (s, 3H), 0.62 (t, J = 7.1 Hz, 3H) ppm. MS: M / e 505 (M+1) + .

[0660] Compound A54: 2-(4-((2S,5R)-4-(1-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0661] Step A: 2-Cyclopropylpyrazolo[1,5-a]pyrimidin-5(4H)-one [ka]

[0662] A mixture of 3-cyclopropyl-1H-pyrazol-5-amine (0.5 g, 4.07 mmol), ethyl (E)-3-ethoxyacrylate (1.17 g, 8.13 mmol), and CsCO (2.65 g, 8.13 mmol) in DMF (15 mL) was stirred at 110° C. under N for 16 h. The solution was collected by filtration, and then acetic acid (5 mL) was added. The organic layer was concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (0.38 g, 53%). MS: M / e 176 (M+1) +

[0663] Step B: 5-Chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine [ka]

[0664] To a solution of 2-cyclopropylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.38 g, 2.1 mmol) in CHCN (5 mL) was added POCl (0.66 g, 4.3 mmol). The mixture was stirred at 100 °C for 3 h. The reaction was concentrated, poured into saturated NaHCO solution, and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and the resulting residue was purified by flash column chromatography to give the title compound (0.36 g, 85%). MS: M / e 194 (M+1) + .

[0665] Step C: 1-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0666] A mixture of 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine (0.35 g, 1.8 mmol), tributyl(1-ethoxyvinyl)stannane (0.78 g, 2.1 mmol), and Pd(PPh)Cl (127 mg, 0.18 mmol) in DMF (5 mL) was stirred at 100 °C under N for 16 h. The solution was diluted with ethyl acetate and washed with water. The organic layer was purified by flash column chromatography to give 2-cyclopropyl-5-(1-ethoxyvinyl)pyrazolo[1,5-a]pyrimidine, which was then diluted with DCM. HCl (5 mL, 4 M in dioxane) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was concentrated, adjusted to pH 8–9 with saturated NaHCO solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and the resulting residue was purified by flash column chromatography to give the title compound (0.09 g, 24%). MS: M / e 202 (M+1) +

[0667] Step D: 2-(4-((2S,5R)-4-(1-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0668] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.20 mmol), 1-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (81.4 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (146.2 mg, 0.60 mmol), and DIPEA (258.8 mg, 2.01 mmol) in CHCN (2 mL) was stirred at 100 °C overnight. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM to give the title compound, which was further separated by preparative HPLC (Method A) into compound A54a (11.8 mg, 11.4%) and compound A54b (12.8 mg, 12.4%).

[0669] Compound A54a (earlier peak): 11H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.40 - 5.80 (m, 3H), 5.10 - 4.89 (m, 1H), 4.85 - 4.65 (m, 1H), 3.99 (s, 1H), 3.70 (q, J = 6.1 Hz, 1H), 3.42 (s, 3H), 3.37 - 3.32 (m, 1H), 3.21 - 3.09 (m, 1H), 2.85 - 2.73 (m, 1H), 2.29 (d, J = 12.2 Hz, 1H), 2.14 - 2.05 (m, 1H), 2.04 - 1.81 (m, 2H), 1.68 - 1.46 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.09 - 0.99 (m, 5H), 0.92 - 0.88 (m, 2H), 0.74 (t, J = 7.0 Hz, 3H) ppm. MS: M / e 515 (M+1) + .

[0670] Compound A54b (slower peak): 1 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.29 (s, 1H), 6.24 - 5.90 (m, 2H), 5.20 - 4.89 (m, 1H), 3.98 (s, 1H), 3.90 (q, J = 6.2 Hz, 1H), 3.60 - 3.35 (m, 5H), 3.05 - 2.85 (m, 2H), 2.55 - 2.38 (m, 1H), 2.20 - 1.95 (m, 3H), 1.68 - 1.46 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 7.8 Hz, 2H), 0.99 - 0.87 (m, 5H), 0.76 (s, 3H) ppm. MS: M / e 515 (M+1) + .

[0671] Compound A55: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0672] Step A: 4-Bromo-2-(prop-1-yn-1-yl)pyridine [ka]

[0673] To a stirred solution of 4-bromo-2-iodopyridine (800 mg, 2.8 mmol) in THF (10 mL) was added Pd(PPh3)2Cl2 (196 mg, 0.28 mmol), CuI (106 mg, 0.56 mmol), and Et3N (566 mg, 5.6 mmol), followed by prop-1-yne (1.0 M, 3.38 mL, 3.38 mmol). After the addition, the reaction mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was poured into H2O (50 mL) and then extracted with EA (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (381 mg, 69.4%). MS: M / e 196 / 198 (M+1) + .

[0674] Step B: 5-Bromo-2-methylpyrazolo[1,5-a]pyridine [ka]

[0675] 4-Bromo-2-(prop-1-yn-1-yl)pyridine (571 mg, 2.91 mmol) was added to a stirred solution of O-(mesitylsulfonyl)hydroxylamine (1.25 g, 2.82 mmol) in CHCl (10 mL). The mixture was then stirred overnight. The reaction mixture was concentrated to give a residue, which was dissolved in DMF (10 mL), and KCO (1.6 g, 11.64 mmol) was added and stirred for 3 h. The reaction mixture was poured into H0 (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (140 mg, 23%). MS: M / e 211 / 213 (M+1) + .

