Cyclin-dependent kinase 2 (CDK2) inhibitors

Abstract

The present invention relates to compounds that inhibit CDK2 (cyclin-dependent kinase 2 or cell division protein kinase 2), as well as to methods for preparing said compounds, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of conditions, diseases and disorders mediated by CDK2.

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit CDK2 (cyclin-dependent kinase 2 or cell division protein kinase 2), as well as to methods for preparing said compounds, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of conditions, diseases and disorders mediated by CDK2. [Background technology]

[0002] CDK2 is a serine / threonine kinase that regulates the mammalian cell cycle. After binding to cyclin E1, cyclin E2, cyclin A1, or cyclin A2, the activated CDK2-cyclin complex phosphorylates various cellular substrates (Chi et al., 2020). For example, this complex phosphorylates and inactivates the retinoblastoma protein (pRB), thereby derepressing the E2F transcription factor family, which promotes the expression of cell cycle-related genes (Sherr & Roberts, 1999, 2004). Thus, CDK2 advances cells through the G1 to S phase of the cell cycle, when nuclear DNA is replicated in preparation for mitosis. CDK2 and its activity are often dysregulated in human cancers (Corsino et al., 2008; Ying et al., 2018; Nie et al., 2019). One mechanism of such dysregulation involves, but is not limited to, the amplification or overexpression of cyclin E1, which leads to the overactivation of CDK2 and promotes cell proliferation (Schraml et al. 2003). Depending on the lineage, dysregulation of CDK2 / E occurs in up to 40% of human cancers, including, but not limited to, uterine carcinosarcoma (approximately 40%), ovarian cancer (approximately 20%), gastric cancer (approximately 12%), esophageal cancer (approximately 10%), endometrial cancer (approximately 10%), and breast cancer (approximately 10%) (cbioportal.org). Amplification and overexpression of cyclin E1 have also been associated with poor prognosis in various cancers (Nakayama et al. 2010, Zhao et al. 2019). For many of these cancers, no targeted therapies are available to patients other than radiation therapy and chemotherapy. Therefore, the development of targeted drugs against CDK2 may be beneficial for cancer patients.

[0003] Chi Y., Carter JH, Swanger J., Mazin AV, Moritz RL, and Clurman BE (2020). A novel landscape of nuclear human CDk2 substrates revelaed by in situ phosphorylation.Sci.Adv 6,eaaz9899 Sherr CJ,Roberts JM.(1999).CDK inhibitors:positive and negative regulators of G1-phase progression.Genes Dev 13:1501-1512. Sherr CJ,Roberts JM.(2004).Living with or without cyclins and cyclin-dependent kinases.Genes Dev 18:2699-2711. Corsino PE,Davis BJ,Norgaard PH,Parker NN,Law M,Dunn W and Law BK.Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component.Neoplasia 2008;10:1240-1252 Ying M,Shao X,JingH,Liu Y,Qi X,Cao J,et al.Ubiquitin-dependent degradation of CDK2 drives the therapeutic diferentiation of AML by targeting PRDX2.Blood J Am SocHematol.2018;131(24):2698-711 Nie L,Wei Y,Zhang F,Hsu Y-H,Chan L-C,Xia W,et al.CDK2-mediated site-specifc phosphorylation of EZH2 drives and maintains triplenegative breast cancer.Nat Commun.2019;10(1):1-15 Schraml P,Bucher C,BissigH,et al.Cyclin E overexpression and amplification in human tumours.J Pathol.2003;200(3):375-383. Nakayama N, Nakayama K, Shamima Y, Ishikawa M, Katagiri A, Iida K, et al. Gene amplificationCCNE1is related to poor survival and potential therapeutic target in ovarian cancer. Cancer 2010:NA-NA. Guo Q,Lin Gao JJ, Cheng J, Bloomquist E, et al..Cdk4 / 6 inhibitor treatment for patients with hormone receptor-positive,HER2-negative,advanced or metastatic breast cancer:a US food and drug administration pooled analysis.Lancet Oncol 2020;21:250-60

[0004] WO 2020 / 168178 relates to a variety of CDK2 inhibitors structurally related to those disclosed herein, for example: [ka] Compounds such as (Example 12).

[0005] International Publication No. 2023 / 278326 (Blueprint) describes (Example 3) [ka] In particular, as shown in Figure 1 and the accompanying brief description, the Blueprint compounds bind to the CDK2 ATP-binding site in a manner that is significantly different from the Incyte compounds. Summary of the Invention

[0006] The Applicant has surprisingly discovered that compounds of formula (I) as described herein are [ka] (Incyte) Bulky [ka] We have found that novel vectors containing (optionally substituted) five-membered heteroaryls instead of the motif provide potency and selectivity superior to other kinases, combined with optimal in vivo PK properties.

[0007] Thus, according to a first aspect of the present invention, there is hereby provided a compound according to formula (I): [ka] [In the formula, Y 1 is a bond or CH2 (e.g., Y 1 is a bond); Y 2 is a bond, O, NR 5 or CR 6 R 7 (e.g., Y 2 is a bond); R 1 and R 2 are each independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl, or R 1 and R2 are taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl (e.g., R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, for example, R 1 and R 2 taken together to form a C3 cycloalkyl); Each R 3 are independently selected from the group consisting of hydroxyl, halo, C1-C6 alkyl, and C1-C6 haloalkyl; R 4 is selected from the group consisting of H, halo, C1-C6 alkyl, and C1-C6 haloalkyl (e.g., R 4 is H); R 5 is selected from the group consisting of H, C1-C6 alkyl, C(=O)-C1-C6 alkyl, or C(=O)-O-C1-C6 alkyl; R 6 and R 7 are taken together with the carbon atoms to which they are each bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, and the C3-C6 cycloalkyl or 3-6 membered heterocyclyl is selected from the group consisting of 0-3 substituents R 8 is replaced by; Each R 8 are independently selected from the group consisting of C1-C6 alkyl, C(═O)C1-C6 alkyl, halo, C1-C6 haloalkyl, S—C1-C6 alkyl, SO—C1-C6 alkyl, SO2-C1-C6 alkyl, cyano, hydroxyl, or two R 8 the substituents, taken together, form =O, n is 0 to 3 (e.g., n is 1, and R 3 is hydroxyl); m is 1 to 5 (e.g., m is 4); [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S (e.g., 2 heteroatoms independently selected from N, O, and S, e.g., 2 heteroatoms that are both N), and said 5-membered heteroaryl is a 5-membered heteroaryl containing 0 to 3 substituents R A is replaced by; Each R A are independently, *L 1 -X 1 where * means [ka] Each L 1 represents a bond, O, S, SO, SO2, C≡C, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, *O-C1-C6 haloalkylene**, *O-C1-C6 hydroxyalkylene**, C1-C6 alkylene-O-C1-C6 alkylene, *O-C3-C6 cycloalkylene**, *O-3-6 membered cycloalkylene are independently selected from heterocyclylene**, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), O-C1-C6 alkylene-O, *O-C1-C6 alkylene-O-C3-C6 cycloalkylene** and *O-C1-C6 alkylene-O-3- to 6-membered heterocyclylene**, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 is H, halo, cyano, hydroxyl, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R 8C3-C6 cycloalkyl, O-C1-C6 alkyl, S-C1-C6 alkyl, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, N(C1-C6 alkyl)2, C(=O)N(C1-C6 alkyl)2, C1-C6 hydroxyalkyl, 0-3 R 8 3-6 membered heterocyclyl (e.g., containing 1 or 2 heteroatoms independently selected from O, N, and S) substituted by a group, 0-3 R 8 5-10 membered heteroaryl (e.g., 5-, 6-, 9-, or 10-membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by a group; 0-3 R 8 a 5- to 10-membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, substituted by a group; 8 7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group, and 0-3 R 8 C7-C substituted by groups 10 independently selected from spirocycloalkyl; or Two Rs located on adjacent ring atoms A the substituents, taken together with the adjacent ring atoms, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof is provided.

[0008] According to a second aspect of the present invention, there is provided herein a compound selected from any one of the Examples or any one of the synthetic intermediates, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0009] According to a third aspect of the present invention, there is provided herein a pharmaceutical composition comprising a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof and one or more pharmaceutically acceptable carriers.

[0010] According to a fourth aspect of the present invention, there is provided herein a combination comprising a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more therapeutically active agents.

[0011] According to a fifth aspect of the present invention, there is provided herein a method of modulating CDK2 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof.

[0012] According to a sixth aspect of the present invention, there is provided herein a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof.

[0013] According to a seventh aspect of the present invention, there is hereby provided a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof for use as a medicament.

[0014] According to an eighth aspect of the present invention, there is provided herein a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof for use in the treatment of cancer.

[0015] According to a ninth aspect of the present invention, there is provided herein the use of a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, in the treatment of cancer.

[0016] According to a tenth aspect of the present invention, there is provided herein the use of a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, in the manufacture of a medicament for the treatment of cancer. [Brief explanation of the drawings]

[0017] [Figure 1] CDK2 ATP binding site (top) [ka] (Incyte) and (below) [ka] The putative binding modes of (Blueprint) are shown. These putative binding modes were modeled using the molecular modeling software package Maestro® (Schrodinger, LLC). The Incyte compound forms two hydrogen bonds with the hinge region of CDK2 (L83). It also forms a hydrogen bond with the catalytic K33 at the back. In contrast, the Blueprint compound forms three hydrogen bonds with the hinge region of CDK2 (L83 and E81), and it does not form any polar interactions at the back, including with K33. Instead, it forms two different hydrogen bonds with residues at the front (K20 and E8). In conclusion, the binding modes of the Incyte and Blueprint compounds to the CDK2 ATP-binding site are quite different from each other. [Figure 2] The putative binding mode of the compound according to formula (I) is shown below. [ka] (Incyte), but [ka] These putative binding modes were modeled using the molecular modeling software package Maestro® (Schrodinger, LLC). [Figure 3]

[0023] Figure 1 shows the effect of oral BID administration of the indicated compounds for 3 days on a PD marker (RB phosphorylation) in a cyclin E-amplified OVCAR3 xenograft model. Data are presented as a percentage of untreated animals. [ka] [ka] [ka] DETAILED DESCRIPTION OF THE INVENTION

[0018] Thus, the present invention provides in a first aspect a compound according to formula (I): [ka] [In the formula, Y 1 is a bond or CH2 (e.g., Y 1 is a bond); Y 2 is a bond, O, NR 5 or CR 6 R 7 (e.g., Y 2 is a bond); R 1 and R 2 are each independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl, or R 1 and R 2 are taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl (e.g., R 1 and R 2are taken together to form a C3-C4 cycloalkyl, for example, R 1 and R 2 taken together to form a C3 cycloalkyl); Each R 3 are independently selected from the group consisting of hydroxyl, halo, C1-C6 alkyl, and C1-C6 haloalkyl; R 4 is selected from the group consisting of H, halo, C1-C6 alkyl, and C1-C6 haloalkyl (e.g., R 4 is H); R 5 is selected from the group consisting of H, C1-C6 alkyl, C(=O)-C1-C6 alkyl, or C(=O)-O-C1-C6 alkyl; R 6 and R 7 are taken together with the carbon atoms to which they are each bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of O, N and S, and said C3-C6 cycloalkyl or 3-6 membered heterocyclyl is selected from the group consisting of 0 to 3 substituents R 8 is replaced by; Each R 8 are independently selected from the group consisting of C1-C6 alkyl, C(═O)C1-C6 alkyl, halo, C1-C6 haloalkyl, S—C1-C6 alkyl, SO—C1-C6 alkyl, SO2-C1-C6 alkyl, cyano, hydroxyl, or wherein two R 8 the substituents, taken together, form =O, n is 0 to 3 (e.g., n is 1, and R 3 is hydroxyl); m is 1 to 5 (e.g., m is 4); [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S (e.g., 2 heteroatoms independently selected from N, O, and S, e.g., 2 heteroatoms that are both N), and said 5-membered heteroaryl is a 5-membered heteroaryl containing 0 to 3 substituents R A is replaced by; Each R A are independently, *L 1 -X 1 where * means [ka] Each L 1 represents a bond, O, S, SO, SO2, C≡C, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, *O-C1-C6 haloalkylene**, *O-C1-C6 hydroxyalkylene**, C1-C6 alkylene-O-C1-C6 alkylene, *O-C3-C6 cycloalkylene**, *O-3-6 membered cycloalkylene are independently selected from heterocyclylene**, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), O-C1-C6 alkylene-O, *O-C1-C6 alkylene-O-C3-C6 cycloalkylene** and *O-C1-C6 alkylene-O-3- to 6-membered heterocyclylene**, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 is H, halo, cyano, hydroxyl, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R 8C3-C6 cycloalkyl, O-C1-C6 alkyl, S-C1-C6 alkyl, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, N(C1-C6 alkyl)2, C(=O)N(C1-C6 alkyl)2, C1-C6 hydroxyalkyl, 0-3 R 8 3-6 membered heterocyclyl (e.g., containing 1 or 2 heteroatoms independently selected from O, N, and S) substituted by a group, 0-3 R 8 5-10 membered heteroaryl (e.g., 5-, 6-, 9-, or 10-membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by a group; 0-3 R 8 a 5- to 10-membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, substituted by a group; 8 7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group, and 0-3 R 8 C7-C substituted by groups 10 independently selected from spirocycloalkyl; or Two Rs located on adjacent ring atoms A the substituents, taken together with the adjacent ring atoms, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof to provide.

[0019] L as defined above 1 With respect to groups, it should be understood that for certain groups, such as C1-C6 alkylene and O-C1-C6 alkylene-O, the substituents are symmetrical, i.e., *C1-C6 alkylene** is the same as **C1-C6 alkylene*, and therefore * and ** are undefined.

[0020] In one embodiment, Y 1is a bond.

[0021] In an alternative (less preferred) embodiment, Y 1 is CH2 and R 2 is H.

[0022] In one embodiment, Y 2 is a bond.

[0023] In some embodiments, m is 4.

[0024] In some embodiments, n is 1 to 3, for example, n is 1.

[0025] In some embodiments, at least one R 3 is OH.

[0026] In certain embodiments, the compound of formula (I) is a compound of formula (Ia): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined above).

[0027] In certain embodiments, the compound of formula (I) is a compound of formula (Ib): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined above).

[0028] In certain embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined above).

[0029] In certain embodiments, the compound of formula (I) is a compound of formula (Id): [ka] (In the formula, R 1 , R 2 , R 4 and [ka] is as defined above).

[0030] In one embodiment, R 1 and R 2 taken together form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl.

[0031] In one embodiment, R 1 and R 2 taken together form a C3-C4 cycloalkyl.

[0032] In one embodiment, R 1 and R 2 taken together form a C3 cycloalkyl.

[0033] In one embodiment, R 4 is H.

[0034] In one embodiment, R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0035] In one embodiment, R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0036] In one embodiment, m is 4 and R 1 and R 2 taken together form a C3-C4 cycloalkyl.

[0037] In one embodiment, m is 4 and R 1 and R 2 taken together form a C3 cycloalkyl.

[0038] In one embodiment, m is 4 and R 4 is H.

[0039] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0040] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0041] In one embodiment, Y 1 is a bond and R 1 and R2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0042] In one embodiment, Y 1 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0043] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 taken together form a C3-C4 cycloalkyl.

[0044] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 taken together form a C3 cycloalkyl.

[0045] In one embodiment, Y 1 is a bond, m is 4, and R 4 is H.

[0046] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0047] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0048] In one embodiment, Y 2 is a bond and R 1 and R 2are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0049] In one embodiment, Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0050] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 taken together form a C3-C4 cycloalkyl.

[0051] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 taken together form a C3 cycloalkyl.

[0052] In one embodiment, Y 2 is a bond, m is 4, and R 4 is H.

[0053] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0054] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0055] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0056] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0057] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 taken together form a C3-C4 cycloalkyl.

[0058] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 taken together form a C3 cycloalkyl.

[0059] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 4 is H.

[0060] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H.

[0061] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2are taken together to form a C3 cycloalkyl, and R 4 is H.

[0062] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, and the 5-membered heteroaryl is selected from 0 to 3 substituents R A wherein R A is as defined above.

[0063] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, and the 5-membered heteroaryl is selected from 0 to 3 substituents R A wherein R A is as defined above, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0064] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N and O, and the 5-membered heteroaryl is selected from 0 to 3 substituents R A wherein R A is as defined above.

[0065] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N and O, and the 5-membered heteroaryl is selected from 0 to 3 substituents R A wherein R A is as defined above, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0066] In one embodiment, [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms, each of which is N, and said 5-membered heteroaryl is A wherein R A is as defined above.

[0067] In one embodiment, [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms, each of which is N, and said 5-membered heteroaryl is A wherein R A is as defined above, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0068] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is substituted with 0 to 3 substituents R A wherein R A is as defined above.

[0069] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is substituted with 0 to 3 substituents R A wherein R A is as defined above, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0070] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is selected from the group consisting of 0 to 2 substituents R A wherein R A is as defined above.

[0071] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is selected from the group consisting of 0 to 2 substituents R A wherein R A is as defined above, and Y1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0072] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is substituted with zero or one substituent R A wherein R A Ha*L 1 -X 1 and L 1 and X 1 is as defined above.

[0073] In one embodiment, [ka] is a 5-membered heteroaryl containing two heteroatoms, each of which is N, and said 5-membered heteroaryl is substituted with zero or one substituent R A wherein R A Ha*L 1 -X 1 and L 1 and X 1 is as defined above, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0074] In one embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0075] In one embodiment, [ka] teeth, [ka] and Y is selected from the group consisting of 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0076] In one embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0077] In one embodiment, [ka] teeth, [ka] and Y is selected from the group consisting of 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2are taken together to form a C3 cycloalkyl, and R 4 is H.

[0078] In one embodiment, [ka] teeth, [ka] [ka] and X is selected from O, NH and S (e.g., X is NH).

[0079] In one embodiment, [ka] teeth, [ka] [ka] X is selected from O, NH, and S (e.g., X is NH), and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0080] In one embodiment, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0081] In one embodiment, [ka] teeth, [ka] [ka] [ka] and Y is selected from the group consisting of 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0082] In one embodiment, [ka] teeth, [ka] and X is selected from O, NH and S.

[0083] In one embodiment, [ka] teeth, [ka] X is selected from O, NH and S; Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0084] In one embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0085] In one embodiment, [ka] teeth, [ka] and Y is selected from the group consisting of 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0086] In one embodiment, i) [ka] teeth, [ka] is selected from the group consisting of (e.g., [ka] teeth, [ka] ), R A teeth, a) halo, b) cyano, c) C1-C6 alkyl, d) C1-C6 haloalkyl, e) C1-C6 hydroxyalkyl, f) O-C1-C6 alkyl, g) C(=O)-O-C1-C6 alkyl, h) C1-C6 alkylene-O—C1-C6 alkyl, i) O—C1-C6 alkylene-O—C1-C6 alkyl, j) 0 to 3 R 8 C3-C6 cycloalkyl substituted by a group, k) 0 to 3 R 8 a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; l) 0 to 3 R 8 a 5-10 membered partially saturated heterocyclyl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; m) 0 to 3 R 8 O-C3-C6 cycloalkyl substituted by a group; n) 0 to 3 R 8 C≡C-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; o) 0 to 3 R 8 S-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; p) 0 to 3 R 8C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; q) O-C1-C6 haloalkyl, r) O-C1-C6 alkylene-N(C1-C6 alkyl)2, s) O—C1-C6 hydroxyalkylene-O—C1-C6 alkyl, t) 0 to 3 R 8 O-C1-C6 alkylene-C3-C6 cycloalkyl substituted by a group; u) 0 to 3 R 8 O-C1-C6 alkylene-3-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; v) O-C1-C6 alkylene-C(=O)-N(C1-C6 alkyl)2, w) 0 to 3 R 8 C1-C6 alkylene-5-10 membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; x) 0 to 3 R 8 O-C1-C6 alkylene-7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; y) O—C1-C6 alkylene-S(O)2-C1-C6 alkyl, z) O-C1-C6 hydroxyalkyl, aa) 0 to 3 R 8 O-C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; bb) 0 to 3 R 8 O-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; cc) 0 to 3 R 8 O-3 to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; dd) 0 to 3 R8 C≡C-C3-C6 cycloalkyl substituted by a group; ee) S-C1-C6 haloalkyl, ff) 0 to 3 R 8 O-C1-C6 alkylene-O-3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N, and S, substituted by a group gg) and 0 to 3 R 8 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, substituted by a group selected from; or ii) [ka] teeth, [ka] and R A The substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S.

[0087] In one embodiment, i) [ka] teeth, [ka] is selected from the group consisting of (e.g., [ka] teeth, [ka] ), R A teeth, a) halo, b) cyano, c) C1-C6 alkyl, d) C1-C6 haloalkyl, e) C1-C6 hydroxyalkyl, f) O-C1-C6 alkyl, g) C(=O)-O-C1-C6 alkyl, h) C1-C6 alkylene-O—C1-C6 alkyl, i) O—C1-C6 alkylene-O—C1-C6 alkyl, j) 0 to 3 R 8 C3-C6 cycloalkyl substituted by a group, k) 0 to 3 R 8 a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; l) 0 to 3 R 8 a 5-10 membered partially saturated heterocyclyl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; m) 0 to 3 R 8 O-C3-C6 cycloalkyl substituted by a group; n) 0 to 3 R 8 C≡C-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; o) 0 to 3 R 8 S-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; p) 0 to 3 R 8 C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; q) O-C1-C6 haloalkyl, r) O-C1-C6 alkylene-N(C1-C6 alkyl)2, s) O—C1-C6 hydroxyalkylene-O—C1-C6 alkyl, t) 0 to 3 R 8O-C1-C6 alkylene-C3-C6 cycloalkyl substituted by a group; u) 0 to 3 R 8 O-C1-C6 alkylene-3-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; v) O-C1-C6 alkylene-C(=O)-N(C1-C6 alkyl)2, w) 0 to 3 R 8 C1-C6 alkylene-5-10 membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; x) 0 to 3 R 8 O-C1-C6 alkylene-7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; y) O—C1-C6 alkylene-S(O)2-C1-C6 alkyl, z) O-C1-C6 hydroxyalkyl, aa) 0 to 3 R 8 O-C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; bb) 0 to 3 R 8 O-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; cc) 0 to 3 R 8 O-3 to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; dd) 0 to 3 R 8 C≡C-C3-C6 cycloalkyl substituted by a group; ee) S-C1-C6 haloalkyl, ff) 0 to 3 R 8 O-C1-C6 alkylene-O-3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N, and S, substituted by a group gg) and 0 to 3 R 83- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, substituted by a group selected from; or ii) [ka] teeth, [ka] and R A the substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0088] In some embodiments, each R 8 are independently selected from the group consisting of halo (e.g., fluoro), C1-C6 alkyl (e.g., methyl), hydroxyl, cyano, S(O2)-C1-C6 alkyl (e.g., S(O2)CH3), C(=O)-C1-C6 alkyl (e.g., C(=O)CH3), O-C1-C6 alkyl (e.g., OCH3) and C1-C6 haloalkyl (e.g., C1 haloalkyl, e.g., CHF2), or two R on the same ring atom 8 The substituents taken together form =O.

[0089] In one embodiment, [ka] teeth, [ka] and R A is selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, O-C1-C6 alkyl, C(═O)—O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, O-C1-C6 alkylene-O-C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S; or ii) [ka] teeth, [ka] and R A The substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S.

