Novel macrocyclic aminopyrazole compounds as CDK2 inhibitors

Abstract

The present disclosure relates to compounds of formula (I), their tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives, and their uses, for example, in the treatment of diseases or disorders associated with CDK2. The present disclosure also relates to pharmaceutical compositions containing such compounds and their uses in the treatment or prevention of diseases or disorders associated with CDK2. The present disclosure, according to some embodiments, provides compounds, compositions, and methods for modulating the activity of CDK2. In some embodiments, these compounds exhibit selective CDK2 inhibitory activity.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 486,534, filed February 23, 2023, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to novel macrocyclic aminopyrazole compounds, pharmaceutical compositions containing such compounds, and their use in the prevention and treatment of diseases and conditions, such as cancer. The compounds disclosed herein exhibit selective CDK2 inhibitory activity. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are a family of protein kinases involved in the regulation of a wide range of physiological processes. For example, CDKs have been identified as contributing to the regulation of cell cycle, mRNA processing, neuronal differentiation, and other biological functions. However, the majority of known CDK complexes regulate the progression of the entire cell cycle and are present in all known eukaryotes. CDKs are also involved in the development and proliferation of cancer cells through unregulated and abnormal expression of CDKs (see, for example, "Cell cycle, CDKs and cancer: a changing paradigm," Nature Review Cancer, 2009, 9, 153-166; and "Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions," Target Oncology, 2018, 13(1), 21-38).

[0004] Cyclin-dependent kinase 2 (CDK2) is a CDK enzyme involved in human cancer. The binding partner of CDK2 is cyclin E, which is produced by the cyclin E1 (CCNE1) gene. Upon binding to activated CDK2, it regulates the G1-to-S-phase transition in DNA replication. Overactivation of the CCNE1 gene due to mutations has been reported to affect cancer cell proliferation through the CDK2 pathway. See, for example, "Mechanism of Cdk2 / Cyclin E inhibition of p27 and p27 phosphorylation," Biochemistry, 1999, 38(27), 8713-8722. Cancers identified as being caused by CCNE1 mutations include ovarian, gastric, endometrial, and breast cancers (see, for example, "Cyclin E and survival in patients with breast cancer," N Engl J Med, 2002, 347(20), 1566-75). Therapeutic approaches targeting CDK2 include cell cycle arrest and tumor growth inhibition, but selective inhibition of CDK2 has not been conclusively concluded (see, e.g., "Selective killing of transformed cells by cyclin / cyclin-dependent kinase 2 antagonists," PNAS, 1999, 96(8), 4325-4329). The close similarity between the CDK2 binding site and that of other CDKs may cause unintended inhibition of other CDK-mediated pathways, thus resulting in serious side effects. Furthermore, despite considerable research efforts, there are currently no approved drugs targeting CDK2 (see, e.g., "Highlights of the Latest Advances in Research on CDK Inhibitors," Cancers, 2014, 6(4), 2224-2242). Thus, there is an unmet medical need for novel compounds, eg, CDK inhibitors that have novel activity profiles and that selectively target CDK2. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] "Cell cycle, CDKs and cancer: a changing paradigm", Nature Review Cancer, 2009, 9, 153-166 [Non-patent document 2] “Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions”, Target Oncology, 2018, 13(1), 21-38 [Non-patent document 3] "Mechanism of Cdk2 / Cyclin E inhibition of p27 and p27 phosphorylation", Biochemistry, 1999, 38(27), 8713-8722) [Non-patent document 4] “Cyclin E and survival in patients with breast cancer”, N Engl J Med, 2002, 347(20), 1566-75 [Non-Patent Document 5] "Selective killing of transformed cells by cyclin / cyclin-dependent kinase 2 antagonists", PNAS, 1999, 96(8), 4325-4329 [Non-patent document 6] “Highlights of the Latest Advances in Research on CDK Inhibitors”, Cancers, 2014, 6(4), 2224-2242 Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides, according to some embodiments, compounds, compositions, and methods for modulating the activity of CDK2. In some embodiments, these compounds exhibit selective CDK2 inhibitory activity.

[0007] In some embodiments, the present disclosure provides compounds represented by formula (I), or tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof: [ka] and wherein in formula (I): A is a substituted or unsubstituted amide or a 5- to 12-membered aromatic ring, where the 5- to 12-membered aromatic ring optionally contains one or more heteroatoms and one, two, three, or four R A1 where each R is substituted as needed. A1 are independently hydrogen, -C(=O)R A2 , C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo, C1-C5 haloalkyl, C1-C5 alkoxy, and —CN, and each R A2 are independently selected from hydrogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl; B is N, N + -O - and CR0, where R0 is selected from hydrogen, halo, —CN, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; R1 is selected from hydrogen, halo, -CN, and C1-C5 alkyl, or R1 and Y together with the carbon atom to which they are attached form a 5- to 6-membered aromatic ring, wherein the aromatic ring optionally contains 1 to 3 heteroatoms; X and Y are independently N, N + -O -or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; Q is absent or selected from -WC(R3)(R4)-, where R3 and R4 are independently selected from hydrogen, deuterium, C1-C5 alkyl, C1-C5 haloalkyl, and halo, or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group or a 3- to 6-membered cycloalkyl, and W is absent or selected from alkyl. and the alkylene, -C(=O)-R6-, -O-, -R6-O-, -O-R6-, -N(R7)-, -NH-C(=O)-, -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle have 1, 2, 3, 4, or 5 R B wherein each R6 is independently selected from C1-C5 alkylene, a 3- to 6-membered heterocycle, and a 3- to 6-membered cycloalkyl; each R7 is independently selected from hydrogen, oxo, and C1-C5 alkyl; and each R B is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl; L is absent or a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with oxo, C1-C5 haloalkyl, halo, deuterium, or C1-C5 alkyl, and one or more carbon atoms are optionally replaced with a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, or 4 R9, wherein each R8 is independently selected from hydrogen and C1-C5 alkyl, and each R9 is independently selected from hydrogen, oxo, and C1-C5 alkyl; and R 10 and R 11 is independently selected from hydrogen, halo, and C1-C5 alkyl; provided that the compound of formula (I) is: (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-4(3,5)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, or (1 1 S,1 3 R,Z)-2 1 H-13-Oxa-3,6,11-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclotridecaphane-5,12-dione isn't it.

[0008] In some embodiments, the compound of formula (II): [ka] and wherein R, R, X, Y, W, R, R, L, and A are as defined above.

[0009] In some embodiments, the compound of formula (III): [ka] and wherein R, R, X, Y, W, R, R, and L are as defined above.

[0010] In some embodiments, the compound of formula (IV): [ka] and wherein in formula (IV), B, R, X, Y, L, A, R are selected from the group consisting of 10 , and R 11 is as defined above.

[0011] In some embodiments, the compound of formula (V): [ka] and wherein in formula (V), R, B, X, Y, R are selected from 10 , R 11 , and L is as defined above.

[0012] Also disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, or a pharmaceutical composition containing at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions of the present disclosure may be for use in treating a disease or disorder (or in the manufacture of a medicament therefor) in a subject in need thereof.

[0013] In some embodiments, a therapeutically effective amount of the pharmaceutical composition of the present disclosure may be administered to a subject diagnosed with a disease or disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer. [Brief explanation of the drawings]

[0014] [Figure 1-1] FIG. 1 is a diagram illustrating General Synthetic Method 1. [Figure 1-2] Same as above.

[0015] [Figure 2-1] FIG. 2 is a diagram illustrating General Synthetic Method 2. [Figure 2-2] Same as above.

[0016] [Figure 3-1] FIG. 3 is a diagram illustrating General Synthetic Method 3. [Figure 3-2] Same as above.

[0017] [Figure 4-1] FIG. 4 is a diagram illustrating the synthesis of compound 16. [Figure 4-2] Same as above.

[0018] [Figure 5-1] FIG. 5 is a diagram illustrating the synthesis of compound 4. [Figure 5-2] Same as above.

[0019] [Figure 6-1] FIG. 6 is a diagram illustrating the synthesis of compounds 8, 9, and 10. [Figure 6-2] Same as above.

[0020] [Figure 7-1] FIG. 7 is a diagram illustrating the synthesis of compound 9. [Figure 7-2] Same as above.

[0021] [Figure 8-1] FIG. 8 is a diagram illustrating the synthesis of compound 13. [Figure 8-2] Same as above.

[0022] [Figure 9-1] FIG. 9 is a diagram illustrating the synthesis of compound 17. [Figure 9-2] Same as above.

[0023] [Figure 10-1] FIG. 10 is a diagram illustrating the synthesis of compound 18. [Figure 10-2] Same as above.

[0024] [Figure 11-1] FIG. 11 is a diagram illustrating the synthesis of compound 22. [Figure 11-2] Same as above.

[0025] [Figure 12-1] FIG. 12 is a diagram illustrating the synthesis of compound 26. [Figure 12-2] Same as above.

[0026] [Figure 13-1] FIG. 13 is a diagram illustrating the synthesis of compound 33. [Figure 13-2] Same as above.

[0027] [Figure 14] FIG. 14 is a diagram illustrating the synthesis of compound 104.

[0028] [Figure 15-1] FIG. 15 is a diagram illustrating the synthesis of compound 21. [Figure 15-2] Same as above.

[0029] [Figure 16-1] FIG. 16 is a diagram illustrating the synthesis of compound 20. [Figure 16-2] Same as above.

[0030] [Figure 17-1] FIG. 17 is a diagram illustrating the synthesis of compound 23. [Figure 17-2] Same as above.

[0031] [Figure 18-1] FIG. 18 is a diagram illustrating the synthesis of compound 109 and compound 110. [Figure 18-2] Same as above.

[0032] [Figure 19-1] FIG. 19 is a diagram illustrating the synthesis of compound 11 and compound 12. [Figure 19-2] Same as above.

[0033] [Figure 20-1] FIG. 20 is a diagram illustrating the synthesis of compound 24 and compound 25. [Figure 20-2] Same as above.

[0034] [Figure 21-1] FIG. 21 is a diagram illustrating the synthesis of compound 71 and compound 72. [Figure 21-2] Same as above.

[0035] [Figure 22-1] FIG. 22 is a diagram illustrating the synthesis of compound 108. [Figure 22-2] Same as above.

[0036] [Figure 23-1] FIG. 23 is a diagram illustrating the synthesis of compound 112 and compound 113. [Figure 23-2] Same as above.

[0037] [Figure 24-1] FIG. 24 is a diagram illustrating the synthesis of compound 114. [Figure 24-2] Same as above.

[0038] [Figure 25] FIG. 25 is a diagram illustrating the synthesis of compound 115.

[0039] [Figure 26-1] FIG. 26 is a diagram illustrating the synthesis of compound 125. [Figure 26-2] Same as above.

[0040] [Figure 27-1] FIG. 27 is a diagram illustrating the synthesis of compound 126. [Figure 27-2] Same as above.

[0041] [Figure 28-1] FIG. 28 is a diagram illustrating the synthesis of compound 127. [Figure 28-2]Same as above.

[0042] [Figure 29-1] FIG. 29 is a diagram illustrating the synthesis of compound 138. [Figure 29-2] Same as above.

[0043] [Figure 30-1] FIG. 30 is a diagram illustrating the synthesis of compound 139 and compound 140. [Figure 30-2] Same as above.

[0044] [Figure 31-1] FIG. 31 is a diagram illustrating the synthesis of compound 146. [Figure 31-2] Same as above.

[0045] [Figure 32-1] FIG. 32 is a diagram illustrating the synthesis of compound 158. [Figure 32-2] Same as above.

[0046] [Figure 33-1] FIG. 33 is a diagram illustrating the synthesis of compound 159. [Figure 33-2] Same as above.

[0047] [Figure 34-1] FIG. 34 is a diagram illustrating the synthesis of compound 162. [Figure 34-2] Same as above.

[0048] [Figure 35-1] FIG. 35 is a diagram illustrating the synthesis of compound 163. [Figure 35-2] Same as above.

[0049] [Figure 36-1] FIG. 36 is a diagram illustrating the synthesis of compound 164 and compound 165. [Figure 36-2] Same as above.

[0050] [Figure 37-1] FIG. 37 is a diagram illustrating the synthesis of compound 166. [Figure 37-2] Same as above.

[0051] [Figure 38-1] FIG. 38 is a diagram illustrating the synthesis of Compound 167, Compound 168, Compound 169, and Compound 170. [Figure 38-2] Same as above.

[0052] [Figure 39-1] FIG. 39 is a diagram illustrating the synthesis of compound 173. [Figure 39-2] Same as above.

[0053] [Figure 40-1] FIG. 40 is a diagram illustrating the synthesis of compound 174. [Figure 40-2] Same as above.

[0054] [Figure 41-1] FIG. 41 is a diagram illustrating the synthesis of compound 178. [Figure 41-2] Same as above.

[0055] [Figure 42-1] FIG. 42 is a diagram illustrating the synthesis of compound 181. [Figure 42-2] Same as above.

[0056] [Figure 43-1] FIG. 43 is a diagram illustrating the synthesis of compound 182. [Figure 43-2] Same as above.

[0057] [Figure 44] FIG. 44 is a diagram illustrating the synthesis of compound 183.

[0058] [Figure 45] FIG. 45 is a diagram illustrating the synthesis of compound 184.

[0059] [Figure 46] FIG. 46 is a diagram illustrating the synthesis of compound 188.

[0060] [Figure 47-1] FIG. 47 is a diagram illustrating the synthesis of compound 219. [Figure 47-2] Same as above.

[0061] [Figure 48-1] FIG. 48 is a diagram illustrating the synthesis of compound 223. [Figure 48-2] Same as above.

[0062] [Figure 49-1] FIG. 49 is a diagram illustrating the synthesis of compound 224 and compound 225. [Figure 49-2] Same as above.

[0063] [Figure 50] FIG. 50 is a diagram illustrating the synthesis of compound 229 and compound 230.

[0064] [Figure 51] FIG. 51 is a diagram illustrating the synthesis of compound 231 and compound 232.

[0065] [Figure 52] FIG. 52 is a diagram illustrating the synthesis of compound 235.

[0066] [Figure 53] FIG. 53 is a diagram illustrating the synthesis of compound 236.

[0067] [Figure 54] FIG. 54 is a diagram illustrating the synthesis of compound 237 and compound 238.

[0068] [Figure 55]FIG. 55 is a diagram illustrating the synthesis of compound 241.

[0069] [Figure 56] FIG. 56 is a diagram illustrating the synthesis of compound 256.

[0070] [Figure 57-1] FIG. 57 is a diagram illustrating the synthesis of compound 226 and compound 227. [Figure 57-2] Same as above.

[0071] [Figure 58] FIG. 58 is a diagram illustrating the synthesis of compound 239 and compound 240.

[0072] [Figure 59-1] FIG. 59 is a diagram illustrating the synthesis of compound 257 and compound 258. [Figure 59-2] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0073] definition As used herein, "cancer" refers to diseases, disorders, and conditions involving abnormal cell growth that have the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, stomach cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer.

[0074] "Subject" refers to an animal, e.g., a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

[0075] As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder or at least one discernible symptom thereof. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to the inhibition of the progression of a disease or disorder, either physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treatment" or "treating" refers to the delay in the onset of a disease or disorder.

[0076] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent, for example, -CN is attached through a carbon atom.

[0077] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs as well as cases where they do not occur. Those of skill in the art will understand that with respect to groups containing one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0078] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6Alkyl is intended to be included.

[0079] As used herein, the term "alkenyl" refers to an unsaturated two-carbon group having a carbon-carbon double bond, designated herein as C2-alkenyl.

[0080] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl covalently linked to an oxygen atom.

[0081] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon, such as a straight-chain or branched-chain group of 1 to 8 carbon atoms, referred to herein as (C1-C8) alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, an "alkyl" is a straight-chain hydrocarbon. In some embodiments, an "alkyl" is a branched chain hydrocarbon.

[0082] As used herein, the term "alkynyl" refers to an unsaturated two-carbon group having a carbon-carbon triple bond, designated herein as C2-alkynyl.

[0083] As used herein, the term "aryl" refers to a carbomonocyclic, carbobicyclic, or other carbopolycyclic aromatic ring system having 5 to 14 ring atoms. The aryl group may be optionally fused to one or more rings selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl. The aryl groups of the present disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups include, but are not limited to, monocyclic aromatic ring systems in which the ring contains 6 carbon atoms, referred to herein as "C6-aryl."

[0084] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3 to 16 carbons or 3 to 8 carbons (referred to herein as "(C3-C8)cycloalkyl") derived from a cycloalkane. Exemplary cycloalkyls include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups can be optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl groups (saturated or partially unsaturated), aryl groups, or heterocyclyl groups to form bicycles, tetracycles, etc. The term "cycloalkyl" also includes bridged and spiro-fused ring structures, which may or may not contain heteroatoms.

[0085] As used herein, the term "halo" or "halogen" refers to -F, -Cl, -Br and / or -I.

[0086] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.

[0087] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or other polycyclic aromatic ring system containing one or more heteroatoms, e.g., 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be optionally substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls can also be fused to a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidylyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, referred to herein as "(C2-C5)heteroaryl," in which the ring contains 2 to 5 carbon atoms and 1 to 3 heteroatoms. In some embodiments, heteroaryls contain 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. In some embodiments, heteroaryls contain 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.

[0088] As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur, respectively. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Heterocycles can be optionally substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles is fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle. Heterocycles also include bridged and spiro-fused ring structures, which may or may not contain heteroatoms. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, Examples include oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl.In some embodiments, the heterocyclic ring contains 5 to 10 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S. In some embodiments, the heterocyclic ring contains 5 to 8 ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.

[0089] As used herein, the terms "hydroxy" and "hydroxyl" refer to --OH.

[0090] As used herein, the term "oxo" refers to a double bond to an oxygen atom (i.e., =0). For example, when two geminal groups on a carbon atom "come together to form oxo," a carbonyl (i.e., C=O) is formed.

[0091] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coating agents, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0092] As used herein, the term " pharmaceutically acceptable salt " refers to the salt form of the compound of the present disclosure, which salt is non-toxic.The pharmaceutically acceptable salt of the compound of the present disclosure includes those derived from suitable inorganic and organic acids and bases.The "free base" form of the compound does not contain, for example, ionically bonded salts.

[0093] The phrase "and pharmaceutically acceptable salts and deuterated derivatives thereof" is used interchangeably with "and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing" referring to one or more compounds or formulas of the present disclosure. These phrases are intended to encompass pharmaceutically acceptable salts of any one of the compounds mentioned, deuterated derivatives of any one of the compounds mentioned, and pharmaceutically acceptable salts of those deuterated derivatives.

[0094] Those skilled in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. Note that the disclosed amounts of the compound or a pharmaceutically acceptable salt thereof herein are based on their free base form.

[0095] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts: [Table 1]

[0096] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lanthanide ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Examples of suitable pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further, non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0097] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. Those skilled in the art can use naming conventions by systematic reduction of compound structures, or by CHEMDRAW TM (Cambridgesoft Corporation, USA) and other commercially available software readily allows the structure of a compound to be ascertained given a name.

[0098] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, e.g., geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated by "(±)" nomenclature, although one of skill in the art will recognize that the structure may exhibit chiral centers. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0099] The present disclosure includes within its scope all possible tautomers. Furthermore, the present disclosure includes within its scope both the individual tautomers and any mixtures thereof. Each compound disclosed herein includes within its scope all possible tautomeric forms. Furthermore, each compound disclosed herein includes within its scope both the individual tautomers and any mixtures thereof. With respect to the methods, uses, and compositions of the present application, reference to a compound(s) is intended to encompass each compound in its possible isomeric forms and mixtures thereof. Where a compound of the present application is depicted in one tautomeric form, the depicted structure is intended to encompass all other tautomeric forms. As a non-limiting example, the compounds depicted in Table 2 below are [ka] Although some embodiments of the present disclosure may include a pyrazole ring depicted as [ka] The compound includes compounds having the formula:

[0100] In some embodiments, the compounds are racemic mixtures of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds in which the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher. In other embodiments, the mixture of compounds has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the mixture of compounds has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or higher.

[0101] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) combining the resulting diastereomeric mixture with a chiral auxiliary, recrystallizing or chromatographically separating the enantiomeric mixture, and separating the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0102] Geometric isomers may also exist in the compounds of the present disclosure.The present disclosure encompasses various geometric isomers and their mixtures resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring.Substituents around a carbon-carbon double bond are designated as being in "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards.Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

[0103] Alternatively, substituents around a carbon-carbon double bond may be designated "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring is designated "cis" or "trans." The term "cis" represents substituents on the same face of the ring and the term "trans" represents substituents on opposite faces of the ring. A mixture of compounds in which substituents are located on both the same and opposite faces of the ring is designated "cis / trans."