[0676] Step C: 1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethan-1-one [ka]

[0677] A mixture of 5-bromo-2-methylpyrazolo[1,5-a]pyridine (140 mg, 0.66 mmol), tributyl(1-ethoxyvinyl)stannane (359 mg, 0.99 mmol), and Pd(PPh)Cl (46.2 mg, 0.066 mmol) in DMF (8 mL) was stirred overnight at 100 °C under N. The reaction mixture was treated with EA / HCl (g) (4.0 M, 5 mL) and stirred for 1 h. After that, it was treated with HO (30 mL) and extracted with EA (30 mL × 2). The aqueous layer was basified to pH 8–9 with aqueous NaHCO and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to dryness. The resulting residue was purified by flash column chromatography to give the title compound (100 mg, 87%). MS: M / e 175 (M+1) + .

[0678] Step D: 1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethan-1-ol [ka]

[0679] To a stirred solution of 1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethan-1-one (100 mg, 0.57 mmol) in MeOH (10 mL) was added NaBH (21.8 mg, 0.57 mmol). The mixture was then stirred for 10 min. The reaction mixture was poured into HO (10 mL), and most of the MeOH was removed to obtain the aqueous layer, which was then extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound (100 mg, 99%). MS: M / e 177 (M+1) + .

[0680] Step E: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0681] A solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.20 mmol), 1-(2-methylpyrazolo[1,5-a]pyridin-5-yl)ethan-1-ol (70.6 mg, 0.40 mmol), (cyanomethyl)trimethylphosphonium iodide (146.2 mg, 0.60 mmol), and DIPEA (258.8 mg, 2.01 mmol) in CHCN (2 mL) was stirred at 100° C. for 2 days. The reaction was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using 0-5% MeOH in DCM, then further purified by preparative HPLC (Method A) to give the title compound (10.3 mg, 10.5%). 1 H NMR (400 MHz, CD3OD) δ 8.35 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 10.9 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.30 (d, J = 7.8 Hz, 1H), 6.20 - 5.75 (m, 2H), 5.05 - 4.89 (m, 1H), 4.86 - 4.65 (m, 1H), 3.78 (q, J = 6.1 Hz, 0.5H), 3.63 (q, J = 6.5 Hz, 0.5H), 3.42 (s, 3H), 3.37 - 3.31 (m, 2H), 3.21 - 3.11 (m, 0.5H), 3.00 (d, J = 11.9 Hz, 0.5H), 2.91 - 2.80 (m, 0.5H), 2.74 - 2.63 (m, 0.5H), 2.55 - 2.38 (m, 4H), 2.15 - 2.00 (m, 1H), 1.99 - 1.85 (m, 1H), 1.64 - 1.40 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.05 - 0.93 (m, 3H), 0.71 (t, J = 6.8 Hz, 3H) ppm. MS: M / e 488 (M+1) + .

[0682] Compound A56: 2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0683] To a solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (30 mg, 0.09 mmol) in CHCN (4 mL) was added 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (49 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (89 mg, 0.36 mmol), and DIPEA (117 mg, 0.9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (crude), which was further purified by preparative HPLC (Method B) to give the title compound (1.9 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ 9.01 - 8.91 (m, 1H), 7.22 (d, J = 7.0 Hz, 1H), 6.45 - 6.37 (m, 1H), 6.04 (s, 1H), 5.91 - 5.44 (m, 1H), 4.81 - 4.27 (m, 1H), 4.12 (s, 2H), 3.89 - 3.64 (m, 1H), 3.27 (s, 3H), 3.03 (s, 1H), 2.81 (s, 1H), 2.65 (s, 1H), 2.22 (d, J = 11.6 Hz, 1H), 1.97 - 1.75 (m, 2H), 1.55 - 1.36 (m, 2H), 1.34 - 1.24 (m, 3H), 0.95 - 0.80 (m, 3H), 0.74 - 0.61 (m, 3H) ppm. MS: M / e 493 (M+1) + .

[0684] Compound A57: 2-(4-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0685] Step A: 6-Cyclopropylnicotinaldehyde [ka]

[0686] To a solution of 6-bromonicotinaldehyde (1.86 g, 10 mmol) and cyclopropylboronic acid (1.72 g, 20 mmol) in toluene / HO (15 mL / 1.5 mL) was added dichlorobis(tricyclohexylphosphine)palladium(II) (74 mg, 0.1 mmol) and KPO (3.18 g, 15 mmol). The reaction mixture was stirred overnight at 100 °C under N. The mixture was cooled to room temperature, diluted with water (40 mL), extracted with EA (80 mL × 2), washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (1.2 g, 81%). MS: M / e 148 (M+1) + .

[0687] Step B: 1-(6-cyclopropylpyridin-3-yl)propan-1-ol [ka]

[0688] To a solution of 6-cyclopropylnicotinaldehyde (200 mg, 1.36 mmol) in THF (5 mL) was added a solution of EtMgBr in THF (0.5 mL, 3 mol / L). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated NH4Cl (20 mL), extracted with EA (70 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (200 mg, 83%). MS: M / e 178 (M+1) + .