[0090] In one embodiment, [ka] teeth, [ka] and R A is selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, O-C1-C6 alkyl, C(═O)—O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, O-C1-C6 alkylene-O-C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S; or ii) [ka] teeth, [ka] and R A the substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0091] In one embodiment, [ka] teeth, [ka] is.

[0092] In one embodiment, [ka] teeth, [ka] and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0093] In one embodiment, [ka] teeth, [ka] and R A is CH3 or OCH3.

[0094] In one embodiment, [ka] teeth, [ka] and R A is CH3, OCH3 or OCH2CH3.

[0095] In one embodiment, [ka] teeth, [ka] and R A is CH3 or OCH3, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0096] In one embodiment, [ka] teeth, [ka] and R Ais CH3, OCH3 or OCH2CH3, and Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H.

[0097] In one embodiment, each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, C1-C6 alkylene-O-C1-C6 alkylene, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), and O-C1-C6 alkylene-O, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 are independently selected from H, halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, C1-C6 hydroxyalkyl, and 3-6 membered heterocyclyl (e.g., containing one heteroatom that is O).

[0098] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] is as described in any one of the present embodiments, and each L 1are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, C1-C6 alkylene-O-C1-C6 alkylene, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), and O-C1-C6 alkylene-O, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 are independently selected from H, halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, C1-C6 hydroxyalkyl, and 3-6 membered heterocyclyl (e.g., containing one heteroatom that is O).

[0099] In one embodiment, each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C2 alkylene, C1 haloalkylene, *O-C1-C2 alkylene**, C1-C2 alkylene-O-C1 alkylene, C1-hydroxyalkylene, C3 cycloalkylene, 5-6 membered heterocyclylene containing one heteroatom which is O, and O-C2 alkylene-O, wherein * is [ka] ** indicates the point of attachment to X 1 refers to the point of attachment to

[0100] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] is as described in any one of the present embodiments, and each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C2 alkylene, C1 haloalkylene, *O-C1-C2 alkylene**, C1-C2 alkylene-O-C1 alkylene, C1-hydroxyalkylene, C3 cycloalkylene, 5-6 membered heterocyclylene containing one heteroatom which is O, and O-C2 alkylene-O, wherein * is [ka] ** indicates the point of attachment to X 1 [refers to the point where it joins to the

[0101] In some embodiments, each X 1 are independently selected from H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and 5-6 membered heterocyclyl containing 1 heteroatom that is O.

[0102] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] is as described in any one of the present embodiments, and each X 1 are independently selected from H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and 5-6 membered heterocyclyl containing 1 heteroatom that is O.

[0103] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] teeth, [ka] and R A is selected from the list consisting of C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkyl, C(═O)—O-C1-C6 alkyl, C1-C6 hydroxyalkyl, a 3- to 6-membered heteroatom containing one heteroatom which is O, halo, O-C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and O-C1-C6 alkylene-O-C1-C6 alkyl.

[0104] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] is as described in any one of the present embodiments, and R A is selected from the list consisting of C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkyl, C(═O)—O-C1-C6 alkyl, C1-C6 hydroxyalkyl, a 3- to 6-membered heteroatom containing one heteroatom which is O, halo, O-C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and O-C1-C6 alkylene-O-C1-C6 alkyl.

[0105] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] [In the formula, [ka] teeth, [ka] and R A is selected from the list consisting of CH3, CH2CHOCH3, CHF2, C(=O)-O-CH3, CH2OH, a five-membered heteroatom having one heteroatom that is O, a six-membered heteroatom having one heteroatom that is O, CHOCH3, OCH3, Cl, Ccycloalkyl, CF3, cyano, OCH2CHOCH3, and OCH2CH3.

[0106] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] and [ka] teeth, [ka] is.

[0107] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] and [ka] teeth, [ka] and R A is selected from the list consisting of CH3 and OCH3.

[0108] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] and [ka] teeth, [ka] and R A is selected from the list consisting of CH3, OCH3 and OCH2CH3.

[0109] In one embodiment, R 1 and R 2 taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl; [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0110] In one embodiment, R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0111] In one embodiment, R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0112] In one embodiment, R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0113] In one embodiment, R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0114] In one embodiment, R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0115] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0116] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0117] In one embodiment, m is 4 and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0118] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0119] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0120] In one embodiment, Y 1 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0121] In one embodiment, Y 1 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0122] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0123] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0124] In one embodiment, Y 1 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0125] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0126] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0127] In one embodiment, Y 2 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0128] In one embodiment, Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0129] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0130] In one embodiment, Y 2is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0131] In one embodiment, Y 2 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0132] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0133] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0134] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0135] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0136] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0137] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0138] In one embodiment, Y 1 is a bond and Y2 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0139] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0140] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0141] In one embodiment, R 1 and R 2 taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl; [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0142] In one embodiment, R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0143] In one embodiment, R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0144] In one embodiment, R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0145] In one embodiment, R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0146] In one embodiment, R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0147] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0148] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0149] In one embodiment, m is 4 and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0150] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0151] In one embodiment, m is 4 and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0152] In one embodiment, Y 1 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0153] In one embodiment, Y 1 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0154] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0155] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0156] In one embodiment, Y 1 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0157] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0158] In one embodiment, Y 1 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0159] In one embodiment, Y 2 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0160] In one embodiment, Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0161] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0162] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0163] In one embodiment, Y 2 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0164] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0165] In one embodiment, Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0166] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0167] In one embodiment, Y 1 is a bond and Y 2 is a bond and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0168] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0169] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0170] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0171] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0172] In one embodiment, Y 1 is a bond and Y 2 is a bond, m is 4, and R 1 and R 2 are taken together to form a C3 cycloalkyl, and R 4 is H, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0173] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] and [ka] teeth, [ka] wherein X is selected from O, NH, and S (e.g., X is NH).

[0174] In certain embodiments, the compound of formula (I) is a compound of formula (Id-I): [ka] and teeth, [ka] teeth, [ka] (e.g., [ka] teeth, [ka] (It is).

[0175] According to a second aspect of the present invention, there is provided herein: 1) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 2) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 3) 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 4) methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate; 5) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 6) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 7) 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 8) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 9) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 10) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 11) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((2-(methoxymethyl)-1H-imidazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 12) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 13) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 14) 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 15) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 16) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 17) 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 18) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 19) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 20) 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile; 21) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 22) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 23) 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0176] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0177] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0178] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0179] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0180] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0181] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0182] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0183] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0184] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0185] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0186] In one embodiment, the compound is [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0187] According to a third aspect of the present invention, there is provided herein a pharmaceutical composition comprising a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0188] According to a fourth aspect of the present invention, there is provided herein a combination comprising a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more therapeutically active agents.

[0189] According to a fifth aspect of the present invention, there is provided herein a method of modulating CDK2 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof.

[0190] According to a sixth aspect of the present invention, there is provided herein a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof.

[0191] According to a seventh aspect of the present invention, there is hereby provided a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof for use as a pharmaceutical.

[0192] According to an eighth aspect of the present invention, there is provided herein a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt and / or tautomer thereof for use in the treatment of cancer.

[0193] According to a ninth aspect of the present invention, there is provided herein the use of a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, in the treatment of cancer.

[0194] According to a tenth aspect of the present invention, there is provided herein the use of a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, in the manufacture of a medicament for the treatment of cancer.

[0195] In certain embodiments (embodiments of the sixth, eighth, ninth or tenth aspect of the invention), the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer and endometrial cancer.

[0196] In one embodiment (an embodiment of the sixth, eighth, ninth or tenth aspect of the invention) the cancer is a cyclin E amplified cancer.

[0197] Accordingly, the present invention provides the following numbered embodiments: It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0198] Embodiment 1. A compound according to formula (I): [ka] [In the formula, Y 1 is a bond or CH2 (e.g., Y 1 is a bond); Y 2 is a bond, O, NR 5 or CR 6 R 7 (e.g., Y 2 is a bond); R 1 and R 2 are each independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl, or R 1 and R 2 are taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl (e.g., R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, for example, R 1 and R 2 taken together to form a C3 cycloalkyl); Each R 3 are independently selected from the group consisting of hydroxyl, halo, C1-C6 alkyl, and C1-C6 haloalkyl; R 4 is selected from the group consisting of H, halo, C1-C6 alkyl, and C1-C6 haloalkyl (e.g., R 4 is H); R 5 is selected from the group consisting of H, C1-C6 alkyl, C(=O)-C1-C6 alkyl, or C(=O)-O-C1-C6 alkyl; R 6 and R 7are taken together with the carbon atoms to which they are each bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein said C3-C6 cycloalkyl or 3-6 membered heterocyclyl is selected from the group consisting of 0-3 substituents R 8 is replaced by; Each R 8 are independently selected from the group consisting of C1-C6 alkyl, C(═O)C1-C6 alkyl, halo, C1-C6 haloalkyl, S—C1-C6 alkyl, SO—C1-C6 alkyl, SO2-C1-C6 alkyl, cyano, hydroxyl, or wherein two R 8 the substituents, taken together, form =O, n is 0 to 3 (e.g., n is 1, and R 3 is hydroxyl); m is 1 to 5 (e.g., m is 4); [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S (e.g., 2 heteroatoms independently selected from N, O, and S, e.g., 2 heteroatoms that are both N), and said 5-membered heteroaryl is a 5-membered heteroaryl containing 0 to 3 substituents R A is replaced by; Each R A are independently, *L 1 -X 1 where * means [ka] Each L 1represents a bond, O, S, SO, SO2, C≡C, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, *O-C1-C6 haloalkylene**, *O-C1-C6 hydroxyalkylene**, C1-C6 alkylene-O-C1-C6 alkylene, *O-C3-C6 cycloalkylene**, *O-3-6 membered cycloalkylene are independently selected from heterocyclylene**, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), O-C1-C6 alkylene-O, *O-C1-C6 alkylene-O-C3-C6 cycloalkylene** and *O-C1-C6 alkylene-O-3- to 6-membered heterocyclylene**, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 is H, halo, cyano, hydroxyl, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R 8 C3-C6 cycloalkyl, O-C1-C6 alkyl, S-C1-C6 alkyl, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, N(C1-C6 alkyl)2, C(=O)N(C1-C6 alkyl)2, C1-C6 hydroxyalkyl, 0-3 R 8 3-6 membered heterocyclyl (e.g., containing 1 or 2 heteroatoms independently selected from O, N, and S) substituted by a group, 0-3 R 8 5-10 membered heteroaryl (e.g., 5-, 6-, 9-, or 10-membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by a group; 0-3 R 8 a 5- to 10-membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, substituted by a group; 87-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group, and 0-3 R 8 C7-C substituted by groups 10 independently selected from spirocycloalkyl; or Two Rs located on adjacent ring atoms A the substituents, taken together with the adjacent ring atoms, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0199] Embodiment 2.Y 1 is a bond, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0200] Embodiment 3.Y 2 The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a bond.

[0201] Embodiment 4. A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein m is 4.

[0202] Embodiment 5. A compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein n is 1 to 3, for example, n is 1.

[0203] Embodiment 6. At least one R 3 The compound of embodiment 5, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is OH.

[0204] Embodiment 7. The compound of formula (I) is a compound of formula (Ia): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0205] Embodiment 7a. The compound of formula (Ia) is a compound of formula (Ia-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0206] Embodiment 8. The compound of formula (I) is a compound of formula (Ib): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0207] Embodiment 8a. The compound of formula (Ib) is a compound of formula (Ib-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0208] Embodiment 9. The compound of formula (I) is a compound of formula (Ic): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0209] Embodiment 9a. The compound of formula (Ic) is a compound of formula (Ic-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0210] Embodiment 10. The compound of formula (I) is a compound of formula (Id): [ka] (In the formula, R 1 , R 2 , R 4 and [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0211] Embodiment 10a. The compound of formula (Id) is a compound of formula (Id-I): [ka] (In the ceremony [ka] is as defined in embodiment 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0212] Embodiment 11.R 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof of any one of embodiments 1-10, wherein:

[0213] Embodiment 12.R 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof, of embodiment 11, wherein:

[0214] Embodiment 13.R 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof, of embodiment 12, wherein:

[0215] Embodiment 14.R4 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein

[0216] Embodiment 15. [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, and the 5-membered heteroaryl is A wherein R A The compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 14.

[0217] Embodiment 16. [ka] is a 5-membered heteroaryl containing two heteroatoms independently selected from N and O, and the 5-membered heteroaryl is A wherein R A The compound of embodiment 15, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 15.

[0218] Embodiment 17. [ka] is a 5-membered heteroaryl containing 1 to 3 heteroatoms, each of which is N, and said 5-membered heteroaryl is A wherein R A The compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 16.

[0219] Embodiment 18. [ka] is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is A wherein R A The compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 17.

[0220] Embodiment 19. [ka] is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is A wherein R A The compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 18.

[0221] Embodiment 20. [ka] is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is substituted with zero or one substituent R A wherein R A Ha*L 1 -X 1 and L 1 and X 1 The compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of embodiments 1 to 19.

[0222] Embodiment 21. [ka] but, [ka] 15. The compound of any one of embodiments 1 to 14, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof.

[0223] Embodiment 22. [ka] but, [ka] 22. The compound of any one of embodiments 1-14 and 21, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof.

[0224] Embodiment 23. [ka] but, [ka] [ka] or a pharmaceutically acceptable salt and / or tautomer thereof, wherein X is selected from the group consisting of:

[0225] Embodiment 24. [ka] but, [ka] [ka] 23. The compound of any one of embodiments 1 to 14 and 22, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof.

[0226] Embodiment 25. [ka] but, [ka] or a pharmaceutically acceptable salt and / or tautomer thereof, wherein X is selected from the group consisting of:

[0227] Embodiment 26. [ka] but, [ka] 26. The compound of any one of embodiments 1 to 14 and 25, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof.

[0228] Embodiment 27. i) [ka] but, [ka] is selected from the group consisting of (e.g., [ka] teeth, [ka] ), R A but, a) halo, b) cyano, c) C1-C6 alkyl, d) C1-C6 haloalkyl, e) C1-C6 hydroxyalkyl, f) O-C1-C6 alkyl, g) C(=O)-O-C1-C6 alkyl, h) C1-C6 alkylene-O—C1-C6 alkyl, i) O—C1-C6 alkylene-O—C1-C6 alkyl, j) 0 to 3 R 8 C3-C6 cycloalkyl substituted by a group, k) 0 to 3 R 8 a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; l) 0 to 3 R 8 a 5-10 membered partially saturated heterocyclyl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; m) 0 to 3 R 8 O-C3-C6 cycloalkyl substituted by a group; n) 0 to 3 R 8 C≡C-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; o) 0 to 3 R 8 S-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; p) 0 to 3 R 8C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; q) O-C1-C6 haloalkyl, r) O-C1-C6 alkylene-N(C1-C6 alkyl)2, s) O—C1-C6 hydroxyalkylene-O—C1-C6 alkyl, t) 0 to 3 R 8 O-C1-C6 alkylene-C3-C6 cycloalkyl substituted by a group; u) 0 to 3 R 8 O-C1-C6 alkylene-3-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; v) O-C1-C6 alkylene-C(=O)-N(C1-C6 alkyl)2, w) 0 to 3 R 8 C1-C6 alkylene-5-10 membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; x) 0 to 3 R 8 O-C1-C6 alkylene-7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; y) O—C1-C6 alkylene-S(O)2-C1-C6 alkyl, z) O-C1-C6 hydroxyalkyl, aa) 0 to 3 R 8 O-C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; bb) 0 to 3 R 8 O-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; cc) 0 to 3 R 8 O-3 to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; dd) 0 to 3 R8 C≡C-C3-C6 cycloalkyl substituted by a group; ee) S-C1-C6 haloalkyl, ff) 0 to 3 R 8 O-C1-C6 alkylene-O-3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N, and S, substituted by a group gg) and 0 to 3 R 8 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, substituted by a group selected from; or ii) [ka] but, [ka] and R A the substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; A compound according to any one of embodiments 1 to 14 and 26, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0229] Embodiment 27a. [ka] but, a) O—C1-C6 haloalkylene-O—C1-C6 alkyl; b) hydroxyl; c) S-C1-C6 alkyl; d) C1-C6 alkylene-S-C1-C6 alkyl; and e) C≡C-C1~C6 alkyl 27. The compound of any one of embodiments 1-14 and 26, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof.

[0230] Embodiment 28. Each R 8 are independently selected from the group consisting of halo (e.g., fluoro), C1-C6 alkyl (e.g., methyl), hydroxyl, cyano, S(O2)—C1-C6 alkyl (e.g., S(O2)CH3), C(═O)—C1-C6 alkyl (e.g., C(═O)CH3), O—C1-C6 alkyl (e.g., OCH3) and C1-C6 haloalkyl (e.g., C1 haloalkyl, e.g., CHF2), or wherein two R are on the same ring atom; 8 The compound of embodiment 27, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the substituents, taken together, form =0.

[0231] Embodiment 29. i) [ka] but, [ka] and R A is selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, O-C1-C6 alkyl, C(═O)—O-C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, O-C1-C6 alkylene-O-C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S; or ii) [ka] but, [ka] and R Athe substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; 28. A compound according to embodiment 27, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0232] Embodiment 29a. [ka] but, [ka] and wherein X is selected from O, NH, and S (e.g., X is NH), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0233] Embodiment 29b. [ka] but, [ka] (e.g., [ka] teeth, [ka] 15. The compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0234] Embodiment 30. [ka] but, [ka] and R A 30. The compound of any one of embodiments 1-14, 28, and 29, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is CH3, OCH2CH3, or OCH3.

[0235] Embodiment 31. Each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, C1-C6 alkylene-O-C1-C6 alkylene, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), and O-C1-C6 alkylene-O, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 are independently selected from H, halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, C1-C6 hydroxyalkyl, and 3-6 membered heterocyclyl (e.g., containing one heteroatom that is O); or a pharmaceutically acceptable salt and / or tautomer thereof.

[0236] Embodiment 31a. Each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C2 alkylene, C1 haloalkylene, *O-C1-C2 alkylene**, C1-C2 alkylene-O-C1 alkylene, C1-hydroxyalkylene, C3 cycloalkylene, 5-6 membered heterocyclylene containing one heteroatom which is O, and O-C2 alkylene-O, wherein * is [ka] ** indicates the point of attachment to X 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R 1 is a methyl group; R 2 is a methyl group; R 3 is a methyl group; R 4 is a methyl group; R 5 is a methyl group; R 6 is a methyl group; R 7 is a methyl group; R 8 is a methyl group; R 9 is a methyl group; R 10 is a methyl group; R 11 is a methyl group; R 12 is a methyl group; R 13 is a methyl group; R 14 is a methyl group; R 15 is a methyl group; R 16 is a methyl group; R 17 is a methyl group; R 18 is a methyl group; R 19 is a methyl group; R 20 is a methyl group; R 21 is a methyl group; R 22 is a methyl group; R 23 is a methyl group; R 24 is a methyl group; R 25 is a methyl

[0237] Embodiment 31b. Each X 1 is independently selected from H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and 5-6 membered heterocyclyl containing 1 heteroatom, wherein O is H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and O; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0238] Embodiment 32.R A is selected from the list consisting of C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkyl, C(═O)—O-C1-C6 alkyl, C1-C6 hydroxyalkyl, a 3- to 6-membered heteroatom containing one heteroatom which is O, halo, O-C1-C6 alkyl, C3-C6 cycloalkyl, cyano, and O-C1-C6 alkylene-O-C1-C6 alkyl; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0239] Embodiment 32a.R A is selected from the list consisting of CH3, CH2CHOCH3, OCH2CH3, CHF2, C(=O)-O-CH3, CH2OH, a five-membered heteroatom having one heteroatom that is O, a six-membered heteroatom having one heteroatom that is O, CHOCH3, OCH3, Cl, C3 cycloalkyl, CF3, cyano, OCH2CHOCH3, and OCH2CH3; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0240] Embodiment 33. 1) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 2) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 3) 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 4) methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate; 5) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 6) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 7) 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 8) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 9) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 10) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 11) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((2-(methoxymethyl)-1H-imidazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 12) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 13) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 14) 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 15) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 16) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 17) 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 18) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 19) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 20) 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile; 21) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 22) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 23) 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one a compound selected from any one of or a pharmaceutically acceptable salt and / or tautomer thereof.

[0241] Embodiment 33a. 24) 2'-((3-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 25) 2'-((3-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 26) 2'-((3-(((3R,4S)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 27) 2'-((3-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 28) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 29) 2'-((3-(3,3-difluorocyclobutoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 30) 2'-((3-(3,3-difluorocyclobutoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 31) 2'-((5'-(difluoromethyl)-1'-methyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 32) 2'-((3-((S)-2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 33) 2'-((3-((S)-2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 34) 2'-((1'-(difluoromethyl)-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 35) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1-methyl-1H-pyrazol-4-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 36) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyridin-3-ylethynyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 37) 2'-((1',5'-dimethyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 38) 2'-((3-(cyclopropylmethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 39) 2'-((3-(2-fluoroethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 40) 2'-((3-cyclobutoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 41) 2'-((3-(2,2-difluoroethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 42) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-hydroxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 43) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 44) 2'-((3-(2,2-difluoro-3-methoxypropoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 45) 2'-((3-((1-fluorocyclopropyl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 46) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 47) 2'-((3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 48) 2'-((3-((3-fluorooxetan-3-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 49) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxy-d3)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 50) 2'-((3-(((3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 51) 2'-((3-(((3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 52) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methylthio)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 53) 2'-((3-((2-acetyl-2-azaspiro[3.3]heptan-6-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 54) 2'-((3-((2-oxaspiro[3.3]heptan-6-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 55) 2'-((3-cyclopropoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 56) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 57) 2'-((5'-chloro-1'-methyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 58) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(prop-1-yn-1-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 59) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyridin-4-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 60) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyridin-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 61) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyridin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 62) 2'-((1'-(difluoromethyl)-5'-methyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 63) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 64) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyrazolo[1,5-a]pyrazin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 65) 2'-((3-(((1r,3R)-3-hydroxy-3-methylcyclobutyl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 66) 2'-((3-(((R)-1,4-dioxan-2-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 67) 1-(((4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazol-3-yl)oxy)methyl)cyclopropane-1-carbonitrile; 68) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((methylthio)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 69) 2'-((3-((S)-2,2-difluorocyclopropoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 70) 2'-((3-((R)-2,2-difluorocyclopropoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 71) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(((R)-tetrahydrofuran-3-yl)methoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 72) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(((S)-tetrahydrofuran-3-yl)methoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 73) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 74) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 75) 2'-((3-((-4-fluorotetrahydrofuran-3-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 76) 2'-((3-((4,4-difluorotetrahydrofuran-3-yl)methoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 77) 2'-((3-hydroxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one.; 78) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 79) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1'-methyl-1H,1'H-[3,3'-pyrazol]-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 80) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1'-methyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 81) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 82) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1r,3R)-3-methoxycyclobutoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 83) 2'-((3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 84) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1'-methyl-5'-(trifluoromethyl)-1H,1'H-[3,4'-pyrazol]-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 85) 2'-((3-(1-(fluoromethyl)cyclopropoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one a compound selected from any one of or a pharmaceutically acceptable salt and / or tautomer thereof.

[0242] Embodiment 34. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0243] Embodiment 35. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0244] Embodiment 35a. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0245] Embodiment 36. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0246] Embodiment 36a. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0247] Embodiment 37. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0248] Embodiment 37a. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0249] Embodiment 38. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0250] Embodiment 38a. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0251] Embodiment 39. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0252] Embodiment 39a. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0253] Embodiment 40. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0254] Embodiment 41. A combination comprising a compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more therapeutically active agents.