[0104] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, deuterium ( 2 H) or tritium ( 3 H), or 13 C- or 14 Compounds having the present structure, except for the replacement of a carbon by a C-carbon atom, are within the scope of this disclosure. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents. compound

[0105] In some embodiments, the present disclosure provides compounds represented by formula (I), or tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof: [ka] and wherein in formula (I): A is a substituted or unsubstituted amide or a 5- to 12-membered aromatic ring, where the 5- to 12-membered aromatic ring optionally contains one or more heteroatoms and one, two, three, or four R A1 where each R is substituted as needed. A1 are independently hydrogen, -C(=O)R A2 , C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo, C1-C5 haloalkyl, C1-C5 alkoxy, and —CN, and wherein each R A2 are independently selected from hydrogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl; B is N, N + -O - and CR0, where R0 is selected from hydrogen, halo, —CN, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; R1 is selected from hydrogen, halo, -CN, and C1-C5 alkyl, or R1 and Y together with the carbon atom to which they are attached form a 5- to 6-membered aromatic ring, wherein the aromatic ring optionally contains 1 to 3 heteroatoms; X and Y are independently N, N + -O - or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; Q is absent or selected from -WC(R3)(R4)-, where R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, and halo, or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group or a 3- to 6-membered cycloalkyl, and W is absent or selected from alkylene, -C(=O)-R6-, -O-, -R6-O-, -O-R6-, -N(R7)-, -NH-C(=O)-, -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, where the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R B wherein each R6 is independently selected from C1-C5 alkylene, a 3- to 6-membered heterocycle, and a 3- to 6-membered cycloalkyl; each R7 is independently selected from hydrogen, oxo, and C1-C5 alkyl; and each R B is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl; L is absent or a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with oxo, C1-C5 haloalkyl, halo, deuterium, or C1-C5 alkyl, and one or more carbon atoms are optionally replaced with a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, or 4 R9, wherein each R8 is independently selected from hydrogen and C1-C5 alkyl, and each R9 is independently selected from hydrogen, oxo, and C1-C5 alkyl; and R 10 and R 11 is independently selected from hydrogen, halo, and C1-C5 alkyl; provided that the compound of formula (I) is: (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-4(3,5)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 1 S,1 3 R,Z)-2 1 H-12-oxa-3,6,10-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, or (1 1 S,1 3 R,Z)-2 1H-13-Oxa-3,6,11-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclotridecaphane-5,12-dione isn't it.

[0106] In some embodiments, compounds of Formula (II), Formula (III), Formula (IV), and Formula (V): [ka] [ka] Disclosed is a compound of formula (I) selected from:

[0107] In some embodiments, the compound of formula (II): [ka] Disclosed is a compound of formula (I) selected from, wherein in formula (II): A is a substituted or unsubstituted amide or a 5- to 12-membered aromatic ring, where the 5- to 12-membered aromatic ring optionally contains one or more heteroatoms and one, two, three, or four R A1 where each R is substituted as needed. A1 are independently hydrogen, -C(=O)R A2 , C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo, C1-C5 haloalkyl, C1-C5 alkoxy, and —CN, and wherein each R A2 are independently selected from hydrogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl; R0 is selected from hydrogen, halo, -CN, and C1-C5 alkyl; R1 is selected from hydrogen, halo, —CN, and C1-C5 alkyl; R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, and halo, or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group or a 3- to 6-membered cycloalkyl; X and Y are independently N or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; W is absent or selected from alkylene, -C(=O)-R6-, -O-, -R6-O-, -O-R6-, -N(R7)-, -NH-C(=O)-; -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R B wherein each R6 is independently selected from C1-C5 alkylene, 3- to 6-membered heterocycle, and 3- to 6-membered cycloalkyl, wherein each R7 is independently selected from hydrogen, oxo, and C1-C5 alkyl, and each R B is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl; and L is absent or a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with oxo, C1-C5 haloalkyl, halo, or C1-C5 alkyl, and one or more carbon atoms are optionally replaced with a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, or 4 R9, wherein each R8 is independently selected from hydrogen and C1-C5 alkyl, and each R9 is independently selected from hydrogen, oxo, and C1-C5 alkyl.

[0108] In some embodiments, the compound of formula (III): [ka] Disclosed is a compound of formula (I) selected from, wherein in formula (III): R0 is selected from hydrogen, halo, -CN, and C1-C5 alkyl; R1 is selected from hydrogen, halo, —CN, and C1-C5 alkyl; R3 and R4 are independently selected from hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, and halo, or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group, or a 3- to 6-membered cycloalkyl; X and Y are independently N or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; W is absent or selected from alkylene, -C(=O)-R6-, -O-, -R6-O-, -O-R6-, -N(R7)-, -NH-C(=O)-, -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R B wherein each R6 is independently selected from C1-C5 alkylene, 3- to 6-membered heterocycle, and 3- to 6-membered cycloalkyl; each R7 is independently selected from hydrogen, oxo, and C1-C5 alkyl; and each R B is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl; and L is absent or a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with oxo, C1-C5 haloalkyl, halo, or C1-C5 alkyl, and one or more carbon atoms are optionally replaced with a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, or 4 R9, wherein each R8 is independently selected from hydrogen and C1-C5 alkyl, and each R9 is independently selected from hydrogen, oxo, and C1-C5 alkyl.

[0109] In some embodiments, the compound of formula (IV): [ka] Disclosed is a compound of formula (I) selected from, wherein in formula (IV): R 10 and R 11 is independently selected from hydrogen, halo, and C1-C5 alkyl; A is a substituted or unsubstituted amide or a 5- to 12-membered aromatic ring, where the 5- to 12-membered aromatic ring optionally contains one or more heteroatoms and one, two, three, or four R A1 where each R is substituted as needed. A1 are independently hydrogen, -C(=O)-R A2 , C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo, C1-C5 haloalkyl, C1-C5 alkoxy, and —CN, and wherein each R A2 are independently selected from hydrogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C2-C5 alkenyl, and C2-C5 alkynyl; B is N, N + -O -and CR0, where R0 is selected from hydrogen, halo, —CN, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; R1 is selected from hydrogen, halo, -CN, and C1-C5 alkyl, or R1 and Y together with the carbon atom to which they are attached form a 5- to 6-membered aromatic ring, wherein the aromatic ring optionally contains 1 to 3 heteroatoms; X and Y are independently N, N + -O - or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; and L is a linker 1 to 10 carbon atoms in length, wherein one or more of the carbon atoms is optionally substituted with oxo, C1-C5 haloalkyl, halo, deuterium, or C1-C5 alkyl, and wherein one or more of the carbon atoms is selected from -C(=O)-R6-, -O-, -RO-, -OR6-, -N(R7)-, -NH-C(=O)-, -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3-membered and wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 R9, wherein each R6 is independently selected from hydrogen, C1-C5 alkylene, 3- to 6-membered heterocycle, and 3- to 6-membered cycloalkyl; each R7 is independently selected from hydrogen and C1-C5 alkyl; each R8 is independently selected from hydrogen and C1-C5 alkyl; and each R9 is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl.

[0110] In some embodiments, the compound of formula (V): [ka] Disclosed is a compound of formula (I) selected from, wherein in formula (V): R 10 and R 11 is independently selected from hydrogen, halo, and C1-C5 alkyl; B is N, N + -O - and CR0, where R0 is selected from hydrogen, halo, —CN, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; R1 is selected from hydrogen, halo, -CN, and C1-C5 alkyl, or R1 and Y together with the carbon atom to which they are attached form a 5- to 6-membered aromatic ring, wherein the aromatic ring optionally contains 1 to 3 heteroatoms; X and Y are independently N, N + -O - or CR2, where each R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, C1-C5 alkoxy, and C3-C5 cycloalkyl; and L is a linker 1 to 10 carbon atoms in length, wherein one or more of the carbon atoms is optionally substituted with oxo, C1-C5 haloalkyl, halo, deuterium, or C1-C5 alkyl, and one or more of the carbon atoms is selected from -C(=O)-R6-, -O-, -R6-O-, -O-R6-, -N(R7)-, -NH-C(=O)-, -C(=O)-N(R6)-, -S-, -S(=O)2-, -P(R7)2-, a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, alkenyl, -O-, -N(R8)-, a 3- to 6-membered cycloalkyl, or a 3- to 7-membered fused cycloalkyl. and wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 R9, wherein each R6 is independently selected from hydrogen, C1-C5 alkylene, a 3- to 6-membered heterocycle, and a 3- to 6-membered cycloalkyl; each R7 is independently selected from hydrogen and C1-C5 alkyl; each R8 is independently selected from hydrogen and C1-C5 alkyl; and each R9 is independently selected from hydrogen, oxo, halo, and C1-C5 alkyl.

[0111] In some embodiments, compounds of formula (I), or tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof: [ka] is disclosed, wherein in formula (I): A is a substituted or unsubstituted amide; B is selected from N and CR0, where R0 is selected from hydrogen, halo, and C1-C5 alkyl; R1 is hydrogen; X and Y are independently N or CR2, where each R2 is independently selected from hydrogen, haloalkyl, and C1-C5 alkyl; Q is absent or selected from -WC(R3)(R4)-, where R3 and R4 are independently selected from hydrogen, halo, C1-C5 alkyl, and deuterium, and W is absent or -O-; L is a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halo, deuterium, or C1-C5 alkyl, and one or more carbon atoms are optionally replaced with -O- or 3- to 6-membered cycloalkyl; and R 10 and R 11 is independently selected from hydrogen, halo, and C1-C5 alkyl.

[0112] In some embodiments, compounds of formula (I), or tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives thereof: [ka] is disclosed, wherein in formula (I): A is a substituted or unsubstituted amide; B is CR0, where R0 is hydrogen; X and Y are independently N or CR2, where R2 is independently selected from hydrogen, haloalkyl, C1-C5 alkyl, and C3-C5 cycloalkyl; Q is absent or -WC(R3)(R4)-, where W is -O-, and R3 and R4 are independently selected from hydrogen and C1-C5 alkyl; L is a linker 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with C1-C5 alkyl, and one or more carbon atoms are optionally replaced with -O-, 3- to 6-membered cycloalkyl; and R 10 and R 11 are hydrogen atoms.

[0113] In some embodiments, A is [ka] is.

[0114] In some embodiments, A is selected from a 5-membered aromatic ring and a 6-membered aromatic ring. In some embodiments, A is selected from a 5-membered aromatic ring and a 6-membered aromatic ring, wherein the 5-membered aromatic ring and the 6-membered aromatic ring contain one or more heteroatoms. In some embodiments, A is selected from a 5-membered aromatic ring, wherein the 5-membered aromatic ring contains one or more heteroatoms. In some embodiments, A is selected from a 5-membered aromatic ring, wherein the 5-membered aromatic ring contains one nitrogen atom. In some embodiments, A is selected from a 5-membered aromatic ring, wherein the 5-membered aromatic ring contains two nitrogen atoms. In some embodiments, A is selected from a 6-membered aromatic ring, wherein the 6-membered aromatic ring contains one or more heteroatoms. In some embodiments, A is selected from a 6-membered aromatic ring, wherein the 6-membered aromatic ring contains one nitrogen atom. In some embodiments, A is selected from a 6-membered aromatic ring, wherein the 6-membered aromatic ring contains two nitrogen atoms. In some embodiments, A is selected from a 6-membered aromatic ring, wherein the 6-membered aromatic ring comprises 3 nitrogen atoms. In some embodiments, A is selected from a 6-membered aromatic ring, wherein the 6-membered aromatic ring comprises 4 nitrogen atoms.

[0115] In some embodiments, A is [ka] is selected from.

[0116] In some embodiments, at least one R A1 is C1-C5 alkoxy. In some embodiments, at least one R A1 is hydrogen. In some embodiments, at least one R A1 is -C(=O)-RA2 In some embodiments, at least one R A1 is C1-C5 alkyl. In some embodiments, at least one R A1 is C2-C5 alkenyl. In some embodiments, at least one R A1 is C2-C5 alkynyl. In some embodiments, at least one R A1 is halo. In some embodiments, at least one R A1 is C1-C5 haloalkyl. In some embodiments, at least one R A1 is -CN.

[0117] In some embodiments, each R A1 is C1-C5 alkoxy. In some embodiments, each R A1 is hydrogen. In some embodiments, each R A1 is -C(=O)-R A2 In some embodiments, each R A1 is C1-C5 alkyl. In some embodiments, each R A1 is C2-C5 alkenyl. In some embodiments, each R A1 is C2-C5 alkynyl. In some embodiments, each R A1 is halo. In some embodiments, each R A1 is C1-C5 haloalkyl. In some embodiments, each R A1 is -CN.

[0118] In some embodiments, at least one R A2 is C1-C5 alkoxy. In some embodiments, at least one R A2 is C1-C5 alkyl. In some embodiments, at least one R A2 is hydrogen. In some embodiments, at least one R A2 is hydroxyl. In some embodiments, at least one R A2is C1-C5 haloalkyl. In some embodiments, at least one R A2 is a C2-C5 alkynyl.

[0119] In some embodiments, each R A2 is C1-C5 alkoxy. In some embodiments, each R A2 is C1-C5 alkyl. In some embodiments, each R A2 is hydrogen. In some embodiments, each R A2 is hydroxyl. In some embodiments, each R A2 is C1-C5 haloalkyl. In some embodiments, each R A2 is a C2-C5 alkynyl.

[0120] In some embodiments, B is N. In some embodiments, B is N + -O - In some embodiments, B is CR0.

[0121] In some embodiments, R0 is hydrogen. In some embodiments, R0 is halo. In some embodiments, R0 is -CN. In some embodiments, R0 is C1-C5 alkyl. In some embodiments, R0 is C1-C5 haloalkyl. In some embodiments, R0 is C1-C5 alkoxy. In some embodiments, R0 is C1-C5 cycloalkyl.

[0122] In some embodiments, R1 is hydrogen. In some embodiments, R1 is halo. In some embodiments, R1 is independently selected from F, Cl, I, and Br. In some embodiments, R1 is C1-C5 alkyl. In some embodiments, R1 is independently selected from -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0123] In some embodiments, R and Y together with the carbon atom to which they are attached form a 5- to 6-membered aromatic ring, which in some embodiments contains 1 to 3 heteroatoms.

[0124] In some embodiments, Y is CR2. In some embodiments, Y is N. In some embodiments, Y is N + -O - is.

[0125] In some embodiments, X is CR2. In some embodiments, X is N. In some embodiments, X is N + -O - is.

[0126] In some embodiments, X and Y are each CR2. In some embodiments, X and Y are each N.

[0127] In some embodiments, at least one R2 is independently hydrogen, [ka] , -CH3, -CH2-CH3, -CH(CH3)2, -CH2-CH2-CH3, [ka] In some embodiments, at least one R2 is selected from hydrogen, [ka] In some embodiments, at least one R2 is C1-C5 alkoxy. In some embodiments, at least one R2 is a halogen selected from F, Cl, Br, and I.

[0128] In some embodiments, each R2 is independently hydrogen, [ka] , -CH3, -CH2-CH3, -CH(CH3)2, -CH2-CH2-CH3, [ka] In some embodiments, each R2 is selected from hydrogen, [ka] In some embodiments, each R2 is a C1-C5 alkoxy. In some embodiments, each R2 is a halogen selected from F, Cl, Br, and I.

[0129] In some embodiments, Q is -WC(R3)(R4)-. In some embodiments, Q is absent.

[0130] In some embodiments, R3 and R4 are independently selected from hydrogen, deuterium, C1-C5 alkyl, C1-C5 haloalkyl, and halo. In some embodiments, R3 and R4, together with the carbon atom to which they are attached, form a carbonyl group or a 3- to 6-membered cycloalkyl. In some embodiments, R3 and R4 are each deuterium. In some embodiments, R3 and R4 are independently selected from halo. In some embodiments, R3 and R4 are independently selected from F, Cl, Br, and I. In some embodiments, R3 and R4 are independently selected from C1-C5 alkyl. In some embodiments, R3 and R4 are independently selected from -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0131] In some embodiments, W is absent. In some embodiments, W is independently selected from alkylene, —C(═O)—R—, —O—, —R—O—, —O—R—, —N(R)—, —NH—C(═O)—; —C(═O)—N(R)—, —S(═O)—, —P(R)—, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R B has been substituted as necessary.

[0132] In some embodiments, W is 1, 2, 3, or 4 R B is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle optionally substituted with

[0133] In some embodiments, W is independently: [ka] is selected from.

[0134] In some embodiments, at least one R6 is independently selected from -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and -CH2-CH2-CH2-CH2-CH2-.

[0135] In some embodiments, at least one R6 is independently: [ka] is selected from.

[0136] In some embodiments, each R6 is independently selected from -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and -CH2-CH2-CH2-CH2-CH2-.

[0137] In some embodiments, each R6 is independently: [ka] is selected from.

[0138] In some embodiments, at least one R B is independently selected from hydrogen, oxo, —CH, —CH—CH, —CH(CH) and —CH—CH—CH. In some embodiments, each R B are independently selected from hydrogen, oxo, —CH 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , and —CH 2 —CH 2 —CH 3 .

[0139] In some embodiments, L is absent. In some embodiments, L is a linker 1 to 10 carbon atoms in length. In some embodiments, L is a linker 1 to 5 carbon atoms in length. In some embodiments, one or more carbon atoms of L are optionally substituted with oxo, C1-C5 haloalkyl, halo, deuterium, or C1-C5 alkyl. In some embodiments, one or more carbon atoms of L are optionally substituted with C1-C5 alkyl, where the C1-C5 alkyl is independently selected from -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3. In some embodiments, one or more carbon atoms of L are optionally replaced by a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, an alkenyl, -O-, -S-, -S(=O)2-, -N(R8), a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, and wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted with 1, 2, 3, or 4 R9.

[0140] In some embodiments, at least one R8 is independently selected from hydrogen, -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0141] In some embodiments, each R8 is independently selected from hydrogen, -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0142] In some embodiments, at least one R9 is independently selected from hydrogen, oxo, -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0143] In some embodiments, each R9 is independently selected from hydrogen, oxo, -CH3, -CH2-CH3, -CH(CH3)2, and -CH2-CH2-CH3.

[0144] In some embodiments, L is a linker 1 to 5 carbon atoms in length, and wherein one or more of the carbon atoms is optionally replaced by a 3- to 6-membered bridged cycloalkyl, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle. In some embodiments, the 3- to 6-membered bridged cycloalkyl, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered heterocycle are independently [ka] [ka] is selected from.

[0145] In some embodiments, the 3- to 6-membered bridged cycloalkyl, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered heterocycle are independently: [ka] is selected from.

[0146] In some embodiments, L is [ka] [ka] [ka] [ka] is selected from.

[0147] In some embodiments, L is [ka] [ka] is selected from.

[0148] In some embodiments, provided herein is a compound selected from a compound listed in Table 2, or a tautomer, stereoisomer or mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, and deuterated derivative thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 The composition of the medicine

[0149] The pharmaceutical compositions of the present disclosure contain at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, together with at least one pharmaceutically acceptable carrier. These formulations include those suitable for oral, rectal, topical, buccal, and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most appropriate administration form in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound used.

[0150] Formulations suitable for oral administration may be presented as discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy, including combining at least one compound of the present disclosure as an active compound with a carrier or excipient, which may constitute one or more accessory ingredients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. The carrier may be solid or liquid, or both, and may be formulated with at least one compound described herein as an active compound in a unit-dose formulation, e.g., a tablet, which may contain from about 0.05 to about 95% by weight of at least one active compound. Other pharmacologically active substances, including other compounds, may also be present. The formulations of the present disclosure may be prepared by any of the well-known pharmacy techniques, which consist essentially of blending the ingredients.

[0151] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Pharmacologically administrable liquid compositions can be prepared, for example, by dissolving or dispersing at least one active compound of the present disclosure described herein and optional pharmaceutical adjuvants in an excipient, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form a solution or suspension. Generally, suitable formulations can be prepared by uniformly and intimately mixing at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, tablets can be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine at least one compound of the present disclosure in a free-flowing form, e.g., powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant(s). Molded tablets may be made by molding in a suitable machine at least one compound of the present disclosure in powder form moistened with an inert liquid diluent.

[0152] Formulations suitable for buccal (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and lozenges comprising at least one compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

[0153] Formulations of the present disclosure suitable for parenteral administration include sterile aqueous preparations of at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, that are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration can also be achieved by subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by combining at least one compound described herein with water and rendering the resulting solution sterile and isotonic with blood. Injectable compositions of the present disclosure can contain from about 0.1 to about 5% w / w of the active compound.

[0154] Formulations suitable for rectal administration are presented as unit-dose suppositories, which can be prepared by combining at least one compound described herein with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0155] Preparations suitable for topical application to the skin can take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers and excipients that can be used include petrolatum, lanolin, polyethylene glycol, alcohol, and combinations of two or more thereof. The active compound (i.e., at least one entity selected from the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing) is generally present in a concentration of about 0.1% to about 15% of the composition, for example, about 0.5 to about 2%.

[0156] The amount of active compound administered will depend on the subject being treated, the subject's weight, the mode of administration, and the judgment of the prescribing physician. For example, a dosing schedule may involve once-daily or twice-daily administration of an encapsulated compound at an approved dosage of about 1 μg to about 1000 mg. In another embodiment, intermittent administration of doses of the encapsulated compound (e.g., monthly or yearly) may be used. Encapsulation facilitates access to the site of action, allowing for simultaneous administration of active ingredients that could theoretically produce a synergistic effect. Following standard dosing regimens, a physician will be able to readily determine optimal dosages and modify the administration to achieve such dosages.