[0689] Step C: 2-(4-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0690] To a solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (66 mg, 0.2 mmol), 1-(6-cyclopropylpyridin-3-yl)propan-1-ol (71 mg, 0.4 mmol), and (cyanomethyl)trimethylphosphonium iodide (193 mg, 0.8 mmol) in CHCN (2 mL) was added DIPEA (103 mg, 0.8 mmol). The reaction mixture was sealed in a bottle and heated at 100 °C for 16 h. After cooling to room temperature, 1-(6-cyclopropylpyridin-3-yl)propan-1-ol (71 mg, 0.4 mmol) was added and stirred at 100 °C for 2 days. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to separate Compound A57a (1.8 mg, 1.8%) and Compound A57b (2.8 mg, 2.8%).

[0691] Compound A57a (earlier peak): 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 5.80 (s, 1H), 5.75 (s, 1H), 5.20 - 4.80 (m, 1H), 3.74 (s, 3H), 3.43 (s, 4H), 2.88 (s, 2H), 2.37 - 2.26 (m, 1H), 1.91 (s, 5H), 1.41 (s, 4H), 1.05 (s, 2H), 0.93 (s, 3H), 0.68 (d, J = 6.3 Hz, 6H) ppm. MS: M / e 489 (M+1) + .

[0692] Compound A57b (slower peak): 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 5.76 (s, 2H), 4.88 (s, 1H), 3.74 (s, 3H), 3.43 (s, 3H), 3.39 - 3.25 (m, 2H), 3.14 - 3.03 (m, 1H), 2.85 (s, 1H), 2.65 (s, 1H), 2.22 - 2.09 (m, 2H), 1.89 (s, 3H), 1.68 (s, 2H), 1.44 - 1.41 (m, 1H), 0.99 (s, 4H), 0.66 (d, J = 7.0 Hz, 7H) ppm. MS: M / e 489 (M+1) + .

[0693] Compound A58: 2-(4-((2S,5R)-4-(1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0694] Step A: 2-Chloropyrazolo[1,5-a]pyrimidin-5-ol [ka]

[0695] To a solution of 3-chloro-1H-pyrazol-5-amine (2.34 g, 20 mmol) in DMF (10 mL) was added ethyl (E)-3-ethoxyacrylate (4.3 g, 30 mmol) and CsCO (13 g, 40 mmol). The reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, added, and filtered. To the filtrate was added CHCOOH (10 mL) and concentrated in vacuo. The resulting residue was purified by flash column chromatography using 0-100% EtOAc in PE to give the title compound (2.1 g, 60%). MS: M / e 170 (M+1) + .

[0696] Step B: 5-Bromo-2-chloropyrazolo[1,5-a]pyrimidine [ka]

[0697] To a solution of 2-chloropyrazolo[1,5-a]pyrimidin-5-ol (2.1 g, 12.4 mmol) in MeCN (20 mL) was added POBr (6.6 g, 24.8 mmol). The reaction mixture was stirred at 90 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was added to saturated aqueous NaHCO (30 mL) and then extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (1 g, 35.1%). MS: M / e 232 (M+1) + .

[0698] Step C: 1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0699] To a solution of 5-bromo-2-chloropyrazolo[1,5-a]pyrimidine (231 mg, 1 mmol) in toluene, Pd(PPh3)2Cl2 (70 mg, 0.1 mmol) and tributyl(1-ethoxyvinyl)stannane (547 mg, 1.5 mmol) were added. The reaction mixture was stirred at 100 °C for 8 h under N2. 4N HCl in 1,4-dioxane (2 mL) was added to the reaction mixture, which was then stirred at room temperature for 15 min. Saturated aqueous NaHCO3 (30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (110 mg, 51.2%). MS: M / e 196 (M+1) + .

[0700] Step D: 1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0701] To a solution of 1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (110 mg, 0.56 mmol) in MeOH was added NaBH (19 mg, 0.5 mmol), and the reaction mixture was stirred at room temperature for 15 minutes. H2O (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (70 mg, 63.6%). MS: M / e 198 (M+1) + .

[0702] Step E: 2-(4-((2S,5R)-4-(1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0703] A mixture of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-chloropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (50 mg, 0.25 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 h. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL×3), dried, and concentrated. The resulting residue was purified by flash column chromatography and further purified by preparative HPLC (Method A) to give the title compound (1.3 mg, 0.25%). 1 H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 6.2 Hz, 1H), 7.28 (m, 1H), 6.58 (d, J = 4.6 Hz, 1H), 6.04 (s, 1H), 3.96 (m, 2H), 3.75 - 3.47 (m, 1H), 3.42 (m, 5H), 3.13 - 2.79 (m, 1H), 2.95 (m, 1H), 2.49 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.57 (m, 3H), 1.39 (t, J = 7.7 Hz, 3H), 0.94 (s, 3H), 0.76 (d, J = 7.4 Hz, 3H) ppm. MS: M / e 509 (M+1) + .

[0704] Compound A59: 2-(4-((2S,5R)-4-(1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0705] Step A: 5-Bromo-2-chloro-3-fluoropyrazolo[1,5-a]pyrimidine [ka]

[0706] To a solution of 5-bromo-2-chloropyrazolo[1,5-a]pyrimidine (115 mg, 0.5 mmol) in MeCN (10 mL) was added Select F (265 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography using 0-100% EtOAc in PE to give the title compound (80 mg, 64.5%). MS: M / e 250 (M+1) + .