[0255] Embodiment 42. A method of modulating CDK2 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 39a, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0256] Embodiment 43. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 39a, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0257] Embodiment 44. A compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof for use as a pharmaceutical.

[0258] Embodiment 45. A compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof for use in the treatment of cancer.

[0259] Embodiment 46. Use of a compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof in the treatment of cancer.

[0260] Embodiment 47. Use of a compound according to any one of embodiments 1 to 39a or a pharmaceutically acceptable salt and / or tautomer thereof in the manufacture of a medicament for the treatment of cancer.

[0261] Embodiment 48. The method according to embodiment 43, the compound for use according to embodiment 45, or the use according to embodiment 46 or 47, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0262] Embodiment 49. The method according to embodiment 43 or 48, the compound for use according to embodiment 45 or 48, or the use according to any one of embodiments 46 to 48, wherein the cancer is a cyclin E-amplified cancer.

[0263] Further embodiments of the present invention are defined in the following embodiments A to LL.

[0264] Embodiment A. A compound according to formula (I): [ka] [In the formula, Y 1 is a bond or CH2 (e.g., Y 1 is a bond); Y 2 is a bond, O, NR 5 or CR 6 R 7 (e.g., Y 2 is a bond); R 1 and R 2 are each independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 haloalkyl, or R 1 and R 2 are taken together to form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl (e.g., R 1 and R 2 are taken together to form a C3-C4 cycloalkyl, for example, R 1 and R 2 taken together to form a C3 cycloalkyl); Each R 3 are independently selected from the group consisting of hydroxyl, halo, C1-C6 alkyl, and C1-C6 haloalkyl; R 4 is selected from the group consisting of H, halo, C1-C6 alkyl, and C1-C6 haloalkyl (e.g., R 4 is H); R 5 is selected from the group consisting of H, C1-C6 alkyl, C(=O)-C1-C6 alkyl, or C(=O)-O-C1-C6 alkyl; R 6 and R 7are taken together with the carbon atoms to which they are each bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, wherein said C3-C6 cycloalkyl or 3-6 membered heterocyclyl is selected from the group consisting of 0-3 substituents R 8 is replaced by; Each R 8 are independently selected from the group consisting of C1-C6 alkyl, C(═O)C1-C6 alkyl, halo, C1-C6 haloalkyl, S—C1-C6 alkyl, SO—C1-C6 alkyl, SO2-C1-C6 alkyl, cyano, hydroxyl, or wherein two R 8 the substituents, taken together, form =O, n is 0 to 3 (e.g., n is 1, and R 3 is hydroxyl); m is 1 to 5 (e.g., m is 4); [ka] teeth, [ka] wherein X is selected from O, NH, and S; Each R A are independently, *L 1 -X 1 where * means [ka] Each L 1represents a bond, O, S, SO, SO2, C≡C, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, *O-C1-C6 haloalkylene**, *O-C1-C6 hydroxyalkylene**, C1-C6 alkylene-O-C1-C6 alkylene, *O-C3-C6 cycloalkylene**, *O-3-6 membered cycloalkylene are independently selected from heterocyclylene**, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), O-C1-C6 alkylene-O, *O-C1-C6 alkylene-O-C3-C6 cycloalkylene** and *O-C1-C6 alkylene-O-3- to 6-membered heterocyclylene**, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1 is H, halo, cyano, hydroxyl, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C1-C6 haloalkyl, 0-3 R 8 C3-C6 cycloalkyl, O-C1-C6 alkyl, S-C1-C6 alkyl, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, N(C1-C6 alkyl)2, C(=O)N(C1-C6 alkyl)2, C1-C6 hydroxyalkyl, 0-3 R 8 3-6 membered heterocyclyl (e.g., containing 1 or 2 heteroatoms independently selected from O, N, and S) substituted by a group, 0-3 R 8 5-10 membered heteroaryl (e.g., 5-, 6-, 9-, or 10-membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by a group; 0-3 R 8 a 5- to 10-membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, substituted by a group; 87-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group, and 0-3 R 8 C7-C substituted by groups 10 independently selected from spirocycloalkyl; or Two Rs located on adjacent ring atoms A the substituents, taken together with the adjacent ring atoms, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0265] Embodiment BY 1 A compound according to embodiment A, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a bond.

[0266] Embodiment CY 2 A compound according to embodiment A or B, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a bond.

[0267] Embodiment A compound according to any one of Embodiments AC wherein Dm is 4, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0268] A compound according to any one of embodiments AD, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein En is 1 to 3, for example, n is 1.

[0269] Embodiment F. At least one R 3 A compound according to embodiment E, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is OH.

[0270] Embodiment G. The compound of Formula (I) is a compound of Formula (Ia): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0271] Embodiment Ga. The compound of formula (Ia) is a compound of formula (Ia-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0272] Embodiment H. The compound of Formula (I) is a compound of Formula (Ib): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0273] Embodiment Ha. The compound of formula (Ib) is a compound of formula (Ib-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0274] Embodiment I. The compound of formula (I) is a compound of formula (Ic): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0275] Embodiment Ia. The compound of formula (Ic) is a compound of formula (Ic-I): [ka] (In the formula, R 3 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0276] Embodiment J. The compound of Formula (I) is a compound of Formula (Id): [ka] (In the formula, R 1 , R 2 , R 4 and [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0277] Embodiment Ja. The compound of formula (Id) is a compound of formula (Id-I): [ka] (In the ceremony [ka] is as defined in embodiment A), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0278] Embodiment KR 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof, of any one of embodiments A-Ja, wherein: taken together form a C3-C4 cycloalkyl or a C3-C4 cyclohaloalkyl.

[0279] Embodiment LR 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof, of the compound according to embodiment K, wherein: taken together form a C3-C4 cycloalkyl.

[0280] Embodiment MR 1 and R 2 or a pharmaceutically acceptable salt and / or tautomer thereof, of a compound according to embodiment L, wherein: taken together form a C3 cycloalkyl.

[0281] Embodiment NR 4A compound according to any one of embodiments AM, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is H.

[0282] Embodiment A compound according to any one of Embodiments A through N, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein OX is NH.

[0283] Embodiment P. [ka] but, [ka] or a pharmaceutically acceptable salt and / or tautomer thereof, according to any one of embodiments A to O, selected from the group consisting of:

[0284] Embodiment Q. [ka] but, [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0285] Embodiment RR A but, a) halo, b) cyano, c) C1-C6 alkyl, d) C1-C6 haloalkyl, e) C1-C6 hydroxyalkyl, f) O-C1-C6 alkyl, g) C(=O)-O-C1-C6 alkyl, h) C1-C6 alkylene-O—C1-C6 alkyl, i) O—C1-C6 alkylene-O—C1-C6 alkyl, j) 0 to 3 R 8 C3-C6 cycloalkyl substituted by a group, k) 0 to 3 R 8 a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; l) 0 to 3 R 8 a 5-10 membered partially saturated heterocyclyl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; m) 0 to 3 R 8 O-C3-C6 cycloalkyl substituted by a group; n) 0 to 3 R 8 C≡C-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; o) 0 to 3 R 8 S-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; p) 0 to 3 R 8 C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; q) O-C1-C6 haloalkyl, r) O-C1-C6 alkylene-N(C1-C6 alkyl)2, s) O—C1-C6 hydroxyalkylene-O—C1-C6 alkyl, t) 0 to 3 R 8 O-C1-C6 alkylene-C3-C6 cycloalkyl substituted by a group; u) 0 to 3 R 8 O-C1-C6 alkylene-3-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; v) O-C1-C6 alkylene-C(=O)-N(C1-C6 alkyl)2, w) 0 to 3 R 8C1-C6 alkylene-5-10 membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; x) 0 to 3 R 8 O-C1-C6 alkylene-7-10 membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; y) O—C1-C6 alkylene-S(O)2-C1-C6 alkyl, z) O-C1-C6 hydroxyalkyl, aa) 0 to 3 R 8 O-C1-C6 alkylene-5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; bb) 0 to 3 R 8 O-5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, substituted by a group; cc) 0 to 3 R 8 O-3 to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; dd) 0 to 3 R 8 C≡C-C3-C6 cycloalkyl substituted by a group; ee) S-C1-C6 haloalkyl, ff) 0 to 3 R 8 O-C1-C6 alkylene-O-3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N, and S, substituted by a group gg) and 0 to 3 R 8 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, substituted by a group or a pharmaceutically acceptable salt and / or tautomer thereof.

[0286] Embodiment S. Each R 8are independently selected from the group consisting of halo (e.g., fluoro), C1-C6 alkyl (e.g., methyl), hydroxyl, cyano, S(O2)—C1-C6 alkyl (e.g., S(O2)CH3), C(═O)—C1-C6 alkyl (e.g., C(═O)CH3), O—C1-C6 alkyl (e.g., OCH3) and C1-C6 haloalkyl (e.g., C1 haloalkyl, e.g., CHF2), or wherein two R are on the same ring atom; 8 Compounds according to embodiment R, or pharmaceutically acceptable salts and / or tautomers thereof, wherein the substituents, taken together, form =O.

[0287] Embodiment T. [ka] and R A A compound according to any one of embodiments AS, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is CH3, OCH3, or OCH2CH3.

[0288] Embodiment U. Each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C6 alkylene, C1-C6 haloalkylene, *O-C1-C6 alkylene**, C1-C6 alkylene-O-C1-C6 alkylene, C1-C6 hydroxyalkylene, C3-C6 cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), and O-C1-C6 alkylene-O, where * is [ka] ** indicates the point of attachment to X 1 refers to the point where it joins; and each X 1is independently selected from H, halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, C1-C6 hydroxyalkyl, and 3-6 membered heterocyclyl (e.g., containing one heteroatom which is O), or a pharmaceutically acceptable salt and / or tautomer thereof.

[0289] Embodiment Ua. Each L 1 are independently selected from a bond, O, C(=O), *C(=O)-O**, C1-C2 alkylene, C1 haloalkylene, *O-C1-C2 alkylene**, C1-C2 alkylene-O-C1 alkylene, C1-hydroxyalkylene, C3 cycloalkylene, 5-6 membered heterocyclylene containing one heteroatom which is O, and O-C2 alkylene-O, wherein * is [ka] ** indicates the point of attachment to X 1 or a pharmaceutically acceptable salt and / or tautomer thereof, wherein R refers to the point of attachment to

[0290] Embodiment Ub. Each X 1 is independently selected from H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and 5-6 membered heterocyclyl containing 1 heteroatom, wherein O is H, halo, cyano, hydroxyl, C1-C2 alkyl (e.g., C1 alkyl), C1 haloalkyl, C3 cycloalkyl, O-C1-C2 alkyl, C1 hydroxyalkyl, and O; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0291] VR implementation Ais selected from the list consisting of C1-C6 alkyl, C1-C6 alkylene-O-C1-C6 alkyl, C1-C6 haloalkyl, C(═O)—O-C1-C6 alkyl, C1-C6 hydroxyalkyl, a 3- to 6-membered heteroatom containing one heteroatom which is O, halo, O-C1-C6 alkyl, C3-C6 cycloalkyl, cyano and O-C1-C6 alkylene-O-C1-C6 alkyl, or a pharmaceutically acceptable salt and / or tautomer thereof.

[0292] Embodiment Va.R A is selected from the list consisting of CH3, OCH2CH3, CH2CHOCH3, CHF2, C(=O)-O-CH3, CH2OH, a five-membered heteroatom having one heteroatom that is O, a six-membered heteroatom having one heteroatom that is O, CHOCH3, OCH3, Cl, C3 cycloalkyl, CF3, cyano, OCH2CHOCH3, and OCH2CH3; or a pharmaceutically acceptable salt and / or tautomer thereof.

[0293] Embodiment W. 1) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 2) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 3) 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 4) methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate; 5) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 6) 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 7) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 8) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 9) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 10) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 11) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 12) 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 13) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 14) 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile; 15) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 16) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 17) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 18) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 19) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; and 20) 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one a compound selected from any one of or a pharmaceutically acceptable salt and / or tautomer thereof.

[0294] Embodiment X. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0295] Embodiment Y. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0296] Embodiment Z. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0297] Embodiment AA. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0298] Embodiment BB. [ka] or a pharmaceutically acceptable salt and / or tautomer thereof.

[0299] Embodiment CC. A pharmaceutical composition comprising a compound according to any one of Embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0300] Embodiment DD. A combination comprising a compound according to any one of Embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more therapeutically active agents.

[0301] Embodiment EE. A method for modulating CDK2 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof.

[0302] Embodiment FF. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof.

[0303] Embodiment GG. A compound according to any one of Embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof for use as a pharmaceutical.

[0304] Embodiment HH. A compound according to any one of Embodiments A through BB or a pharmaceutically acceptable salt and / or tautomer thereof for use in the treatment of cancer.

[0305] Embodiment II. The use of a compound according to any one of embodiments A-BB or a pharmaceutically acceptable salt and / or tautomer thereof in the treatment of cancer.

[0306] Embodiment JJ. Use of a compound of any one of Embodiments A through BB or a pharmaceutically acceptable salt and / or tautomer thereof in the manufacture of a medicament for the treatment of cancer.

[0307] Embodiment KK. The method of embodiment FF, the compound for use of embodiment HH, or the use of embodiment II or JJ, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0308] Embodiment LL. The method of embodiment FF or KK, the compound for use of embodiment HH or KK, or the use of any one of embodiments II-KK, wherein the cancer is a cyclin E-amplified cancer.

[0309] definition For purposes of interpreting this specification, the following definitions will apply where appropriate, unless otherwise specified, and terms used in the singular will also include the plural, and vice versa. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes reference to one or more compounds, and so forth.

[0310] As used herein, the term "substituent" refers to a radical group that replaces a hydrogen atom in a given molecule. [ka] In groups such as , hydrogen atoms are (always) explicitly shown on the heteroatoms in the structure. A ) can replace any hydrogen atom, including those explicitly shown. [ka] teeth, [ka] It could be.

[0311] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and attached to the remainder of the molecule by a single bond. For example, a C1-C6 alkyl contains from 1 to 6 carbon atoms. Examples of C1-C6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl.

[0312] As used herein, the terms "halogen," "halo," "hal," and the like refer to fluorine, chlorine, bromine, or iodine. Halogen substituents and moieties, such as alkyl substituted by a halogen (haloalkyl), can be monohalogenated, polyhalogenated, or perhalogenated.

[0313] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more of the alkyl's hydrogen atoms are replaced by halogen atoms. In particular, the one or more halogen atoms are each fluorine atoms, in which case the "haloalkyl" is a "fluoroalkyl." For example, a C1-C6 haloalkyl contains 1 to 6 carbon atoms (and one or more halogen atoms).

[0314] As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined herein, in which one or more of the alkyl's hydrogen atoms has been replaced with a hydroxyl group. For example, a C1-C6 hydroxyalkyl contains 1 to 6 carbon atoms (and one or more hydroxyl groups).

[0315] As used herein, the term "alkylene" refers to a straight or branched divalent radical of an alkyl group. For example, a "C1-C4 alkylene" contains 1 to 4 carbon atoms, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)2-, or -CH2CH(CH3)CH2-.

[0316] Similarly, as used herein, the term "haloalkylene" refers to a straight or branched divalent radical of a haloalkyl group.

[0317] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring group. For example, C3-C6 cycloalkyl refers to any such ring group containing 3 to 6 carbon atoms, particularly monocyclic, i.e., cyclobutyl, cyclopentyl, and cyclohexyl. However, cycloalkyl (e.g., C3-C6 cycloalkyl) also refers to fused bicyclic ring systems (e.g., [ka] ) or a bridged bicyclic ring system (e.g., [ka] ) may also be used.

[0318] The term "cycloalkylene" refers to a divalent radical of a cycloalkyl group.

[0319] As used herein, the term "cyclohaloalkyl" refers to a cycloalkyl group, as defined herein, in which one or more of the cycloalkyl's hydrogen atoms are replaced with halogen atoms. In particular, the one or more halogen atoms are each a fluorine atom, in which case the "cyclohaloalkyl" is a "cyclofluoroalkyl." Similar to cycloalkyl, cyclohaloalkyl can be a fused or bridged bicyclic ring system.

[0320] As used herein, the terms "heterocyclyl," "heterocycle," "heterocyclic," and the like refer to saturated or partially unsaturated, but not aromatic, heterocyclic groups, which can be monocyclic or polycyclic, including fused or bridged bicyclic ring systems. However, in particular, heterocyclyl is a monocyclic ring. Heterocyclyl contains at least one non-carbon atom, typically nitrogen, oxygen, or sulfur, as a ring member, unless otherwise specified, and the remaining ring atoms are carbon. Preferably, the number of heteroatoms in a heterocyclyl is 1 to 3, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. When a heterocyclyl contains S as a heteroatom, the S can be in the form of S, SO, or SO (in other words, the oxygen atom bonded to the sulfur does not constitute substitution). For example, the term "4-6 membered heterocyclyl containing one heteroatom selected from the group consisting of O, N, and S" refers to a ring group containing 4 to 6 ring atoms including one heteroatom (either O, N, or S [the latter including S, SO, and SO]), with the remaining ring atoms being carbon.

[0321] The term "heterocyclylene" refers to a divalent radical of a heterocyclyl group.

[0322] As used herein, the term "O-alkyl" refers to an alkyl group, as defined herein, that is attached to the remainder of the molecule via an O-linker. An example is OCH.

[0323] As used herein, the term "O-haloalkyl" refers to a haloalkyl group, as defined herein, that is attached to the remainder of the molecule via an O linker. An example is OCF3.

[0324] As used herein, the term "alkylene-O-alkyl" refers to an alkyl group, as defined herein, in which one of the alkyl group's hydrogen atoms has been replaced with -O-alkylene- (bonded to the alkyl group through an oxygen). An example is "C1 alkylene-O-C1-alkyl", i.e., -CH2-O-CH3.

[0325] The term "5- to 10-membered heteroaryl" refers to a monocyclic or bicyclic aromatic ring group containing 5 to 10 ring atoms (e.g., 9 or 10 ring atoms in a bicyclic aromatic ring group), and unless otherwise specified, includes 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring group.

[0326] The term "5-membered heteroaryl," unless otherwise specified, refers to a monocyclic aromatic ring group containing one, two, or three heteroatoms (preferably two) individually selected from nitrogen, oxygen, and sulfur (which may be in the form of S, SO, or SO, especially S) in the ring group. Preferably, at least one of the heteroatoms in the 5-membered heteroaryl is nitrogen. Preferably, the 5-membered heteroaryl has two heteroatoms, at least one of which is nitrogen. Most preferably, the 5-membered heteroaryl has two heteroatoms, both of which are nitrogen.

[0327] As used herein, the term "partially saturated heterocyclyl" is intended to include partially saturated monocyclic, bicyclic or polycyclic heterocyclyl containing one or more heteroatoms selected from O, N, S (wherein S, if present, can be in the form of S, SO or SO). Representative examples are imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and the like. The term "5- to 10-membered partially saturated heterocyclyl" should be construed accordingly.

[0328] As used herein, the term "spiroheterocyclyl" refers to a ring system comprising a first carbocyclic or heterocyclic ring containing 3 to 6 ring atoms, wherein two of the substituents on the carbon ring atoms in said first carbocyclic or heterocyclic ring are combined together to form a second carbocyclic or heterocyclic ring containing 3 to 6 ring atoms, with the proviso that at least one of the first and second rings is a heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, N, and S (the latter may be in the form of S, SO, or SO), particularly O and N. In particular, spiroheterocyclyl is saturated. As used herein, the term 7-9-membered spiroheterocyclyl means that the total number of ring atoms in the first carbocyclic or heterocyclic ring and the second carbocyclic or heterocyclic ring is 7 to 9. For example, spiroheterocyclyl [ka] is a seven-membered spiroheterocyclyl because there are seven ring atoms. As one of ordinary skill in the art would understand, a "spiroheterocyclyl" is a monoradical, while a "spiroheterocyclylene" is a diradical (similar to alkyl and alkylene).

[0329] As used herein, the term "spirocycloalkyl" refers to a ring system comprising a first carbocyclic ring containing 3 to 6 ring carbon atoms, wherein two of the substituents on the carbon ring atoms in said first carbocyclic ring are combined to form a second carbocyclic ring containing 3 to 6 ring carbon atoms. In particular, spirocycloalkyls are saturated. The term 6- to 8-membered spirocycloalkyl, as used herein, means that the total number of carbon ring atoms in the first carbocyclic ring and the second carbocyclic ring is 7 to 8. As one of ordinary skill in the art would understand, "spirocycloalkylene" is the equivalent diradical to "spirocycloalkyl."

[0330] The term "two R's located on adjacent ring atoms" A As used herein, the phrase "substituents taken together to form a 4- to 6-membered heterocyclyl with the adjacent ring atoms" means ( [ka] For example, [ka] (in this example, a 6-membered heterocycle containing two heteroatoms, both of which are N).

[0331] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, for example, as pure optical isomers or as stereoisomeric mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a double bond, the substituent may be in the E- or Z-configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. Many compounds of the present invention exhibit tautomerism. For example, [ka] teeth, [ka] All tautomeric forms are within the scope of the claimed invention.

[0332] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acidic groups are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

[0333] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0334] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0335] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0336] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0337] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from groups 1 to 12 of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0338] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0339] In another aspect, the present invention provides an iodide or iodide salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutaric acid, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate. The compounds of the present invention are provided in the form of bionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salts.

[0340] In another aspect, the present invention provides an iodide or iodide salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutaric acid, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate. The compounds of the present invention are provided in the form of bionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salts.

[0341] In another aspect, the invention provides a compound according to any one of embodiments 1 to 39a in the form of its sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt.

[0342] Any formula provided herein is intended to represent both unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure depicted by the formula provided herein, except that one or more atoms are replaced with atoms having selected atomic mass or mass number.Isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen isotopes.

[0343] Additionally, certain isotopes, particularly deuterium (i.e. 2Incorporation of H or D) can provide certain therapeutic advantages resulting from significantly increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or improved therapeutic index or tolerability. It is understood that in this context deuterium is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent in a compound of this invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation per designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0344] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, respectively. 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Therefore, the present invention provides, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13It should be understood to include compounds incorporating one or more of any of the foregoing isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, substituting appropriate isotopically labeled reagents for previously used non-labeled reagents.

[0345] Pharmaceutical Composition As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0346] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, as would be known to one skilled in the art, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof (see, e.g., Remington: The Science and Practice of Pharmacy, 22 nd (See Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0347] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, or ameliorate a condition, disorder, or disease that is (i) mediated by CDK2, or (ii) associated with CDK2 activity, or (iii) characterized by CDK2 activity (normal or abnormal); or (2) reduce or inhibit the activity of CDK2; or (3) reduce or inhibit the expression of CDK2. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a cell, or tissue, or non-cellular biological material, or culture medium, is effective to at least partially reduce or inhibit the activity of CDK2; or to at least partially reduce or inhibit the expression of CDK2.

[0348] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0349] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0350] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient.

[0351] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0352] As used herein, a subject is "in need of" a treatment if it is believed that the subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0353] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or otherwise clearly contradicted by context.

[0354] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of illustrative language (e.g., "etc."), are intended merely to better clarify the invention and do not impose limitations on the scope of the invention as originally claimed.