[0157] The therapeutically effective amount of the compound or composition disclosed herein can be determined by the therapeutic efficacy of the compound.However, dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the compound being used.In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to achieve maximum plasma concentration.For example, the preliminary dose determined according to animal test, and the dosage scale for human administration are carried out according to the practice recognized in the art.

[0158] Toxicity and therapeutic efficacy can be measured, for example, by LD 50 (a dose lethal to 50% of the population) and ED 50 The dose that is therapeutically effective in 50% of a population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio of toxic to therapeutic effects is the therapeutic index, which is defined as the ratio LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0159] The data obtained from cell culture assays or animal studies can be used to formulate a range of dosages for use in humans.For use in other animals, including humans, the therapeutically effective dosage achieved in one animal model can be converted using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following table (Table 3) for equivalent surface area dosage factors). [Table 3]

[0160] The dosage of such compounds is preferably ED 50 The circulating concentration range includes the range of 0.1 to 1.0 mg / kg of steroids, with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration used. Generally, the therapeutically effective amount can vary with the age, condition, and sex of the subject, as well as the severity of the medical condition in the subject. The dosage can be determined by a physician and, if necessary, adjusted to suit the observed therapeutic effect. Treatment method

[0161] In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, is administered to treat cancer in a subject in need thereof. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is small intestine cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is peritoneal cancer. In some embodiments, the cancer is brain cancer.

[0162] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a tautomer, stereoisomer, pharmaceutically acceptable salt, hydrate, or deuterated derivative of any of the foregoing, is administered as a pharmaceutical composition.

[0163] In some embodiments, the subject has previously been treated with an anti-cancer drug. In some embodiments, the anti-cancer drug is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or any combination of the foregoing. In some embodiments, the anti-cancer drug is enzalutamide.

[0164] In some embodiments, provided herein is the use of at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, for treating cancer. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is small intestine cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is peritoneal cancer. In some embodiments, the cancer is brain cancer.

[0165] In some embodiments, provided herein is the use of at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of cancer. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is small intestine cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is peritoneal cancer. In some embodiments, the cancer is brain cancer.

[0166] In some embodiments, provided herein is a method of treating a disease or condition in a subject that is at least partially modulated by CK2, comprising administering to a subject in need thereof at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing.

[0167] In some embodiments, at least one entity selected from the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with another therapeutic agent. The other therapeutic agent may provide additive or synergistic benefits compared to administration of the compound of the present disclosure alone. The therapeutic agent may be selected from, for example, hormones and hormone analogs; signal transduction pathway inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; antimetabolite neoplastic agents; antibiotic neoplastic agents; alkylating agents; antimicrotubule agents; platinum coordination complexes; aromatase inhibitors; and antimitotic agents.

[0168] In some embodiments, the therapeutic agent can be a hormone or hormone analog. In some embodiments, the therapeutic agent can be a signal transduction pathway inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase I inhibitor. In some embodiments, the therapeutic agent can be a topoisomerase II inhibitor. In some embodiments, the therapeutic agent can be an antimetabolite neoplastic agent. In some embodiments, the therapeutic agent can be an antibiotic neoplastic agent. In some embodiments, the therapeutic agent can be an alkylating agent. In some embodiments, the therapeutic agent can be an anti-microtubule agent. In some embodiments, the therapeutic agent can be a platinum coordination complex. In some embodiments, the therapeutic agent can be an aromatase inhibitor. In some embodiments, the therapeutic agent can be an anti-mitotic agent.

[0169] In some embodiments, the aromatase inhibitor may be selected from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane. In some embodiments, the aromatase inhibitor is anastrazole. In some embodiments, the aromatase inhibitor may be letrozole. In some embodiments, the aromatase inhibitor may be vorozole. In some embodiments, the aromatase inhibitor may be fadrozole. In some embodiments, the aromatase inhibitor may be exemestane. In some embodiments, the aromatase inhibitor may be formestane.

[0170] In some embodiments, the antimitotic agent can be selected from paclitaxel, docetaxel, and Abraxane. In some embodiments, the antimitotic agent can be paclitaxel. In some embodiments, the antimitotic agent can be docetaxel. In some embodiments, the antimitotic agent can be Abraxane.

[0171] In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with hormones and hormone analogs. In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with signal transduction pathway inhibitors. In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with antimetabolite neoplastic agents. In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with a topoisomerase I inhibitor. In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with a topoisomerase II inhibitor. In some embodiments, at least one entity selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V), and tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, may be administered in combination with an aromatase inhibitor. [Example]

[0172] The examples and preparations provided below further illustrate and exemplify the compounds disclosed herein and methods of preparing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations. General synthetic scheme

[0173] At least one entity selected from the compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), as well as tautomers, stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives of any of the foregoing, can be prepared according to the following schemes. The following schemes represent general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as those skilled in the art of synthetic chemistry can also prepare these compounds by a variety of other methods, for example, in a stepwise or modular manner.

[0174] As depicted in Scheme 1, displacement of the fluorine on the heteroaromatic ring 1-A with alkoxide 1-B affords ether 1-C, which undergoes palladium-catalyzed Buchwald amination with intermediate 1-D to form intermediate 1-E. Protection of the NH group of 1E with BocO anhydride affords 1-F, which undergoes TBAF-promoted deprotection to remove the silyl ether group. Thus, key intermediate 1-G, bearing a cyclopentan-3-ol functionality, is educt. Reaction of the hydroxyl group of 1-G with 4-nitrophenyl chloroformate results in the formation of activated carbonate 1-H. Deprotection of the Boc group of 1-H, followed by intramolecular cyclization, affords carbamate 1-J. Removal of the tert-butyl group on the pyrazolyl ring of 1-J generates the desired macrocycle.

[0175] As depicted in Scheme 2, Mitsunobu reaction of 2-A with the hydroxyl group of 1-B in the presence of cyanomethylenetributylphosphorane (CMBP) affords the aryl ether 2-B. Reaction of 2-B with 1-D under Buchwald amination conditions, followed by steps similar to those described in Scheme 1, affords the desired macrocycle.

[0176] As depicted in Scheme 3, Sonogashira coupling of 3-A with alkyne 3-B forms the coupled product 3-C, which undergoes Buchwald amination to provide intermediate 3-D. Hydrogenation of 3-D gives 3-E, which can be converted to the desired macrocyclic target following transformations similar to those described in Scheme 1 and Scheme 2. Abbreviation

[0177] The following abbreviations have the meanings set forth below: Ac2O: acetic anhydride BH3THF: Borane-tetrahydrofuran Boc: tert-butyloxycarbonyl protecting group Cs2CO3: Cesium carbonate CMBP: Cyanomethylenetributylphosphorane m-CPBA: meta-chloroperoxybenzoic acid (COCl)2: Oxalyl chloride CuI: Copper iodide DAST: Diethylaminosulfur trifluoride DCM: dichloromethane DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobutylaluminum hydride DIEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DME: Dimethoxyethane DMF: dimethylformamide DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine EA: Ethyl acetate EtOAc: ethyl acetate FA: Formic acid HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate KCN: Potassium cyanide LiAlH4: Lithium aluminum hydride LiBH4: Lithium borohydride LiCl: Lithium chloride LiOH: Lithium hydroxide MeOH: Methanol MeMgBr: Methyl magnesium bromide Ms2O: methanesulfonic anhydride NaBH4: sodium borohydride NH4F: Ammonium fluoride OTBS: tert-butyldimethylsilyl ether PA: Petroleum ether POBr3: phosphoryl bromide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) PPh3: Triphenylphosphine TBAF: Tetra-n-butylammonium fluoride t-BuOK: Potassium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran Pd(OH)2 / C: Palladium hydroxide supported on carbon Pd / C: Palladium supported on carbon Pt / C: platinum supported on carbon Py: pyridine Xantphos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0178] The compounds described in this experimental section were prepared from commercially available materials. The purity of all final compounds was analyzed by HPLC with detection at wavelengths of 214 nM and 254 nM. All final compounds exhibited greater than 95% purity. All final compounds were characterized by LC / MS and H-NMR. The following are representative examples of how the claimed molecules can be made, but one skilled in the art will understand that these compounds can be prepared by other synthetic methods. Preparation of Example Compounds Example 1: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 Synthesis of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 16) [ka]

[0179] Step 1: Preparation of 4-bromo-2-(difluoromethyl)pyridine 1-oxide To a solution of 4-bromo-2-(difluoromethyl)pyridine (5 g, 24.04 mmol, 1 equiv.) in DCM (180 mL) was added m-CPBA (29.28 g, 144.23 mmol, 85% purity, 6 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 12 hours. After the reaction was complete, the reaction solution was poured into aqueous sodium sulfite (180 mL) and extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography. The desired 4-bromo-2-(difluoromethyl)pyridine 1-oxide (4.84 g, 45.84% yield) was obtained as a white solid. LCMS: 223.9, 225.9 [M+H] + .

[0180] Step 2: Preparation of 4-bromo-6-(difluoromethyl)pyridin-2-ol A solution of 4-bromo-2-(difluoromethyl)pyridine 1-oxide (1.77 g, 7.90 mmol, 1 equiv.) in AcO (8 mL) was heated and stirred at 150° C. under a N atmosphere for 12 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting crude product was purified by column chromatography to give 4-bromo-6-(difluoromethyl)pyridin-2-ol (263 mg, 13.7% yield) as an orange oil. LCMS: 224.0, 226.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.75 (s, 1H), 7.46 (s, 1H), 6.73 - 6.31 (m, 1H) ppm.

[0181] Step 3: Preparation of tert-butyl (4-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate To a solution of 4-bromo-6-(difluoromethyl)pyridin-2-ol (260 mg, 1.16 mmol, 1 equiv.) and tert-butyl (4-hydroxybutyl)carbamate (263.60 mg, 1.39 mmol, 1.2 equiv.) in toluene (3 mL), 2-(tributyl-phosphanylidene)acetonitrile (CMBP, 560.28 mg, 2.32 mmol, 2 equiv.) was added, and the mixture was stirred at 80 °C for 12 h under a N atmosphere. The mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na SO , filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by Prep-TLC using PE:EA=3:1 to give tert-butyl (4-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate (196 mg, 40.59% yield) as an orange solid. LCMS: 339.0, 341.0 [M-56] + ; 1 H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.02 (s, 1H), 6.65 - 6.27 (m, 1 H), 4.69 - 4.50 (m, 1 H), 4.33 (t, J = 6.38 Hz, 2 H), 3.31 (br t, J = 6.57 Hz, 2H), 3.19 (br d, J = 6.25 Hz, 2H), 1.86 - 1.82 (m, 2H), 1.64 (br d, J = 7.63 Hz, 2H), 1.45 (s, 9H) ppm.

[0182] Step 4: Preparation of tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate A mixture of tert-butyl (4-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate (180 mg, 0.455 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (153.74 mg, 0.455 mmol, 1 equiv.), Pd(dba) (41.70 mg, 0.0455 mmol, 0.1 equiv.), Xantphos (39.53 mg, 0.0683 mmol, 0.15 equiv.), and CsCO (445.16 mg, 1.37 mmol, 3 equiv.) in dioxane (2 mL) was stirred at 80 °C under a N atmosphere for 6 h. The reaction solution was then cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by Prep-TLC (PE:EA = 3:1) to give tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate (251 mg, 80.32% yield) as an orange solid. LCMS: 652.4 [M+H] + .

[0183] Step 5: Preparation of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)butyl)carbamate (240 mg, 0.368 mmol, 1 equiv), DMAP (44.98 mg, 0.368 mmol, 1 equiv), and TEA (111.76 mg, 1.10 mmol, 153.73 μL, 3 equiv) in THF (8 mL) was added BocO (160.70 mg, 0.736 mmol, 169.16 μL, 2 equiv) slowly at 0 °C, and the mixture was allowed to warm to 25 °C, and stirring was maintained under a N atmosphere for 2 h. The reaction mixture was then diluted with water (8 mL) and extracted with EtOAc (8 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by Prep-TLC (PE:EA = 5:1) to give tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (260 mg, 89.22% yield) as a colorless oil. LCMS: 752.3 [M+H] + .

[0184] Step 6: Preparation of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (240 mg, 0.319 mmol, 1 equiv.) and TBAF (1 M, 319.14 μL, 1 equiv.) in THF (5 mL) was stirred at 25° C. under a N atmosphere for 12 hours. After the reaction was complete, the mixture was poured into HO (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (170 mg, 83.52% yield) as a colorless gum. LCMS: 638.3 [M+H] + .

[0185] Step 7: Preparation of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (160 mg, 0.251 mmol, 1 equiv.) in THF (8 mL), pyridine (99.22 mg, 1.25 mmol, 101.25 μL, 5 equiv.) and DMAP (15.32 mg, 0.125 mmol, 0.5 equiv.) were added at 0° C. under a N atmosphere, followed by the slow addition of a solution of 4-nitrophenyl chloroformate (151.70 mg, 0.753 mmol, 3 equiv.) in DCM (8 mL) at 0° C. After the addition was complete, the mixture was warmed to 25 °C and stirred under a N atmosphere for 12 hours. The mixture was then poured into HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EA = 1:1) to afford tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (160 mg, 79.44% yield) as a colorless gum. LCMS: 803.3 [M+H] + .

[0186] Step 8: Preparation of (1R,3S)-3-(5-((2-(4-aminobutoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(4-((tert-butoxycarbonyl)amino)butoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (160 mg, 0.199 mmol, 1 equiv) and TFA (0.2 mL) in DCM (1 mL) was stirred at 25 °C under a N atmosphere for 1 h. After completion of the reaction, the mixture was evaporated under reduced pressure to give (1R,3S)-3-(5-((2-(4-aminobutoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg, 83.27% yield) as a yellow gum. LCMS: 603.2 [M+H] + .

[0187] Step 9: Preparation of (11S,13R,Z)-21-(tert-butyl)-46-(difluoromethyl)-21H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-(4-aminobutoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg, 0.166 mmol, 1 equiv.) in THF (150 mL) was slowly added DIEA (214.47 mg, 1.66 mmol, 289.04 μL, 10 equiv.), and the mixture was stirred at 25° C. for 12 h under a N atmosphere. The reaction mixture was then poured into HO (200 mL) and extracted with EtOAc (200 mL × 3). The organic phase was washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EA=1:1) to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-46 -(difluoromethyl)-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (50 mg, 65.01% yield) was obtained as a yellow gum. LCMS: 464.4 [M+H] + .

[0188] Step 10: Preparation of (11S,13R,Z)-46-(difluoromethyl)-21H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 A solution of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (70 mg, 0.151 mmol, 1 equiv.) in HCOOH (5 mL) was stirred at 100 °C for 0.5 h under a N atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm, 5 mm; mobile phase: [water (FA)-ACN]; gradient: 23% to 53% B in 9 min) to give (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (16.42 mg, 26.15% yield) was obtained as a white solid. LCMS: 408.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.33 - 11.97 (m, 1H), 9.31 - 9.25 (m, 1H), 7.27 - 6.95 (m, 1H), 6.81 - 6.48 (m, 2H), 6.42 (s, 1H), 6.08 (s, 1H), 5.05 (br s, 1H), 4.23 - 3.87 (m, 2H), 3.21 - 2.97 (m, 2H), 2.91 - 2.78 (m, 1H), 2.20 - 1.91 (m, 2H), 1.80 (br d, J = 14.1 Hz, 4H), 1.57 (br d, J = 3.6 Hz, 2H), 1.41 - 1.07 (m, 2H) ppm. Example 2: (1 1 S,1 3 R,Z)-2 1 Synthesis of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 4) [ka]

[0189] Step 1: Preparation of tert-butyl (5-(4-bromopyridin-2-yl)pent-4-yn-1-yl)carbamate A mixture of 2,4-dibromopyridine (1.55 g, 6.55 mmol, 1 equiv.), tert-butyl pent-4-yn-1-ylcarbamate (1 g, 5.46 mmol, 0.83 equiv.), Pd(PPh3)4 (1.14 g, 0.982 mmol, 0.15 equiv.), CuI (374.15 mg, 1.96 mmol, 0.3 equiv.), and TEA (1.33 g, 13.10 mmol, 1.82 mL, 2 equiv.) in DMF (10 mL) was degassed and backfilled with N2 three times and stirred under a N2 atmosphere at 40 °C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through a short pad of Celite, and rinsed with ethyl acetate (30 mL). The filtrate was washed with water (30 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (5-(4-bromopyridin-2-yl)pent-4-yn-1-yl)carbamate (1.1 g, 49.52% yield) as a yellow solid. LCMS: 339.0, 341.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.35 (br s, 1H), 7.57 (br s, 1H), 7.39 (br d, J = 3.9 Hz, 1H), 4.71 (br s, 1H), 3.28 (q, J = 6.0 Hz, 2H), 2.50 (t, J = 7.0 Hz, 2H), 1.82 (quin, J = 6.9 Hz, 2H), 1.44 (s, 9H) ppm.

[0190] Step 2: Preparation of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pent-4-yn-1-yl)carbamate A mixture of tert-butyl (5-(4-bromopyridin-2-yl)pent-4-yn-1-yl)carbamate (300 mg, 0.884 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (298.54 mg, 0.884 mmol, 1 equiv.), Pd(dba) (80.98 mg, 0.0884 mmol, 0.1 equiv.), Xantphos (84.32 mg, 0.177 mmol, 0.2 equiv.), and CsCO (864.43 mg, 2.65 mmol, 3 equiv.) in dioxane (4 mL) was heated and stirred at 90 °C under a N atmosphere for 12 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through a short pad of Celite, and rinsed with dioxane (10 mL). The combined filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pent-4-yn-1-yl)carbamate (284 mg, 45.27% yield) as a yellow oil. LCMS: 596.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.05 (d, J = 5.6 Hz, 1H), 6.86 (br t, J = 5.1 Hz, 1H), 6.54 (s, 1H), 6.48 (dd, J = 2.1, 5.6 Hz, 1H), 5.99 (s, 1H), 4.35 - 4.28 (m, 1H), 3.04 - 2.95 (m, 3H), 2.40 - 2.34 (m, 2H), 2.26 - 2.19 (m, 1H), 1.95 - 1.89 (m, 1H), 1.81 - 1.74 (m, 2H), 1.66 - 1.58 (m, 4H), 1.47 (s, 9H), 1.37 (s, 9H), 0.83 (s, 9H), 0.03 (d, J = 3.1 Hz, 6H) ppm.

[0191] Step 3: Preparation of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pentyl)carbamate A mixture of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pent-4-yn-1-yl)carbamate (280 mg, 0.47 mmol, 1 equiv), Pd / C (28.00 mg, 0.0263 mmol, 10% purity), and Pd(OH) / C (28.00 mg, 0.020 mmol, 10% purity) in MeOH (4 mL) was degassed and backfilled with H three times, and then the mixture was stirred under an atmosphere of H at 60 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with methanol (15 mL), and the filtrate was concentrated to give tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pentyl)carbamate (250 mg, 88.69% yield) as a yellow oil, which was used directly in the next step. LCMS: 600.5 [M+H] + .

[0192] Step 4: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)pentyl)carbamate (200 mg, 0.333 mmol, 1 equiv) in THF (5 mL) was added BocO (145.52 mg, 0.667 mmol, 153.18 μL, 2 equiv), DMAP (40.73 mg, 0.333 mmol, 1 equiv) and TEA (101.20 mg, 1.00 mmol, 139.21 μL, 3 equiv). After stirring the mixture at 25 °C for 5 h under N atmosphere, additional amounts of BocO (145.52 mg, 0.667 mmol, 153.18 μL, 2 equiv.), DMAP (40.73 mg, 0.333 mmol, 1 equiv.), and TEA (101.20 mg, 1.00 mmol, 139.21 μL, 3 equiv.) were added, and the mixture was kept stirring at 25 °C under N atmosphere for another 12 h. Then, the mixture was diluted with HO (30 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, PE:EA = 1:1, R f =0.81) to afford tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (103 mg, 44.13% yield) as a colorless oil. LCMS: 586.4 [M+H] + .

[0193] Step 5: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (103 mg, 0.147 mmol, 1 equiv.) in THF (3 mL) was added TBAF (1 M, 0.74 mmol, 735.68 μL, 5 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 16 h. The mixture was then diluted with HO (30 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, PE:EA=1:1, R f =0.17) to afford tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (92 mg, 95.00% yield) as a colorless oil. LCMS: 586.4 [M+H] + .

[0194] Step 6: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (92 mg, 0.157 mmol, 1 equiv) in THF (2 mL) was added pyridine (62.12 mg, 0.785 mmol, 63.38 μL, 5 equiv) and DMAP (9.59 mg, 0.0785 mmol, 0.5 equiv), followed by a solution of 4-nitrophenyl carbonochloridate (94.97 mg, 0.471 mmol, 3 equiv) in DCM (2 mL) at 0° C. After completion of the addition, the mixture was warmed to 25° C. and stirred under a N atmosphere for 16 h. An additional amount of 4-nitrophenyl chloroformate (94.97 mg, 0.471 mmol, 3 equiv.) in a mixed solvent of DCM (1 mL) and THF (1 mL) was then added to the mixture. The mixture was kept stirring at 25° C. under N atmosphere for another 16 h. After the starting material was consumed, the mixture was diluted with H2O (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO2, PE:EA=1:1, R f =0.89) to afford tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (95 mg, 80.56% yield) as a yellow oil. LCMS: 751.5 [M+H] + .