[0707] Step B: 1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one [ka]

[0708] To a solution of 5-bromo-2-chloro-3-fluoropyrazolo[1,5-a]pyrimidine (80 mg, 0.32 mmol) in toluene, Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) and tributyl(1-ethoxyvinyl)stannane (180 mg, 0.5 mmol) were added. The reaction mixture was stirred at 100 °C for 8 h under N2. 4N HCl / dioxane (1 mL) was added to the reaction mixture, which was then stirred at room temperature for 15 min. Saturated aqueous NaHCO3 (30 mL) was added to the mixture, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (40 mg, 58.8%). MS: M / e 214 (M+1) + .

[0709] Step C: 1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0710] To a solution of 1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (40 mg, 0.18 mmol) in MeOH was added NaBH (19 mg, 0.5 mmol), and the reaction mixture was stirred at room temperature for 15 minutes. H2O (30 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried, and concentrated. The resulting residue was purified by flash column chromatography using 0-100% EA in PE to give the title compound (30 mg, 75%). MS: M / e: 216 (M+1) + .

[0711] Step D: 2-(4-((2S,5R)-4-(1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0712] A mixture of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (30 mg, 0.1 mmol), 1-(2-chloro-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (50 mg, 0.25 mmol), (cyanomethyl)trimethylphosphonium iodide (120 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in MeCN (3 mL) was stirred at 100° C. for 16 hours. The resulting mixture was diluted with EtOAc (10 mL), washed with brine (5 mL×3), dried, and concentrated. The resulting residue was purified by flash column chromatography and further purified by preparative HPLC (Method A) to give the title compound (0.5 mg). 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.10 (s, 1H), 5.78 (s, 1H), 3.75 (m, 3H), 3.44 (s, 3H), 3.08 (m, 1H), 2.88 (m, 1H), 2.39 (m, 1H), 2.22 (m, 1H), 2.01 (m, 2H), 1.59 (m, 4H), 1.26 (m, 6H), 0.76 (m, 3H) ppm. MS: M / e 527 (M+1) + .

[0713] Compound A60: 2-(4-((2S,5R)-4-(1-(2,3-difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0714] Step A: 1-(2,3-Difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one. [ka]

[0715] To a solution of 1-(2-fluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.41 g, 2.2 mmol) in CH3CN (15 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.3 g, 6.6 mmol) and stirred at 50 °C for 5 hours. The solution was concentrated and purified by flash column chromatography to give the title compound (0.12 g, 26%). MS: M / e 198 (M+1). +

[0716] Step B: 1-(2,3-difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol [ka]

[0717] To a solution of 1-(2,3-difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (0.12 g, 0.6 mmol) in MeOH (3 mL) was added NaBH (11 mg, 0.3 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with DCM, washed with water, dried over NaSO, and concentrated to give the title compound (55 mg). MS: M / e 200 (M+1) + .

[0718] Step C: 2-(4-((2S,5R)-4-(1-(2,3-difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0719] To a solution of 2-(4-((2S,5R)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (30 mg, 0.09 mmol) in CH3CN (4 mL) was added 1-(2,3-difluoropyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (54 mg, 0.27 mmol), (cyanomethyl)trimethylphosphonium iodide (89 mg, 0.36 mmol), and DIPEA (117 mg, 0.9 mmol). The resulting mixture was stirred at 105 °C overnight. The reaction solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (crude), which was further purified by preparative HPLC (Method A) to give the title compound (0.9 mg, 2%). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 18.9, 7.4 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 6.06 (s, 1H), 5.95 - 5.27 (m, 1H), 4.91 - 4.26 (m, 1H), 4.14 (s, 2H), 3.98 - 3.69 (m, 1H), 3.55 - 3.37 (m, 3H), 3.15 - 2.67 (m, 3H), 2.34 - 2.12 (m, 1H), 2.02 - 1.41 (m, 4H), 1.32 (dd, J = 20.1, 6.6 Hz, 3H), 1.02 - 0.57 (m, 6H) ppm. MS: M / e 511 (M+1) + .

[0720] Compound A61: 2-(4-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0721] To a solution of 2-(4-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (63 mg, 0.2 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol (53 mg, 0.3 mmol), and (cyanomethyl)trimethylphosphonium iodide (97 mg, 0.4 mmol) in CHCN (2 mL) was added DIPEA (103 mg, 0.8 mmol). The reaction mixture was sealed in a bottle and heated at 100 °C overnight. The reaction was diluted with water (20 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The resulting residue was purified by preparative HPLC (Method A) to give the title compound (20 mg), which was further separated into Compound A61a (6.8 mg, 7.1%) and Compound A61b (6.3 mg, 6.7%) by chiral preparative SFC. The chiral separation conditions are shown below. [Table 6]

[0722] Compound A61: 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.00 (s, 1H), 6.40 (s, 1H), 5.77 (s, 1H), 3.75 (s, 3H), 3.44 (s, 3H), 3.15-2.70 (m, 2H), 2.52 (s, 3H), 2.00 (s, 2H), 1.57 (s, 3H), 1.53 - 1.42 (m, 3H), 1.36 (s, 4H), 1.09-0.72 (m, 3H) ppm. MS: M / e 475 (M+1) + .