[0355] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present invention may be present in racemic form or enantiomerically enriched, for example, in the (R), (S) or (R,S) configuration. In certain embodiments, in the (R) or (S) configuration, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Atom substitution by unsaturated double bonds may, where possible, be present in cis (Z) or trans (E) form.

[0356] Thus, as used herein, the compounds of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as a substantially pure geometric (cis or trans) isomer, diastereomer, optical isomer (enantiomer), racemate or mixtures thereof.

[0357] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0358] Any resulting racemic compounds of the present invention or intermediates can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases, or by liberation of optically active acidic or basic compounds. Specifically, basic moieties may be utilized to resolve compounds of the present invention into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0359] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of illustrative language (e.g., "etc."), are intended merely to better illustrate the invention and do not impose limitations on the scope of the invention as originally claimed.

[0360] The compounds of the present application may be prepared by one skilled in the art of organic synthesis using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by utilizing standard synthetic methods and procedures that are either known to those skilled in the art or that will become apparent to the skilled chemist in light of the teachings herein.

[0361] Compounds of formula (I) can be prepared by the methods shown in the following synthetic reaction schemes. In the schemes described below, it is well understood that, where necessary, protecting groups are utilized for sensitive or reactive groups in accordance with general chemical principles. Protecting groups are manipulated according to standard organic synthesis methods, for example, as described in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. Protecting groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art.

[0362] Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0363] The compounds of the present disclosure may be synthesized by following the steps outlined in Scheme 1. Starting materials are either commercially available or made by known procedures found in the published literature or as illustrated.

[0364] The present invention further includes any variations of the process in which the remaining steps are carried out using intermediate products obtained at any stage thereof as starting materials, or in which starting materials are formed in situ under the reaction conditions, or in which reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of the present invention can also be converted into each other by methods generally known to those skilled in the art.

[0365] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt and / or tautomer thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), or rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present invention may be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be either film-coated or enteric-coated by methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; tablets may also contain c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colouring agents, flavourings and sweeteners.

[0366] Methods of using the present invention The compounds of formula (I), in free form or in the form of pharmaceutically acceptable salts and / or tautomeric forms, exhibit valuable pharmacological properties, e.g., CDK2 modulating properties, as shown, for example, in in vitro tests as provided in the next section, and are therefore indicated for therapy or for use as research chemicals, e.g., as tool compounds.

[0367] The compounds of the present invention may be useful in treating or preventing cancer. In some embodiments, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0368] Thus, in a further aspect, the present invention provides a compound of formula (I), particularly as described in any one of embodiments 1 to 39a, or a pharmaceutically acceptable salt and / or tautomer thereof, for use in therapy. In a further embodiment, the therapy is treatment of a disease, disorder, or condition that can be treated by inhibition of CDK2. In another embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0369] Thus, in a further aspect, the present invention provides a compound of formula (I) (particularly as described in any one of embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof, for use in therapy. In a further embodiment, the therapy is selected from diseases that can be treated by inhibition of CDK2. In another embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0370] In another aspect, the present invention provides a method for treating or preventing a disease treated by inhibiting CDK2, comprising administering a therapeutically effective amount of a compound of any one of Formula (I) (particularly as described in any one of Embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof. In a further embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0371] Thus, in a further aspect, the present invention provides the use of any one compound of formula (I) (particularly as described in any one of embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof, for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment or prevention of a disease that can be treated by inhibition of CDK2. In another embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g., ER+ breast cancer, e.g., ER+ / Her2- breast cancer), lung cancer, and endometrial cancer.

[0372] The pharmaceutical compositions or combinations of the present invention may contain, for example, a unit dosage of about 1 to 1,000 mg of one or more active ingredients for a subject weighing about 50 to 70 kg. The therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated or its severity. A physician, clinician, or veterinarian skilled in the art can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0373] Combination preparations and combination therapies of the present invention "Combination" refers to either a combination in the form of a single dosage unit, or an administration combination in which a compound of the present invention and a combination partner (e.g., another drug as described below, also referred to as a "therapeutic agent" or "co-agent") are administered independently, at the same time, or separately within a time interval, particularly when such time interval allows the combination partners to exert a cooperative, e.g., synergistic, effect. These single components may be packaged as a kit or individually. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. Terms such as "co-administration" or "combined administration" of components, as used herein, are meant to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "combined pharmaceutical product" as used herein refers to a preparation obtained by mixing or combining two or more therapeutic agents, and includes both combined and uncombined therapeutic agents. The term "combined product" means that the therapeutic agents, e.g., a compound of the present invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "uncombined product" means that the therapeutic agents, e.g., a compound of the present invention and a combination partner, are both administered to a patient as separate entities, either simultaneously, in parallel, or sequentially without specific time limits, where such administration results in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0374] The term "pharmaceutical combination," as used herein, refers to either a combination product in single dosage unit form, or a non-combined product or parts-of-a-kit for administration combination, in which two or more therapeutic agents may be administered independently, at the same time, or separately within a time interval, particularly when such time interval allows the combination partners to exert a cooperative effect, e.g., a synergistic effect.

[0375] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or individual containers (e.g., tablets, capsules, powders, liquids) for each active ingredient. The powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also includes the use of the therapeutic agents in a sequential manner, either at about the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0376] The compounds of the present invention may be administered simultaneously with, prior to, or subsequent to one or more other therapeutic agents. The compounds of the present invention may be administered separately by the same or different route of administration as the other agents, or together in the same pharmaceutical composition. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that exhibit therapeutic activity or enhance therapeutic activity when administered to a patient in combination with a compound of the present invention.

[0377] Accordingly, in another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising (e.g., a therapeutically effective amount of) a compound of formula (I), particularly as described in any one of embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more other therapeutically active agents.

[0378] In one embodiment, the invention provides a product comprising a compound of formula (I), particularly as described in any one of embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof, and at least one other therapeutic agent, as a pharmaceutical combination for simultaneous, separate or sequential use in therapy.

[0379] In one embodiment, the therapy is the treatment or prevention of a disease or condition mediated by CDK2. Products provided as pharmaceutical combinations include compositions comprising a compound of formula (I), a pharmaceutically acceptable salt and / or tautomer thereof, and one or more other therapeutic agents together in the same pharmaceutical composition, or a compound of formula (I), a pharmaceutically acceptable salt and / or tautomer thereof, and one or more other therapeutic agents in separate forms, for example, in the form of a kit.

[0380] In one embodiment, the present invention provides a pharmaceutical combination comprising a compound of Formula (I) (particularly as described in any one of embodiments 1 to 39a), or a pharmaceutically acceptable salt and / or tautomer thereof, and one or more other therapeutic agents. Optionally, the pharmaceutical combination may include a pharmaceutically acceptable carrier, as described above.

[0381] In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of Formula (I) (particularly as described in any one of embodiments 1-39a), or a pharmaceutically acceptable salt and / or tautomer thereof. In one embodiment, the kit comprises a means for separately retaining said compositions, such as a container, a compartmented bottle, or a compartmented foil pouch. An example of such a kit is a blister pack, such as those typically used for packaging tablets, capsules, and the like. [Example]

[0382] The following examples and synthetic methods further illustrate the present disclosure, but should not be construed as limiting the disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and are not intended to limit the scope of the disclosure. Furthermore, it should be understood that various other embodiments, modifications thereof, and equivalents that may occur to those skilled in the art may be resorted to without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0383] The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as illustrated in the following examples. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized in the synthesis of the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. It is understood that in all of these methods, protecting groups can be used for sensitive or reactive groups, where necessary, in accordance with general chemical principles. Protecting groups are manipulated by standard organic synthesis methods (T.W. Green and P.G. M. Buts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage in the synthesis of the compounds using methods readily apparent to those skilled in the art. Unless otherwise noted, reagents and solvents were used as received from suppliers.

[0384] Chemical names were generated using PerkinElmer's ChemDraw Professional v19.1.2.36.

[0385] Temperatures are given in degrees Celsius. As used herein, unless otherwise specified, the term "room temperature" or "ambient temperature" means a temperature between 15°C and 30°C, such as 20°C to 30°C, e.g., 20°C to 25°C. Unless otherwise specified, all evaporations are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0386] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, catalysts utilized in the synthesis of the compounds of the invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art.

[0387] In the following general method, Y 1 , Y 2 , m, n, R 1 , R 2 , R 3 , R 4 and [ka] is as defined previously in the above embodiments or is limited to the notation in the schemes. PG is a suitable protecting group. Unless otherwise specified, starting materials are either commercially available or prepared by known methods.

[0388] List of abbreviations DIPEA (N,N-diisopropylethylamine) Boc(tert-butylcarbamate) IPA (isopropyl alcohol) NBS (N-bromosuccinimide) TEA (triethylamine) AcOH (acetic acid) DMF (N,N-dimethylformamide) NaH (sodium hydride) ACN (acetonitrile) THF (tetrahydrofuran) TBDMSCl (tert-butyldimethylsilyl chloride) tBuOH (tert-butyl alcohol) SFC (Supercritical Fluid Chromatography) SEM(2-(trimethylsilyl)ethoxymethyl) MeOH (methanol) DIBAL-H (diisobutylaluminum hydride) m-CPBA (metachloroperoxybenzoic acid) NaOtBu (sodium tert-butoxide) NaOAc (sodium acetate) NaBH4 (sodium borohydride) NH4Cl (Ammonium chloride) MeI (methyl iodide) Cs2CO3 (cesium carbonate) EtOH (ethanol) DMS (dimethyl sulfate) AC2O (acetic anhydride) Zn (zinc)

[0389] General synthetic scheme The examples were prepared as shown in Scheme 1 (5-membered ring) or Scheme 2 (6-membered ring). [ka] [ka]

[0390] Intermediate 1 [ka] Experimental details for intermediate 1 Step 1: Synthesis of (1R,3R)-3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexan-1-ol: To a stirred solution of (1R,3R)-3-aminocyclohexan-1-ol hydrochloride (60 g, 397.3 mmol) and DIPEA (183 mL, 993.25 mmol) in isopropanol (300 ml), 2,4-dichloro-5-iodopyrimidine (108 g, 397.3 mmol) was added at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure to give the crude product. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluting with 0-40% ethyl acetate in petroleum ether to give (1R,3R)-3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexan-1-ol (113 g, 81% yield, regioisomeric mixture; 82% and 15% isomers) as a pale yellow solid. LC-MS m / z [M+H]+ = 353.98, 1 H NMR(400MHz,DMSO-d6)δ=8.28-8.40(m,1H),6.58(d,J=8.4Hz,1H),4.50-4.51(m, 1H),4.25-4.30(m,1H),3.90-4.20(m,1H),1.71-1.80(m,4H),1.20-1.70(m,5H).

[0391] Step 2: Synthesis of (1R,3R)-3-((2-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)cyclohexan-1-ol: To a degassed solution of (1R,3R)-3-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexan-1-ol (56.5 g, 160.5 mmol; 82% and 15% isomers), CuI (3.04 g, 16.0 mmol), triethylamine (115 mL, 800 mmol), and Pd(PPh) (1.84 g, 1.60 mmol) in dry THF (560 mL) was added trimethylsilylacetylene (22.7 mL, 160.5 mmol) and heated at 55 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give (1R,3R)-3-((2-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)cyclohexan-1-ol (35 g, 68%) as a pale yellow solid. LC-MS m / z [M+H]+ = 325.66, 1 H NMR(400MHz,DMSO-d6)δ=8.16(s,1H),6.48(d,J=8.0Hz,1H),4.55(d,J=2.80Hz,1H),4 .25-4.40(m,1H),3.90-4.0(m,1H),1.61-1.85(m,4H),1.30-1.60(m,4H),0.26(s,9H).

[0392] Step 3: Synthesis of (1R,3R)-3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol: To a stirred solution of (1R,3R)-3-((2-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)cyclohexan-1-ol (44 g, 136.2 mmol) in acetonitrile (2,200 mL), CsCO (22.1 g, 68.1 mmol) was added and heated at 75 °C for 6 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give (1R,3R)-3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol (29 g, 85% yield) as a pale yellow solid; LC-MS m / z [M+H]+ = 252.17, 1 H NMR(400MHz,DMSO-d6)δ=8.90(s,1H),7.82(d,J=3.6Hz,1H),6.70(d,J=3.6Hz,1H), 4.75(d,J=2.8Hz,1H),4.15(d,J=2.4Hz,1H),2.01-2.11(m,1H),1.40-1.99(m,7H).

[0393] Step 4: Synthesis of 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine: To a stirred solution of (1R,3R)-3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol (20 g, 79.68 mmol) and imidazole (10.8 g, 159.3 mmol) in DMF (200 mL) was added TBDMS-Cl (18 g, 159.3 mmol) at room temperature and stirred for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mass was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with ice-cold water (2 × 60 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (29 g, 96% yield) as a brown gummy liquid. LC-MS m / z [M+H] + =366.24, 1 H NMR(400MHz,DMSO-d6)δ=8.88(s,1H),7.79(d,J=3.6Hz,1H),6.68(d,J=3.6Hz,1H),4.95-5.10(m,1H),4.27(s,1H),1 .96-2.05(m,1H),1.80-1.95(m,4H),1.64(d,J=8.0Hz,2H),1.45-1.55(m,1H),0.90-0.98(m,9H),0.01-0.50(m,6H),

[0394] Step 5: Synthesis of 5,5-dibromo-7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one: To a stirred solution of 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (50 g, 136.9 mmol) in t-BuOH:HO (600 mL, 4:1), NBS (73 g, 410.9 mmol) was added at room temperature and stirred for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with water (100 mL) and extracted with MTBE (3 × 300 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude 5,5-dibromo-7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (73 g crude) as a pale yellow semi-solid. This crude product was used directly in the next step without further purification. LC-MS m / z [M+H]+ = 540.21

[0395] Step 6: Synthesis of 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one: To a stirred solution of 5,5-dibromo-7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (73 g crude, 135.4 mmol) in AcOH (730 mL) was added zinc dust (44 g, 677.1 mmol) at room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a Celite pad, the filtrate was diluted with ethyl acetate (500 mL), washed with water (100 mL), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-30% ethyl acetate:petroleum ether to give 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (33 g, 63% yield after two steps) as a brown gummy liquid. LC-MS m / z [M+H]=382.29. 1 H NMR(400MHz,DMSO-d6)δ=8.25(s,1H),4.58-4.68(m,1H),4.26(s,1H),3.63(s,2H),2.30-2.40( m,1H),2.10-2.21(m,1H),1.55-1.80(m,5H),1.45-1.50(m,1H),0.91(s,9H),0.01-0.10(m,6H).

[0396] Step 7: Synthesis of 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: To a stirred solution of 7-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (11 g, 28.87 mmol) and dibromoethane (7.4 mL, 86.61 mmol) in dry DMF (110 mL) was added NaH (60%, 3.4 g, 86.61 mmol) in small portions at room temperature and stirred for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with saturated NH4Cl and extracted with MTBE (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-15% ethyl acetate in petroleum ether to give 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (10 g, 85% yield) as a dark brown gummy liquid. LC-MS m / z [M+H] + =408.31, 1 H NMR(400MHz,DMSO-d6)δ=8.16(s,1H),4.65-4.75(m,1H),4.26(s,1H),3.58-3.62(m,1H),2.30-2.42(m,1H),2.15- 2.25(m,1H),1.81-1.91(m,2H),1.55-1.80(m,7H),1.55-1.80(m,7H),0.91(s,9H),1.39-1.49(m,1H),0.04(s,6H).

[0397] Intermediate 2 [ka] is prepared using the method for producing intermediate 1, provided that: [ka] instead of [ka] We departed from.

[0398] Example 1 [ka] Synthesis of (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka]

[0399] Step 1: Synthesis of 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (Compound-2): Procedure: 7'-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (trans-racemic) (0.5 g, 1.70 mmol), 1-methyl-1H-pyrazol-4-amine (0.25 g, 2.55 mmol), and NaO in dry THF (10 ml). tTo a degassed solution of Bu (0.24 g, 2.55 mmol) was added Brettphospd-G3 (0.15 g, 0.17 mmol) under an argon atmosphere and stirred at 50 °C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (silica gel, 230-400 mesh) eluting with 0-5% methanol in DCM to give 7'-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (trans-racemic) (0.35 g, 58% yield) as a brown solid. LC-MS m / z [M+H]+ = 355.26, 1 H NMR(400MHz,DMSO-d6)δ=9.35(s,1H),7.87(s,1H),7.86(s,1H),7.48(s,1H),4.65-4.78(m,1H), 4.60(s,1H),4.13(s,1H),3.79(s,3H),2.20-2.35(m,1H),1.52-1.85(m,7H),1.35-1.50(m,3H).

[0400] Step 2: SFC Separation. 7'-3-Hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (trans-racemic) (0.35 g, 0.98 mmol) was used as a co-solvent in methanol for SFC separation. After completion of the separation, the solvent of peak 2 was evaporated to give 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.136 g, 38%) as a white solid. LC-MS m / z [M+H]+ = 355.30. 1H NMR(400MHz,DMSO-d6)δ=9.35(s,1H),7.87(s,1H),7.85(s,1H),7.48(s,1H),4.55-4.80(m,2H),4. 13(s,1H),3.79(s,3H),2.40-2.50(m,1H),2.20-2.35(m,1H),1.51-1.85(m,7H),1.35-1.50(m,3H).

[0401] Example 2 [ka] Synthesis of (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka]

[0402] 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-methyl-4-nitro-1H-pyrazole (1 g, 7.86 mmol) and CsCO (5.12 g, 15.75 mmol) in DMF (10 ml) was added SEM-Cl (2.09 mL, 11.80 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted into ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.43 g, 70% yield) as a colorless liquid. 1H NMR(400MHz,DMSO-d6)δ=8.03(s,1H),8.32(s,1H),5.58(s,1H),5.44(s,2H),3. 58-3.68(m,4H),2.70(s,2H),2.49(s,3H),0.85-0.93(m,4H),0.0-0.04(m,9H).

[0403] Step 2: Synthesis of 53-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.43 g, 5.55 mmol) in MeOH (15 ml) was added Pd / C (0.2 g) at room temperature and stirred under hydrogen balloon pressure for 6 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure and chased with toluene to give crude 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (1.2 g, 95% yield) as a pale pink solid. This crude product was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ=6.90-7.038(m,1H),5.21(s,1H),5.11(s,1H),3.68(s,2H) ),3.38-3.45(m,2H),1.90-2.10(m,3H),0.79(t,J=8.4Hz,2H),-0.05-0.04(m,9H).

[0404] [ka] Step 1: 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one in dry THF (450 mL) To a degassed solution of propane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (30 g, 73.52 mmol) and 3-methyl(methy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (18.2 g, 80.87 mmol), NaOtBu (10.8 g, 110.28 mmol) and BrettphospdG3 (2.0 g, 2.2 mmol) were added, and the reaction mass was degassed with argon for 5 minutes. The reaction mass was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. The resulting 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was dissolved in DCM and stirred with Si-supported thiourea (palladium scavenger) for 3 h and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the target compound as a brown gummy solid (40 g, 90% yield). LC-MS m / z:[M+H] + =599.77

[0405] Step 2: 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: To a stirred solution of 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (50 g, 83.48 mmol) in methanol (500 mL) at room temperature was added 4 M HCl in dioxane (250 mL) and stirred at 50 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure. The crude product was basified with aqueous NaHCO3 and extracted with ethyl acetate (3 x 200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was washed with DCM:MTBE (10V, 1:4) and filtered. The resulting solid was dissolved in 50% MeCN in water and concentrated under reduced pressure to give 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one as an off-white solid (21 g, 71% yield). LC-MS m / z: [M+H] + =355.2(96.47%) 1 H NMR(400MHz,DMSO-d6)δ=12.27-12.18(m,1H),8.59-8.54(m,1H),7.81-7.55(m,2H),4.66(br s,1H),4.54(br s,1H),4.08(br s,1H),2.49(s,3H),2.25-2.14(m,4H),1.79-1.35(m,8H).

[0406] Example 3 [ka] Step 1: Synthesis of 3-(difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (1.5 g, 9.21 mmol) and CsCO (5.9 g, 18.42 mmol) in DMF (15 mL), SEM-Cl (2.5 mL, 13.81 mmol) was added at 0 °C and then stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-(difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.5 g, 92% yield) as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ=9.26(s,1H),8.53(s,1H),7.22-7.75(m,3H),5.56(s,4H),3.60-3.68(m,7H),0.80-0.93(m,8H),0.01-0.03(m,6H).

[0407] Step 2: Synthesis of 3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (Intermediate-4): To a Parr shaker containing 3-(difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.5 g, 8.53 mmol) in methanol (25 mL), Pd / C (10%, 0.25 g) was added and stirred at room temperature under 80 psi hydrogen pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (1.8 g, 80% yield) as a pale orange liquid. 1 H NMR(400MHz,DMSO-d6)δ=6.78-7.30(m,3H),5.25-5.35(m,2H),4.38(br-s,2H),3.40-3.52(m,3H),0.75-0.85(m,3H),-0.09-0.10(m,11H).

[0408] Coupling to intermediate 1 and deprotection of the SEM group gives [ka] was prepared as 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one by the method described in Example 2.

[0409] Example 4 [ka] Synthesis of (methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate). [ka] Methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate: To a stirred solution of 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile (0.25 g, 0.65 mmol) in methanol (2.5 mL) was added 4 M HCl in 1,4-dioxane (1.5 mL) at 0°C, followed by stirring at 50°C for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude material was purified by preparative HPLC (column: YMC triart (250 x 19 mm) 5u), Buffer A: 10MM ABC, Buffer B: acetonitrile, mobile phase conditions (% of B): 0 / 20, 2 / 20, 15 / 60, 20 / 60, 20.1 / 100, 24 / 100, 24.1 / 20, 28 / 20, flow rate - 19 mL APMS-022 to give methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate (15 mg, 6% yield) as an off-white solid. LC-MS m / z [M+H]+ = 399.29, 1H NMR(400MHz,DMSO-d6)δ=13.54(br-s,1H),8.57(br-s,1H),8.27(s,1H),7.98(s,1H),4.65-4.78(m,1H),4.65(d,J =2.4Hz,1H),4.13(s,1H),3.88(s,3H),2.42-2.52(m,1H),2.20-2.35(m,1H),1.55-1.82(m,7H),1.38-1.55(m,3H).

[0410] Example 5 [ka] Synthesis of (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka] 5-Methyl-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 5-methyl-3-nitro-1H-pyrazole (2 g, 15.73 mmol) and CsCO (10.25 g, 31.47 mmol) in DMF (20 ml) was added SEM-Cl (4.14 mL, 23.60 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted into ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 5-methyl-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3 g, 75% yield) as a pale yellow liquid. 1H NMR(400MHz,CDCl3)δ=6.92(s,1H),5.81(s,2H),3.62(dd,J=7.2,8.8Hz,2H),2.33(s,3H),0.91(t,3H,J=8.0Hz,2H),0.01(s,9H).

[0411] 5-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine: To a stirred solution of 5-methyl-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3 g, 11.65 mmol) in MeOH (30 ml) was added Pd / C (0.43 g) at room temperature and stirred under 80 psi H pressure for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure and chased with toluene to give crude 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (2.1 g, 80.7% yield) as a pale pink liquid. This crude product was used directly in the next step without further purification. LC-MS m / z[M+H]+=228.42.