[0195] Step 7: Preparation of (1R,3S)-3-(5-((2-(5-aminopentyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A mixture of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (75 mg, 0.10 mmol, 1 equiv.) and TFA in DCM (4 mL) was stirred at 30° C. under a N atmosphere for 12 hours. After completion of the reaction, the mixture was evaporated to afford (1R,3S)-3-(5-((2-(5-aminopentyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (55 mg, crude) as a yellow oil as the crude TFA salt, which was used directly in the next step. LCMS: 551.3 [M+H] + .

[0196] Step 8: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 Preparation of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-(5-aminopentyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (55 mg, 0.1 mmol, 1 equiv.) in THF (50 mL) was added DIPEA (64.54 mg, 0.50 mmol, 86.99 μL, 5 equiv.) at 0° C. The mixture was then warmed to 30° C. and stirred under N atmosphere for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, PE:EA=0:1, R f =0.22) to give 35 mg of the desired (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one was obtained. LCMS: 412.4 [M+H] + .

[0197] Step 9: (1 1 S,1 3 R,Z)-2 1 Preparation of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 A solution of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (80 mg, 0.194 mmol, 1 equiv.) in HCOOH (4 mL) was stirred at 100 °C under N atmosphere for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm; mobile phase: [water (FA)-ACN]; gradient: 5% to 35% B in 10 min) to give (1 1 S,1 3 R,Z)-2 1 H-12-Oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (23.14 mg, 32.82% yield) was obtained as a white solid. LCMS: 356.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.79 (m, 1H), 8.18 (s, 1H), 8.01 (d, J = 5.75 Hz, 1H), 7.35 - 6.92 (m, 1H), 6.72 - 6.81 (m, 1H), 6.59 (dd, J = 5.63, 2.13 Hz, 1H), 5.94 (s, 1 H), 5.14 - 4.90 (m, 1H), 2.97 - 2.90 (m, 1H), 2.79 - 2.72 (m, 1H), 2.63 - 2.56 (m, 2H), 2.05 - 1.99 (m, 1H), 1.86 - 1.57 (m, 7H), 1.48 - 1.22 (m, 5H) ppm. Example 3: (1 1 S,1 3 R,Z)-9-methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 8), (1 1 S,1 3 R,9S,Z)-9-methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 9) and (1 1 S,1 3 R,9R,Z)-9-methyl-2 1 Synthesis of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 10) [ka] Synthetic Route 1:

[0198] Step 1: Preparation of 4-aminopentan-1-ol A mixture of 5-hydroxypentan-2-one (5 g, 48.96 mmol, 4.97 mL, 1 equiv.), NH3.HO (46.37 g, 489.57 mmol, 50.96 mL, 37% purity, 10 equiv.), and Raney-Ni (0.5 g, 5.84 mmol) in 100 mL of 50% aqueous ethanol was degassed and backfilled with H2 three times, and the mixture was stirred under an atmosphere of H2 (50 Psi) at 80 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with ethanol, and the filtrate was concentrated to give 4-aminopentan-1-ol (4.7 g, 93.06% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 3.93–3.48 (m, 2H), 3.21–3.10 (m, 2H), 3.08–2.80 (m, 1H), 1.82–1.58 (m, 2H), 1.29–0.77 (m, 3H) ppm.

[0199] Step 2: Preparation of tert-butyl (5-hydroxypentan-2-yl)carbamate To a solution of 4-aminopentan-1-ol (500 mg, 4.85 mmol, 1 equiv.) in DCM (6 mL) was added TEA (1.47 g, 14.54 mmol, 2.02 mL, 3 equiv.) and BocO (3.17 g, 14.54 mmol, 3 equiv.) at 0 °C, and the mixture was warmed to 25 °C and maintained stirring under a N atmosphere for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was treated with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated. The resulting residue was purified by prep-TLC (SiO 2 , PE:EA=3:1, R f =0.6) to give tert-butyl (5-hydroxypentan-2-yl)carbamate (450 mg, 45.67% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 4.38 - 4.26 (m, 1H), 4.07 (t, J = 6.5 Hz, 2H), 3.68 (br t, J = 5.8 Hz, 2H), 1.78 - 1.67 (m, 2H), 1.61 (br d, J = 5.1 Hz, 2H), 1.49 (s, 9H), 1.15 - 1.13 (m, 3H) ppm.

[0200] Step 3: Preparation of tert-butyl (5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate To a solution of tert-butyl (5-hydroxypentan-2-yl)carbamate (350 mg, 1.72 mmol, 1 equiv.) in THF (6 mL) was added 4-bromo-2-fluoro-pyridine (333.31 mg, 1.89 mmol, 1.1 equiv.) and t-BuOK (289.81 mg, 2.58 mmol, 1.5 equiv.) at 0 °C, and the mixture was stirred at 25 °C for 12 h under a N atmosphere. After the starting material was consumed, the volatiles were evaporated under reduced pressure. The resulting residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (20 mL), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate (200 mg, 32.33% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 8.05–7.90 (m, 1H), 7.02 (dd, J = 1.5, 5.5 Hz, 1H), 6.95 (s, 1H), 4.45–4.33 (m, 1H), 4.30 (t, J = 6.3 Hz, 2H), 4.12–4.03 (m, 1H), 3.75–3.63 (m, 1H), 1.87–1.77 (m, 2H), 1.74–1.67 (m, 1H), 1.45 (s, 9H), 1.17–1.14 (m, 3H) ppm.

[0201] Step 4: Preparation of tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate A mixture of tert-butyl (5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate (200 mg, 0.557 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (187.93 mg, 0.557 mol, 1 equiv.), Pd(dba) (50.98 mg, 0.0557 mmol, 0.1 equiv.), Xantphos (53.08 mg, 0.111 mmol, 0.2 equiv.), and CsCO (544.15 mg, 1.67 mmol, 3 equiv.) in dioxane (5 mL) was heated and stirred at 90 °C for 12 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature, filtered through a short pad of Celite, and rinsed with dioxane (10 mL), and the filtrate was concentrated. The crude product was purified by column chromatography to give tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate (250 mg, 72.91% yield) as a yellow oil. LCMS: 616.6 [M + H] + ; 1H NMR (400 MHz, chloroform-d) δ 7.92 - 7.76 (m, 1H), 6.39 - 6.19 (m, 1H), 6.12 - 5.94 (m, 2H), 4.48 - 4.36 (m, 1H), 4.35 - 4.30 (m, 1H), 4.29 - 4.21 (m, 2H), 3.80 - 3.60 (m, 1H), 3.16 - 2.97 (m, 1H), 2.40 - 2.25 (m, 1H), 2.03 - 1.95 (m, 1H), 1.90 - 1.86 (m, 1H), 1.85 - 1.76 (m, 4H), 1.75 - 1.64 (m, 4H), 1.58 (s, 9H), 1.44 (s, 9H), 1.15 (d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.06 (d, J = 2.8 Hz, 6H) ppm.

[0202] Step 5: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate (250 mg, 0.406 mmol, 1 equiv.) in THF (5 mL), BocO (177.17 mg, 0.812 mmol, 186.50 μL, 2 equiv.), TEA (123.22 mg, 1.22 mmol, 169.49 μL, 3 equiv.), and DMAP (49.59 mg, 0.406 mmol, 1 equiv.) were added at 0° C., and the mixture was slowly warmed to 25° C. and kept stirring under N atmosphere for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (230 mg, 79.14% yield) as a yellow oil. LCMS: 716.6 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.00 (br d, J = 6.0 Hz, 1H), 6.91 - 6.83 (m, 1H), 6.83 - 6.77 (m, 1H), 6.03 - 5.97 (m, 1H), 4.40 - 4.33 (m, 1H), 4.28 (br s, 2H), 3.77 - 3.62 (m, 1H), 3.16 - 3.02 (m, 1H), 2.42 - 2.29 (m, 1H), 1.89 - 1.77 (m, 4H), 1.71 - 1.55 (m, 6H), 1.46 (s, 9H), 1.46 - 1.43 (m, 18H), 1.17 - 1.11 (m, 3H), 0.90 - 0.88 (m, 9H), 0.07 (d, J = 2.3 Hz, 6H) ppm.

[0203] Step 6: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (230 mg, 0.321 mmol, 1 equiv) and TBAF (1 M, 1.61 mL, 5 equiv) in THF (8 mL) was stirred at 25° C. under a N atmosphere for 12 h, and then the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (135 mg, 69.84% yield) as a yellow oil. LCMS: 602.5 [M + H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 5.9 Hz, 1H), 6.87 - 6.82 (m, 1H), 6.80 - 6.76 (m, 1H), 5.96 (d, J = 2.3 Hz, 1H), 5.31 (s, 1H), 4.39 (br s, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.77 - 3.63 (m, 1H), 3.38 - 3.21 (m, 1H), 2.22 - 2.08 (m, 2H), 2.00 - 1.88 (m, 2H), 1.82 - 1.77 (m, 2H), 1.63 - 1.55 (m, 4H), 1.46 (s, 9H), 1.45 (br s, 9H), 1.44 (s, 9H), 1.15 (d, J = 6.6 Hz, 3H) ppm.

[0204] Step 7: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (135 mg, 0.224 mmol, 1 equiv) in THF (3 mL) was added Py (88.72 mg, 1.12 mmol, 90.54 μL, 5 equiv) and DMAP (13.70 mg, 0.112 mmol, 0.5 equiv), followed by the addition of a solution of 4-nitrophenyl carbonochloridate (135.65 mg, 0.673 mmol, 3 equiv) in DCM (3 mL) at 0° C. After the mixture was stirred at 25°C under N2 atmosphere for 5 hours, an additional solution of 4-nitrophenyl carbonochloridate (135.65 mg, 0.673 mmol, 3 equiv) in DCM (3 mL) was added. The mixture was kept stirring at 25°C under N2 atmosphere for another 12 hours, and the volatiles were evaporated. The resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (100 mg) as a white solid. LCMS: 767.5 [M + H] + .

[0205] Step 8: Preparation of (1R,3S)-3-(5-((2-((4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A mixture of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (80 mg, 0.104 mmol, 1 equiv) and TFA (614.00 mg, 5.38 mmol, 400.00 μL, 51.62 equiv) in THF (2 mL) was stirred at 30° C. for 12 hours under a N atmosphere. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 mm; mobile phase: [water (TFA)-ACN]; gradient: 18% to 48% B over 9 min) to give (1R,3S)-3-(5-((2-((4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (35 mg, 59.21% yield) as a colorless oil. LCMS: 567.4 [M + H] + .

[0206] Step 9: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-((4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (35 mg, 0.0618 mmol, 1 equiv.) in THF (30 mL) was added DIPEA (39.91 mg, 0.309 mmol, 53.79 μL, 5 equiv.) and the mixture was stirred at 30° C. under N atmosphere for 24 h. The mixture was then concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO, DCM:MeOH=10:1, Rf=0.4) to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (26 mg, 98.46% yield) was obtained as a colorless oil. LCMS: 428.3 [M + H] + .

[0207] Step 10: (1 1 S,1 3 R,Z)-9-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 8) (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9-methyl-2 1A mixture of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (26 mg, 0.0608 mmol, 1 equiv.) in formic acid (3 mL) was stirred at 100 °C for 0.5 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 mm; mobile phase: [water (FA)-ACN]; gradient: 8% to 38% B in 7 min) to give (1 1 S,1 3 R,Z)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 8) (12 mg, 45.09% yield) was obtained as a white solid. LCMS: 372.2 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 7.74 (d, J = 5.8 Hz, 1H), 6.47 - 6.37 (m, 2H), 6.34 (s, 1H), 6.11 - 5.98 (m, 1H), 5.19 - 4.99 (m, 1H), 4.21 - 3.97 (m, 2H), 3.71 - 3.49 (m, 1H), 3.28 - 3.20 (m, 1H), 2.44 - 2.33 (m, 1H), 2.07 - 1.95 (m, 1H), 1.88 - 1.66 (m, 6H), 1.65 - 1.45 (m, 2H), 1.12 - 0.96 (m, 3H) ppm.

[0208] Step 11: (1 1 S,1 3 R,9S,Z)-9-methyl-2 1H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one and (1 1 S,1 3 R,9R,Z)-9-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-9-methyl-2 1 The racemic mixture of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (8 mg, 6.04 μmol, 90.024% purity) was further separated by chiral SFC (conditions: column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 mm); mobile phase: [CO2-ACN / MeOH (0.1% NH3 / H2O)]; B%: 45%, isocratic elution mode) to give (1 1 S,1 3 R,9S,Z)-9-methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (2.49 mg, 44.02% yield) as a white solid, and (1 1 S,1 3 R,9R,Z)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (2.52 mg, 44.30% yield) was obtained as a white solid. (1 1 S,1 3 R,9S,Z)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one: LCMS: 372.2 [M + H]+ ; 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.91 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 6.95 (br d, J = 8.5 Hz, 1H), 6.42 (d, J = 5.6 Hz, 1H), 6.32 (s, 1H), 5.99 (s, 1H), 5.01 (br s, 1H), 4.03 (br t, J = 6.6 Hz, 2H), 3.71 - 3.56 (m, 1H), 3.23 - 3.15 (m, 1H), 2.41 - 2.34 (m, 1H), 2.03 - 1.98 (m, 1H), 1.85 - 1.68 (m, 6H), 1.53 - 1.44 (m, 2H), 1.23 (br s, 3H) ppm. (1 1 S,1 3 R,9R,Z)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one: LCMS: 372.2 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.92 (br s, 1H), 7.73 (br d, J = 5.3 Hz, 1H), 6.86 - 6.58 (m, 1H), 6.42 (br d, J = 5.1 Hz, 1H), 6.37 (s, 1H), 6.20 - 5.96 (m, 1H), 5.23 - 4.89 (m, 1H), 4.16 - 3.94 (m, 2H), 3.50 (br d, J = 7.9 Hz, 1H), 3.20 - 3.14 (m, 1H), 2.21 - 2.09 (m, 1H), 2.03 - 1.96 (m, 1H), 1.90 - 1.65 (m, 6H), 1.63 (br d, J = 6.3 Hz, 2H), 1.23 (br s, 3H) ppm. Chiral synthesis route 2:

[0209] Step 1: Preparation of (S)-tert-butyl 2-methyl-5-oxopyrrolidine-1-carboxylate To a solution of (S)-5-methylpyrrolidin-2-one (20 g, 201.75 mmol, 1 equiv.) in acetonitrile (400 mL), BocO (52.84 g, 242.10 mmol, 1.2 equiv.) and DMAP (4.93 g, 40.35 mmol, 0.2 equiv.) were added at room temperature, and the mixture was stirred at 25° C. for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (S)-tert-butyl 2-methyl-5-oxopyrrolidine-1-carboxylate (40 g, 99.5% yield) as a colorless oil. LCMS: 421.3 [M+H] + .

[0210] Step 2: Preparation of methyl (S)-4-((tert-butoxycarbonyl)amino)pentanoate To a solution of (S)-tert-butyl 2-methyl-5-oxopyrrolidine-1-carboxylate (40 g, 200.76 mmol, 1 equiv.) in a mixed solvent of DCM (600 mL) and MeOH (120 mL), potassium carbonate (33.29 g, 240.91 mmol, 1.2 equiv.) was added, and the mixture was stirred at 25° C. for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 800 mL of water and extracted with DCM (500 mL × 2). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 46 g of methyl (S)-4-((tert-butoxycarbonyl)amino)pentanoate as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 4.43–4.31 (m, 1H), 3.67 (s, 3H), 2.37 (t, J = 7.6 Hz, 2H), 1.84–1.74 (m, 1H), 1.71–1.64 (m, 1H), 1.43 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H) ppm.

[0211] Step 3: Preparation of tert-butyl (S)-(5-hydroxypentan-2-yl)carbamate To a solution of (S)-methyl 4-((tert-butoxycarbonyl)amino)pentanoate (20 g, 86.47 mmol, 1 equiv.) in 200 mL of THF was added LiBH (4 M in THF, 64.85 mL, 3 equiv.) dropwise at 0 °C under a N atmosphere. After the addition was complete, the resulting mixture was stirred at 50 °C for 3 h under a N atmosphere. The mixture was then cooled to room temperature and carefully quenched with saturated aqueous NH Cl (1 M, 300 mL). The mixture was extracted with EtOAc (300 mL × 2). The combined organic layers were dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (S)-(5-hydroxypentan-2-yl)carbamate (17.5 g, 99.6% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 4.48–4.32 (m, 1H), 3.73–3.62 (m, 3H), 1.89–1.80 (m, 2H), 1.66–1.56 (m, 2H), 1.44 (s, 8H), 1.13 (d, J = 6.6 Hz, 3H) ppm.

[0212] Step 4: Preparation of tert-butyl (S)-(5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate To a solution of (S)-tert-butyl(5-hydroxypentan-2-yl)carbamate (17.5 g, 86.09 mmol, 1 equiv.) and 4-bromo-2-fluoro-pyridine (15.15 g, 86.09 mmol, 1 equiv.) in THF (350 mL) was added t-BuOK (9.66 g, 86.09 mmol, 1 equiv.) portionwise at 0 °C under a N atmosphere. After completion of the addition, the mixture was warmed to 25 °C and stirred under a N atmosphere for 2 h. The mixture was then quenched with saturated aqueous NH Cl (400 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to give tert-butyl (S)-(5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate (26 g, 84.1% yield) as a yellow oil. LCMS: 359.0, 361.0 [M+H] + .

[0213] Step 5: Preparation of tert-butyl ((S)-5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate (S)-tert-Butyl (5-((4-bromopyridin-2-yl)oxy)pentan-2-yl)carbamate (10.00 g, 27.84 mmol, 1 equivalent), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (10.00 g, 29.62 mmol), A mixture of Pd(dba) (2.55 g, 2.78 mmol, 0.1 equiv.), Xantphos (3.22 g, 5.57 mmol, 0.2 equiv.), Pd(dba) (2.55 g, 2.78 mmol, 0.1 equiv.), and CsCO (18.14 g, 55.67 mmol, 2 equiv.) in dioxane (200 mL) was degassed and backfilled with N three times and stirred at 90 °C under a N atmosphere for 4 h. After completion of the reaction, the mixture was cooled to room temperature. The mixture was filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The combined filtrates were concentrated in vacuo. The resulting residue was purified by column chromatography to give tert-butyl ((S)-5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate (14.37 g, 83.6% yield) as a yellow oil. LCMS: 616.6 [M+H] + .

[0214] Step 6: Preparation of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl ((S)-5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentan-2-yl)carbamate (14.37 g, 23.33 mmol, 1 equiv) in DCM (280 mL) were added DMAP (1.43 g, 11.67 mmol, 0.5 equiv) and BocO (7.64 g, 35.00 mmol, 1.5 equiv), and the mixture was stirred at 25° C. under a N atmosphere for 12 hours. After completion of the reaction, the mixture was concentrated in vacuo. The resulting residue was purified by column chromatography to give tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (15.14 g, 90.6% yield) as a yellow oil. LCMS: 716.4 [M+H] + .

[0215] Step 7: Preparation of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (15.14 g, 21.14 mmol, 1 equiv.) in THF (300 mL) was added TBAF (1 M, 63.43 mL, 3 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 12 h. The mixture was then diluted with HO (300 mL) and extracted with EtOAc (400 mL×2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give 11.7 g of crude tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate as a yellow oil, which was used in the next step without further purification. LCMS: 602.5 [M+H] + .

[0216] Step 8: Preparation of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (11.7 g, 19.44 mmol, 1 equiv.), 4-nitrophenyl carbonochloridate (11.76 g, 58.33 mmol, 3 equiv.), and DMAP (2.38 g, 19.44 mmol, 1 equiv.) in DCM (300 mL) was added pyridine (9.23 g, 116.65 mmol, 6 equiv.) dropwise at 25° C. After completion of the addition, the reaction mixture was kept stirring at this temperature under a N atmosphere for 0.5 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to give tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (14 g, 93.9% yield) as a pale yellow oil. LCMS: 767.5 [M+H] + .

[0217] Step 9: Preparation of (1R,3S)-3-(5-((2-(((S)-4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of tert-butyl (2-(((S)-4-((tert-butoxycarbonyl)amino)pentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (14.00 g, 18.26 mmol, 1 equiv) in DCM (200 mL) was added TFA (85.81 g, 752.60 mmol, 41.23 equiv) and the mixture was stirred at 25° C. under a N atmosphere for 12 h. After completion of the reaction, the mixture was concentrated in vacuo to give 10.3 g of crude (1R,3S)-3-(5-((2-(((S)-4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl)carbonate as a yellow oil, which was used in the next step without further purification. LCMS: 567.3 [M+H] + .