[0723] Compound A61a (earlier peak): 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.27 (s, 1H), 6.44 (s, 1H), 5.79 (s, 1H), 4.48 - 4.15 (m, 1H), 3.73 (s, 3H), 3.44 (s, 3H), 3.15 - 2.71 (m, 2H), 2.53 (s, 3H), 1.99 (s, 5H), 1.49 - 1.21 (m, 6H), 0.75 (s, 3H) ppm. MS: M / e 475 (M+1) + .

[0724] Compound A61b (slower peak): 1 H NMR (400 MHz, CDCl3) δ 8.76-8.35 (m, 1H), 7.04 (s, 1H), 6.39 (s, 1H), 5.79 (s, 1H), 4.34 - 3.93 (m, 1H), 3.76 (s, 3H), 3.44 (s, 3H), 3.27 - 3.02 (m, 1H), 2.83 (s, 1H), 2.53 (s, 3H), 2.00 (s, 2H), 1.75 (s, 3H), 1.45-1.16 (m, 6H), 1.03 (s, 3H) ppm. MS: M / e 475 (M+1) + .

[0725] Compound A62: 2-(4-((2S,5R)-5-ethyl-2-methyl-4-(1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile [ka]

[0726] To a solution of 2-(4-((2S,5R)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile (110 mg, 0.35 mmol), 1-(2-methylpyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol (100 mg, 0.52 mmol),...

Claims

1. Compounds of formula (I) 【Chemical 310】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically substituted or enantiomer thereof, During the ceremony, X １ is C or N, X ２ is selected from —CH— or N; R １ is hydrogen or alkyl optionally substituted with deuterium or halogen; R ２ is hydrogen, halogen, alkyl, or cyano, with the proviso that X １ If is N, then R ２ does not exist, R ４ is hydrogen, halogen, or alkyl, said alkyl being optionally substituted with deuterium or halogen; R ５ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyano, or heterocyclyl, wherein said alkyl or said alkenyl is unsubstituted or substituted with halogen, cyano, heterocyclyl, alkoxy, hydroxy, cycloalkyl; R ７ , R ９ , R ８ , and R １０ are each independently hydrogen, alkyl, or alkoxy, wherein said alkyl is unsubstituted or substituted with halogen, with the proviso that R ７ and R ９ At least one of them is not hydrogen, L １ is a direct bond, -C(R Ｌ１ ) (R Ｌ２ )-, and R Ｌ１ and the R Ｌ２ each independently represents hydrogen, or C optionally substituted with deuterium, halogen, alkyl, alkylene, alkynyl, or cyano. １～４ is alkyl, Cy １ is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R ３ａ and each R ３ａ is independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cyano, heterocyclyl, or heterocyclyloxy; where: each alkyl portion thereof is unsubstituted or substituted with deuterium, halogen, alkoxy, hydroxy, cyano, or heterocyclyl; each of said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen or hydroxy; A compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically substituted derivative, or enantiomer thereof.

2. R １ is hydrogen, or C optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl; １～４ alkyl, preferably R １ is hydrogen or C １～３ The compound of claim 1 , wherein the aryl group is alkyl.

3. R １ is hydrogen, methyl, ethyl, isopropyl, n-propyl, preferably R １ is hydrogen, methyl, methyl-d3, or ethyl, more preferably R １ The compound according to any one of claims 1 to 2, wherein is hydrogen or methyl.

4. X １ The compound according to any one of claims 1 to 3, wherein is C.

5. R ２ But hydrogen, halogen, C １～４ alkyl, or cyano, preferably R ２ is hydrogen, F, Br, Cl, CN, cyanomethyl, methyl, ethyl, more preferably R ２ The compound according to any one of claims 1 to 5, wherein is hydrogen, F, Br, CN, or methyl.

6. X １ The compound according to any one of claims 1 to 3, wherein is N.

7. R ４ is alkyl optionally substituted with hydrogen, halogen, or deuterium, preferably R ４ The compound according to any one of claims 1 to 6, wherein is hydrogen, methyl or methyl-d3, more preferably hydrogen.

8. R ５ is hydrogen, alkyl, alkenyl, alkynyl, or cyano, said alkyl being unsubstituted or substituted with cyano, cycloalkyl, or heterocyclyl containing one oxygen atom, preferably R ５ But C １～６ Alkyl, C ２～６ alkenyl, or C ２～６ alkynyl, wherein the alkyl is cyano, C ３～６ cycloalkyl, or heterocyclyl containing one oxygen atom, more preferably R ５ But C １～６ Alkyl, C ２～６ alkenyl, or C ２～６ alkynyl, wherein the alkyl is cyano, C ３～６ The compound of any one of claims 1 to 7, which is substituted with a cycloalkyl or a heterocyclyl containing one oxygen atom.