[0412] [ka] Synthesis of rac7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: Dissolve 7'-((1R ,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.5 g, 1.22 mmol), 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (0.33 g, 1.47 mmol), and NaO tTo a degassed solution of Bu (0.17 g, 1.83 mmol), Brettphospd-G3 (0.1 g, 0.12 mmol) was added at room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.57 g, 81% yield) as a light brown solid. LC-MS m / z [M+H]+ = 599.5 (21% + 22%, regioisomers).

[0413] 7'-((1R,3R)-3-Hydroxycyclohexyl)-2'-((5-methyl-1H-pyrazol-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: To a stirred solution of 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.57 g, 0.95 mmol, 69% purity) in methanol (5 ml) was added 4 M 1,4-dioxane (2.85 mL) at 0 °C. HCl was added, followed by stirring at 50° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure, basified with saturated NaHCO and extracted with ethyl acetate (3×10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude material was purified by preparative HPLC (column XB 19x150) using buffer A:ABC, buffer B:acetonitrile, mobile phase conditions (% of B): 0 / 20, 2 / 20, 8 / 30, 11 / 30, flow rate - 30 ml / min dac to give 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((5-methyl-1H-pyrazol-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (50 mg, 15% yield) as an off-white solid. LC-MS m / z [M+H] = 355.30 (97.54%), 1 H NMR(400MHz,DMSO-d6)δ=11.79(br-s,1H),9.45(br-s,1H),7.86(s,1H),6.34(br-s,1H),4.63-4.73(m,1H),4.5 7(s,1H),4.11(s,1H),2.50-2.60(m,1H),2.25-2.38(m,1H),2.19(s,3H),1.51-1.85(m,7H),1.35-1.50(m,3H).

[0414] Example 6 [ka] Methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate: To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (2 g, 11.69 mmol) and CsCO (7.6 g, 23.39 mmol) in DMF (20 mL) was added SEM-Cl (3.2 mL, 17.54 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (3.2 g, 91% yield) as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ=9.18(s,1H),8.46(s,1H),5.60(s,2H),5.51(s,2H),3.9 7(s,3H),3.89(s,3H),3.50-3.64(m,4H),0.80-0.90(m,4H),-0.05-0.01(m,9H).

[0415] (4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol: To a stirred solution of methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (1.5 g, 4.97 mmol) in dry THF (15 ml) was added DIBAH (14.93 ml, 14.93 mmol) dropwise at −30° C., then the reaction mass was allowed to warm to room temperature and stirred for 5 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with 1N HCl and extracted with ethyl acetate (3×30 mL). The organic layer was dried over NaSO and concentrated to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give (4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (0.5 g, 36% yield) as a light brown liquid. 1 H NMR(400MHz,CDCl3)δ=8.32(s,1H),5.41(s,2H),4.93(d,J=5.6Hz,2H),3.64 (t,J=8.4Hz,2H),2.83(br-s,1H),0.95(t,J=8.4Hz,2H),-0.08-0.01(m,9H).

[0416] 4-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol: To a stirred solution of (4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (0.46 g, 8.53 mmol) in methanol (10 mL), Pd / C (10%, 0.1 g) was added and stirred at room temperature under hydrogen balloon pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give crude 4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (0.25 g, 62% yield) as a pale green liquid. This crude product was used directly without further purification. 1H NMR(400MHz,CDCl3)δ=7.14(s,1H),5.27(s,2H),4.74(s,2H),3.50-3.60(m,2H),0.88-1.0(m,2H),-0.01-0.05(m,9H).

[0417] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0418] Example 7 [ka] Synthesis of (7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka] Ethyl 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)cyclopropane-1-carboxylate: To a stirred solution of ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)acetate (commercially obtained) (9 g, 36.48 mmol) and dibromoethane (15.7 mL, 182.40 mmol) in dry DMF, NaH (60%, 7.2 g, 182.4 mmol) was added portionwise at room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with ice-cold water (2×10 mL) and brine solution (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude material was purified by flash column chromatography (230-400 g silica gel) eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)cyclopropane-1-carboxylate (5.6 g, 56% yield) as a pale yellow liquid. LC-MS m / z [M+H]+ = 279.03. 1 H NMR(400MHz,DMSO-d6)δ=8.62(s,1H),4.05(q,J=6.8Hz,2H),2.54(s,3H),1.55-1.60(m,2H),1.32-1.38(m,2H),1.1(t,J=6.8Hz,3H).

[0419] Ethyl 1-(4-chloro-2-(methylsulfonyl)pyrimidin-5-yl)cyclopropane-1-carboxylate: To a stirred solution of ethyl 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)cyclopropane-1-carboxylate (5.6 g, 20.53 ml) in DCM (84 ml) was added m-CPBA (15.18 g, 61.59 mmol) in small portions at 0 °C, followed by stirring at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with saturated NaHCO3, extracted with DCM (2 x 100 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude material was purified by flash column chromatography (230-400 g silica gel) eluting with 0-20% ethyl acetate in petroleum ether to give ethyl 1-(4-chloro-2-(methylsulfonyl)pyrimidin-5-yl)cyclopropane-1-carboxylate (5.8 g, 93% yield) as a white solid. LC-MS m / z [M+H]+ = 305.09. 1 H NMR(400MHz,DMSO-d6)δ=9.10(s,1H),4.08(q,J=6.8Hz,2H),3.46(s,3H),1.65-1.70(m,2H),1.45-1.52(m,2H),1.1(t,J=6.8Hz,3H).

[0420] Ethyl 1-(4-chloro-2-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)cyclopropane-1-carboxylate: To a stirred solution of ethyl 1-(4-chloro-2-(methylsulfonyl)pyrimidin-5-yl)cyclopropane-1-carboxylate (6.5 g, 21.42 mmol) and N-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)formamide (5.47 g, 21.42 mmol) in dry THF (65 mL) was added NaH (60%, 1.02 g, 25.71 mmol) in small portions at room temperature and heated at 50° C. for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude material was purified by flash column chromatography (230-400 g silica gel) eluting with 0-20% ethyl acetate in petroleum ether to give ethyl 1-(4-chloro-2-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)cyclopropane-1-carboxylate (7 g, 68% yield) as a brown gummy liquid. LC-MS m / z [M+H]=452.34, 1 H NMR(400MHz,DMSO-d6)δ=9.36(s,1H),8.36(s,1H),8.01(s,1H),5.32(s,2H),4.08(q,J=7.2Hz,2H),3.55(t,J=8.0Hz, 2H),2.17(s,3H),1.52-1.62(m,2H),1.25-1.35(m,2H),1.14(t,J=7.2Hz,3H),0.86(t,J=8.0Hz,3H),0.01-0.0(s,9H).

[0421] [ka] 3-Amino-5,5-dimethylcyclohex-2-en-1-one: To a two-necked round-bottom flask equipped with a Dean-Stark apparatus containing 5,5-dimethylcyclohexane-1,3-dione (5 g, 35.66 mmol) in toluene (100 mL), acetic acid (0.9 mL, 16.05 mmol) and NHOAc (5.5 g, 71.32 mmol) were added and stirred at 110 °C for 12 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with saturated NaCO (10 mL) and 1 N NaOH (10 mL) and extracted with DCM (10 × 20 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give crude 3-amino-5,5-dimethylcyclohex-2-en-1-one (3.5 g, 71% yield) as a pale yellow solid. This crude product was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ=6.71(br-s,2H),4.89(s,1H),2.12(s,2H),1.90(s,2H),0.96(s,6H).

[0422] 5-Amino-3,3-dimethylcyclohexan-1-ol: To a stirred solution of 3-amino-5,5-dimethylcyclohex-2-en-1-one (4 g, 28.23 mmol) in ethanol (40 mL), 20% NaOH (1.2 mL) and Raney Ni (3.6 g) were added and stirred under 100 psi hydrogen pressure for 48 hours. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the reaction mass was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure and chased with toluene to give crude 5-amino-3,3-dimethylcyclohexan-1-ol (3 g, 73% yield) as a brown liquid. This crude product was used directly in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ=4.35-4.52(brs,1H),4.20-4.28(m,1H),3.68-3.74(m,2H) ,3.20-3.30(m,1H),2.17(d,J=8.4Hz,4H),1.88-2.0(m,2H),1.20-1.70(m,22H).

[0423] tert-Butyl ((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)carbamate: To a stirred solution of tert-butyl ((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)carbamate (10 g, 69.81 mmol) in dioxane (50 ml), water (50 mL), NaHCO3 (5.8 g, 69.81 mmol) and (Boc)2O (19.2 mL, 83.78 mmol) were added and stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with saturated NaCl and extracted with DCM (3 x 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-40% ethyl acetate in petroleum ether to give tert-butyl ((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)carbamate (3.5 g, 17% yield) as a pale yellow liquid. 1 H NMR(400MHz,CDCl3)δ=4.38(br-s,1H),4.19(s,1H),3.98(br-s,1H),1.92-2.02(m,1H),1.68-1.75(m,2H),1 .50-1.55(m,2H),1.40-1.49(m,10H),1.30-1.40(m,2H),1.15(s,3H),1.02-1.12(m,1H),0.90-0.98(m,4H).

[0424] (1R,5R)-5-amino-3,3-dimethylcyclohexan-1-ol hydrochloride: A stirred solution of compound-4A (3 g, 12.34 mmol) in 1,4-dioxane (15 ml) was added to 4M HCl in dioxane (15 mL) at room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure, triturated with diethyl ether, decanted, and dried under reduced pressure to give crude (1R,5R)-5-amino-3,3-dimethylcyclohexan-1-ol hydrochloride (1.6 g, 59% yield) as an off-white solid. This crude product was used directly in the next step without further purification. LC-MS m / z [M+H]+ = 144.29.

[0425] rac 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: (1R,5R)-5-amino-3,3-dimethylcyclohexane-1 in ethanol (20 mL) To a stirred solution of methyl-1-pyrazol hydrochloride (0.6 g, 3.32 mmol) and DIPEA (1.2 mL, 6.65 mmol), ethyl 1-(4-chloro-2-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)cyclopropane-1-carboxylate (1 g, 2.21 mmol) was added and irradiated under microwave irradiation at 150 °C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure to give the crude SnAr adduct, which was dissolved in acetonitrile (10 mL) and added with CsCO (0.29 g, 0.89 mmol) and heated at 75 °C for 6 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mass was filtered and the filtrate was concentrated to give the crude compound. The crude product was purified by column chromatography (silica gel, 100-200 mesh) eluting with 0-70% ethyl acetate in petroleum ether to give rac7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.3 g, 27% yield after two steps) as a pale yellow liquid. LC-MS m / z [M+H]=513.47.

[0426] 7'-((1R,5R)-5-Hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: To a stirred solution of 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.3 g, 0.58 mmol) in MeOH (1.5 ml) was added 4 M HCl in dioxane (1.5 mL) and heated at 50° C. for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated, basified with aqueous NaHCO3, extracted with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound. This crude product was purified by preparative HPLC (Buffer A: 10 mm abc, Buffer B: - ACN, Solubility: - ACN-THF-water, Mobile phase conditions (% of B): - 0 / 30, 2 / 30, 10 / 55, 15 / 55, 15.01 / 100, 18 / 100, 18.01 / 30, 21 / 30, Flow rate: 10 ml / min anl-mcl-prep-014, Column: XB Purification with C-18 (19 x 250 mm) 5 um buffer) gave trans-rac7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (70 mg, 32% yield) as an off-white solid. LC-MS m / z [M+H]+ = 383.43

[0427] 7'-((1R,5R)-5-Hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: trans-racemic 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (70 mg) was subjected to SFC separation in methanol as a co-solvent. After completion of the separation, the solvent of peak 1 was evaporated to give 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (22 mg) as an off-white solid. LC-MS m / z [M+H] = 383.43, 1 H NMR(400MHz,DMSO-d6)δ=12.15(br-s,1H),8.55(s,1H),7.82(s,1H),7.62(s,1H),4.82(t,J=12.4Hz,1H),4.54(s,1H) ),4.10(s,1H),2.38-2.48(m,1H),2.10-2.35(m,4H),1.40-1.70(m,6H),1.20-1.38(m,2H),1.23(s,3H),0.85(s,3H).

[0428] Example 8 [ka] Procedure: To a degassed solution of 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.8 g, 2.88 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.85 g, 4.32 mmol) in dioxane (6 mL) and HO (2 ml), KCO (1 g, 7.20 mmol) and PdCl(dppf).DCM (0.235 g 0.288 mmol) were added, and the reaction mass was sealed under argon atmosphere and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered; the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 3-(2,5-dihydrofuran-3-yl)-4-nitro-1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.6 g, 60.7% yield) as a yellow solid. LC-MS m / z: [M+H]+ = 312.35 1 H NMR (400 MHz, chloroform-d) δ = 8.30-8.15 (m, 1H), 7.15-7.06 (m, 1H), 5.46-5.36 (m, 2H), 5.06-4.84 (m, 4H), 3.73-3.58 (m, 2H), 1.01-0.82 (m, 2H), 0.07-0.09 (m, 11H)

[0429] 3-(Tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-(2,5-dihydrofuran-3-yl)-4-nitro-1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (600 mg, 1.93 mmol) in methanol (6 mL) was added Pd / C (10%, 0.180 g) and stirred at room temperature under 80 psi hydrogen pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give the crude product 3-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.5 g crude, 91% yield) as a brown oil. LC-MS m / z: [M+H]+ = 284.48 1 H NMR(400MHz,DMSO-d6)δ=7.12-6.96(m,1H),5.17-5.08(m,2H),4.03-3.35(m,12H ),2.21-1.96(m,3H),1.79-1.71(m,1H),0.86-0.70(m,3H),0.06--0.17(m,12H).

[0430] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0431] Example 9 [ka] Synthesis of (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka] Step 1: Synthesis of tert-butyl 3-((diphenylmethylene)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Compound-3): tert-Butyl 3-((diphenylmethylene)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate: To a stirred solution of tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.5 g, 1.65 mmol), diphenylmethanimine (0.447 g, 2.47 mmol) in THF (5 mL) was added NaOt-Bu (0.32 g, 3.31 mmol). The reaction mixture was purged with N gas for 15 minutes, followed by the addition of BrettPhosPdG (0.15 g, 0.165 mmol) and purging for 2 minutes. The resulting reaction mixture was irradiated in a microwave at 70 °C for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was passed through a Celite pad and the pad was washed with 10% MeOH in DCM (10 mL). The filtrate was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give tert-butyl 3-((diphenylmethylene)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.6 g, 82% yield) as a yellow solid. LC-MS m / z: [M+H] + =403.53(91%) 1H NMR (400 MHz, chloroform-d) δ = 7.76-7.74 (m, 2H), 7.50-7.22 (m, 8H), 6.02 (s, 1H), 4.79 (s, 2H), 4.07-3.8 (m, 4H), 1.57-1.49 (m, 9H).

[0432] tert-Butyl 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate: To a stirred solution of tert-butyl 3-((diphenylmethylene)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.6 g, 1.49 mmol) in methanol (6 mL), NaOAc (0.37 g, 4.47 mmol) was added, followed by NHOH.HCl (0.42 g, 5.96 mmol), and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% MeOH in DCM to give tert-butyl 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.27 g, 57% yield) as a brown oil. LC-MS m / z: [M+H] + =239.13 1 H NMR(400MHz,DMSO-d6)δ=6.920(s,1H),4.41(s,2H),3.94-3.92(m,2H),3.78-3.75(m,2H),3.17(s,2H),1.906(s,3H),1.44(s,9H).

[0433] [ka] tert-Butyl 3-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate: 2'-chloro-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3 To a degassed solution of [-d]pyrimidin]-6'(7'H)-one (0.17 g, 0.578 mmol) and tert-butyl 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.2 g, 0.868 mmol), NaOt-Bu (85 mg, 0.868 mmol) and BrettphosPdG3 (53 mg, 0.057 mmol) were added, and the reaction mass was sealed under argon and irradiated in a microwave at 60 °C for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a Celite pad; the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-5% MeOH in DCM to give tert-butyl 3-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.2 g, 72% yield, 89% purity) as a brown solid. LC-MS m / z: [M+H] + =496.36.

[0434] 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (S0-EE-PYZF): To a stirred solution of tert-butyl trans-racemic-3-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.2 g, 0.4 mmol) in methanol (2 mL) was added 4 M HCl in dioxane (2 mL) at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with ethyl acetate and concentrated under reduced pressure. The crude product was subjected to preparative HPLC purification. Column: XB Buffer A: ABC Buffer B: Acetonitrile, Mobile phase conditions (% of B): 0 / 10, 2 / 10, 10 / 30 Flow rate: 20 ml ANL-MCL5; PREP-017 Diluent: ACN + THF + water Temperature: ambient The obtained pure fractions were evaporated under reduced pressure and lyophilized to give (78.7 mg, 48% yield) as a white solid. LC-MS m / z: [M+H] + =396.22(96.27%) 1 H NMR(400MHz,DMSO-d6)δ=8.707(s,1H),7.80(s,1H),7.53(s,1H),4.75-4.58(m,2H),4.12-4.03(m,1H),3.92(t, J=5.4Hz,2H),3.85-3.76(m,2H),3.13-3.01(m,2H),2.46-2.30(m,1H),2.29-2.13(m,1H),1.763-1.516(m,10H).

[0435] Example 10 [ka] Procedure: To a degassed solution of 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.0 g, 3.61 mmol) and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 5.41 mmol) in dioxane (6 mL) and HO (2 ml), KCO (1.49 g, 10.83 mmol) and PdCl(dppf).DCM (0.294 g 0.361 mmol) were added, and the reaction mass was sealed under argon atmosphere and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered; the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 3-(3,4-dihydro-2H-pyran-6-yl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.36 g, 30% yield) as a pale yellow oil. LC-MS m / z: [M+H] + =326.43

[0436] Step 2: Synthesis of 3-(tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (Compound-4): [ka] 3-(Tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-(3,4-dihydro-2H-pyran-6-yl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.360 g, 1.107 mmol) in methanol (7 mL) was added Pd / C (10%, 0.15 g) and stirred under 80 psi hydrogen pressure at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to give the crude product 3-(tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.265 g crude, 80% yield) as a pale yellow oil. LC-MS m / z: [M+H] + =298.19

[0437] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0438] Example 11 [ka] Ethyl 5-nitro-1H-imidazole-2-carboxylate: To a stirred solution of ethyl 1H-imidazole-2-carboxylate (8 g, 57.14 mmol) in HSO (35 mL) was added dropwise HNO (35 mL) at 0 °C, followed by stirring at 50-60 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with an ice / water mixture, and the precipitated crystals were collected by suction filtration and washed with 1500 mL of ice water to give ethyl 5-nitro-1H-imidazole-2-carboxylate (2.8 g, 26.6% yield) as a white solid. LC-MS m / z: [M+H] + =186.27(98%).

[0439] Ethyl 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: To a stirred solution of ethyl 5-nitro-1H-imidazole-2-carboxylate (2.4 g, 12.96 mmol) and CsCO (8.42 g, 25.92 mmol) in DMF (24 mL) was added SEM-Cl (3.44 mL, 19.44 mmol) at 0 °C, followed by stirring at room temperature for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 200 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (3.5 g, 85% yield) as a pale yellow liquid.

[0440] (5-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol: To a stirred solution of ethyl 5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (3.5 g, 11.09 mmol) in methanol (35 ml) was added NaBH (0.839 g 22.194 mmol). The reaction mixture was then stirred at room temperature for 2 h and the progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mass was quenched with saturated NH Cl solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with ice-cold water (2 x 200 mL), dried over Na SO and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-30% ethyl acetate in petroleum ether to give (5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (1.4 g, 46% yield) as a pale yellow liquid. LC-MS m / z: [M+H] + = 274.37(89%) 1 H NMR (400 MHz, chloroform-d) δ = 7.863 (s, 1H), 5.592-5.458 (s, 2H), 4.855-4.765 (d, 2H), 3.633-3.592 (m, 2H), 2.793 (br s, 2H), 0.994-0.953 (m, 2H), 0.029 (m, 9H)

[0441] 2-(Methoxymethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole: To a stirred solution of (5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (1.4 g, 5.12 mmol) in THF (14 mL) was added NaH (409 mg 10.24 mmol) and MeI (1.09 g 7.68 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with ice-cold water (2 x 200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-20% ethyl acetate in petroleum ether to give 2-(methoxymethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.630 g, 66% yield) as a pale yellow liquid. LC-MS m / z: [M+H] + = 288.23(96%) 1 H NMR (400 MHz, chloroform-d) δ = 7.874 (s, 1H), 5.420 (s, 2H), 4.601 (s, 2H), 3.589-3.548 (m, 2H), 3.376 (s, 3H), 0.967-0.926 (m, 2H), 0.08-0.006 (s, 9H)

[0442] 2-(Methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine: To a round-bottom flask containing 2-(methoxymethyl)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (400 mg 1.393 mmol) in ethanol (4 mL) and water (4 mL) was added Fe (770.3 mg, 13.93 mmol) and NHCl (749.4 mg 13.93 mmol), then stirred at 50 °C for 2 h. The reaction progress was monitored by TLC. The reaction mass was filtered through a pad of Celite and washed with 10% MeOH in DCM (200 ml); the filtrate was concentrated under reduced pressure to give the crude product, which was diluted with DCM (50 ml), filtered through a fritted funnel, and the filtrate was concentrated under reduced pressure to give 2-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-amine as a brown oil (260 mg crude, 72% yield). The crude compound was used directly in the next step. LC-MS m / z: [M+H] + =258.53

[0443] Coupling to intermediate 1 and deprotection of the SEM group gives [ka] (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((2-(methoxymethyl)-1H-imidazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one) was prepared as described in Example 2.

[0444] Example 12: [ka] Synthesis of (7'-(3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one). [ka] 3-Methoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (5 g, 34.96 mmol) and CsCO (22.7 g, 69.92 mmol) in DMF (50 mL) was added SEM-Cl (9.3 mL, 52.44 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-methoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.2 g, 75% yield) as a colorless liquid. LC-MS m / z: [M+H] + =274.37(78%) 1 H NMR (400 MHz, chloroform-d) δ = 8.14 (s, 1H), 5.32 (s, 2H), 4.04 (s, 3H), 3.67-3.61 (m, 2H), 1.01-0.85 (m, 2H), 0.22-0.18 (m, 9H).

[0445] 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-methoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.2 g, 28.5 mmol) in methanol (72 mL), Pd / C (10%, 0.72 g) was added and stirred at room temperature under 80 psi hydrogen pressure for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, washed with 10% MeOH in DCM, and the filtrate was concentrated under reduced pressure to give the crude product 3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (4.9 g, 76% yield) as a brown liquid. LC-MS m / z: [M+H] + =243.21(90%) 1 H NMR (400 MHz, chloroform-d) δ = 7.04 (s, 1H), 5.16-5.09 (m, 2H), 3.97-3.88 (m, 3H), 3.56-3.43 (m, 2H), 2.81-2.59 (m, 2H), 0.99-0.78 (m, 2H), 0.12-0.05 (m, 9H).