[0218] Step 10: (1 1 S,1 3 R,9S,Z)-2 1 -(tert-butyl)-9-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-(((S)-4-aminopentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (10.3 g, 17.65 mmol, 1 equiv.) in THF (5 L) was added DIEA (11.4 g, 88.23 mmol, 5 equiv.), and the mixture was stirred at 50° C. under N atmosphere for 12 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with HO (200 mL) and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to give (1 1 S,1 3 R,9S,Z)-2 1 -(tert-butyl)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (6.4 g, 84.8% yield) was obtained as a white solid. LCMS: 428.4 [M+H] + .

[0219] Step 11: (1 1 S,1 3 R,9S,Z)-9-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 9) (1 1 S,1 3 R,9S,Z)-2 1 -(tert-butyl)-9-methyl-2 1A mixture of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (5.0 g, 11.69 mmol, 1 equiv.) and formic acid (100 mL) was stirred at 100 °C under a N atmosphere for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250 × 70 × 10 μm; mobile phase: [hexane-EtOH]; gradient: 5% to 45% B in 15 min) to give (1 1 S,1 3 R,9S,Z)-9-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (4.27 g, 94.2% yield) was obtained as an off-white solid. LCMS: 372.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.29 - 11.82 (m, 1H), 8.91 (s, 1H), 7.74 (d, J = 5.8 Hz, 1H), 6.95 (br d, J = 8.5 Hz, 1H), 6.42 (dd, J = 1.8, 5.7 Hz, 1H), 6.32 (s, 1H), 5.99 (s, 1H), 5.01 (br s, 1H), 4.10 - 3.91 (m, 2H), 3.71 - 3.54 (m, 1H), 3.22 - 3.16 (m, 1H), 2.39 (dt, J = 5.4, 10.2 Hz, 1H), 2.12 - 1.97 (m, 1H), 1.82 - 1.69 (m, 6H), 1.61 - 1.43 (m, 2H), 1.08 - 0.98 (m, 3H) ppm. Example 4: (1 1 S,1 3 R,Z)-9,9-dimethyl-2 1Synthesis of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 13) [ka]

[0220] Step 1: Preparation of 4-methyl-4-nitropentan-1-ol To a mixture of methyl 4-methyl-4-nitropentanoate (500 mg, 2.85 mmol, 1 equiv.) and LiCl (240 mg, 5.71 mmol, 2 equiv.) in THF (5 mL) and EtOH (5 mL) was added LiBH (2 M, 2.85 mL, 2 equiv.) at 0 °C under a N atmosphere. The mixture was then warmed to 20 °C and stirred under a N atmosphere for 4 h. After completion of the reaction, the mixture was quenched with NH Cl (aq, 20 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure to give 4-methyl-4-nitropentan-1-ol (400 mg, 95.23% yield) as a colorless oil. 1 H NMR (400 MHz, methanol-d4) δ 3.54 (t, J = 6.4 Hz, 2H), 2.00 - 1.92 (m, 2H), 1.58 (s, 6H), 1.51 - 1.42 (m, 2H) ppm.

[0221] Step 2: Preparation of 4-amino-4-methyl-pentan-1-ol A mixture of 4-methyl-4-nitropentan-1-ol (250 mg, 1.70 mmol, 1 equiv.) and Raney-Ni (25.00 mg, 0.058 mmol, 20% purity) in MeOH (10 mL) was degassed and backfilled with H three times and stirred at 60 °C under an atmosphere of H (15 psi) for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The solid was filtered off, rinsed with MeOH (15 mL), and the filtrate was concentrated to give 4-amino-4-methyl-pentan-1-ol (199 mg, 99.97% yield), which was used in the next step without further purification.

[0222] Step 3: Preparation of tert-butyl (5-hydroxy-2-methylpentan-2-yl)carbamate A mixture of 4-amino-4-methyl-pentan-1-ol (199 mg, 1.70 mmol, 1 equiv.), NaHCO (570.61 mg, 6.79 mmol, 4 equiv.), and BocO (555.91 mg, 2.55 mmol, 1.5 equiv.) in THF (5 mL) was stirred at 25 °C under a N atmosphere for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired tert-butyl (5-hydroxy-2-methylpentan-2-yl)carbamate (500 mg, crude) was obtained as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 4.58–4.31 (m, 1H), 3.65 (t, J = 6.4 Hz, 2H), 1.76–1.69 (m, 2H), 1.62–1.57 (m, 2H), 1.43 (s, 9H), 1.27 (s, 6H) ppm.

[0223] Step 4: Preparation of tert-butyl (5-((4-bromopyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate To a solution of tert-butyl (5-hydroxy-2-methylpentan-2-yl)carbamate (500 mg, 2.30 mmol, 1 equiv.) in THF (10 mL) was added 4-bromo-2-fluoro-pyridine (404.93 mg, 2.30 mmol, 1 equiv.) and t-BuOK (387.29 mg, 3.45 mmol, 1.5 equiv.) at 0 °C, and the mixture was warmed to 25 °C and stirred under a N atmosphere for 12 h. After completion of the reaction, the mixture was filtered, rinsed with THF (10 mL), and the filtrate was concentrated. The resulting residue was purified by column chromatography to afford tert-butyl (5-((4-bromopyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate (320 mg, 37.26% yield) as a colorless oil. LCMS: 373.2 / 375.2 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 5.5 Hz, 1H), 7.03 (dd, J = 1.6, 5.6 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 4.39 (br s, 1H), 4.30 (br t, J = 5.7 Hz, 2H), 1.78 (br d, J = 3.3 Hz, 3H), 1.70 - 1.66 (m, 4H), 1.49 (s, 9H), 1.29 (s, 3H) ppm.

[0224] Step 5: Preparation of tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate A mixture of tert-butyl (5-((4-bromopyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate (250 mg, 0.67 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (226.08 mg, 0.67 mmol, 1 equiv.), Pd(dba) (61.33 mg, 0.067 mmol, 0.1 equiv.), Xantphos (63.85 mg, 0.134 mmol, 0.2 equiv.), and CsCO (654.63 mg, 2.01 mmol, 3 equiv.) in dioxane (6 mL) was heated and stirred at 90 °C for 12 h under a N atmosphere. The reaction mixture was then cooled to room temperature. The mixture was filtered through a short pad of Celite, rinsed with dioxane (10 mL), and the filtrate was concentrated. The resulting residue was purified by column chromatography to afford tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate (190 mg, 45.03% yield) as a yellow oil. LCMS: 630.5 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 5.9 Hz, 1H), 6.38 - 6.23 (m, 1H), 6.11 - 5.93 (m, 2H), 4.52 - 4.41 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 (br s, 2H), 3.11 - 2.98 (m, 1H), 2.25 (s, 1H), 2.04 - 1.95 (m, 1H), 1.91 - 1.79 (m, 3H), 1.76 (br d, J = 2.8 Hz, 3H), 1.73 - 1.68 (m, 2H), 1.68 - 1.62 (m, 4H), 1.58 (s, 9H), 1.43 (s, 9H), 0.90 (s, 3H), 0.88 (s, 9H), 0.07 - 0.05 (m, 6H) ppm.

[0225] Step 6: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (5-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)-2-methylpentan-2-yl)carbamate (190 mg, 0.302 mmol, 1 equiv.) in THF (5 mL) was added BocO (131.65 mg, 0.603 mmol, 138.58 μL, 2 equiv.), TEA (91.56 mg, 0.905 mmol, 125.94 μL, 3 equiv.), and DMAP (36.85 mg, 0.302 mmol, 1 equiv.) at 0° C., and the mixture was stirred at 30° C. under a N atmosphere for 12 hours. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to give tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (165 mg, 74.93% yield) as a yellow oil.

[0226] Step 7: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (165 mg, 0.226 mmol, 1 equiv.) in THF (6 mL), TBAF (1 M, 1.13 mL, 5 equiv.) was added, and the mixture was stirred at 20° C. under a N atmosphere for 12 hours. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, PE:EA=2:1, R f =0.3) to give tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (150 mg, crude) as a colorless oil. LCMS: 616.5 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 5.9 Hz, 1H), 6.84 (br s, 1H), 6.82 - 6.75 (m, 1H), 5.96 (d, J = 2.4 Hz, 1H), 4.49 - 4.42 (m, 1H), 4.41 - 4.36 (m, 1H), 4.33 - 4.23 (m, 2H), 3.37 - 3.23 (m, 1H), 2.23 - 2.08 (m, 2H), 2.02 - 1.89 (m, 2H), 1.62 - 1.55 (m, 6H), 1.46 (s, 9H), 1.45 (d, J = 4.1 Hz, 9H), 1.43 (s, 9H), 1.28 (s, 6H) ppm.

[0227] Step 8: Preparation of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (150 mg, 0.244 mmol, 1 equiv.) in THF (3 mL) was added Py (96.34 mg, 1.22 mmol, 5 equiv.) and DMAP (14.88 mg, 0.128 mmol, 0.5 equiv.), followed by a solution of 4-nitrophenyl chloroformate (245.49 mg, 1.22 mmol, 5 equiv.) in DCM (3 mL) at 0° C. After completion of the addition, the mixture was stirred under a N atmosphere at 30° C. for 12 h, and then the volatiles were removed under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, PE:EA = 2:1, R f =0.4) to afford tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (130 mg, 68.34% yield) as a yellow oil. LCMS: 781.5 [M+H] + .

[0228] Step 9: Preparation of (1R,3S)-3-(5-((2-((4-amino-4-methylpentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of tert-butyl (2-((4-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (100 mg, 0.128 mmol, 1 equiv) in DCM (3 mL) was added TFA (921.00 mg, 8.08 mmol, 0.6 mL, 63.08 equiv). The mixture was stirred at 30° C. under a N atmosphere for 3 h, after which the volatiles were removed under reduced pressure. The desired (1R,3S)-3-(5-((2-((4-amino-4-methylpentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (74 mg, 99.52% yield) was obtained as a yellow oil. LCMS: 581.4 [M+H] + .

[0229] Step 10: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9,9-dimethyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-((4-amino-4-methylpentyl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (74 mg, 0.127 mmol, 1 equiv.) in THF (70 mL) was added DIPEA (82.35 mg, 0.637 mmol, 110.99 μL, 5 equiv.) and DMAP (15.57 mg, 0.127 mmol, 1 equiv.), and the mixture was stirred first at 30° C. for 3 h and then at 50° C. for 12 h under a N atmosphere. Additional DMAP (25 mg, 0.205 mmol, 1.61 equiv.) was then added, and the mixture was kept stirring at 50° C. under a N atmosphere for an additional 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was analyzed by prep-TLC (SiO, DCM:MeOH=10:1, R f =0.4) and purified by (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9,9-dimethyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (50 mg, 88.85% yield) was obtained as a yellow oil. LCMS: 442.6 [M+H] + .

[0230] Step 11: (1 1 S,1 3 R,Z)-9,9-dimethyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-9,9-dimethyl-2 1A mixture of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (50 mg, 0.113 mmol, 1 equiv.) in formic acid (3 mL) was stirred at 100 °C for 0.5 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm; mobile phase: [water (FA)-ACN]; gradient: 12% to 42% B over 7 min) to give (1 1 S,1 3 R,Z)-9,9-dimethyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1.97 mg, 3.77% yield) was obtained as a white solid. LCMS: 386.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 8.96 (s, 1H), 8.35 (s, 1H), 7.73 (d, J = 5.8 Hz, 1H), 6.49 (s, 1H), 6.43 (dd, J = 1.9, 5.8 Hz, 1H), 6.37 (d, J = 1.6 Hz, 1H), 6.05 (s, 1H), 5.08 - 4.98 (m, 1H), 4.13 - 4.04 (m, 1H), 3.98 - 3.88 (m, 1H), 2.43 - 2.37 (m, 1H), 1.97 (br dd, J = 5.1, 6.7 Hz, 1H), 1.89 (br d, J = 6.8 Hz, 1H), 1.87 - 1.83 (m, 2H), 1.82 - 1.77 (m, 2H), 1.70 - 1.64 (m, 1H), 1.55 - 1.48 (m, 1H), 1.30 (br s, 3H), 1.25 - 1.21 (m, 2H), 1.15 (s, 3H) ppm. Example 5: (1 1 S,1 3R,Z)-4 6 -(difluoromethyl)-2 1 Synthesis of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 17) [ka]

[0231] Step 1: Preparation of (4,6-dichloropyridin-2-yl)methanol To a solution of methyl 4,6-dichloropicolinate (5 g, 24.27 mmol, 1 equiv.) in MeOH (60 mL) was added NaBH (1.84 g, 48.54 mmol, 2 equiv.) at 0 °C, and the mixture was stirred at 20 °C for 2 h under a N atmosphere. The reaction mixture was then quenched with saturated aqueous NH Cl (200 mL) at 0 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford (4,6-dichloropyridin-2-yl)methanol (4.3 g, 99.53% yield) as a white solid. LCMS: 178.1 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.32 (d, J = 0.6 Hz, 1H), 7.30 - 7.28 (m, 1H), 4.75 (s, 2H), 3.01 - 2.55 (m, 1H) ppm.

[0232] Step 2: Preparation of 4,6-dichloropicolinaldehyde To a mixture of (4,6-dichloropyridin-2-yl)methanol (3.3 g, 18.54 mmol, 1 equiv.) in DCM (60 mL) was added DMP (15.73 g, 37.08 mmol, 11.49 mL, 2 equiv.) in one portion at 0 °C, and the mixture was stirred at 25 °C under a N atmosphere for 2 h. The reaction mixture was then quenched with saturated aqueous NaSO (100 mL) at 0 °C and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 4,6-dichloropicolinaldehyde (2.9 g, 88.89% yield) as a white solid. LCMS: 176.0 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 9.97 (s, 1 H) 7.87 (s, 1 H) 7.60 (s, 1 H) ppm.

[0233] Step 3: Preparation of 2,4-dichloro-6-(difluoromethyl)pyridine To a mixture of 4,6-dichloropicolinaldehyde (2.9 g, 16.48 mmol, 1 equiv.) in DCM (30 mL) was added DAST (5.31 g, 32.95 mmol, 4.35 mL, 2 equiv.) in one portion at −20° C. under N atmosphere. The mixture was then warmed to 25° C. and maintained stirring under N atmosphere for 2 h. After the starting material was consumed, the mixture was diluted with HO (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 2,4-dichloro-6-(difluoromethyl)pyridine (2 g, 61.30% yield) as a yellow oil. LCMS: 198.0 [M+H] + ; 1H NMR (400 MHz, chloroform-d) δ 7.59 (d, J = 1.25 Hz, 1 H), 7.49 (d, J = 0.63 Hz, 1 H), 6.56 (t, J = 54.8 Hz, 1 H) ppm.

[0234] Step 4: Preparation of tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pent-4-yn-1-yl)carbamate A mixture of 2,4-dichloro-6-(difluoromethyl)pyridine (1 g, 5.05 mmol, 1 equiv.), tert-butyl pent-4-yn-1-ylcarbamate (832.95 mg, 4.55 mmol, 0.9 equiv.), CuI (192.38 mg, 1.01 mmol, 0.2 equiv.), TEA (1.02 g, 10.10 mmol, 1.41 mL, 2 equiv.), and Pd(PPh)Cl (354.50 mg, 0.505 mmol, 0.1 equiv.) in DMF (10 mL) was stirred under a N atmosphere at 25 °C for 12 h. After the starting material was consumed, the reaction mixture was diluted with HO (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pent-4-yn-1-yl)carbamate (910 mg, 52.26% yield) as a yellow oil. LCMS: 345.3 [M+H] + .

[0235] Step 5: Preparation of tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate A mixture of tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pent-4-yn-1-yl)carbamate (950 mg, 2.76 mmol, 1 equiv.) and Pt / C (95.00 mg, 0.0226 mmol, 5% purity) in THF (10 mL) was degassed and backfilled with H three times and stirred under an atmosphere of H (15 psi) at 30° C. for 4 h. After completion of the reaction, the mixture was filtered through a short pad of Celite, rinsed with THF (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate (430 mg, 44.74% yield) as a yellow oil. LCMS: 349.2 [M+H] + .

[0236] Step 6: Preparation of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate A mixture of tert-butyl (5-(4-chloro-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate (210 mg, 0.602 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (203.23 mg, 0.602 mmol, 1 equiv.), CsCO (588.47 mg, 1.81 mmol, 3 equiv.), Xantphos (57.40 mg, 0.120 mmol, 0.2 equiv.), and Pd(dba) (55.13 mg, 0.0602 mmol, 0.1 equiv.) in dioxane (4 mL) was heated and stirred at 90 °C for 12 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with dioxane (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=4 / 1) to give tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate (182 mg, 46.51% yield) as a yellow oil. LCMS: 650.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 6.85 - 6.55 (m, 3H), 6.46 (s, 1H), 6.00 (s, 1H), 4.31 (quin, J = 5.13 Hz, 1H), 3.00 (quin, J = 8.35 Hz, 1H), 2.87 (q, J = 6.59 Hz, 2H), 2.55 (br t, J = 7.69 Hz, 2H), 2.41 - 1.86 (m, 3H), 1.82 - 1.72 (m, 2H), 1.62 - 1.52 (m, 4H), 1.48 (s, 9H), 1.36 (s, 9H), 1.27 - 1.16 (m, 4H), 0.82 (s, 9H), 0.02 (d, J = 4.50 Hz, 6H) ppm.

[0237] Step 7: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (5-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)pentyl)carbamate (140 mg, 0.215 mmol, 1 equiv.) in THF (3 mL) was added BocO (94.02 mg, 0.431 mmol, 98.97 μL, 2 equiv.), TEA (65.39 mg, 0.646 mmol, 89.95 μL, 3 equiv.), and DMAP (26.32 mg, 0.215 mmol, 1 equiv.) at 0° C., and the mixture was stirred at 25° C. for 12 hours under a N atmosphere. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (52 mg, 32.19% yield) as a yellow oil. LCMS: 750.5 [M+H] + .

[0238] Step 8: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (52 mg, 0.0693 mmol, 1 equiv.) and TBAF (1 M, 346.65 μL, 5 equiv.) in THF (1.75 mL) was stirred at 25° C. under a N atmosphere for 12 hours. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (49 mg, crude) as a yellow oil. LCMS: 636.4 [M+H] + .

[0239] Step 9: Preparation of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (49 mg, 0.0771 mmol, 1 equiv) in THF (1 mL) was added Py (36.58 mg, 0.462 mmol, 37.32 μL, 6 equiv) and DMAP (4.71 mg, 0.0385 mmol, 0.5 equiv), followed by a solution of 4-nitrophenyl chloroformate (77.67 mg, 0.385 mmol, 5 equiv) in DCM (1 mL) at 0 °C under a N atmosphere. After completion of the addition, the reaction was maintained stirring at 30° C. under a N atmosphere for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with HO (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=3 / 1) to afford tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (38 mg, 61.56% yield) as a yellow oil. LCMS: 801.8 [M+H] + .

[0240] Step 10: Preparation of (1R,3S)-3-(5-((2-(5-aminopentyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(5-((tert-butoxycarbonyl)amino)pentyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (38 mg, 0.047 mmol, 1 equiv) and TFA (307.00 mg, 2.69 mmol, 0.2 mL, 56.75 equiv) in DCM (1 mL) was stirred at 30° C. under a N atmosphere for 12 h, then the volatiles were removed under reduced pressure. The desired (1R,3S)-3-(5-((2-(5-aminopentyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (59 mg, crude) was obtained as a yellow oil. LCMS: 601.2 [M+H] + .

[0241] Step 11: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 Preparation of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-(5-aminopentyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (59 mg, 0.0982 mmol, 1 equiv.) in THF (30 mL) was added DIPEA (88.87 mg, 0.688 mmol, 119.76 μL, 7 equiv.) and the mixture was stirred at 30° C. under N atmosphere for 12 h. The volatiles were then removed under reduced pressure to give a residue which was purified by prep-TLC (petroleum ether / ethyl acetate=1 / 1) to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6-(difluoromethyl)-2 1 H-12-Oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (20 mg, 44.12% yield) was obtained as a yellow oil. LCMS: 462.3 [M+H] + .

[0242] Step 12: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 Preparation of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 A solution of H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (20 mg, 0.0433 mmol, 1 equiv.) in HCOOH (1 mL) was stirred at 100 °C under N atmosphere for 0.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by pre-HPLC (column: YMC-Actus Triart C18 150 x 30 mm, 7 μm; mobile phase: [water (FA)-ACN]; gradient: 10% to 40% B in 10 min) to give (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 H-12-Oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (9.8 mg, 54.67% yield) was obtained as a white solid. LCMS: 406.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.37 - 12.06 (m, 1 H), 9.20 - 9.07 (m, 1 H), 7.10 (dd, J = 4.8, 2.8 Hz, 1 H), 6.89 (s, 1 H), 6.85 - 6.55 (m, 2 H), 5.97 (s, 1 H), 5.13 - 4.93 (m, 1 H), 3.02 - 2.86 (m, 1 H), 2.81 - 2.70 (m, 1 H), 2.62 (d, J = 6.4 Hz, 2 H), 2.48 - 2.34 (m, 2 H), 2.11 - 1.98 (m, 1 H), 1.86 - 1.58 (m, 6 H), 1.50 - 1.22 (m, 4 H) ppm. Example 6: (1 1 S,1 3 R,Z)-2 1 Synthesis of H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (compound 18) [ka]

[0243] Step 1: Preparation of tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (4 g, 16.58 mmol, 1 equiv.) in THF (80 mL) was added LiAlH (1.26 g, 33.16 mmol, 2 equiv.), and the mixture was stirred at 20 °C under a N atmosphere for 2 h. After completion of the reaction, the reaction was quenched with HO (20 mL), 15% NaOH (20 mL), HO (60 mL), sequentially, and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (3.5 g, crude) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (br s, 1 H), 4.45 (t, J=5.2 Hz, 1 H), 3.42 (d, J=5.2 Hz, 2 H), 1.73 (s, 6 H), 1.36 (s, 9 H) ppm.