9. R ５ is hydrogen, -CN, -CH ２ -CN, -CH(CH ３ )CN, -CH ２ -CH ２ -CN, -CH ２ -CH ２ -CH ２ -CN, -CH(CH ３ )-CH ２ -CN, -CH ２ -CH(CH ３ )-CN,-CH(CH ２ CH ３ )-CN, oxiran-2-ylmethyl, oxiran-2-yl, oxetan-3-ylmethyl, oxetan-2-methyl, oxetan-3-yl, oxetan-2-yl, prop-2-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, prop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-2-en-1-yl, pent-3 -en-1-yl, pent-4-en-1-yl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, azetidin-2-yl, azetidin-3-yl, azetidin-3-ylmethyl, azetidin-1-yl, azetidin-1-ylmethyl, aziridin-1-yl, aziridin-1-ylmethyl, aziridin-2-yl, aziridin-2-ylmethyl, 1-cyanocyclopropyl, 2-cyanocyclopropyl or 2-cyanocyclobutyl, preferably R ５ is hydrogen, -CN, -CH ２ -CN, -CH(CH ３ )CN, -CH ２ -CH ２ -CN, CH ２ -CH ２ -CH ２ -CN, -CH(CH ３ )-CH ２ -CN, -CH ２ -CH(CH ３ )-CN,-CH(CH ２ CH ３ )-CN, prop-2-yn-1-yl, but-3-yn-1-yl or pent-3-yn-1-yl, more preferably R ５ -CN, -CH ２－ CN, -CH ２ -CH ２ The compound according to any one of claims 1 to 8, wherein the group is -CN.

10. R ７ and R ９ are each independently hydrogen or alkyl, said alkyl being unsubstituted or substituted with halogen, alkoxy, amino, cycloalkyl, cycloalkoxy, heterocyclyl, preferably R ７ and R ９ Each of the groups independently represents C １～４ alkyl, and more preferably, R ７ and R ９ Each of the groups independently represents C １～２ The compound according to any one of claims 1 to 9, which is alkyl.

11. R ７ and R ９ are each independently hydrogen, methyl, ethyl, isopropyl, n-propyl, methoxymethyl, or 2-methoxyethyl, with the proviso that R ７ and R ９ The compound according to any one of claims 1 to 10, wherein at least one of is not hydrogen.

12. R ７ is methyl and R ９ is methyl; or R ７ is hydrogen and R ９ is methyl; or R ７ is methyl and R ９ is hydrogen; or R ７ is hydrogen and R ９ is ethyl; or R ７ is ethyl and R ９ is hydrogen; or R ７ is ethyl and R ９ is ethyl; or R ７ is methyl and R ９ The compound according to any one of claims 1 to 11, wherein is ethyl.

13. R ８ and R １０ The compound of any one of claims 1 to 12, wherein each is hydrogen.

14. The carbon at the 5-position of the piperazine ring is in the R configuration, provided that R ９ The compound of any one of claims 1 to 13, wherein is not hydrogen.

15. The carbon atom at the 2-position of the piperazine ring is a chiral carbon atom, and the carbon atom at the 5-position of the piperazine ring is in the R configuration, provided that R ７ is hydrogen, and R ９ 15. The compound of claim 14, wherein is not hydrogen.

16. The carbon atom at the 2-position of the piperazine ring is in the S configuration, and the carbon atom at the 5-position of the piperazine ring is in the R configuration, provided that R ７ and R ９ and n are not both hydrogen.

17. The carbon atoms at the 2-position and the 5-position of the piperazine ring are both in the R configuration, provided that R ７ is methoxymethyl, and R ９ 15. The compound of claim 14, wherein is not hydrogen.

18. The carbon atom at the 5-position of the piperazine ring is in the S configuration, provided that R ９ is not hydrogen, and more preferably, the carbon at the 5-position of the piperazine ring is in the S configuration, provided that R ９ The compound of any one of claims 1 to 13, wherein is methoxymethyl.

19. The carbon atom at the 2-position of the piperazine ring is an achiral carbon atom, and the carbon atom at the 5-position of the piperazine ring is in the S configuration, provided that R ７ is hydrogen, and R ９ 19. The compound of claim 18, wherein is not hydrogen.

20. The carbon atom at the 2nd position of the piperazine ring is in the S configuration, provided that R ７ 19. The compound of claim 18, wherein is methoxymethyl.

21. L １ is a direct bond or -C(R Ｌ１ ) (R Ｌ２ ) and said R Ｌ１ Or the R Ｌ２ each independently represents hydrogen or C optionally substituted with halogen, deuterium, alkyl, alkylene, alkynyl, cyano １～４ alkyl, preferably L １ is a direct bond, -CH ２ -, -CH(CH ３ ) -, -CH(CD ３ ) -, -CH(CH ２ CH ３ ) -, -CH(C ３ H ７ )-,-CH(CHF ２ ) - or -C(CH ３ ) ２ -, and more preferably, L １ But -CH(CH ３ )- or -CH(CD ３ 21. The compound according to any one of claims 1 to 20, wherein

22. The compound of formula (I) is a compound of formula (II): 【Chemical 311】 wherein R ７ , R ９ , and R １１ 22. The compound of any one of claims 1 to 21, wherein each of is independently methyl or ethyl, and the other variables are as defined in claim 1.

23. Cy １ is aryl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or contains one, two, or three substituents R ３ａ and each R ３ａ are independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cycloalkyl, heterocyclyl, or heterocyclyloxy, wherein each alkyl portion thereof is unsubstituted or substituted with halogen, alkoxy, hydroxy, or heterocyclyl, and each of said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, preferably R ３ａ is F, Br, Cl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutane, difluoromethyl, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, isopropoxy, or cyclopropoxy.