[0446] [ka] Step 1: 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino) To a degassed solution of ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (10 g, 24.5 mmol) and 3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (8.9 g, 36.7 mmol), NaOt-Bu (3.5 g, 36.75 mmol) and BrettphosPdG3 (2.21 g, 2.45 mmol) were added, and the reaction mass was sealed under argon and stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered; the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. The resulting product was dissolved in DCM, stirred with Si-supported thiourea (palladium scavenger) for 3 h, and filtered through a Celite pad.The filtrate was concentrated under reduced pressure to give 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (10.2 g, 68% yield) as a brown gummy solid. LC-MS m / z: [M+H]. + =615.43; 1 H NMR (400 MHz, chloroform-d) δ = 7.97 (s, 1H), 7.63 (s, 1H), 6.65-6.53 (m, 1H), 5.40-5.11 (m, 2H), 4.05-3.98 (m, 3H), 3.64-3.49 (m, 2H), 2.67-2.25 (m, 1H), 1.89-1.21 (m, 9H), 1.03-0.78 (m, 9H), 0.02-0.05 (m, 9H).

[0447] Step 2: 7'-((1R,3R)-3-Hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: To a stirred solution of 7'-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2'-((3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (10.2 g, 16.5 mmol) in methanol (102 mL) was added 4 M HCl in dioxane (153 mL) at 0 °C and stirred at 50 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with ethyl acetate and concentrated under reduced pressure. The crude product was basified with aqueous NaHCO3 and extracted with ethyl acetate (3 x 200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by trituration with 5% MeOH in DCM to give 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (3.3 g, 53% yield) as an off-white solid. LC-MS m / z: [M+H] + =371.38, 1 H NMR(400MHz,DMSO-d6)δ=11.71-11.51(s,1H),8.19(s,1H),7.78(s,1H),7.647-7.643(d,1H),4.649-4.619(m,1H),4.52(d,J=2.8Hz,1H),4.06(br s,1H),3.78(s,3H),2.35-2.10(m,1H),1.83-1.19(m,10H).

[0448] Example 13: [ka] 3-Chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-chloro-4-nitro-1H-pyrazole (3.0 g 20.4 mmol) and CsCO (13.26 g, 40.8 mmol) in DMF (30 ml) was added SEM-Cl (5.4 ml 30.61 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction was quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a pale yellow oil (5.2 g, 90% yield). 1 H NMR (400 MHz, chloroform-d) δ = 8.33-8.19 (m, 1H), 5.53 (s, 1H), 5.52-5.39 (m, 2H), 3.67-3.63 (m, 2H), 0.97-0.91 (m, 2H), 0.02-0.01 (m, 9H)

[0449] 3-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.5 g 9.02 mmol) in ethanol (10 V) and water (10 V) was added NH4Cl (4.78 g, 90.25 mmol) followed by Fe (5.03 g, 90.25 mmol) and the reaction mixture was stirred at 50 °C for 1 h. The progress of the reaction was monitored by TLC. The reaction mass was filtered through a plug of Celite and washed with 10% MeOH in DCM; the filtrate was washed with water (50 mL), extracted with 10% MeOH in DCM and concentrated under reduced pressure to give 3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a brown gummy solid (2.0 g, 78.66% yield). LC-MS m / z: [M+H] +=248.11(87%) 1 H NMR(400MHz,DMSO-d6)δ=7.40-7.20(m,1H),5.31-5.27(m,2H),5.22(s,1H),4.14(br s,2H),3.54-3.48(m,2H),0.91-0.82(m,2H),0.08--0.13(m,9H)

[0450] Coupling to intermediate 1 and deprotection of the SEM group affords 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0451] Example 14: [ka] 3-Cyclopropyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-cyclopropyl-4-nitro-1H-pyrazole (3.0 g 19.6 mmol) and CsCO (12.74 g 39.2 mmol) in DMF (30 ml) was added SEM-Cl (5.1 ml 29.4 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-cyclopropyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless liquid (4.9 g, 89% yield). LC-MS m / z: did not ionize. 1 H NMR(400MHz, CDCl3,298 K)δ(ppm)=8.23-8.06(m,1H),5.55-5.30(m,2H),3.68-3.57(m,2H),2.64-2.02(m,1H),1.24-1.03(m,4H),1.02-0.92(m,2H),0.05(s,9H)

[0452] 3-Cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-cyclopropyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.0 g 7.067 mmol) in ethanol (20 ml) and water (20 ml) was added Fe (1.97 g 35.3 mmol) and NH4Cl (1.88 g 35.3 mmol), then stirred at 60 °C for 2 h. The reaction progress was monitored by TLC. The reaction mass was filtered through a pad of Celite and washed with 10% MeOH in DCM (200 ml); the filtrate was washed with water (50 ml) and extracted with 10% MeOH in DCM, and the organic layer was concentrated under reduced pressure to give the crude product 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a brown oil (1.65 g, 92% yield). This crude compound was used directly in the next step. LC-MS m / z: [M+H] + =254.21 1 H NMR(400MHz,DMSO-d6)δ=7.12-6.93(m,1H),5.35-5.15(m,2H),4.072(brs,2H),3 .52-3.41(m,2H),1.78-1.61(m,1H),0.82-0.75(m,4H),0.67-0.64(m,2H),0.01- -0.03(s,9H).

[0453] Coupling to intermediate 1 and deprotection of the SEM group affords 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0454] Example 15: [ka] 4-Nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (3.0 g 16.56 mmol) and CsCO (10.7 g 33.13 mmol) in DMF (30 ml) was added SEM-Cl (4.4 ml 24.85 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 4-nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless liquid (5.0 g, 97% yield). LC-MS m / z: did not ionize. 1 H NMR(400MHz,DMSO-d6)δ=9.36-8.61(m,1H),5.74-5.56(m,2H),3.65-3.61(m,2H),0.89-0.84(2H),0.05-0.01(m,9H)

[0455] 3-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 4-nitro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3.0 g 9.64 mmol) in methanol (30 mL), Pd / C (10%, 0.3 g) was added, and the reaction mixture was stirred at room temperature under 80 psi hydrogen pressure for 2 hours. The reaction progress was monitored by TLC. The reaction mass was filtered through a pad of Celite and washed with 10% MeOH in DCM (200 mL); the filtrate was concentrated under reduced pressure to give the crude product 3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a pale yellow liquid (2.4 g (crude), 88% yield). This crude compound was used directly in the next step. LC-MS m / z:[M+H] + =282.18(92%), 1 H NMR(400MHz,DMSO-d6)δ=7.33-7.14(m,1H),5.32-5.29(m,2H),4.69-4.31(m,2H),3.54-3.42(m,2H),0.83-0.79(m,2H),0.0- -0.065(m,9H).

[0456] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0457] Example 16: [ka] (7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one) was prepared using the method of Example 1. [ka] instead of [ka] (Commercially available product) was used.

[0458] Example 17: [ka] (7'-(3-Hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one) was prepared using the method of Example 2, except that Intermediate 2 was used rather than Intermediate 1.

[0459] Example 17 Alternative Synthesis: [ka] 3-(2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-one: To a stirred solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 65.11 mmol) and KCO (13.5 g, 97.69 mmol) in toluene (100 mL), cyclohept-2-en-1-one (21.4 g, 195.40 mmol) was added and heated at 85 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluting with 0-40% ethyl acetate in petroleum ether to give 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-one (13.3 g, 78%) as a pale yellow solid. LC-MS m / z [M+H]+ = 264.31. 1 H NMR(400MHz,CDCl3)δ=8.79(m,1H),7.23(d,J=3.6Hz,1H),6.59(d,J=3.6Hz,1H),5.05-5.15(m,1H),3.2 2(dd,J=11.2,15.0Hz,1H),2.85-2.92(m,1H),2.62-2.72(m,1H),2.02-2.30(m,4H),1.70-1.82(m,2H).

[0460] 3-(2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-ol (racemic, diasteromeric mixture): To a stirred solution of 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-one (10 g, 38.02 mmol) in dry THF (100 mL) was added L-selectride (57 mL, 57.03 mmol) at −78° C. and stirred at the same temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with saturated NH4Cl (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-ol (64% trans) and (15% cis) (8.5 g, 84% yield as a mixture of cis-trans isomers) as a pale yellow solid. LC-MS m / z [M+H]+ = 266.39

[0461] 5,5-Dibromo-2-chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (racemic, diasteromeric mixture): To a stirred solution of 3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cycloheptan-1-ol (8.5 g, 23.28 mmol) in tert-butanol (85 mL) and water (17 mL) was added NBS (12.4 g, 69.86 mmol) at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with water (50 mL), extracted with ethyl acetate (3 × 75 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give crude 5,5-dibromo-2-chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (14.5 g crude, mixture of cis-trans isomers) as a brown gummy liquid. This crude compound was used directly in the next step without further purification.

[0462] 2-Chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (racemic, diasteromeric mixture): To a stirred solution of 5,5-dibromo-2-chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (14 g crude, 31.85 mmol) in AcOH (140 mL) was added zinc dust (10 g, 159.27 mmol) at room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was diluted with ethyl acetate (300 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 2-chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (77% cis) and (10% trans) (4.5 g, 68% yield after two steps) as a brown solid. LC-MS m / z [M+H]+ = 282.33

[0463] 2'-Chloro-7'-(3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (racemic, diastereomeric mixture): To a stirred solution of 2-chloro-7-(3-hydroxycycloheptyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (3 g, 10.64 mmol) and dibromoethane (4.6 mL, 53.24 mmol) in dry DMF (30 mL), NaH (60%, 2.1 g, 53.24 mmol) was added portionwise at room temperature and stirred for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 230-400 mesh) eluting with 0-70% ethyl acetate in petroleum ether to give 2'-chloro-7'-(3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (79% trans) and (13% cis) (2.2 g, 67% yield) as a light brown solid. LC-MS m / z [M+H] + =308.21, 1 H NMR(400MHz,CDCl3)δ=7.78-7.84(m,1H),4.79-4.89(m,1H),4.29(s,1H),2.62-2.72(m,1H),2 .27-2.42(m,1H),1.93-2.08(m,2H),1.70-1.90(m,7H),1.55-1.70(m,3H),1.42-1.58(m,1H).

[0464] 7'-(3-Hydroxycycloheptyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (racemic, diastereomeric mixture): 2'-Chloro-7'-(3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[ To a degassed solution of 2,3-d]pyrimidin]-6'(7'H)-one (0.35 g, 1.14 mmol) and 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.31 g, 1.36 mmol), NaOtBu (0.16 g, 1.71 mmol) and BrettphosPdG3 (0.10 g, 0.11 mmol) were added, and the reaction mass was sealed under argon atmosphere and stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered; the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-70% ethyl acetate in petroleum ether to give 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.35 g, 53% yield) as a pale yellow liquid. LC-MS m / z [M+H] + =499.67 and 499.57.

[0465] 7'-(3-Hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (trans-racemic): To a stirred solution of 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.3 g, 0.60 mmol) in methanol (1.5 mL) was added 4 M HCl in dioxane (1.5 mL) at 0 °C and stirred at 50 °C for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure. The crude product was basified with aqueous NaHCO3 and extracted with 5% MeOH in DCM (3 x 15 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by preparative HPLC (column: YMC triat C18, buffer A: 10 mm ABC, buffer B: -ACN, solubility: -ACN-THF-water, mobile phase conditions (% of B): -0 / 35, 2 / 50, 12 / 60, 12.01 / 100, 16 / 100, 16.01 / 35, 20 / 35, flow rate: -20 min) to give 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (peak 2, 40 mg, trans isomer) as an off-white solid. LC-MS m / z [M+H]+ = 369.43, 1 H NMR(400MHz,DMSO-d6)δ=11.50-12.80(br-s,1H),8.54(br-s,1H),7.80(s,1H),7.69(s,1H),4.68-4.80(m,1H),4.49(s,1H),3.98(s,1H) ),2.50-2.62(m,1H),2.10-2.20(m,3H),2.20-2.28(m,1H),1.60-1.80(m,6H),1.55-1.64(m,3H),1.40-1.54(m,3H),1.30-1.40(m,1H).

[0466] 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one: trans-racemic 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (30 mg) was separated by SFC (Chiralpak The mixture was subjected to IC, 65% CO₂, 35% CO₂ (30 mM methanolic ammonia in methanol as a co-solvent). After completion of the separation, the solvent of peak 1 was evaporated to give 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one (0.136 g, 38%) as a white solid. LC-MS m / z [M+H]+ = 369.40, 1 H NMR(400MHz,DMSO-d6)δ=12.09(br-s,1H),8.54(s,1H),7.80(s,1H),7.69(s,1H),4.68-4.78(m,1H),4.49(s,1H),3.98( s,1H),2.50-2.60(m,1H),2.10-2.25(m,4H),1.63-1.82(m,5H),1.56-1.62(m,3H),1.41-1.55(m,3H),1.30-1.50(m,1H).

[0467] Example 18: [ka] (7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one) was prepared using the method of Example 12, except intermediate 2 was used rather than intermediate 1.

[0468] Alternatively, the alternative synthetic route of Example 17 may be used, except: [ka] instead of [ka] Use.

[0469] Example 19: [ka] (2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one) was prepared using the method of Example 13, except intermediate 2 was used rather than intermediate 1.

[0470] Alternatively, the alternative synthetic route of Example 17 may be used, except: [ka] instead of [ka] Use.

[0471] Example 20: [ka] 4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile: To a stirred solution of 4-nitro-1H-pyrazole-3-carbonitrile (3 g, 21.70 mmol) and CsCO (14.1 g, 43.40 mmol) in DMF (150 mL) was added SEM-Cl (5.7 mL, 32.60 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction was quenched with ice-cold water and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile as a pale yellow liquid (5.2 g, 89% yield). 1 H NMR(400MHz, CDCl3)δ=8.40(s,1H),5.52(s,2H),3.62-3.72(m,2H),0.92-1.0(m,2H),0.00-0.05(m,9H).

[0472] 4-Amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile: To a Parr shaker containing 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (2 g, 7.46 mmol) in methanol (20 mL) was added Pd / C (0.2 g) and the reaction mass was stirred at room temperature under 80 psi hydrogen pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile as a light brown solid (1.3 g, 73% yield). LC-MS m / z [M+H]+ =239.48, 1 H NMR(400MHz,DMSO-d6)δ=7.35(s,1H),5.31(s,2H),4.82(s,2H),4.50(t,J=8.0Hz,2H),0.82(t,J=8.0Hz,2H),-0.08-0.0(m,9H).

[0473] Coupling to intermediate 1 and deprotection of the SEM group affords 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile [ka] Formed as described in Example 2.

[0474] Example 21: [ka] Methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate: To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (2 g, 11.69 mmol) and CsCO (7.6 g, 23.39 mmol) in DMF (20 mL) was added SEM-Cl (3.2 mL, 17.54 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with ice-cold water (2 × 10 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (3.2 g, 91% yield) as a colorless liquid.1 H NMR(400MHz,DMSO-d6)δ=9.18(s,1H),8.46(s,1H),5.60(s,2H),5.51(s,2H),3.9 7(s,3H),3.89(s,3H),3.50-3.64(m,4H),0.80-0.90(m,4H),-0.05-0.01(m,9H).

[0475] (4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol: To a stirred solution of methyl 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (1.2 g, 3.98 mmol) in dry THF (12 ml) was added Dibal-H (12 ml, 15.80 mmol) dropwise at −30° C., and then the reaction mass was allowed to warm to room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with 1N HCl and extracted with ethyl acetate (3×30 mL). The organic layer was dried over NaSO and concentrated to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give (4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (0.45 g, 41% yield) as a pale orange liquid. 1 H NMR(400MHz,CDCl3)δ=8.32(s,1H),5.42(s,2H),4.93(d,J=6.8Hz,2H),3.60 -3.68(m,2H),2.82(t,J=6.8Hz,1H),0.92-0.98(m,2H),-0.06-0.05(m,9H).

[0476] 3-(Methoxymethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of (4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methanol (0.4 g, 1.46 mmol) in dry THF (15 ml) was added NaH (60%, 0.09 g, 3.65 mmol) at 0° C. and stirred for 30 min. Then, dimethyl sulfate (0.16 mL, 1.75 mmol) was added and stirred at 50° C. for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with water and extracted with ethyl acetate (3×30 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to give 3-(methoxymethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.35 g, 83% yield) as a light brown liquid. 1 H NMR(400MHz,CDCl3)δ=8.33(s,1H),5.44(s,2H),4.81(s,2H),3.64(t,J=8.0Hz,2H),3.51(s,3H),0.94(t,J=8.0Hz,2H),-0.09-0.02(m,9H).

[0477] 3-(Methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(methoxymethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.35 g, 1.21 mmol) in methanol (6 mL), Pd / C (10%, 0.1 g) was added and stirred at room temperature under hydrogen balloon pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give crude 3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.23 g, 73% yield) as a pale green liquid. This crude product was used directly without further purification. 1H NMR(400MHz,CDCl3)δ=7.14(s,1H),5.29(s,2H),4.55(s,2H),3.53(t,J=8.0Hz,2H),3.92(s,3H),0.92(t,J=8.0Hz,2H),-0.01-0.08(m,9H).

[0478] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0479] Example 22: [ka] 1-(3-Hydroxy-1H-pyrazol-1-yl)ethan-1-one: To a stirred solution of 1H-pyrazol-3-ol (5 g, 59.5 mmol) in pyridine (26 mL) at 95 °C, AcO (5.9 ml, 62.05 mmol) in 9 mL of pyridine was added over 30 minutes. The reaction mass was stirred at 95 °C for 3.5 hours under an argon atmosphere. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure to give the crude compound. The crude compound was purified by trituration with methanol (15 mL), filtered through a Buchner funnel, washed with methanol, and dried to give 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (6.1 g, 81% yield) as an off-white solid. LC-MS m / z: [M+H] + =127.00 1 H NMR(400MHz,DMSO-d6)δ=10.956(s,1H),8.132-8.125(d,J=2.8HZ,1H),6.012-6.005(d,J=2.8HZ,1H),2.507(s,3H).

[0480] 1-(3-(2-Methoxyethoxy)-1H-pyrazol-1-yl)ethan-1-one: To a degassed solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (2 g, 15.87 mmol) and 1-bromo-2-methoxyethane (2.28 g, 16.66 mmol) in DMF (20 mL), K2CO3 (3.28 g, 23.8 mmol) was added and the reaction mass was stirred at 85 °C under argon atmosphere for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with ice-cold water (2 x 500 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-30% ethyl acetate in petroleum ether to give 1-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)ethan-1-one (2.5 g, 85% yield) as a pale yellow liquid. LC-MS m / z: [M+H]+ = 185.31 1 H NMR(400MHz,CDCl3)δ=8.054-8.046(d,J=3.3HZ,1H),6.007-6.000(d,J=3 .3HZ,1H),4.414(m,2H),3.757-3.727(m,2H),3.44(s,3H),2.594(s,3H).

[0481] 3-(2-Methoxyethoxy)-1H-pyrazole: To a degassed solution of 1-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)ethan-1-one (2.5 g, 13.58 mmol) in MeOH (17.5 ml), 8 M NaOH (6.8 ml, 135.8 mmol) solution was added, and the reaction mass was sealed under argon and stirred at 50 °C for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give crude 3-(2-methoxyethoxy)-1H-pyrazole (1.5 g crude, 78% yield) as a pale yellow solid. LC-MS m / z: [M+H] + =143.21(82% purity) 1 H NMR(400MHz,CDCL3)δ=9.169(br s,1H),7.357-7.351(d,J=2.4HZ,1H),5.772-5.766(d,J=2.4HZ,1H),4.344-4.321(m,2H),3.752-3.728(m,2H),3.441(s,3H).

[0482] 3-(2-Methoxyethoxy)-4-nitro-1H-pyrazole: To a solution of 3-(2-methoxyethoxy)-1H-pyrazole (1.5 g, 10.56 mmol) in HSO (6 mL, 4 V), HNO (1.5 mL, 1 V) was added and the reaction mass was stirred at 50 °C under argon atmosphere for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give crude 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1.1 g crude, 55% yield) as a yellow solid. LC-MS m / z: [M+H] + =188.32(76%)

[0483] 3-(2-Methoxyethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1.1 g, 5.88 mmol) and CsCO (3.44 g, 10.58 mmol) in DMF (11 mL) was added SEM-Cl (1.55 mL, 8.82 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-40% ethyl acetate in petroleum ether to give 3-(2-methoxyethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2 g, 64% yield) as a pale yellow liquid. LC-MS m / z: [M+H] + =318.48

[0484] 3-(2-Methoxyethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-(2-methoxyethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2 g, 3.78 mmol) in methanol (24 mL) was added Pd / C (10%, 120 mg) and stirred at room temperature under 80 psi hydrogen pressure for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a pad of Celite, washed with 10% MeOH in DCM, and the filtrate was concentrated under reduced pressure to give the crude product 3-(2-methoxyethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (900 mg crude, 83% yield) as a brown liquid. LC-MS m / z:[M+H] + =288.08

[0485] Coupling to intermediate 1 and deprotection of the SEM group affords 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0486] Example 23: [ka] 3-Ethoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-ethoxy-4-nitro-1H-pyrazole (900 mg, 5.73 mmol) and CsCO (3.7 g, 11.46 mmol) in DMF (9 mL) was added SEM-Cl (1.51 mL, 8.59 mmol) at 0 °C, followed by stirring at room temperature for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-ethoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.4 g, 85% yield) as a pale yellow liquid. LC-MS m / z: No ionization (78%) 1 H NMR (400 MHz, chloroform-d) δ = 8.136 (s, 1H), 5.245 (s, 2H), 4.410-4.392 (m, 2H), 3.365-3.609 (m, 2H), 1.485-1.450 (t, J = 6.8 Hz, 3H), 0.961-0.919 (m, 2H), 0.036-0.011 (s, 9H).

[0487] 3-Ethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-ethoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500 g, 1.74 mmol) in methanol (5 mL), Pd / C (10%, 50 mg) was added and stirred at room temperature under 80 psi hydrogen pressure for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a pad of Celite, washed with 10% MeOH in DCM, and the filtrate was concentrated under reduced pressure to give the crude product 3-ethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (210 mg, 46% yield) as a brown liquid. LC-MS m / z: [M+H] + =258.45

[0488] Coupling to intermediate 1 and deprotection of the SEM group affords 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] Formed as described in Example 2.

[0489] Example 24: [ka] (cis-racemic)-4-fluorotetrahydrofuran-3-yl 4-nitrobenzoate: To a stirred solution of PPh3 (11.53 g, 35.34 mmol) and DIAD (7.1 g, 35.34 mmol) in THF (100 mL) at room temperature, a mixture of (trans-racemic)-4-fluorotetrahydrofuran-3-ol (2.5 g, 23.56 mmol) and 4-nitrobenzoic acid (5.90 g, 35.34 mmol) dissolved in THF (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated in vacuo to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 15-20% ethyl acetate in petroleum ether and evaporated to give (cis-racemic)-4-fluorotetrahydrofuran-3-yl 4-nitrobenzoate (5.0 g, 83% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ=8.29-8.33(m,2H),8.24-8.27(m,2H),4.80-5.10(m,2H),4.01-4.25(m,4H).

[0490] (cis-racemic)-4-fluorotetrahydrofuran-3-ol: To a stirred solution of (cis-racemic)-4-fluorotetrahydrofuran-3-yl 4-nitrobenzoate (5.0 g, 19.59 mmol) in MeOH (250 mL) at room temperature, K2CO3 (13.54 g, 97.96 mmol) was added. The reaction mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean silica gel (100-200 mesh) eluting with 50% ethyl acetate in petroleum ether to give (cis-racemic)-4-fluorotetrahydrofuran-3-ol (1.3 g, 52% yield for two steps) as a light brown syrup. 1H NMR(400MHz,CDCl3)δ=4.95-5.10(m,1H),4.28-4.41(m,1H),3.95-4.11(m,4H),2.237(br-s,1H).