[0244] Step 2: Preparation of tert-butyl (3-(((4-bromopyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (500 mg, 2.34 mmol, 1 equiv.), 4-bromopyridin-2-ol (448.71 mg, 2.58 mmol, 1.1 equiv.), and PPh3 (737.89 mg, 2.81 mmol, 1.2 equiv.) in THF (10 mL) was added DIAD (568.87 mg, 2.81 mmol, 545.42 μL, 1.2 equiv.) at 0 °C under a N2 atmosphere. The mixture was stirred at 20 °C under a N2 atmosphere for 2 h and concentrated under reduced pressure. The resulting residue was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography to give tert-butyl (3-(((4-bromopyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (550 mg, 63.53% yield) as a white solid. LCMS: 369.1 [M+H] + .

[0245] Step 3: Preparation of tert-butyl (3-(((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-(((4-bromopyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (540 mg, 1.46 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (740.51 mg, 2.19 mmol), A mixture of Pd(dba) (133.92 mg, 0.146 mmol, 0.1 equiv), Xantphos (169.24 mg, 0.292 mmol, 0.2 equiv), Pd(dba) (133.92 mg, 0.146 mmol, 0.1 equiv), and CsCO (1.43 g, 4.39 mmol, 3 equiv) in dioxane (20 mL) was degassed and backfilled with N three times, then heated and stirred at 90 °C under a N atmosphere for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with dioxane (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (910 mg, 1.45 mmol, 99.42% yield) as a yellow solid. LCMS: 626.6 [M+H] + .

[0246] Step 4: Preparation of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (900 mg, 1.44 mmol, 1 equiv) in DCM (20 mL) were added DMAP (17.57 mg, 0.144 mmol, 0.1 equiv) and BocO (376.58 mg, 1.73 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred at 20 °C under a N atmosphere for 2 h. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (932 mg, 89.28% yield) as a yellow oil. LCMS: 727.0 [M+H] + .

[0247] Step 5: Preparation of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (922 mg, 1.27 mmol, 1 equiv.) and TBAF (1.33 g, 5.08 mmol, 4 equiv.) in THF (15 mL) was stirred at 20 °C under a N atmosphere for 12 h, and then the volatiles were removed under reduced pressure. The remaining residue was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (810 mg, crude) as a yellow oil. LCMS: 612.3 [M+H] + .

[0248] Step 6: Preparation of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 0.490 mmol, 1 equiv) in DCM (6 mL) was added 4-nitrophenyl carbonochloridate (148.26 mg, 0.736 mmol, 1.5 equiv), Py (116.37 mg, 1.47 mmol, 118.74 μL, 3 equiv), and DMAP (5.99 mg, 0.049 mmol, 0.1 equiv), and the mixture was stirred at 20° C. under a N atmosphere for 12 h. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC (neutral condition) to give tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 52.50% yield) as a white solid. LCMS: 777.6 [M+H] + .

[0249] Step 7: Preparation of (1R,3S)-3-(5-((2-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (80 mg, 0.103 mmol, 1 equiv) and TFA (1 mL) in DCM (3 mL) was stirred at 20° C. under a N atmosphere for 12 h, then the volatiles were removed under reduced pressure. The desired (1R,3S)-3-(5-((2-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (155 mg, crude) was obtained as a yellow oil. LCMS: 577.3 [M+H] + .

[0250] Step 8: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 Preparation of H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one A solution of (1R,3S)-3-(5-((2-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (300 mg, 0.520 mmol, 1 equiv) and DIEA (672.39 mg, 5.20 mmol, 906.19 μL, 10 equiv) in DMSO (150 mL) was heated and stirred at 100° C. for 2 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting residue was diluted with H2O (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired product (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 H-5,10-Dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (210 mg, crude) was obtained as a yellow oil. LCMS: 438.3 [M+H] + .

[0251] Step 9: (1 1 S,1 3 R,Z)-2 1 Preparation of H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1A solution of H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (200 mg, 0.457 mmol, 1 equiv.) in formic acid (4 mL) was stirred at 100 °C under N atmosphere for 0.5 h. After completion of the conversion, the mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The crude product was purified by Prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm; mobile phase: [water (NH . HO)-ACN]; B%: 10% to 90%, 20 min) and purified (1 1 S,1 3 R,Z)-2 1 H-5,10-Dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (49.28 mg, 26.88% yield) was obtained as a white solid. LCMS: 382.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (br s, 1H), 8.58 (s, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.50 (s, 1H), 6.43 (dd, J=5.6, 1.6 Hz, 1H), 6.14 (s, 1H), 5.94 (s, 1H), 5.12 (d, J=5.6 Hz, 1H), 4.20 - 4.06 (m, 2H), 3.28 - 3.15 (m, 1H), 2.48 - 2.39 (m, 1H), 2.14 - 2.03 (m, 1H), 1.86 - 1.80 (m, 8H), 1.79 - 1.71 (m, 2 H) ppm. Example 7: (1 1 S,1 3 R,Z)-2 1Synthesis of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (compound 22) [ka]

[0252] Step 1: Preparation of (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate To a solution of tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2.2 g, 10.32 mmol, 1 equiv.) in DCM (30 mL) was added TEA (2.09 g, 20.63 mmol, 2.87 mL, 2 equiv.) and methylsulfonyl methanesulfonate (2.16 g, 12.38 mmol, 1.2 equiv.) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h under a N atmosphere. After completion of the reaction, the reaction mixture was quenched with NaHCO (50 mL). The organic phase was collected, and the aqueous phase was extracted with DCM (40 mL × 2). The combined organic layers were washed with brine (70 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (3.1 g, crude) was obtained as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 5.16 - 4.79 (m, 1H), 4.30 (s, 2H), 3.01 (s, 3H), 2.04 (s, 6H), 1.44 (s, 9H) ppm.

[0253] Step 2: Preparation of tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate A solution of (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (3.1 g, 10.64 mmol, 1 equiv.) and KCN (1.34 g, 20.58 mmol, 1.93 equiv.) in DMF (30 mL) was stirred at 70 °C under N atmosphere for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water (80 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2.1 g, 88.79% yield) was obtained as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 5.00 (br s, 1H), 2.66 (s, 2H), 2.07 (br s, 6H), 1.45 (s, 9H) ppm.

[0254] Step 3: Preparation of 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid To a solution of tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (600 mg, 2.70 mmol, 1 equiv.) in DCM (10 mL) was added DIBAL-H (1 M, 8.10 mL, 3 equiv.) dropwise at −78 °C under a N atmosphere. After completion of the addition, the mixture was maintained stirring at −78 °C under a N atmosphere for 2 h. The reaction was then carefully quenched with HO (100 mL) and adjusted to pH < 3 with HCl (6 M). The reaction mixture was filtered, rinsed with DCM (50 mL), and the filtrate was extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid (550 mg, 2.28 mmol, 84.45% yield) was obtained as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, methanol-d4) δ 2.08 - 1.64 (m, 8H), 1.43 (s, 9H) ppm.

[0255] Step 4: Preparation of tert-butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acetic acid (550 mg, 2.28 mmol, 1 equiv.) in THF (10 mL) was added BH3 in THF (1 M, 9.12 mL, 4 equiv.) at −78 °C, and the mixture was kept stirring at −78 °C for 10 h under N2 atmosphere. After completion of the reaction, the reaction mixture was quenched with 5 mL of MeOH, and the volatiles were evaporated under reduced pressure. The resulting tert-butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (380 mg, 73.34% yield) was obtained as a colorless oil, which was used in the next step without further purification. 1H NMR (400 MHz, methanol-d4) δ 3.55 (t, J = 7.0 Hz, 2H), 1.87–1.84 (m, 6H), 1.75 (t, J = 7.0 Hz, 2H), 1.43 (s, 9H) ppm.

[0256] Step 5: Preparation of tert-butyl (3-(2-((4-bromopyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of tert-butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (356.47 mg, 1.57 mmol, 1.2 equiv.) and 4-bromo-2-fluoropyridine (230 mg, 1.31 mmol, 1 equiv.) in DMF (8 mL) was added tBuOK (219.98 mg, 1.96 mmol, 1.5 equiv.), and the mixture was stirred at 20 °C under a N atmosphere for 12 hours. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (60 mL × 2), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-((4-bromopyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (380 mg, 64.48% yield) as a white solid. LCMS: 383.2 / 385.2 [M+H] + .

[0257] Step 6: Preparation of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (3-(2-((4-bromopyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)tert-butylcarbamate (408.74 mg, 1.07 mmol, 1.2 equivalents), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine ( A mixture of Xantphos (300 mg, 0.889 mmol, 1 equiv), CsCO (868.66 mg, 2.67 mmol, 3 equiv), Xantphos (102.84 mg, 0.178 mmol, 0.2 equiv), and Pd(dba) (81.38 mg, 0.0888 mmol, 0.1 equiv) in dioxane (5 mL) was heated and stirred at 90 °C for 2 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with dioxane (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (450 mg, 75.17% yield) as a white solid. LCMS: 640.6 [M+H] + .

[0258] Step 7: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (450 mg, 0.703 mmol, 1 equiv.) in THF (10 mL) was added BocO (306.94 mg, 1.41 mmol, 323.09 μL, 2 equiv.), DMAP (85.91 mg, 0.703 mmol, 1 equiv.), and TEA (213.47 mg, 2.11 mmol, 293.62 μL, 3 equiv.). The mixture was stirred at 25° C. under a N atmosphere for 2 h, and then the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (430 mg, 80.98% yield) as a yellow oil. LCMS: 740.4 [M+H] + .

[0259] Step 8: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (380 mg, 0.513 mmol, 1 equiv.) and TBAF (1 M, 2.05 mL, 4 equiv.) in THF (4 mL) was stirred at 25° C. under a N atmosphere for 2 hours and then poured into water (5 mL). The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by prep-TLC (SiO, petroleum ether:ethyl acetate=1:1, Rf=0.3) to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (240 mg, 74.69% yield) as a colorless oil. LCMS: 626.5 [M+H] + .

[0260] Step 9: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate tert-Butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (120 mg, 0.192 mmol, 1 equiv.), Py (75.84 mg) To a mixture of 4-nitrophenyl carbonochloridate (115.95 mg, 0.575 mmol, 3 equiv) and DMAP (11.71 mg, 0.959 mmol, 77.39 μL, 5 equiv) in THF (1 mL) was added dropwise a solution of 4-nitrophenyl carbonochloridate (115.95 mg, 0.575 mmol, 3 equiv) in DCM (1 mL) at 0° C., and the mixture was stirred at 25° C. for 12 h under a N atmosphere. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by prep-TLC (SiO, petroleum ether:ethyl acetate=2:1, Rf=0.35) to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (85 mg, 50.16% yield) as a white solid. LCMS: 791.4 [M+H] + .

[0261] Step 10: Preparation of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl)carbonate A mixture of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (85 mg, 0.107 mmol, 1 equiv.) and TFA (0.1 mL) in DCM (0.5 mL) was stirred at 25° C. under a N atmosphere for 12 h. The volatiles were then removed under reduced pressure to afford (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70 mg, crude) as a colorless oil, which was used in the next step without further purification. LCMS: 591.4 [M+H] + .

[0262] Step 11: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one To a solution of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (60 mg, 0.102 mmol, 1 equiv.) in DMF (20 mL) was added TEA (205.58 mg, 2.03 mmol, 282.77 μL, 20 equiv.) and the mixture was stirred at 100° C. under N atmosphere for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The remaining crude product was purified by prep-TLC (SiO, petroleum ether:ethyl acetate=1:1, Rf=0.57) to give (1 1S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (35 mg, 75.31% yield) was obtained as a yellow solid. LCMS: 452.3 [M+H] + .

[0263] Step 12: (1 1 S,1 3 R,Z)-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 A solution of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (35 mg, 0.0775 mmol, 1 equiv.) in formic acid (1 mL) was stirred at 100 °C under a N atmosphere for 0.5 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm; mobile phase: [water (FA)-ACN]; gradient: 10% to 30% B over 10 min) to give (1 1 S,1 3 R,Z)-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (13.18 mg, 42.88% yield) was obtained as a white solid. LCMS: 396.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.58 - 12.09 (m, 1H), 8.81 (s, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.42 (s, 1H), 6.46 (d, J = 5.2 Hz, 1H), 6.29 (s, 1H), 6.02 (s, 1H), 5.12 (d, J = 4.0 Hz, 1H), 4.32 - 4.14 (m, 2H), 3.21 - 3.08 (m, 1H), 2.63 - 2.55 (m, 1H), 2.04 - 1.93 (m, 1H), 1.91 - 1.72 (m, 10H), 1.72 - 1.63 (m, 2H) ppm. Example 8: Synthesis of (1'S,3'R,Z)-spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (Compound 26) [ka]

[0264] Step 1: Preparation of 4-bromopyridine-2-carboxylic acid To a solution of methyl 4-bromopyridine-2-carboxylate (10 g, 46.29 mmol, 1 equiv.) in the cosolvent of THF (150 mL)-MeOH (50 mL)-HO (50 mL), LiOH.HO (7.77 g, 185.16 mmol, 4 equiv.) was added, and the mixture was stirred at 25 °C for 16 h. The volatiles were evaporated under reduced pressure, and the residue was acidified with 4 N HCl to pH < 3. The aqueous phase was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 4-bromopyridine-2-carboxylic acid (5.8 g, 62.02% yield). LCMS: 202.1, 204.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 1.6, 4.8Hz, 1H) ppm.

[0265] Step 2: Preparation of 4-bromo-N-methoxy-N-methylpicolinamide To a solution of 4-bromopyridine-2-carboxylic acid (5.80 g, 28.71 mmol, 1 equiv.), N-methoxymethanamine hydrochloride (4.20 g, 43.07 mmol, 1.5 equiv.), and HATU (16.38 g, 43.07 mmol, 1.5 equiv.) in DCM (100 mL) was added DIEA (11.13 g, 86.14 mmol, 15.00 mL, 3 equiv.), and the mixture was stirred at 25° C. for 2 h. The mixture was then poured into water (50 mL). The organic phase was collected, and the aqueous phase was extracted with DCM (50 mL×4). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to give 4-bromo-N-methoxy-N-methylpicolinamide (6.4 g, 61.96% yield) as a yellow oil. LCMS: 244.7, 246.7 [M+H] + .

[0266] Step 3: Preparation of 1-(4-bromo-2-pyridyl)ethanone To a solution of 4-bromo-N-methoxy-N-methylpicolinamide (4.97 g, 20.30 mmol, 1 equiv.) in THF (100 mL) was added MeMgBr (3 M, 10.15 mL, 1.5 equiv.) dropwise at 0 °C under a nitrogen atmosphere. After completion of the addition, the reaction mixture was warmed to 25 °C and stirred for an additional 2 h under a N atmosphere. The reaction mixture was then quenched with saturated aqueous NH Cl (100 mL), and the aqueous phase was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 1-(4-bromo-2-pyridyl)ethanone (4.1 g, 87.86% yield) as a yellow oil. LCMS: 199.8, 201.8 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.56–8.43 (m, 1H), 8.31–7.99 (m, 1H), 7.61 (dd, J = 1.9, 5.2 Hz, 1H), 2.68 (s, 3H) ppm.

[0267] Step 4: Preparation of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine To a solution of 1-(4-bromo-2-pyridyl)ethanone (3.1 g, 15.50 mmol, 1 equiv.) and [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (4.96 g, 18.75 mmol, 4.31 mL, 1.21 equiv.) in DCM (60 mL) was added TEA (4.70 g, 46.49 mmol, 6.47 mL, 3 equiv.) at 0 °C, and the mixture was warmed to 25 °C and stirred under a N atmosphere for 2 h. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (4.67 g, 90.66% yield) as a yellow oil. LCMS: 314.0, 316.0 [M+H] + ; 1H NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.31–7.23 (m, 1H), 5.59 (d, J = 1.1 Hz, 1H), 4.51 (s, 1H), 0.94 (s, 9H), 0.17 (s, 6H) ppm.

[0268] Step 5: Preparation of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine To a solution of ZnEt (1 M, 44.80 mL, 3.2 equiv.) in DCM (64 mL), chloro(iodo)methane (15.83 g, 89.74 mmol, 6.51 mL, 6.41 equiv.) was added dropwise at 0 °C, and the mixture was stirred at 0 °C under N atmosphere for 20 min, after which a solution of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (4.4 g, 14.00 mmol, 1 equiv.) in DCM (32 mL) was added dropwise at 0 °C under N atmosphere. After completion of the addition, the reaction was kept stirring at 0 °C under N atmosphere for 1 h. The reaction was then quenched with saturated aqueous NH Cl (15 mL). The organic phase was isolated, and the aqueous phase was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (2.5 g, 44.06% yield) as a white solid. LCMS: 327.8, 329.8 [M+H] + .

[0269] Step 6: Preparation of 1-(4-bromopyridin-2-yl)cyclopropan-1-ol To a solution of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (2.5 g, 7.61 mmol, 1 equiv.) in MeOH (80 mL) was added NHF (8.46 g, 228.44 mmol, 30 equiv.), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was then cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give 1-(4-bromopyridin-2-yl)cyclopropan-1-ol (1.58 g, 52.34% yield) as a yellow oil. LCMS: 213.8, 215.8 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.3 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.34–7.26 (m, 1H), 3.78–3.18 (m, 1H), 1.45–1.23 (m, 4H) ppm.

[0270] Step 7: Preparation of tert-butyl (3-(1-(4-bromopyridin-2-yl)cyclopropoxy)propyl)carbamate To a solution of 1-(4-bromopyridin-2-yl)cyclopropan-1-ol (800 mg, 3.74 mmol, 1 equiv.) in DMF (9 mL) was added NaH (448.47 mg, 11.21 mmol, 60% purity, 3 equiv.) at 0° C., and the mixture was stirred at this temperature under a N atmosphere for 0.5 h, after which a solution of tert-butyl (3-bromopropyl)carbamate (4.45 g, 18.69 mmol, 5 equiv.) in DMF (9 mL) was added. After completion of the addition, the mixture was kept stirring under a N atmosphere at 0° C. for 1 h. The mixture was then quenched with 0.5 mL of saturated aqueous NH4Cl, and the volatiles were then removed under reduced pressure. The remaining residue was purified by column chromatography to give tert-butyl (3-(1-(4-bromopyridin-2-yl)cyclopropoxy)propyl)carbamate (474 ​​mg, 27.67% yield) as a white solid. LCMS: 370.8, 372.8 [M+H]+ .

[0271] Step 8: Preparation of tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)cyclopropoxy)propyl)carbamate A mixture of tert-butyl (3-(1-(4-bromopyridin-2-yl)cyclopropoxy)propyl)carbamate (360 mg, 0.97 mmol, 1.2 equiv), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (272.77 mg, 0.808 mmol, 1 equiv), CsCO (789.83 mg, 2.42 mmol, 3 equiv), Pd(dba) (73.99 mg, 0.081 mmol, 0.1 equiv), and Xantphos (93.51 mg, 0.161 mmol, 0.2 equiv) in dioxane (6 mL) was heated and stirred at 90 °C under a N atmosphere for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, rinsed with dioxane (10 mL), and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)cyclopropoxy)propyl)carbamate (484 mg, 90.20% yield) as a white solid. LCMS: 628.4 [M+H] + .

[0272] Step 9: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)cyclopropoxy)propyl)carbamate (480 mg, 0.764 mmol, 1 equiv) in DCM (10 mL) was added BocO (333.67 mg, 1.53 mmol, 351.23 μL, 2 equiv) and DMAP (93.39 mg, 0.764 mmol, 1 equiv), and the mixture was stirred at 25° C. for 1 h. The volatiles were then removed under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (480 mg, 52.61% yield) as a yellow oil. LCMS: 728.5 [M+H] + .

[0273] Step 10: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (250 mg, 0.343 mmol, 1 equiv.) and TBAF (1 M, 0.687 mmol, 686.77 μL, 2 equiv.) in THF (3 mL) was stirred at 60° C. for 2 h. After completion of the reaction, the mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The remaining residue was purified by prep-TLC (PE / EA=1 / 1) to give tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (186 mg, 88.25% yield) as a yellow oil. LCMS: 614.5 [M+H] + .