24. Cy １ is one, two or three substituents R ３ａ and each R ３ａ are independently selected from hydroxy, alkoxy, alkyl, halogen, aminoalkyl, cycloalkyl, cycloalkyl, heterocyclyl, or heterocyclyloxy, wherein each alkyl portion thereof is unsubstituted or substituted with halogen, alkoxy, hydroxy, or heterocyclyl, and each of said cycloalkyl or said heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, preferably R ３ａ is F, Br, Cl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutane, difluoromethyl, 2-fluoro-2-methylethyl, oxetan-3-ylmethyloxy, difluoromethoxy, 2-methoxyethoxy, (2-methoxyethoxy)methyl, isopropoxy, or cyclopropoxy.

25. Cy １ is one, two or three substituents R ３ａ 25. The compound of any one of claims 1 to 24, wherein the compound is phenyl optionally substituted with

26. Cy １ is phenyl, and said phenyl has one R ３ａ and at other position(s) one or more R ３ａ 26. The compound of claim 25, optionally substituted with

27. Cy １ is a monocyclic 5- to 9-membered heterocyclyl or heteroaryl, or a bicyclic 7- to 10-membered heterocyclyl or heteroaryl, each of which is unsubstituted or contains one, two, or three R ３ａ The compound of any one of claims 1 to 24, substituted with

28. The monocyclic 5- to 9-membered heterocyclyl or heteroaryl is 【Chemical 312】 each of which is unsubstituted or contains one, two or three R ３ａ wherein X ４ , X ５ , X ６ , X ７ , and X ８ are each independently selected from N or C; ９ is selected from C, N, S or O.

29. The monocyclic 5- to 9-membered heteroaryl is thiazole, isothiazole, triazole, pyridine, pyrazine, pyrimidine, each of which is unsubstituted or contains one, two, or three R ３ａ 29. The compound of claim 28 substituted with:

30. the monocyclic 5- to 9-membered heteroaryl is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, isothiazol-3-yl, isothiazol-4-yl, pyrazin-1-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, each of which is unsubstituted or substituted by one, two, or three R ３ａ 29. The compound of claim 28 substituted with:

31. Cy １ but 【Chemistry 313】 The compound according to any one of claims 1 to 24,

32. The bicyclic 7-10 membered heterocyclyl or heteroaryl is 【Chemical 314】 each of which is unsubstituted or contains one, two or three R ３ａ wherein A is a 6-membered carbocyclic or heterocyclic ring and B is selected from a 5- or 6-membered monocyclic carbocyclic or monocyclic heterocyclic ring fused to ring A to form an A-B bicyclic ring; and Y １ , Y ２ , Y ３ 28. The compound of claim 27, wherein each of is independently N or C.

33. The B is 【Chemical Industry 315】 33. The compound of claim 32, wherein:

34. The bicyclic 7-10 membered ring 【Chemical 316】 34. The compound of claim 33, wherein:

35. The bicyclic 7-10 membered heterocyclyl or heteroaryl is 【Chemical 317】 and Z １ , Z ２ , and Z ３ is N or CH, with the proviso that Z １ , Z ２ , and Z ３ 28. The compound of claim 27, wherein at least two of are N.

36. The bicyclic 7-10 membered heterocyclyl or heteroaryl is 【Chemical 318】 and Z １ and Z ３ is N or CH, with the proviso that Z １ and Z ２ is N, preferably 【Chemical 319】 36. The compound of claim 35, wherein:

37. The bicyclic 7-10 membered heterocyclyl or heteroaryl may be 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, chroman, isochroman, 2,3-dihydrobenzo[b][1,4]dioxin, thiochroman, isothiochroman, 2,3-dihydrobenzo[b][1,4]dithiin, quinoxalinyl, isoquinoline, quinoxaline, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 2,3-dihydro-[1,4]dioxino [2,3-c]pyridine, 3,4-dihydro-2H-pyrano[3,2-b]pyridine, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridine, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroquinoline Hydro-1,7-naphthyridine, 3H-indole, 1H-isoindole, benzofuran, benzo[b]thiophene, 3H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[3,4-b]pyridine, furo[2,3-b]pyridine, thieno[2,3-b]pyridine, benzo[d]thiazole, benzo[d]oxazole, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, oxazolo[4,5-b]pyridine, thiazolo[4,5-b]pyridine, 2,3-dihydro-1H-indene, 2,3- dihydrobenzofuran, 1,3-dihydroisobenzofuran, 1,3-dihydrobenzo[c]thiophene, 2,3-dihydrobenzo[b]thiophene, benzo[b]thiophene, thieno[3,2-b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, or pyrrolo[1,2-a]pyrimidine, each of which is unsubstituted or contains one, two, or three R ３ａ 25. The compound of claim 24 substituted with:

38. The bicyclic 7-10 membered heterocyclyl or heteroaryl is 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl, 6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl, chroman-7-yl, chroman-8-yl, isochroman-7-yl, isochroman-8-yl, 2,3-dihydrobenzo[b][1,4]dioxin-7-yl, 2,3-dihydrobenzo[b][1,4]dioxy quinoxalinyl-7-yl, quinoxalinyl-8-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinoxalin-7-yl, quinoxalin-8-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]di Oxino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl, 3 ,4-dihydro-2H-thiopyrano[3,2-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-8-yl, 3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dithiino[2,3-b]pyridin-7-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-5-yl, 2,3-dihydro-[1,4]dithiino[2,3-c]pyridin-7-yl, 1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 5,6,7 ,8-tetrahydro-1,7-naphthyridin-6-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-8-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-6-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-5-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydro-1,7-naphthyridin-8-yl, 3H-indol-4-yl, 3H-indol-4-yl indol-5-yl, 3H-indol-6-yl, 3H-indol-7-yl, 1H-isoindol-4-yl, 1H-isoindol-5-yl, 1H-isoindol-6-yl, 1H-isoindol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, 3H-pyrrolo[3,2- b]pyridin-5-yl, 3H-pyrrolo[3,2-b]pyridin-6-yl, 3H-pyrrolo[3,2-b]pyridin-7-yl, 7H-pyrrolo[3,4-b]pyridin-2-yl, 7H-pyrrolo[3,4-b]pyridin-3-yl, 7H-pyrrolo[3,4-b]pyridin-4-yl, furo[2,3-b]pyridin-4-yl, furo[2,3-b]pyridin-5-yl, furo[2,3-b]pyridin-6-yl, thieno[2,3-b]pyridin-4-yl, thieno[2,3-b]pyridin-5-yl, thieno[2,3-b]pyridin-6-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, oxazolo[5,4-b]pyridin-5-yl, oxazolo[5,4-b]pyridin-6-yl, oxazolo[5,4-b]pyridin-7-yl, thiazolo[5,4-b]pyridin-5-yl, thiazolo[5,4-b]pyridin- ]pyridin-6-yl, thiazolo[5,4-b]pyridin-7-yl, oxazolo[4,5-b]pyridin-5-yl, oxazolo[4,5-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-7-yl, thiazolo[4,5-b]pyridin-5-yl, thiazolo[4,5-b]pyridin-6-yl, thiazolo[4,5-b]pyridin-7-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-di 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, 1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl, 1,3-dihydrobenzo[c]thiophen-4-yl, 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-4-yl, 2,3-dihydrobenzo[b]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-6-yl, 2,3-dihydrobenzo[b]thiophen-7-yl, benzo[b]thiophen-6-yl, benzo[ b]thiophen-5-yl, benzo[b]thiophen-7-yl, thieno[3,2-b]pyridin-5-yl, thieno[3,2-b]pyridin-6-yl, thieno[3,2-b]pyridin-7-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-b]pyridazin-7-yl, imidazo[1,2-b]pyridazin-8-yl, pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[1,5-a]pyrimidin-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl, pyrazolo[1,5-a]pyridin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrrolo[1,2-b]pyridazin-3-yl, pyrrolo[1,2-b]pyridazin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-5-yl lysin-6-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl, pyrrolo[1,2-a]pyrimidin-2-yl, pyrrolo[1,2-a]pyrimidin-3-yl, or pyrrolo[1,2-a]pyrimidin-4-yl, each of which is unsubstituted or contains one, two, or three R, ３ 25. The compound of claim 24, substituted with a.

39. Cy １ quinoxalin-6-yl, 3-methylquinoxalin-6-yl, 3-(difluoromethyl)quinoxalin-6-yl, 3-methoxyquinoxalin-6-yl, 3-chloroquinoxalin-6-yl, 3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 4-fluoro-2-(trifluoromethyl)phenyl benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, or 2-methylbenzo[d]thiazol-6-yl, benzo[d]thiazole, 4-fluoro-2-methoxyphenyl, 2-(difluoromethoxy)-4-fluorophenyl, 2-(difluoromethyl)-4-fluorophenyl, 4-cyclopropyl-2-fluorophenyl, 6-cyclopropylpyridin-3-yl, 5-isopropoxypyridin-2-yl, 6-cyclopropyl-2-fluoropyridin-3-yl, benzo[d]thiazol-6-yl, thiazolo[5,4-b]pyridin-5-yl, or 2-methylbenzo[d]thiazol-6-yl, benzo[d]thiazole -5-yl, 2-difluoromethyl-methylthieno[2,3-b]pyridin-6-yl, imidazo[1,2-b]pyridazin-6-yl, 2-methyl-imidazo[1,2-b]pyridazin-6-yl, 2-ethyl-imidazo[1,2-b]pyridazin-6-yl, pyrazolo[1,5-a]pyrimidin-5-yl, 2-methyl-pyrazolo[1,5-a]pyrimidin-5-yl, 2-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-methyl-3-fluoro-pyrazolo[1,5-a]pyrimidine- 25. The compound of claim 24, wherein the compound is 2-methyl-3-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 3-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-cyclopropyl-pyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-pyrazolo[1,5-a]pyrimidin-5-yl, 2,3-difluoro-pyrazolo[1,5-a]pyrimidin-5-yl, 2-chloro-3-fluoro-pyrazolo[1,5-a]pyrimidin-5-yl, pyrazolo[1,5-a]pyridin-5-yl, or 2-methyl-pyrazolo[1,5-a]pyridin-5-yl.

40. Cy １ but, 【Chem.320】 25. The compound of claim 24, wherein:

41. The compound of any one of claims 1 to 40, wherein the compound is selected from Table 1.

42. A compound, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the exemplified compounds, or a stereoisomer or a pharmaceutically acceptable salt thereof.

43. 42. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 41, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

44. 44. A method of treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 41 or a pharmaceutical composition of claim 43.

Images