[0491] (trans-racemic) 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (300 mg, 1.15 mmol), (cis-racemic))-4-fluorotetrahydrofuran-3-ol in toluene (6 mL) was added CMBP at room temperature. The reaction mixture was heated to 100° C. in a microwave for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 25% ethyl acetate in petroleum ether to give trans-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (220 mg, 54% yield) as a pale yellow solid. LC-MS m / z [M+H] + =348.45

[0492] trans-Racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of trans-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.3 g, 3.47 mmol) in methanol (26 mL) was added 10% Pd / C (40% w / w, 520 mg) at room temperature and stirred under hydrogen balloon pressure for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was evaporated under reduced pressure to give trans-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (1.0 g, 84% yield) as a pale pink syrup. The crude product was used directly without further purification. LC-MS m / z [M+H] + =318.17

[0493] Coupling to intermediate 1 and deprotection of SEM followed by chiral SFC as described in Example 2 gave peak 1, 2'-((3-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. [ka] was provided.

[0494] Example 25: Peak 2 from SFC of Example 24 identified 2'-((3-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] was obtained.

[0495] Example 26: [ka] Synthesis of cis-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (1.0 g, 3.85 mmol), (trans-racemic)-4-fluorotetrahydrofuran-3-ol (0.613 g, 5.78 mmol) and (tributylphosphoranylidene)acetonitrile (1.86 g, 7.72 mmol) in toluene (15 mL) at room temperature. The reaction mixture was subjected to microwave irradiation at 100° C. for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was evaporated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 30-40% ethyl acetate in petroleum ether to give cis-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (900 mg, 27% yield) as a light brown syrup. LC-MS m / z [M+H] + =348.19.

[0496] Cis-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of cis-racemic 3-(-4-fluorotetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.9 g, 2.59 mmol) in MeOH (9.0 mL) was added 10% Pd / C (40% w / w, 0.36 g) and stirred at room temperature under hydrogen balloon pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 40-50% ethyl acetate in petroleum ether to give cis-racemic 3-((-4-fluorotetrahydrofuran-3-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.3 g) as a light brown syrup. LC-MS m / z [M+H] + =318.52

[0497] Coupling to intermediate 1 and deprotection of SEM followed by chiral SFC as described in Example 2 gave peak 1, 2'-((3-(((3R,4S)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. [ka] was provided.

[0498] Example 27: Peak 2 from SFC of Example 26 identified 2'-((3-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] was provided.

[0499] Example 28: [ka] 3-(4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine: To a stirred solution of 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.1 g, 2.97 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (0.729 g, 2.97 mmol) in toluene:HO (20 mL:2 mL) at room temperature was added NaOt-Bu (0.715 g, 7.42 mmol). The reaction mixture was degassed with argon for 2 minutes, Pd(dppf)Cl.DCM (0.243 g, 0.297 mmol) was added, and the mixture was then stirred at 90 °C for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 20-30% ethyl acetate in petroleum ether to give 3-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine (0.45 g, 42% yield) as a pale yellow solid. LC-MS m / z [M+H] + =360.16

[0500] 3-(Pyrazolo[1,5-a]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine (350 mg, 0.974 mmol) in ethanol:HO (3.5 mL:0.7 mL) at room temperature was added iron powder (0.272 g, 4.87 mmol) and NH4Cl (0.26 g, 0.487 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 40-45% ethyl acetate in petroleum ether to give the pure fraction, 3-(pyrazolo[1,5-a]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (0.21 g, 65% yield) as a light brown solid. LC-MS m / z [M+H] + =330.21

[0501] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 afforded 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. [ka] was provided.

[0502] Example 29: [ka] 3-(3,3-Difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (5.0 g, 19.3 mmol), 3,3-difluorocyclobutan-1-ol (2.08 g, 19.3 mmol) in toluene (50 mL) at room temperature was added CMBP. The reaction mixture was heated to 100° C. in a microwave for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (100-200 mesh) eluting with 0-10% ethyl acetate in petroleum ether to give 3-(3,3-difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.8 g, 41% yield) as a light brown liquid. 1 H NMR(400MHz,CDCl3)δ=8.15(s,1H),5.24(s,2H),4.97-5.00(m,1H),3.60-3.65 (m,2H),3.06-3.16(m,2H),2.80-2.93(m,2H),0.91-0.98(m,2H),0.07(s,9H).

[0503] 3-(3,3-Difluorocyclobutoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(3,3-difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.8 g, 8.022 mmol) in methanol (28 mL), 1% Pd / C (10%, 280 mg) was added and stirred at room temperature under hydrogen balloon pressure for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was concentrated under reduced pressure to give 3-(3,3-difluorocyclobutoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (2.5 g) as a light brown liquid, which was carried on to the next step without further purification. 1H NMR(400MHz,CDCl3)δ=7.001(s,1H),5.107(s,2H),3.46-3.51(m,2H),3.05-3.06(m,2H),2.71-2.77(m,4H),0.85-0.90(m,2H),0.001(s,9H).

[0504] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 affords 2'-((3-(3,3-difluorocyclobutoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. [ka] was provided.

[0505] Example 30 [ka] 3-((3,3-Difluorocyclopentyl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (1.000 g, 3.856 mmol), 3,3-difluorocyclopentan-1-ol (470.8 mg, 3.856 mmol) in toluene (10.00 mL) was added 2-(tributyl-15-phosphanylidene)acetonitrile (CMBP) (1.861 g, 7.712 mmol). The reaction was heated to 100° C. in a microwave for 1 hour. The reaction progress was monitored by TLC and LCMS. The reaction mass was evaporated under reduced pressure to give the crude compound, which was purified by column chromatography using silica gel (100-200 mesh). The compound was eluted with 30-35% ethyl acetate in petroleum ether to give 3-((3,3-difluorocyclopentyl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a colorless liquid (920 mg, 65% yield). 1 H NMR(400MHz, CDCl3)δ=8.147(s,1H),5.20-5.30(m,3H),3.60-3.68(m,2H),2.58-2.61(m,1H),2.10-2.50(m,5H),0.90-0.95(m,2H),0.002(s,9H).

[0506] 3-((3,3-Difluorocyclopentyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-((3,3-difluorocyclopentyl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (920.0 mg, 1.0, 2.531 mmol) in MeOH (10.00 mL) was added 10% Pd / C (360.0 mg, 40% w / w). The reaction mixture was stirred under an atmosphere of H (90 psi) at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to give 3-((3,3-difluorocyclopentyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a brown liquid (820 mg). LC-MS m / z [M+H] + =334.13

[0507] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 affords 2'-((3-(3,3-difluorocyclobutoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. [ka] was provided.

[0508] Example 31 [ka] 1'-Methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-bipyrazole]-5'-carbaldehyde: To a degassed solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carbaldehyde (1.0 g, 4.23 mmol), 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.56 g, 4.23 mmol) in EtOH (4.0 mL), HO (1.0 mL) at room temperature was added CsF (1.28 g, 8.47 mmol). Pd(PPh3)4 (342 mg, 0.296 mmol) was added to the reaction mixture and stirred at 80 °C for 16 h under an argon atmosphere. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a celite bed, and the filtrate was evaporated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-20% ethyl acetate in petroleum ether to give 1'-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-bipyrazole]-5'-carbaldehyde (270 mg, 18% yield) as a light brown liquid. LC-MS m / z [M+H] + =352.54.

[0509] 5'-(Difluoromethyl)-1'-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole: To a stirred solution of 1'-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-bipyrazole]-5'-carbaldehyde (0.42 g, 1.19 mmol) in DCM (8.4 mL) at -78 °C was added DAST (0.1 mL, 0.47 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was quenched with saturated NaHCO3 solution, extracted with DCM, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-20% ethyl acetate in petroleum ether to give 5'-(difluoromethyl)-1'-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole (280 mg, 62% yield) as a brown liquid. LC-MS m / z [M+H] + =374.53.

[0510] 5'-(Difluoromethyl)-1'-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine: To a stirred solution of 5'-(difluoromethyl)-1'-methyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole (0.28 g, 0.749 mmol) in MeOH (10 mL), 10% Pd / C (40% w / w, 112 mg) was added and stirred at room temperature under hydrogen balloon pressure for 5 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was evaporated under reduced pressure to give 5'-(difluoromethyl)-1'-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine (0.230 g) as a light brown syrup, which was used in the next step without further purification. LC-MS m / z [M+H] + =344.25

[0511] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 affords 2'-((5'-(difluoromethyl)-1'-methyl-1H,1'H-[3,4'-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one [ka] was provided.

[0512] Example 32 [ka] 4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-pyrazole: To a stirred solution of 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5.000 g, 13.54 mmol), potassium vinyltrifluoroborate (2.177 g, 16.25 mmol) in 1,4-dioxane (90.00 mL), KPO (7.186 g, 33.85 mmol) and HO (10 mL) were added and the reaction mass was purged with argon for 5 minutes. Pd(dppf)Cl.DCM (1.106 g, 1.354 mmol) was added and the reaction mass was purged with argon for 5 minutes. The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-pyrazole as a pale yellow liquid (2.0 g, 54% yield). 1H NMR(400MHz,CDCl3)δ=8.12(s,1H),7.11-7.18(m,1H),6.24-6.28(m,1H),5.93 -5.97(m,1H),5.47(s,2H),3.70-3.74(m,2H),0.91-0.95(m,2H),0.01(s,9H).

[0513] 3-(2,2-Difluorocyclopropyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-3-vinyl-1H-pyrazole (2.000 g, 7.424 mmol) in THF (40.00 mL) at 0 °C, NaI (71.27 mg, 2.970 mmol) was added, followed by TMSCF (22.3 mL, 148.5 mmol). The reaction was stirred at 60 °C for 48 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with water (30) and the compound was extracted with ethyl acetate (2 × 40 mL). The organic layer was dried over NaSO and evaporated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 15-30% ethyl acetate in petroleum ether to give 3-(2,2-difluorocyclopropyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as an off-white solid (1.1 g, 41% yield). 1 H NMR(400MHz,CDCl3)δ=8.12(s,1H),5.42-5.66(m,2H),3.61-3.66(m,2H),2.82-2. 88(m,1H),2.17-2.18(m,1H),2.02-2.06(m,1H),0.87-0.95(m,2H),0.008(s,9H).

[0514] 3-(2,2-Difluorocyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(2,2-difluorocyclopropyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.000 g, 3.131 mmol) in MeOH (30.00 mL) was added 10% Pd—C (400.0 mg, 40% w / w). The reaction mixture was stirred under H (90 psi) at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a ceilite bed and the filtrate was evaporated under reduced pressure to give 3-(2,2-difluorocyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as an off-white solid (900 mg) which was carried on to the next step without further purification. LC-MS m / z[M+H] + =290.38

[0515] Coupling to intermediate 1 and deprotection of SEM followed by chiral SFC as described in Example 2 provided peak 1, [ka] 2'-((3-((S)-2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0516] Example 33 Peak 2 from SFC of Example 32 [ka] 2'-((3-((S)-2,2-difluorocyclopropyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0517] Example 34 [ka] 1'-(Difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole: To a stirred solution of 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.09 mmol) in 1,4-dioxane (10.00 mL) was added 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.96 g, 5.327 mmol), KPO (2.17 g, 10.24 mmol), and HO (2.0 mL) and degassed with nitrogen for 5 minutes. Tetrakis (473.5 mg, 409.8 mmol) was added to the reaction mixture, which was again degassed with nitrogen at room temperature for 3 minutes and then stirred at 90 °C for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure to give the crude compound. This crude product was purified on a column using 100-200 silica gel. The compound was eluted with 50% ethyl acetate in petroleum ether to give 1'-(difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole as an off-white solid (440 mg, 30% yield). LC-MS m / z [M+H]+ = 360.40

[0518] 1'-(Difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine: To a stirred solution of 1'-(difluoromethyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole (440 mg, 1.224 mmol) in MeOH (10 mL) was added 10% Pd / C (130.3 mg). The reaction mixture was stirred under H2 (70 psi) at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a bed of celite. The filtrate was concentrated under reduced pressure to give the crude compound, which was purified on a column of 100-200 silica gel and eluted with 60% ethyl acetate in petroleum ether to give 1'-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine as a brown solid (290 mg, 72% yield). LC-MS m / z [M+H] + =330.31.

[0519] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((1'-(difluoromethyl)-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0520] Example 35 [ka] 3-((1-Methyl-1H-pyrazol-4-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1 g, 2.708 mmol) in toluene (10 mL) was added 1-methyl-1H-pyrazol-4-ol (1.79 g, 2.709 mmol), CsCO (1.324 g, 4.06 mmol) and degassed with nitrogen for 5 minutes. 5-(di(adamantan-1-yl)phosphanyl)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (35.90 mg, 54.17 μmol) and hexakis(acetate)tripalladium(II) (18.24 mg, 27.08 μmol) were added to the mixture and stirred at 80°C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure to give the crude compound. The crude product was purified by column chromatography using 100-200 silica gel and eluted with 40% ethyl acetate in petroleum ether to give 3-((1-methyl-1H-pyrazol-4-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as an off-white solid (700 mg, 76% yield). LC-MS m / z [M+H] + =340.37(82%).

[0521] 3-((1-Methyl-1H-pyrazol-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-((1-methyl-1H-pyrazol-4-yl)oxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (600 mg, 1.768 mmol) in EtOH (10 mL), HO (2.5 mL) at 0 °C was added NH Cl (472 mg, 8.838 mmol), Fe (493.6 mg, 8.838 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was filtered through a plug of celite bed and the filtrate was evaporated under reduced pressure to give the crude compound, which was purified by column chromatography using 100-200 silica gel and the compound was eluted with 80% ethyl acetate in petroleum ether to give 3-((1-methyl-1H-pyrazol-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a brown liquid (200 mg, 37%). LC-MS m / z [M+H] + =310.18

[0522] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1-methyl-1H-pyrazol-4-yl)oxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0523] Example 36 [ka] 3-(Pyridin-3-ylethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (600 mg, 1.76 mmol), 3-ethynylpyridine (273 mg, 2.65 mmol) in DMF (5.0 mL) was added EtN (6.0 mL), followed by CuI (67.37 mg, 0.36 mmol) and degassed with nitrogen for 5 minutes. To this was added Pd(PPh)Cl (124.1 mg, 6.9 μmol) and again degassed with nitrogen for 3 minutes. The reaction mixture was stirred at 50 °C for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 50-80% ethyl acetate in petroleum ether to give 3-(pyridin-3-ylethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a pink gum (300 mg, 16.6% yield). LC-MS m / z [M+H] + =314.46.

[0524] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(pyridin-3-ylethynyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0525] Example 37 [ka] 1',5'-Dimethyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole: A stirred solution of 3-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500 mg, 1.35 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (360 mg, 1.62 mmol), tribasic potassium phosphate (718.6 mg, 3.385 mmol) in 1,4-dioxane (9.000 mL) and water (1.000 L) was degassed with nitrogen for 5 minutes. To the reaction mixture was added 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (110.6 mg, 135.4 μmol) and degassed again with nitrogen for 3 minutes. The reaction mixture was stirred at 90 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 20-30% ethyl acetate in petroleum ether to give 1',5'-dimethyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole as a pale yellow liquid (250 mg, 32% yield). LC-MS m / z [M+H] + =338.45

[0526] 1',5'-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine: To a stirred solution of 1',5'-dimethyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-3,4'-bipyrazole (250 mg, 0.74 mmol) in ethanol (2.500 mL) and water (2.500 mL) was added NH4Cl (198 mg, 3.70 μmol) and iron powder (207 mg, 3.70 mmol) at room temperature. The mixture was heated to 60 °C and stirred for 4 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mass was concentrated under reduced pressure to give the crude compound. The crude compound was purified by Sepa-Bean silica gel (230-400 mesh) eluting with 20-30% ethyl acetate in petroleum ether to give 1',5'-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-pyrazol]-4-amine as a pink liquid (170 mg, 77% yield). LC-MS m / z [M+H] + =308.2

[0527] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((1',5'-dimethyl-1H,1'H-[3,4'-pyrazol]-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0528] Example 38 [ka] 3-(Cyclopropylmethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (1.0 g, 3.85 mmol) and (bromomethyl)cyclopropane (1.04 g, 7.712 mmol) in DMF (10 mL) at room temperature, CsCO (3.141 g, 9.640 mmol) was added and stirred for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice-water (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 5-10% ethyl acetate in petroleum ether to give 3-(cyclopropylmethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a pale yellow liquid (1.1 g, 81% yield). LC-MS m / z [M+H] + =314.42

[0529] 3-(Cyclopropylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(cyclopropylmethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1 g, 3.19 mmol) in methanol (30 ml) was added 10% Pd / C (300 mg) at room temperature, and the reaction mixture was stirred on a Parr shaker under H atmosphere for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite, and the filtrate was evaporated under reduced pressure to give 3-(cyclopropylmethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a pink liquid (0.9 g, 75% yield). LC-MS m / z [M+H] = 284.46

[0530] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((3-(cyclopropylmethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0531] Example 39 [ka] 3-(2-Fluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (15.0 g, 57.83 mmol) and 1-fluoro-2-iodoethane (20.12 g, 115.68 mmol) in DMF (150 mL) was added CsCO (47.113 g, 144.60 mmol) at room temperature and stirred for 6 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was quenched with ice-water (100 mL) and extracted with ethyl acetate (3×50 ml). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 5-10% ethyl acetate in petroleum ether to give 3-(2-fluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (15 g, 83.61% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ=8.16(s,1H),5.25(s,2H),4.78-4.82(m,2H),4.75-4.77(m,1H),4 .61-4.65(m,1H),4.55-4.58(m,1H),3.60-3.65(m,2H),0.92-0.97(m,2H),0.011(s,9H).

[0532] 3-(2-Fluoroethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-(2-fluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (15 g, 49.119 mmol) in MeOH (150 ml) was added 10% Pd / C (3.0 g, 20% w / w) at room temperature. The reaction mixture was stirred on a Parr shaker under an atmosphere of H for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to give 3-(2-fluoroethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine as a pink liquid (12.5 g, 79.7% yield). 1 H NMR(400MHz,CDCl3)δ=7.03(s,1H),5.13(s,2H),4.68-4.82(m,2H),4.42-4.5 1(m,2H),3.49-3.53(m,2H),2.77(br-s,2H),0.88-0.92(m,2H),0.00(s,9H).

[0533] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((3-(2-fluoroethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0534] Example 40 [ka] 3-Cyclobutoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (600.0 mg, 2.31 mmol) in toluene (6 mL) was added CMBP (1.1 g, 1.23 mL, 4.62 mmol) and cyclobutanol (250.2 mg, 3.47 mmol). The reaction mixture was then stirred at 100° C. for 4 hours and the reaction progress was monitored by LC-MS. LC-MS indicated the formation of the desired product. The reaction mixture was quenched with water and extracted with ethyl acetate (2×100 ml), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under low vacuum to give the crude product. The crude material was absorbed onto a silica gel plug and purified by sepabean chromatography on a Redi-Sep packed silica gel column (12 g) eluted with a gradient of 0-30% EtOAc in petroleum ether. Pure fractions were collected and concentrated under low vacuum to give compound-3 (520.0 mg, 54%, 76% purity). LC-MS m / z [M+H]+ = 314.45

[0535] 3-Cyclobutoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-cyclobutoxy-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (100.0 mg, 0.31 mmol) in ethanol (1 mL) and water (1 mL) was added ammonium chloride (85.33 mg, 1.59 mmol) and iron (89.09 mg, 1.59 mmol). The reaction mixture was then stirred at 60° C. for 4 hours and the reaction progress was monitored by LC-MS and TLC. LC-MS indicated the formation of the desired product and TLC indicated completion of starting material. The reaction mixture was filtered through a pad of Celite, washed with 10% MeOH in DCM (250 ml), and the organic layer was separated and concentrated under low vacuum to give the crude product. The crude product was dried again over sodium sulfate, filtered, washed with DCM (50 ml), and concentrated under low vacuum to give crude 3-cyclobutoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (85.00 mg, 54%) as a light brown oil. LC-MS m / z [M+H] + =284.33

[0536] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((3-cyclobutoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0537] Example 41 [ka] 1-(3-Hydroxy-1H-pyrazol-1-yl)ethan-1-one: To a degassed solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (3 g, 23.8 mmol) and 1,1-difluoro-2-iodoethane (6.8 g, 35.71 mmol) in DMF (30 mL), CsCO (19.3 g, 59.5 mmol) was added, and the reaction mass was sealed under argon and stirred at 60 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-30% ethyl acetate in petroleum ether to give 1-(3-(2,2-difluoroethoxy)-1H-pyrazol-1-yl)ethan-1-one (3.5 g, 77% yield) as a pale yellow liquid. LC-MS m / z [M+H]+ = 190.98

[0538] 3-(2,2-Difluoroethoxy)-1H-pyrazole: To a degassed solution of 1-(3-(2,2-difluoroethoxy)-1H-pyrazol-1-yl)ethan-1-one (4.2 g, 22.1 mmol) in MeOH (42 mL) was added K2CO3 (4.57, 33.15 mmol), and the reaction mass was sealed under argon and stirred at 50 °C for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a Buchner funnel, washed with 10% MeOH in DCM (200 mL), and the filtrate was concentrated under vacuum to give the crude product 3-(2,2-difluoroethoxy)-1H-pyrazole (3.1 g, crude) as a pale yellow solid. LC-MS m / z [M+H]+ = 149.13

[0539] 3-(2,2-Difluoroethoxy)-4-nitro-1H-pyrazole: To a degassed solution of 3-(2,2-difluoroethoxy)-1H-pyrazole (3.5 g, 23.6 mmol) in HSO (14 ml 4 vol) was added HNO (3.5 ml, 1 vol), and the reaction mass was sealed under argon and stirred at 50 °C for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product 3-(2,2-difluoroethoxy)-4-nitro-1H-pyrazole (1.5 g crude, 32% yield) as a yellow solid. LC-MS m / z[M+H]+=194.20

[0540] 3-(2,2-Difluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 3-(2,2-difluoroethoxy)-4-nitro-1H-pyrazole (1 g, 5.18 mmol) and CsCO (3.36 g, 10.36 mmol) in DMF (10 mL) was added SEM-Cl (1.37 mL, 87.77 mmol) at 0 °C, followed by stirring at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with ice-cold water (2 × 500 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-40% ethyl acetate in petroleum ether to give 3-(2,2-difluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.3 g, 77% yield) as a pale yellow liquid. LC-MS m / z [M+H]+ = 324.34

[0541] 3-(2,2-Difluoroethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a Parr shaker containing 3-(2,2-difluoroethoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500 mg, 1.547 mmol) in methanol (10 mL) was added Pd / C (10%, 50 mg) and stirred under 80 psi hydrogen pressure at room temperature for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was filtered through a pad of Celite, washed with 10% MeOH in DCM, and the filtrate was concentrated under reduced pressure to give the crude product 3-(2,2-difluoroethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (350 mg, crude) as a brown liquid. LC-MS m / z: [M+H] + =295.37

[0542] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 2'-((3-(2,2-difluoroethoxy)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0543] Example 42 [ka] 1-(3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-pyrazol-1-yl)ethan-1-one: To a degassed solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (6 g, 47.6 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (12.46 g, 52.3 mmol) in DMF (30 mL), K2CO3 (9.8 g, 71.4 mmol) was added, and the reaction mass was sealed under argon and stirred at 80 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with ice-cold water (2 x 200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-30% ethyl acetate in petroleum ether to give 1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-pyrazol-1-yl)ethan-1-one (2.5 g, 18% yield) as a pale yellow liquid. LC-MS m / z [M+H]+ = 285.27