[0274] Step 11: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (186 mg, 0.303 mmol, 1 equiv.), Py (119.85 mg, 1.52 mmol, 122.30 μL, 5 equiv.), and DMAP (18.51 mg, 0.152 mmol, 0.5 equiv.) in THF (2 mL) was added a solution of 4-nitrophenyl carbonochloridate (183.24 mg, 0.909 mmol, 3 equiv.) in DCM (2 mL), and the mixture was stirred at 20° C. under a N atmosphere for 12 h. After completion of the reaction, the mixture was quenched with 0.5 mL of saturated aqueous NH4Cl, and then the volatiles were removed under reduced pressure. The remaining residue was purified by column chromatography to give tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 59.31% yield) as a yellow solid. LCMS: 779.5 [M+H] + .

[0275] Step 12: Preparation of (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)cyclopropyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)cyclopropyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 0.257 mmol, 1 equiv) and TFA (3.07 g, 26.92 mmol, 2 mL, 104.86 equiv) in DCM (8 mL) was stirred at 30° C. for 0.5 h. The volatiles were then removed under reduced pressure to give (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)cyclopropyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate, which was used in the next step without further purification. LCMS: 579.2 [M+H] + .

[0276] Step 13: Preparation of (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one To a solution of (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)cyclopropyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (132 mg) in THF (50 mL) was added TEA (461.65 mg, 4.56 mmol, 635.01 μL, 20 equiv.) and the mixture was stirred at 25° C. under N atmosphere for 1 h. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (33 mg, 30.28% yield) as a yellow oil. LCMS: 440.3 [M+H]+ .

[0277] Step 14: Preparation of (1'S,3'R,Z)-spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one A solution of (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (30 mg, 0.0683 mmol, 1 equiv) in formic acid (1 mL) was stirred at 100°C under a N atmosphere for 0.5 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The remaining residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm, 10 μm; mobile phase: [water (FA)-ACN]; gradient: 6% to 36% B over 10 min) to give (1'S,3'R,Z)-spiro[cyclopropane-1,5'-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (15.35 mg, 57.25% yield) as a white solid. LCMS: 384.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.5 (br s, 1H), 8.89 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 5.6 Hz, 1H), 7.16 - 7.10 (m, 1H), 6.58 - 6.57 (m, 1H), 6.57 (dd, J = 2.3, 3.2 Hz, 1H), 5.96 - 5.90 (s, 1H), 5.05 - 5.04 (m, 1H), 3.23 - 3.20 (m, 2H), 3.18 - 2.66 (m, 2H), 2.10 - 1.92 (m, 2H), 1.90 - 1.71 (m, 6H), 1.65 - 1.50 (m, 1H), 1.30 - 1.20 (m, 1H), 1.07 (br s, 3H) ppm. Example 9: Synthesis of (1'S,3'R,Z)-spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (Compound 33) [ka]

[0278] Step 1: Preparation of ethyl (E)-3-[1-(tert-butoxycarbonylamino)cyclopropyl]prop-2-enoate A mixture of tert-butyl N-(1-formylcyclopropyl)carbamate (4.5 g, 24.30 mmol, 1 equiv.) and ethyl 2-(triphenylphosphanylidene)acetate (9.31 g, 26.73 mmol, 1.1 equiv.) in DCM (40 mL) was stirred under a N atmosphere at 20° C. for 12 h. The volatiles were then evaporated, and the remaining residue was purified by column chromatography to give (E)-3-[1-(tert-butoxycarbonylamino)cyclopropyl]prop-2-enoate (5.5 g, 88.67% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (br s, 1H), 6.50 (d, J = 15.4 Hz, 1H), 5.63 (br d, J = 15.2 Hz, 1H), 4.15 - 4.03 (m, 2H), 1.38 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H), 1.14 - 1.04 (m, 4H) ppm.

[0279] Step 2: Preparation of ethyl 3-[1-(tert-butoxycarbonylamino)cyclopropyl]propanoate A mixture of Pd / C (5%, 250.10 mg) and (£)-ethyl 3-[1-(tert-butoxycarbonylamino)cyclopropyl]prop-2-enoate (5 g, 19.58 mmol, 1 equiv) in ethyl acetate (100 mL) was degassed and backfilled with H three times and stirred under an atmosphere of H (15 psi) at 20 °C for 3 h. The solid was filtered off, rinsed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure to give the desired ethyl 3-[1-(tert-butoxycarbonylamino)cyclopropyl]propanoate (600 mg, 75.72% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 4.88 (br s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.96 - 1.78 (m, 2H), 1.62 (br s, 2H), 1.57 - 1.40 (m, 9H), 1.31 - 1.25 (m, 3H), 0.78 (br s, 2H), 0.70 - 0.60 (m, 2H) ppm.

[0280] Step 3: Preparation of tert-butyl (1-(3-hydroxypropyl)cyclopropyl)carbamate To a solution of ethyl 3-[1-(tert-butoxycarbonylamino)cyclopropyl]propanoate (200 mg, 0.777 mmol, 1 equiv.) in THF (2 mL) was added LiBH (2 M, 2.13 mL, 5.48 equiv.), and the mixture was stirred at 25 °C under a N atmosphere for 18 h. The reaction mixture was quenched with 50% aqueous acetic acid (2 mL) and then diluted with HO (10 mL). The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO (10 mL) and brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (1-(3-hydroxypropyl)cyclopropyl)carbamate (96 mg, 57.37% yield) as a brown oil. 1 H NMR (400 MHz, chloroform-d) δ 3.72 - 3.65 (m, 2H), 1.71 - 1.66 (m, 2H), 1.63 - 1.58 (m, 2H), 1.44 (d, J = 3.2 Hz, 9H), 0.79 - 0.72 (m, 2H), 0.67 - 0.58 (m, 2H) ppm.

[0281] Step 4: Preparation of tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)propyl)cyclopropyl)carbamate A mixture of tert-butyl (1-(3-hydroxypropyl)cyclopropyl)carbamate (3.2 g, 14.86 mmol, 1.5 equiv.), 4-bromo-2-fluoro-pyridine (1.74 g, 9.91 mmol, 1 equiv.), and t-BuOK (1.67 g, 14.86 mmol, 1.5 equiv.) in DMF (30 mL) was stirred at 0 °C for 16 h under a N atmosphere. The reaction was then quenched with HO (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to afford tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)propyl)cyclopropyl)carbamate (880 mg, 2.37 mmol, 23.92% yield) as a white solid. LCMS: 370.8 / 372.8 [M+H] + .

[0282] Step 5: Preparation of tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)propyl)cyclopropyl)carbamate A mixture of tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)propyl)cyclopropyl)carbamate (420 mg, 1.13 mmol, 1.2 equiv), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (318.24 mg, 0.943 mmol, 1 equiv), CsCO (921.46 mg, 2.83 mmol, 3 equiv), Pd(dba) (86.33 mg, 0.0943 mmol, 0.1 equiv), and Xantphos (109.09 mg, 0.189 mmol, 0.2 equiv) in dioxane (4 mL) was heated and stirred at 90 °C under a N atmosphere for 2 h. The reaction was then cooled to room temperature, and the volatiles were evaporated under reduced pressure. The resulting residue was diluted with HO (40 mL), and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The remaining residue was purified by column chromatography to afford tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)propyl)cyclopropyl)carbamate (530 mg, 89.53% yield) as a yellow oil. LCMS: 628.3 [M+H] + .

[0283] Step 6: Preparation of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)propyl)cyclopropyl)carbamate (530 mg, 0.844 mmol, 1 equiv.), BocO (368.42 mg, 1.69 mmol, 387.81 μL, 2 equiv.), and DMAP (103.11 mg, 0.844 mmol, 1 equiv.) in THF (6 mL) was added TEA (256.22 mg, 2.53 mmol, 352.44 μL, 3 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 2 h. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (450 mg, 73.23% yield) as a yellow oil. LCMS: 728.7 [M+H] + .

[0284] Step 7: Preparation of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A mixture of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (448 mg, 0.615 mmol, 1 equiv.) and TBAF (1 M, 2.46 mL, 4 equiv.) in THF (4 mL) was stirred at 25° C. under a N atmosphere for 16 hours. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (330 mg, 87.37% yield) as a white solid. LCMS: 614.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 5.8 Hz, 1H), 7.14 (br s, 1H), 6.81 (br d, J = 5.0 Hz, 1H), 6.64 (s, 1H), 6.18 (s, 1H), 4.64 - 4.59 (m, 1H), 4.31 - 4.24 (m, 2H), 4.23 - 4.16 (m, 1H), 3.02 (br t, J = 8.4 Hz, 1H), 1.84 - 1.74 (m, 4H), 1.69 - 1.51 (m, 6H), 1.43 (d, J = 4.2 Hz, 18H), 1.39 (s, 9H), 0.68 - 0.46 (m, 4H) ppm.

[0285] Step 8: Preparation of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 0.489 mmol, 1 equiv.), Py (193.31 mg, 2.44 mmol, 197.25 μL, 5 equiv.) and DMAP (29.86 mg, 0.244 mmol, 0.5 equiv.) in THF (2 mL) was added a solution of 4-nitrophenyl chloroformate (295.55 mg, 1.47 mmol, 3 equiv.) in DCM (2 mL) at 0° C., and the mixture was stirred at 0° C. under a nitrogen atmosphere for 12 h. The mixture was then quenched with saturated aqueous NH4Cl (0.5 mL), and the volatiles were evaporated under reduced pressure. The resulting crude was purified by prep-TLC (SiO2, PE:EA=2:1) ​​to give tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (370 mg, 97.19% yield) as a colorless oil. LCMS: 779.3 [M+H] + .

[0286] Step 9: Preparation of (1R,3S)-3-(5-((2-(3-(1-aminocyclopropyl)propoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A mixture of tert-butyl (2-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propoxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (170 mg, 0.218 mmol, 1 equiv.) and TFA (0.2 mL) in DCM (2 mL) was stirred at 25° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was then concentrated under reduced pressure to afford (1R,3S)-3-(5-((2-(3-(1-aminocyclopropyl)propoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (180 mg, crude) as a yellow oil. LCMS: 579.3 [M+H] + .

[0287] Step 10: Preparation of (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one To a solution of (1R,3S)-3-(5-((2-(3-(1-aminocyclopropyl)propoxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (180 mg) in DMSO (69.13 mL) was added TEA (279.79 mg, 2.77 mmol, 384.85 μL, 20 equiv.), and the mixture was stirred at 100° C. under a nitrogen atmosphere for 0.5 h. The mixture was then cooled to room temperature, diluted with HO (50 mL), and the aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (NH.H.sub.2O condition) to give (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (30 mg, 49.37% yield) as a white solid. LCMS: 440.3 [M+H] + .

[0288] Step 11: Preparation of (1'S,3'R,Z)-spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one A solution of (1'S,3'R,Z)-1'-(tert-butyl)spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (30 mg, 0.0683 mmol, 1 equiv) in formic acid (0.5 mL) was stirred at 100° C. under a nitrogen atmosphere for 0.5 h. The reaction mixture was then cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150 x 30 mm, 7 μm; mobile phase: [water (FA)-ACN]; gradient: 13% to 43% B over 10 min) to give (1'S,3'R,Z)-spiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (16 mg, 60.53% yield) as a white solid. LCMS: 384.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.23 - 12.01 (m, 1H), 9.02 - 8.93 (m, 1H), 7.79 - 7.70 (m, 1H), 7.54 - 7.45 (m, 1H), 6.47 - 6.32 (m, 2H), 6.07 (s, 1H), 5.08 - 4.94 (m, 1H), 4.24 - 4.12 (m, 1H), 3.99 - 3.89 (m, 1H), 3.24 - 3.14 (m, 1H), 2.10 - 1.97 (m, 2H), 1.97 - 1.89 (m, 1H), 1.89 - 1.67 (m, 6H), 1.23 - 1.08 (m, 1H), 0.64 - 0.48 (m, 4H) ppm. Example 10: (1 1 S,1 3 R,Z)-2 1 Synthesis of H-5,12-dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 104) [ka]

[0289] Step 1: Preparation of tert-butyl (4-((5-bromopyridin-3-yl)oxy)butyl)carbamate A mixture of 5-bromopyridin-3-ol (500 mg, 2.87 mmol, 1 equiv), tert-butyl N-(4-hydroxybutyl)carbamate (543.84 mg, 2.87 mmol, 1 equiv), and 2-(tributyl-phosphanylidene)acetonitrile (1.04 g, 4.31 mmol, 1.5 equiv) in toluene (3 mL) was degassed and purged with N three times, then stirred under a N atmosphere at 80° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc (60 mL). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 1 to 20 / 1) to give tert-butyl (4-((5-bromopyridin-3-yl)oxy)butyl)carbamate (724 mg, 2.10 mmol, 72.9% yield) as a red solid. LCMS: 345.1 / 347.1 [M+H] + .

[0290] Step 2: Preparation of tert-butyl (4-((5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-3-yl)oxy)butyl)carbamate A mixture of tert-butyl (4-((5-bromopyridin-3-yl)oxy)butyl)carbamate (245.44 mg, 0.711 mmol, 1.2 equiv), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (200 mg, 0.592 mmol, 1 equiv), CsCO (579.11 mg, 1.78 mmol, 3 equiv), Pd(dba) (54.25 mg, 0.0593 mmol, 0.1 equiv), and XPhos (56.49 mg, 0.118 mmol, 0.2 equiv) in dioxane (1 mL) was degassed and purged with N three times, then stirred at 90 °C under N for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (4-((5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-3-yl)oxy)butyl)carbamate (337 mg, 87.4% yield) as a yellow oil. LCMS: 602.5 [M+H] + .

[0291] Step 3: Preparation of tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (4-((5-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-3-yl)oxy)butyl)carbamate (300 mg, 0.498 mmol, 1 equiv), DMAP (60.89 mg, 0.498 mmol, 1 equiv), and BocO (217.56 mg, 0.997 mmol, 229.01 μL, 2 equiv) in THF (5 mL) was added TEA (151.31 mg, 1.50 mmol, 208.12 μL, 3 equiv). The mixture was kept stirring at 25 °C for 2 h and then quenched with water (10 mL). The mixture was extracted with EtOAc (20 mL × 3), and the combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO, petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (283 mg, 73.12% yield) as a red oil. LCMS: 702.5 [M+H] + .

[0292] Step 4: Preparation of tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A mixture of tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (250 mg, 0.356 mmol, 1 equiv.) and TBAF (1 M, 1.42 mL, 4 equiv.) in THF (1 mL) was stirred at 25° C. for 16 hours. The mixture was then poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by prep-TLC (SiO, DCM:MeOH=15:1) to give tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (150 mg, 71.1% yield) as a red oil. LCMS: 588.4 [M+H] + .

[0293] Step 5: tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a mixture of tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (120 mg, 0.204 mmol, 1 equiv.), Py (80.75 mg, 1.02 mmol, 82.40 μL, 5 equiv.), and DMAP (12.47 mg, 0.102 mmol, 0.5 equiv.) in THF (1 mL) was added a solution of 4-nitrophenyl carbonochloridate (123.46 mg, 0.613 mmol, 3 equiv.) in DCM (1 mL) at 0° C. dropwise. After the addition was complete, the mixture was kept stirring at 25° C. for 12 h. The volatiles were evaporated under reduced pressure to give a residue which was purified by prep-TLC (SiO, petroleum ether / ethyl acetate=2 / 1) to give tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (134 mg, 71.0% yield) as a white solid. LCMS: 753.4 [M+H] + .

[0294] Step 6: Preparation of (1R,3S)-3-(5-((5-(4-aminobutoxy)pyridin-3-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A mixture of tert-butyl (5-(4-((tert-butoxycarbonyl)amino)butoxy)pyridin-3-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (110 mg, 0.146 mmol, 1 equiv) and TFA (0.1 mL) in DCM (0.5 mL) was stirred at 25° C. for 12 h. The volatiles were evaporated under reduced pressure to afford (1R,3S)-3-(5-((5-(4-aminobutoxy)pyridin-3-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70 mg, crude, TFA salt) as a yellow oil. LCMS: 553.3 [M+H] + .

[0295] Step 7: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((5-(4-aminobutoxy)pyridin-3-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70 mg, crude) in THF (54 mL) was added DIEA (70.16 mg, 0.543 mmol, 94.56 μL, 5 equiv.) and the mixture was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure and the remaining residue was purified by prep-TLC to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 H-5,12-Dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (31 mg, 49.3% yield) was obtained as a yellow solid. LCMS: 414.3 [M+H] + .

[0296] Step 8: (1 1 S,1 3 R,Z)-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 A solution of H-5,12-dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (26 mg, 0.0629 mmol, 1 equiv.) in formic acid (0.3 mL) was stirred at 100 °C under a N atmosphere for 0.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The remaining residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 3% to 33% B in 10 min) to give (1 1 S,1 3 R,Z)-2 1 H-5,12-Dioxa-3,10-diaza-4(3,5)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (10.69 mg, 45.8% yield) was obtained as a white solid. LCMS: 358.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.61 - 8.49 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.03 - 6.93 (m, 1H), 5.94 (s, 1H), 5.13 - 4.96 (m, 1H), 4.19 - 3.87 (m, 2H), 3.18 - 3.03 (m, 2H), 2.84 - 2.66 (m, 1H), 2.40 - 2.31 (m, 1H), 2.10 - 1.96 (m, 1H), 1.88 - 1.71 (m, 6H), 1.58 - 1.45 (m, 2H) ppm. Example 11: (1 1 S,1 3 R,Z)-2 1 Synthesis of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (compound 21) [ka]

[0297] Step 1: Preparation of tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate To a solution of (COCl) (773.68 mg, 6.10 mmol, 533.57 μL, 1.3 equiv) in DCM (10 mL) was added dropwise a solution of dimethyl sulfoxide (952.52 mg, 12.19 mmol, 952.52 μL, 2.6 equiv) in DCM (10 mL) at −78° C. under a N atmosphere. After the addition was complete, the mixture was stirred at this temperature for 30 min, and then a solution of tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1 g, 4.69 mmol, 1 equiv) in DCM (10 mL) was added dropwise at −78° C. under a N atmosphere. The reaction was maintained at this temperature for an additional 30 min, and then a solution of TEA (2.85 g, 28.13 mmol, 3.92 mL, 6 equiv) in DCM (10 mL) was added dropwise at −78° C. under a N atmosphere. After the addition was complete, the resulting mixture was first stirred at −78° C. for 30 min, then warmed to 20° C. and stirred for an additional 1 h. After complete consumption of the starting material, tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 100 mL of water and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate (1 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1 H) 7.57 - 7.71 (m, 1 H) 4.03 (q, J=7.09 Hz, 1 H) 2.12 (s, 5 H) 1.38 (s, 9 H) ppm.

[0298] Step 2: Preparation of tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate (1 g, 4.73 mmol, 1 equiv.), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.00 g, 5.21 mmol, 1.1 equiv.), and KCO (1.37 g, 9.94 mmol, 2.1 equiv.) in MeOH (10 mL) was stirred at 20 °C under a N atmosphere for 12 h. The volatiles were then removed under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL) and washed with HO (100 mL). The organic layer was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate (1.3 g, crude) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.69 (m, 1 H) 3.09 (s, 1 H) 2.12 (s, 5 H) 1.98 (s, 1 H) 1.36 (s, 9 H) ppm.

[0299] Step 3: Preparation of tert-butyl (3-((4-bromopyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate (500 mg, 2.41 mmol, 1 equiv.), 2,4-dibromopyridine (685.75 mg, 2.89 mmol, 1.2 equiv.), Pd(PPh3)4 (278.76 mg, 0.241 mmol, 0.1 equiv.), TEA (488.20 mg, 4.82 mmol, 671.53 μL, 2 equiv.), and CuI (137.83 mg, 723.70 μmol, 0.3 equiv.) in DMF (10 mL) was stirred at 40 °C for 12 h under a N2 atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL) and washed with HO (100 mL). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (3-((4-bromopyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (546 mg, 62.3% yield) as a yellow solid. LCMS: 363.0 [M+H] + .

[0300] Step 4: Preparation of tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-((4-bromopyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (250 mg, 0.688 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (348.50 mg, 1.03 mmol, 1.5 equiv.), Xantphos (79.64 mg, 0.138 mmol, 0.2 equiv.), Pd(dba) (63.02 mg, 0.0688 mmol, 0.1 equiv.), and CsCO (672.72 mg, 2.06 mmol, 3 equiv.) in dioxane (5 mL) was stirred at 90 °C under a N atmosphere for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, rinsed with dioxane (10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to produce tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (346 mg, 81.1% yield) as a yellow oil. LCMS: 620.5 [M+H] + .

[0301] Step 5: Preparation of tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (346 mg, 0.558 mmol, 1 equiv) and Pt / C (5%, 500 mg) in THF (6 mL) was degassed and back-filled with H three times, then stirred under an atmosphere of H (15 Psi) at 20 °C for 1 h. After completion of the reaction, the solid was filtered off and rinsed with THF (5 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (280 mg, crude) as a deep brown oil. LCMS: 624.4 [M+H] + .

[0302] Step 6: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (200 mg, 0.321 mmol, 1 equiv), BocO (104.94 mg, 0.481 mmol, 110.46 μL, 1.5 equiv), and DMAP (3.92 mg, 0.0321 mmol, 0.1 equiv) in THF (6 mL) was added TEA (97.31 mg, 0.962 mmol, 133.85 μL, 3 equiv), and the mixture was stirred at 40° C. under a N atmosphere for 2 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The remaining residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (180 mg, 77.5% yield) as a red oil. LCMS: 724.5 [M+H] + .