[0544] 3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-pyrazole: To a degassed solution of 1-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-pyrazol-1-yl)ethan-1-one (2.2 g, 7.746 mmol) in MeOH (22 mL) was added K2CO3 (11.6 g, 11.61 mmol), the reaction mass was sealed under argon and stirred at 50 °C for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was filtered through a Buchner funnel, washed with 10% MeOH in DCM (200 mL), and the filtrate was concentrated under vacuum to give crude product 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-pyrazole (1.55 g crude) as a pale yellow solid. LC-MS m / z[M+H]+=243.42

[0545] 2-((4-Nitro-1H-pyrazol-3-yl)oxy)ethan-1-ol: To a degassed solution of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-pyrazole (600 mg, 2.479 mmol) in HSO (2.4 ml 4 vol) was added HNO (0.6 ml, 1 vol) and the reaction mass was sealed under argon and stirred at 50 °C for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with ice-cold water (2 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give crude product 2-((4-nitro-1H-pyrazol-3-yl)oxy)ethan-1-ol (400 mg, crude) as a pale yellow liquid. LC-MS m / z[M+H]+=174.03

[0546] 2-((4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)ethan-1-ol: To a stirred solution of 2-((4-nitro-1H-pyrazol-3-yl)oxy)ethan-1-ol (400 mg, 2.312 mmol) and CsCO (1.502 g, 4.624 mmol) in DMF (10 mL) was added SEM-Cl (0.61 mL, 3.468 mmol) at 0 °C, followed by stirring at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with ice-cold water (2 × 200 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude compound was purified by Sepa-Bean using silica gel (230-400 mesh) eluting with 10-40% ethyl acetate in petroleum ether to give 2-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)ethan-1-ol (180 mg, 25% yield) as a pale yellow liquid. LC-MS m / z [M+H]+ = 304.12

[0547] 2-((4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)ethan-1-ol: To a stirred solution of compound-7 (180 mg 0.594 mmol) in ethanol (10V) and water (10V), NHCl (317.1 mg, 5.94 mmol) followed by Fe (331.4 g, 5.94 mmol) were added and the reaction mixture was stirred at 60° C. for 1 h. The reaction progress was monitored by TLC. The reaction mass was filtered through a plug of Celite and washed with 10% MeOH in DCM; the filtrate was washed with water (50 mL), extracted with 10% MeOH in DCM and concentrated under reduced pressure to give compound-8 as a brown gummy liquid (169 mg, crude). LC-MS m / z [M+H]=274.19

[0548] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-hydroxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0549] Example 43 [ka] 4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol: To a stirred solution of (1-methylpyrazol-3-yl)methanol (1.000 g, 1 eq, 8.918 mmol) in DCM (100.0 mL) was added triphenylphosphine (3.977 g, 3.359 mL, 15.16 mmol) and carbon tetrabromide (5.324 g, 1.68 mL, 16.05 mmol), and the reaction mixture was then stirred at room temperature for 3 hours, and the reaction progress was monitored by LC-MS and TLC. LC-MS indicated the formation of the desired product. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (2 x 50 ml), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under low vacuum to give the crude product. The crude material was absorbed onto a silica gel plug and purified by sepabean chromatography on a Redi-Sep packed silica gel column (24 g) eluted with a gradient of 15-30% EtOAc in petroleum ether; pure fractions were collected and concentrated under low vacuum to give 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (900.0 mg, 38.91%) as a yellow oil. LC-MS m / z [M+H] + =176.91

[0550] 3-((1-Methyl-1H-pyrazol-3-yl)methoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (600.0 mg, 2.314 mmol) in DMF (3.000 mL) was added cesium carbonate (1.885 g, 462.8 μL, 5.784 mmol) and 3-(bromomethyl)-1-methyl-1H-pyrazole (688.4 mg, 3.933 mmol), and the reaction mixture was then stirred at room temperature for 3 hours. The reaction progress was monitored by LC-MS. LC-MS indicated the formation of the desired product. The reaction mixture was quenched with cold water (100 ml) and extracted with ethyl acetate (2 x 100 ml), the organic layers were combined, dried over sodium sulfate, filtered and concentrated under low vacuum to give 3-((1-methyl-1H-pyrazol-3-yl)methoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (550.0 mg, 33.64%) as a brown gummy solid. LC-MS m / z [M+H] + =353.47.

[0551] 3-((1-Methyl-1H-pyrazol-3-yl)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine: To a stirred solution of 3-((1-methyl-1H-pyrazol-3-yl)methoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (500.0 mg, 1.415 mmol) in ethanol (5.000 mL) and water (5.000 mL) was added ammonium chloride (378.3 mg, 262.9 μL 7.073 mmol) and iron (395.0 mg, 50.3 μL, 7.073 mmol), and the reaction mixture was then stirred at 50° C. for 3 hours. The reaction progress was monitored by LC-MS and TLC. LC-MS indicated the formation of the desired product. The reaction mixture was filtered through a pad of Celite and washed with 10% MEOH in DCM. The filtrate was collected and concentrated under low vacuum to give the crude product. The crude material was washed with DCM to remove the ammonium chloride remaining as a solid. The desired compound, which is soluble in DCM, was collected and concentrated under low vacuum to give 3-((1-methyl-1H-pyrazol-3-yl)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine (300.0 mg, 28.38%) as a brown gummy solid. LC-MS m / z [M+H] + =323.47

[0552] Coupling to intermediate 1 and deprotection of the SEM as described in Example 2 gives: [ka] 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one was provided.

[0553] Example 44 [ka] 2,2-Difluoro-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)propan-1-ol: To a stirred solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-ol (300.0 mg, 1.157 mmol) in toluene (9.000 mL), CMBP (558.4 mg, 612 μL, 2.314 mmol) and 2,2-difluoropropane-1,3-diol (194.5 mg, 1.735 mmol) are added, and the reaction mixture is then stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. TLC and LC-MS indicate the formation of the desired product. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under low vacuum to give the crude product. The crude material was absorbed onto a silica gel plug and purified by sepabean chromatography through a Redi-Sep packed silica gel column (12 g) eluted with a gradient of 21.2% EtOAc in petroleum ether. Pure fractions were collected and concentrated under low vacuum to give 2,2-difluoro-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)propan-1-ol (300.0 mg, 57%) as a light brown liquid. LC-MS m / z [M+H] = 354.38

[0554] 3-(2,2-Difluoro-3-methoxypropoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole: To a stirred solution of 2,2-difluoro-3-((4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)oxy)propan-1-ol (250.00 mg, 707.41 μmol) in THF (3.250 mL) was added sodium hydride (43.91 mg, 1.0611 mmol) at 0° C. After 15 minutes, methyl iodide (200.82 mg, 1.4148 mmol) was added, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LC-MS. LC-MS indicated the formation of the desired product. The reaction mixture was quenched with ice water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under low vacuum to give the crude product. The crude material was absorbed onto a silica gel plug and purified by sepabean chromatography through a Redi-Sep packed silica gel column (12 g) eluted with a gradient of 20-22% EtOAc in petroleum ether. Pure fractions were collected and concentrated under low vacuum to give 3-(2,2-difluoro-3-methoxypropoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (240.0 mg, 83%) as a light bro...

Claims

1. A compound according to formula (I), 【Chemistry 1】 [In the formula, Y １ is a bond or CH ２ (e.g., Y １ is a bond); Y ２ is a bond, O, NR ５ or CR ６ R ７ (e.g., Y ２ is a bond); R １ and R ２ are each independently H, halo, C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl, or R １ and R ２ are put together, C ３ ~C ４ Cycloalkyl or C ３ ~C ４ forming a cyclohaloalkyl; Each R ３ are independently hydroxyl, halo, C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl; R ４ is H, halo, C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl; R ５ is H, C １ ~C ６ Alkyl, C(=O)-C １ ~C ６ Alkyl or C(═O)—O—C １ ~C ６ selected from the group consisting of alkyl; R ６ and R ７ together with the carbon atoms to which they are bonded, C ３ ~C ６ cycloalkyl, or a 3- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S, ３ ~C ６ Cycloalkyl or 3- to 6-membered heterocyclyl may have 0 to 3 substituents R ８ is substituted with; Each R ８ are independently １ ~C ６ Alkyl, C(=O)C １ ~C ６ Alkyl, halo, C １ ~C ６ Haloalkyl, S-C １ ~C ６ Alkyl, SO-C １ ~C ６ Alkyl, SO ２ -C １ ~C ６ alkyl, cyano, hydroxyl, or two R on the same ring atom; ８ the substituents taken together form =0, n is 0 to 3; m is 1 to 5; 【Chemistry 2】 is a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, said 5-membered heteroaryl containing 0 to 3 substituents R Ａ is substituted with; Each R Ａ are independently *L １ -X １ where * represents 【Transformation 3】 and each L １ is a bond, O, S, SO, SO ２ , C≡C, C(=O), *C(=O)-O**, C １ ~C ６ Alkylene, C １ ~C ６ Haloalkylene, *O-C １ ~C ６ Alkylene **, *O-C １ ~C ６ Haloalkylene**, *O-C １ ~C ６ Hydroxyalkylene**, C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene, *O-C ３ ~C ６ Cycloalkylene**, *O-3 to 6-membered heterocyclylene**, C １ ~C ６ Hydroxyalkylene, C ３ ~C ６ Cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), O—C １ ~C ６ Alkylene-O, *O-C １ ~C ６ Alkylene -O-C ３ ~C ６ Cycloalkylene ** and *O—C １ ~C ６ alkylene-O-3 to 6-membered heterocyclylene**, wherein * is 【Chemistry 4】 ** indicates the point of attachment to X １ refers to the point of attachment to and each X １ is H, halo, cyano, hydroxyl, C １ ~C ６ Alkyl, C(=O)-C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, 0 to 3 R ８ C substituted by a group ３ ~C ６ Cycloalkyl, O-C １ ~C ６ Alkyl, S-C １ ~C ６ Alkyl, S(O)—C １ ~C ６ Alkyl, S(O) ２ -C １ ~C ６ Alkyl, N(C １ ~C ６ alkyl) ２ , C(=O)N(C １ ~C ６ alkyl) ２ , C １ ~C ６ hydroxyalkyl, 0 to 3 R ８ 3-6 membered heterocyclyl (e.g., containing 1 or 2 heteroatoms independently selected from O, N, and S) substituted by a group, 0-3 R ８ 5-10 membered heteroaryl (e.g., 5, 6, 9, or 10 membered heteroaryl) containing 1-4 heteroatoms independently selected from O, N, and S, substituted by groups, 0-3 R ８ a 5- to 10-membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, substituted by a group; ８ O, N and S substituted by groups 7- to 10-membered spiroheterocyclyl containing 1 or 2 heteroatoms independently selected from the group consisting of 0 to 3 R ８ C substituted by a group ７ ~C １０ independently selected from spirocycloalkyl; or Two Rs located on adjacent ring atoms Ａ the substituents, taken together with the adjacent ring atoms, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S, provided that at least one heteroatom is N; or a pharmaceutically acceptable salt and / or tautomer thereof.

2. Y １ 2. The compound of claim 1, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a bond.

3. Y ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is a bond.

4. The compound according to any one of claims 1 to 3, wherein m is 4, or a pharmaceutically acceptable salt and / or tautomer thereof.

5. 5. The compound according to any one of claims 1 to 4, wherein n is 1 to 3, for example, n is 1, or a pharmaceutically acceptable salt and / or tautomer thereof.

6. At least one R ３ 6. The compound of claim 5, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein is OH.

7. The compound of formula (I) is a compound of formula (Ia): 【Transformation 5】 (In the formula, R １ , R ２ , R ３ , R ４ and 【Transformation 6】 is as defined in claim 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

8. The compound of formula (I) is a compound of formula (Ib): 【Transformation 7】 (In the formula, R １ , R ２ , R ３ , R ４ and 【Transformation 8】 is as defined in claim 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

9. The compound of formula (I) is a compound of formula (Ic): 【Chemistry 9】 (In the formula, R １ , R ２ , R ３ , R ４ and 【Chemistry 10】 is as defined in claim 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

10. The compound of formula (I) is a compound of formula (Id): 【Chemistry 11】 (In the formula, R １ , R ２ , R ４ and 【Chemistry 12】 is as defined in claim 1), or a pharmaceutically acceptable salt and / or tautomer thereof.

11. R １ and R ２ But together, C ３ ~C ４ Cycloalkyl or C ３ ~C ４ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or tautomer thereof, which forms a cyclohaloalkyl.

12. R １ and R ２ But together, C ３ ~C ４ 12. The compound of claim 11, or a pharmaceutically acceptable salt and / or tautomer thereof, which forms a cycloalkyl.

13. R １ and R ２ But together, C ３ 13. The compound of claim 12, or a pharmaceutically acceptable salt and / or tautomer thereof, which forms a cycloalkyl.

14. R ４ The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein 【Request Item 15】 【Chemistry 13】 is a 5-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, and said 5-membered heteroaryl is Ａ wherein R Ａ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: 【Request Item 16】 【Chemistry 14】 is a 5-membered heteroaryl containing two heteroatoms independently selected from N and O, and said 5-membered heteroaryl is Ａ wherein R Ａ The compound of claim 15, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: is as defined in any one of claims 1 to 15. 【Request Item 17】 【Chemistry 15】 is a 5-membered heteroaryl containing 1 to 3 heteroatoms, each of which is N, and said 5-membered heteroaryl is Ａ wherein R Ａ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: 【Request Item 18】 【Chemistry 16】 is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is Ａ wherein R Ａ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: 【Request Item 19】 【Chemistry 17】 is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is Ａ wherein R Ａ A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: 【Request Item 20】 【Chemistry 18】 is a 5-membered heteroaryl containing two heteroatoms each being N, and said 5-membered heteroaryl is substituted with zero or one substituent R Ａ wherein R Ａ Ha*L １ -X １ and L １ and X １ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein: 【Request Item 21】 【Chemistry 19】 but, 【Chemistry 20】 15. The compound according to any one of claims 1 to 14, selected from the group consisting of: or a pharmaceutically acceptable salt and / or tautomer thereof. 【Request Item 22】 【Chemistry 21】 but, 【Chemistry 22】 22. The compound of any one of claims 1 to 14 and 21, or a pharmaceutically acceptable salt and / or tautomer thereof, selected from the group consisting of: 【Request Item 23】 【Chemistry 23】 but, 【Chemistry 24】 【Chemistry 25】 and X is selected from O, NH and S (e.g., X is NH), or a pharmaceutically acceptable salt and / or tautomer thereof.

24. but, 【Chemistry 26】 but, 【Chemistry 27】 【Chemistry 28】 23. The compound of any one of claims 1 to 14 and 22, or a pharmaceutically acceptable salt and / or tautomer thereof, selected from the group consisting of: 【Request Item 25】 【Chemistry 29】 but, 【Transformation 30】 and X is selected from O, NH and S, or a pharmaceutically acceptable salt and / or tautomer thereof. 【Request Item 26】 【Chemistry 31】 but, 【Chemistry 32】 26. The compound of any one of claims 1 to 14 and 25, or a pharmaceutically acceptable salt and / or tautomer thereof, selected from the group consisting of:

27. i) 【Transformation 33】 but, 【Transformation 34】 is selected from the group consisting of (e.g., 【Chemistry 35】 teeth 【Transformation 36】 ), R Ａ but, a) halo, b) cyano, c) C １ ~C ６ Alkyl, d) C １ ~C ６ haloalkyl, e) C １ ~C ６ hydroxyalkyl, f) O-C １ ~C ６ Alkyl, g) C(=O)-OC １ ~C ６ Alkyl, h) C １ ~C ６ Alkylene -O-C １ ~C ６ Alkyl, i) O-C １ ~C ６ Alkylene -O-C １ ~C ６ Alkyl, j) 0 to 3 R ８ C substituted by a group ３ ~C ６ cycloalkyl, k) 0 to 3 R ８ a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; l) 0 to 3 R ８ a 5-10 membered partially saturated heterocyclyl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; m) 0 to 3 R ８ O—C substituted by a group ３ ~C ６ cycloalkyl, n) 0 to 3 R ８ C≡C-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; o) 0 to 3 R ８ S-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; p) 0 to 3 R ８ C containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by groups １ ~C ６ alkylene-5 to 10 membered heteroaryl, q) O-C １ ~C ６ haloalkyl, r) O-C １ ~C ６ Alkylene-N(C １ ~C ６ alkyl) ２ , s) O-C １ ~C ６ Hydroxyalkylene-O-C １ ~C ６ Alkyl, t) 0 to 3 R ８ O—C substituted by a group １ ~C ６ Alkylene-C ３ ~C ６ cycloalkyl, u) 0 to 3 R ８ O—C containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group １ ~C ６ alkylene-3 to 6-membered heterocyclyl, v) O-C １ ~C ６ Alkylene -C(=O)-N(C １ ~C ６ alkyl) ２ , w) 0 to 3 R ８ C containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by groups １ ~C ６ alkylene-5 to 10 membered partially saturated heterocyclyl, x) 0 to 3 R ８ O—C containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group １ ~C ６ alkylene-7 to 10-membered spiroheterocyclyl, y) O-C １ ~C ６ Alkylene-S(O) ２ -C １ ~C ６ Alkyl, z) O-C １ ~C ６ hydroxyalkyl, aa) 0 to 3 R ８ O—C containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by groups １ ~C ６ alkylene-5 to 10 membered heteroaryl, bb) 0 to 3 R ８ O-5 to 10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, substituted by a group; cc) 0 to 3 R ８ O-3 to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group; dd) 0 to 3 R ８ C≡C—C substituted by a group ３ ~C ６ cycloalkyl, ee) S-C １ ~C ６ haloalkyl, ff) 0 to 3 R ８ O—C containing 1 or 2 heteroatoms independently selected from O, N and S, substituted by a group １ ~C ６ alkylene-O-3 to 6-membered heterocyclyl gg) and 0 to 3 R ８ 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, substituted by a group or ii) 【Chemistry 37】 but, 【Transformation 38】 and R Ａ the substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S; 27. A compound according to any one of claims 1 to 14 and 26, or a pharmaceutically acceptable salt and / or tautomer thereof.

28. Each R ８ are independently halo (e.g., fluoro), C １ ~C ６ Alkyl (e.g., methyl), hydroxyl, cyano, S(O ２ )-C １ ~C ６ Alkyl (e.g., S(O ２ ) CH ３ ), C(═O)—C １ ~C ６ Alkyl (e.g., C(=O)CH ３ ), O-C １ ~C ６ Alkyl (e.g., OCH ３ ) and C １ ~C ６ Haloalkyl (e.g., C １ Haloalkyl, for example, CHF ２ ) or two R on the same ring atom ８ 28. The compound of claim 27, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the substituents, taken together, form =0.

29. i) 【Chemistry 39】 but, 【Chemistry 40】 and R Ａ But halo, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, O—C １ ~C ６ Alkyl, C(═O)—O—C １ ~C ６ Alkyl, C １ ~C ６ Alkylene -O-C １ ~C ６ Alkyl, O-C １ ~C ６ Alkylene -O-C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl and a 3- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S; or ii) 【Chemistry 41】 but, 【Chemistry 42】 and R Ａ the substituents, taken together with the ring atoms to which they are attached, form a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O and S; 28. The compound of claim 27 or a pharmaceutically acceptable salt and / or tautomer thereof. 【Request Item 30】 【Chemistry 43】 but, 【Chemistry 44】 and R Ａ But CH ３ , OCH ３ or OCH ２ CH ３ 30. The compound according to any one of claims 1 to 14, 28 and 29, wherein:

31. Each L １ is a bond, O, C(=O), *C(=O)-O**, C １ ~C ６ Alkylene, C １ ~C ６ Haloalkylene, *O-C １ ~C ６ Alkylene**, C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene, C １ ~C ６ Hydroxyalkylene, C ３ ~C ６ Cycloalkylene, 3- to 6-membered heterocyclylene (e.g., containing one heteroatom that is O), and O—C １ ~C ６ alkylene-O, wherein * is 【Chemistry 45】 ** indicates the point of attachment to X １ refers to the point of attachment to and each X １ H, halo, cyano, hydroxyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, O-C １ ~C ６ Alkyl, C １ ~C ６ independently selected from hydroxyalkyl and 3- to 6-membered heterocyclyl (e.g., containing one heteroatom that is O); 28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt and / or tautomer thereof.

32. R Ａ But C １ ~C ６ Alkyl, C １ ~C ６ Alkylene -O-C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C(═O)—O—C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, 3-6 membered heteroatoms including one heteroatom that is O, halo, O—C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, cyano and O—C １ ~C ６ Alkylene -O-C １ ~C ６ 32. The compound of any one of claims 1 to 27 and 31, or a pharmaceutically acceptable salt and / or tautomer thereof, wherein the compound is selected from the list consisting of alkyl.

33. 1) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 2) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 3) 2'-((3-(difluoromethyl)-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 4) methyl 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carboxylate; 5) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methyl-1H-pyrazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 6) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(hydroxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 7) 7'-((1R,5R)-5-hydroxy-3,3-dimethylcyclohexyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 8) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 9) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 10) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 11) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((2-(methoxymethyl)-1H-imidazol-5-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 12) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-methoxy-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 13) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 14) 2'-((3-cyclopropyl-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 15) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 16) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 17) 7'-(3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 18) 7'-((1R,3R)-3-hydroxycycloheptyl)-2'-((3-methyl-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 19) 2'-((3-chloro-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycycloheptyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 20) 4-((7'-((1R,3R)-3-hydroxycyclohexyl)-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-1H-pyrazole-3-carbonitrile; 21) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(methoxymethyl)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 22) 7'-((1R,3R)-3-hydroxycyclohexyl)-2'-((3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; 23) 2'-((3-ethoxy-1H-pyrazol-4-yl)amino)-7'-((1R,3R)-3-hydroxycyclohexyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one; or a pharmaceutically acceptable salt and / or tautomer thereof. 【Request Item 34】 【Transformation 46】 2. The compound of claim 1, wherein: 【Request Item 35】 【Chemistry 47】 2. The compound of claim 1, wherein: 【Request Item 36】 【Transformation 48】 2. The compound of claim 1, wherein: 【Request Item 37】 【Chemistry 49】 2. The compound of claim 1, wherein: 【Request Item 38】 【Chemistry 50】 2. The compound of claim 1, wherein: 【Request Item 39】 【Chemistry 51】 2. The compound of claim 1, wherein:

40. 40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof and one or more pharmaceutically acceptable carriers.

41. A combination comprising a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof and one or more therapeutically active agents.

42. 40. A method of modulating CDK2 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof.

43. 40. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof.

44. 40. A compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof for use as a pharmaceutical.

45. 40. A compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof for use in the treatment of cancer.

46. 40. Use of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof in the treatment of cancer.

47. 40. Use of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt and / or tautomer thereof in the manufacture of a medicament for the treatment of cancer.

48. 48. The method of claim 43, the compound for use of claim 45, or the use of claim 46 or claim 47, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, breast cancer (e.g. ER+ breast cancer, e.g. ER+ / Her2- breast cancer), lung cancer and endometrial cancer.

49. 49. The method of claim 43 or claim 48, the compound for use of claim 45 or 48, or the use of any one of claims 46 to 48, wherein the cancer is a cyclin E amplified cancer.

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