[0303] Step 7: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A mixture of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (170 mg, 0.235 mmol, 1 equiv.) and TBAF (245.55 mg, 0.939 mmol, 4 equiv.) in THF (3 mL) was stirred at 20° C. for 12 h. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in 100 mL of EtOAc. The organic phase was washed with water (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (210 mg, crude) was obtained as a yellow oil. LCMS: 610.3 [M+H] + .

[0304] Step 8: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 0.328 mmol, 1 equiv.), Py (129.72 mg, 1.64 mmol, 132.36 μL, 5 equiv.), and DMAP (20.03 mg, 0.164 mmol, 0.5 equiv.) in DCM (4 mL) was added 4-nitrophenylcarbonochloridate (198.33 mg, 0.984 mmol, 3 equiv.), and the mixture was stirred at 20° C. under a N atmosphere for 12 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 52.5% yield) as a white solid. LCMS: 775.4 [M+H] + .

[0305] Step 9: Preparation of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (71 mg, 0.0916 mmol, 1 equiv) and TFA (1.54 g, 13.46 mmol, 1 mL, 146.93 equiv) in DCM (3 mL) was stirred at 20 °C under a N atmosphere for 7 h. The volatiles were evaporated under reduced pressure to give (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (118 mg, crude) as a yellow oil. LCMS: 575.3 [M+H] + .

[0306] Step 10: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 Preparation of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one To a solution of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (113 mg, 0.197 mmol, 1 equiv.) in DMSO (56 mL) was added DIEA (1.06 g, 8.17 mmol, 1.42 mL, 41.57 equiv.) and the mixture was stirred at 100° C. under a N atmosphere for 2 h. The mixture was then cooled to room temperature and the volatiles were removed under reduced pressure. The remaining residue was dissolved in 100 mL of ethyl acetate and washed with 30 mL of water. The organic phase was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give (11 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 H-10-Oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (60 mg, crude) was obtained as a yellow oil. LCMS: 436.3 [M+H] + .

[0307] Step 11: (1 1 S,1 3 R,Z)-2 1 Preparation of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-2 1 A solution of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (50 mg, 0.115 mmol, 1 equiv.) in formic acid (1 mL) was stirred at 100 °C under N atmosphere for 2 h. The mixture was then cooled to room temperature, and the volatiles were evaporated under reduced pressure. The crude product was purified by Prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (NH . HO)-ACN]; B%: 10% to 90%, 20 min) and purified (1 1 S,1 3 R,Z)-2 1 H-10-Oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (11.49 mg, 25.4% yield) was obtained as a white solid. LCMS: 380.3 [M+H] + ;1 H NMR (400 MHz, DMSO-d6) δ 12.08 - 12.16 (m, 1 H), 8.63 (s, 1 H), 8.03 (d, J=5.62 Hz, 1 H), 7.40 (s, 1 H), 6.75 (d, J=1.83 Hz, 1 H), 6.55 (dd, J=5.56, 2.02 Hz, 1 H), 6.00 (s, 1 H), 5.13 (br d, J=5.14 Hz, 1 H), 3.17 - 3.24 (m, 1 H), 2.54 (br d, J=6.97 Hz, 2 H), 1.93 - 2.02 (m, 1 H), 1.86 - 1.91 (m, 2 H), 1.68 - 1.83 (m, 11 H) ppm. Example 12: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 Synthesis of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (compound 20) [ka]

[0308] Step 1: Preparation of 2,4-dibromo-6-(difluoromethyl)pyridine A solution of 4-bromo-2-(difluoromethyl)pyridine 1-oxide (1.5 g, 6.70 mmol, 1 equiv.) in POBr (15 mL) was stirred at 100 °C for 1 h under a N atmosphere. After the reaction was complete, the mixture was cooled to room temperature and carefully poured into saturated aqueous NaCO (30 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was concentrated to give a residue that was purified by column chromatography. The desired 2,4-dibromo-6-(difluoromethyl)pyridine (582 mg, 30.4% yield) was obtained as a yellow solid.1 HNMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.64 - 7.59 (m, 1H), 4.05 - 4.00 (m, 1H), 2.11 (s, 5H), 1.37 (s, 9H) ppm.

[0309] Step 2: Preparation of tert-butyl (3-((4-bromo-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate (350 mg, 1.69 mmol, 1 equiv.), 2,4-dibromo-6-(difluoromethyl)pyridine (581.36 mg, 2.03 mmol, 1.2 equiv.), CuI (96.48 mg, 0.50 mmol, 0.3 equiv.), TEA (341.75 mg, 3.38 mmol, 2 equiv.), and Pd(PPh3)4 (195.13 mg, 0.16 mmol, 0.1 equiv.) in DMF (10 mL) was stirred at 40 °C for 12 h under a N2 atmosphere. After completion of the reaction, the mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by pre-TLC (PE:EA=3:1) to give tert-butyl (3-((4-bromo-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (400 mg, 57.3% yield) as a yellow solid. LCMS: 413.1, 415.1 [M+H] + .

[0310] Step 3: Preparation of tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-((4-bromo-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (400 mg, 0.96 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (392.09 mg, 1.15 mmol, 1.2 equiv.), Xantphos (112.01 mg, 0.18 mmol, 0.2 equiv.), Pd(dba) (88.63 mg, 0.09 mmol, 0.1 equiv.), and CsCO (946.10 mg, 2.90 mmol, 3 equiv.) in dioxane (8 mL) was stirred at 90 °C for 1 h under a N atmosphere. After the reaction was complete, the reaction was cooled to room temperature. The mixture was filtered through a pad of Celite and rinsed with ethyl acetate (30 ml). The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography. The desired tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (613 mg, 94.6% yield) was obtained as a yellow solid. LCMS: 670.3 [M+H] + .

[0311] Step 4: Preparation of tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate (520 mg, 0.77 mmol, 1 equiv) and Pt / C (5%, 700 mg) in THF (10 mL) was degassed and backfilled with H three times, then stirred under H (15 Psi) at 25 °C for 1 h. After the reaction was complete, the reaction mixture was filtered through a pad of Celite and rinsed with THF (10 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (515 mg, 0.76 mmol) as a yellow oil, which was used in the next step without further purification. LCMS: 674.5 [M+H] + .

[0312] Step 5: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (515 mg, 0.76 mmol, 1 equiv) in DCM (12 mL) was added BocO (153.01 mg, 1.14 mmol, 0.26 mL, 1.5 equiv), DMAP (9.40 mg, 0.07 mmol, 0.1 equiv) and TEA (141.89 mg, 2.29 mmol, 0.32 mL, 3 equiv), and the mixture was stirred at 25 °C under a N atmosphere for 1 h. After the reaction was completed, the volatiles were removed in vacuo. The resulting residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (382 mg, 64.6% yield) as a yellow oil. LCMS: 774.4 [M+H] + .

[0313] Step 6: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (382 mg, 0.49 mmol, 1 equiv.) in THF (8.5 mL) was added TBAF (457.5 mg, 1.75 mmol, 4 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 7 hours. After completion of the reaction, the mixture was quenched with HO (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. Crude tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (330 mg) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 660.3 [M+H] + .

[0314] Step 7: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (330 mg, 0.50 mmol, 1 equiv) in DCM (7 mL) was added 4-nitrophenyl carbonochloridate (302.44 mg, 1.50 mmol, 3 equiv), DMAP (30.55 mg, 0.25 mmol, 0.5 equiv) and pyridine (237.37 mg, 3.00 mmol, 0.24 mL, 6 equiv), and the mixture was stirred at 25 °C under a N atmosphere for 12 h. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (174 mg, 0.21 mmol, 42.2% yield) as a yellow oil. LCMS: 825.4 [M+H] + .

[0315] Step 8: Preparation of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (164 mg, 0.19 mmol, 1 equiv) in DCM (7.3 mL) was added TFA (3.57 g, 31.35 mmol, 2.33 mL, 157.69 equiv) and the mixture was stirred at 25° C. under a N atmosphere for 12 h. After the reaction was complete, the mixture was concentrated in vacuo to give crude (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (260 mg, 0.42 mmol) as a yellow oil, which was used in the next step without further purification. LCMS: 625.3 [M+H] + .

[0316] Step 9: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 Preparation of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one To a solution of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethyl)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (260 mg, 0.41 mmol, 1 equiv.) in DMSO (130 mL) was added DIEA (0.53 g, 4.16 mmol, 0.72 mL, 10 equiv.) and the mixture was stirred at 100° C. for 1 h under N atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with H O (200 mL), and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The crude (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 H-10-Oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (90 mg, 0.18 mmol) was obtained as a yellow oil. LCMS: 486.3 [M+H] + . Step 10: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 Preparation of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1A solution of H-10-oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (90 mg, 0.18 mmol, 1 equiv.) in formic acid (4 mL) was stirred at 100°C under a N2 atmosphere for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 um; mobile phase: [water (NH3 . HO)-ACN]; B%: 10% to 90%, 20 min) and purified (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 H-10-Oxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-7(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacyclodecaphan-9-one (33.53 mg, 40.7% yield) was obtained as a white solid. LCMS: 430.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 1H), 8.97 (s, 1H), 7.41 (s, 1H), 6.90 - 6.54 (m, 3H), 6.03 (s, 1H), 5.14 - 5.12 (m, 1H), 3.40 - 3.35 (m, 1H), 3.26 - 3.17 (m, 1H), 2.60 (br d, J = 8.0 Hz, 2H), 1.99 (br dd, J = 6.6, 11.7 Hz, 1H), 1.88 (br d, J = 8.8 Hz, 2H), 1.82 (br d, J = 8.8 Hz, 2H) s, 2H), 1.78 (br d, J = 4.0 Hz, 1H), 1.77 - 1.68 (m, 7H) ppm. Example 13: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (compound 23) [ka]

[0317] Step 1: Preparation of tert-butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of 4-bromo-6-(difluoromethyl)pyridin-2-ol (125 mg, 0.56 mmol, 1 equiv.) and tert-butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (152.21 mg, 0.67 mmol, 1.2 equiv.) in toluene (3 mL), 2-(tributyl-phosphanylidene)acetonitrile (202.02 mg, 0.84 mmol, 1.5 equiv.) was added, and the mixture was stirred at 80° C. for 12 hours under a N atmosphere. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (200 mg, 721.9% yield) as a yellow oil. LCMS: 376.7 [M+H] + .

[0318] Step 2: Preparation of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (185 mg, 0.43 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazole- A mixture of 5-amine (144.13 mg, 0.43 mmol, 1 equiv.), Pd(dba) (39.10 mg, 0.042 mmol, 0.1 equiv.), Xantphos (37.06 mg, 0.064 mmol, 0.15 equiv.), and CsCO (417.35 mg, 1.28 mmol, 3 equiv.) in dioxane (6 mL) was stirred at 80 °C for 6 h under a N atmosphere. After the reaction was complete, the mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by Prep-TLC (PE:EA=3:1) to give tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (230 mg, 74.2% yield) as an orange solid. LCMS: 690.4 [M+H] + ; 1H NMR (400 MHz, chloroform-d) δ = 6.52 - 6.18 (m, 2H), 5.97 (s, 1H), 5.87 (d, J = 1.0 Hz, 1H), 5.33 (s, 1H), 4.20 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 8.4 Hz, 1H), 2.34 - 2.21 (m, 1H), 1.94 - 1.85 (m, 8H), 1.82 - 1.74 (m, 2H), 1.67 - 1.55 (m, 4H), 1.50 (s, 9H), 1.38 (s, 9H), 0.82 (s, 9H), 0.05 (d, J = 3.1 Hz, 6H) ppm.

[0319] Step 3: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)ethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (220 mg, 0.32 mmol, 1 equiv.) in THF (6 mL) was added BocO (139.18 mg, 0.64 mmol, 2 equiv.), DMAP (38.96 mg, 0.32 mmol, 1 equiv.), and TEA (96.80 mg, 0.95 mmol, 3 equiv.), and the mixture was stirred at 25° C. under a N atmosphere for 2 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether:ethyl acetate=3:1) to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (230 mg, 83.1% yield) as a yellow oil. LCMS: 791.6 [M+H] + .

[0320] Step 4: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (210 mg, 0.26 mmol, 1 equiv.) and TBAF (1 M, 1.06 mL, 4 equiv.) in THF (3 mL) was stirred at 25° C. for 12 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (130 mg, 65.1% yield) as a yellow oil. LCMS: 676.5 [M+H] + .

[0321] Step 5: Preparation of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (110 mg, 0.16 mmol, 1 equiv.) in THF (2 mL) was added pyridine (64.38 mg, 0.81 mmol, 5 equiv.) and DMAP (9.94 mg, 0.08 mmol, 0.5 equiv.), followed by a solution of 4-nitrophenyl carbonochloridate (98.43 mg, 0.488 mmol, 3 equiv.) in DCM (2 mL) at 0 °C under a N atmosphere. After the addition was complete, the mixture was stirred under N2 atmosphere at 20°C for 3 hours, and then the volatiles were removed under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether:ethyl acetate = 3:1) to give tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (130 mg, 64.6% yield) as a yellow oil. LCMS: 841.5 [M+H] + .

[0322] Step 6: Preparation of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (120 mg, 0.14 mmol, 1 equiv) and TFA (1.54 g, 13.46 mmol, 94.34 equiv) in DCM (4 mL) was stirred at 20° C. for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (90 mg) as a yellow oil, which was used in the next step without further purification. LCMS: 641.4 [M+H] + .

[0323] Step 7: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one To a solution of (1R,3S)-3-(5-((2-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (80 mg, 0.12 mmol, 1 equiv.) in DMF (10 mL) was added TEA (252.71 mg, 2.50 mmol, 20 equiv.) and the mixture was stirred at 100° C. under N atmosphere for 0.5 h. After the starting material was consumed, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1 H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (80 mg, 0.16 mmol) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: 502.4 [M+H] + .

[0324] Step 8: (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-2 1A solution of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (70 mg, 0.14 mmol, 1 equiv.) in formic acid (1 mL) was stirred at 100 °C under a N atmosphere for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC Triart C18 150 × 25 mm × 5 μm; mobile phase: [water (FA)-ACN]; gradient: 34% to 64% B in 10 min) to give (1 1 S,1 3 R,Z)-4 6 -(difluoromethyl)-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (33.06 mg, 53.1% yield) was obtained as a white solid. LCMS: 446.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ = 12.36 - 12.13 (m, 1H), 9.13 (s, 1H), 7.43 (s, 1H), 6.82 - 6.54 (m, 2H), 6.34 (s, 1H), 6.03 (s, 1H), 5.05 - 5.14 (m, 1H), 4.29 - 4.18 (m, 2H), 3.21 - 3.08 (m, 1H), 2.64 - 2.52 (m, 1H), 1.97 - 1.90 (m, 1H), 1.88 -1.73 (m, 10H), 1.71 - 1.60 (m, 2H) ppm. Example 14: Synthesis of (1'S,3'R,6'R,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (Compound 109) and (1'S,3'R,6'S,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (Compound 110) [ka]

[0325] Step 1: Preparation of (E)-3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)ethyl acrylate A mixture of tert-butyl (1-formylcyclopropyl)carbamate (1.7 g, 9.18 mmol, 1 equiv.) and ethyl 2-(triphenyl-phosphanylidene)acetate (3.52 g, 10.10 mmol, 1.1 equiv.) in DCM (15 mL) was stirred under a N atmosphere at 20° C. for 12 h. After the reaction was complete, the mixture was filtered and rinsed with DCM (30 mL). The combined filtrate was concentrated to give a residue that was purified by column chromatography. The desired (E)-ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)acrylate (2.2 g, 58.5% yield) was obtained as a yellow oil. LCMS: 156.2 [M+H-100] + .

[0326] Step 2: Preparation of ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoate To a solution of (E)-ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)acrylate (2.2 g, 8.62 mmol, 1 equiv) in EtOAc (50 mL) was added Pd / C (140 mg, 10% purity). The mixture was degassed and backfilled with H three times and then stirred under an atmosphere of H (15 psi) at 20 °C for 2 h. The reaction mixture was then filtered through a short pad of Celite and rinsed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to give ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoate (2.0 g, 72.2% yield) as a yellow oil. 1 HNMR (400 MHz, chloroform-d) δ 4.22 - 4.16 (m, 2H), 2.52 - 2.41 (m, 2H), 1.93 (br s, 2H), 1.50 (br s, 9H), 1.34 - 1.31 (m, 3H), 0.82 (br s, 2H), 0.70 (br s, 2H) ppm.

[0327] Step 3: Preparation of 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoic acid To a solution of ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoate (1.0 g, 3.89 mmol, 1 equiv.) in THF (20 mL) and HO (20 mL) was added LiOH.HO (652.30 mg, 15.54 mmol, 4 equiv.), and the mixture was stirred at 25 °C for 16 h. The mixture was then acidified with 0.5 N HCl to pH = 3 and extracted with EtOAc (20 mL x 2). The combined organic phases were dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure to give 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoic acid (880 mg, 1.74 mmol) as a yellow oil, which was used in the next step without further purification. LCMS: 251.9 [M+Na] + .

[0328] Step 4: Preparation of tert-butyl (1-(3-(methoxy(methyl)amino)-3-oxopropyl)cyclopropyl)carbamate To a solution of 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoic acid (850 mg, 3.71 mmol, 1 equiv) in DCM (20 mL) was added DIEA (1.44 g, 11.12 mmol, 1.94 mL, 3 equiv), HATU (2.11 g, 5.56 mmol, 1.5 equiv), and N-methoxymethanamine hydrochloride (542.45 mg, 5.56 mmol, 1.5 equiv) and the mixture was stirred at 20 °C for 12 h until the reaction was complete. The mixture was poured into saturated aqueous NaHCO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated. The resulting crude product was purified by column chromatography to give the desired tert-butyl (1-(3-(methoxy(methyl)amino)-3-oxopropyl)cyclopropyl)carbamate (1.2 g, 83.2% yield) as a yellow oil. 1 HNMR (400 MHz, chloroform-d) δ 3.65 - 3.59 (m, 3H), 3.11 (s, 3H), 2.55 - 2.38 (m, 2H), 1.85 - 1.70 (m, 2H), 1.36 (br s, 9H), 0.69 (br s, 2H), 0.57 (br s, 2H) ppm.

[0329] Step 5: Preparation of tert-butyl (1-(3-oxobutyl)cyclopropyl)carbamate To a solution of tert-butyl (1-(3-(methoxy(methyl)amino)-3-oxopropyl)cyclopropyl)carbamate (1.1 g, 4.04 mmol, 1 equiv.) in THF (20 mL) was added MeMgBr (3 M, 4.04 mL, 3 equiv.) slowly at 0 °C. After completion of the addition, the mixture was kept stirring at 0 °C for 1 h. The reaction was then quenched with saturated aqueous NH Cl (20 mL). The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na SO , filtered, and the filtrate was concentrated. The resulting crude was purified by column chromatography to give the desired tert-butyl (1-(3-oxobutyl)cyclopropyl)carbamate (450 mg, 44.1% yield) as a yellow oil. 1 HNMR (400 MHz, chloroform-d) δ 2.53 (t, J = 7.6 Hz, 2H), 2.09 (s, 3H), 1.73 (br t, J = 6.7 Hz, 2H), 1.36 (br d, J = 4.4 Hz, 9H), 0.69 (br s, 2H), 0.60 - 0.50 (m, 2H) ppm.

[0330] Step 6: Preparation of tert-butyl (1-(3-hydroxybutyl)cyclopropyl)carbamate To a solution of tert-butyl (1-(3-oxobutyl)cyclopropyl)carbamate (450 mg, 1.98 mmol, 1 equiv.) in MeOH (10 mL) was added NaBH (89.88 mg, 2.38 mmol, 1.2 equiv.) portionwise at 0 °C under a N atmosphere. After completion of the addition, the mixture was stirred at 0 °C for 2 h until the reaction was complete. The reaction mixture was quenched with saturated aqueous NH Cl (10 mL) at 0 °C and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (1-(3-hydroxybutyl)cyclopropyl)carbamate (300 mg, 59.5% yield) as a yellow oil. 1HNMR (400 MHz, methanol-d4) δ 4.93 - 4.86 (m, 3H), 3.83 - 3.69 (m, 1H), 3.34 (br s, 2H), 1.53 - 1.39 (m, 9H), 1.24 - 1.10 (m, 2H), 0.69 (br d, J = 5.5 Hz, 2H), 0.60 (br d, J = 6.8 Hz, 2H) ppm.

[0331] Step 7: Preparation of tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)butyl)cyclopropyl)carbamate To a solution of tert-butyl (1-(3-hydroxybutyl)cyclopropyl)carbamate (300 mg, 1.31 mmol, 1 equiv) and 4-bromo-2-fluoro-pyridine (230.23 mg, 1.31 mmol, 1 equiv) in DMF (10 mL) was added t-BuOK (220.20 mg, 1.96 mmol, 1.5 equiv) and the mixture was stirred at 0° C. under a N atmosphere for 1 h. The mixture was then concentrated, and the resulting crude was purified by prep-HPLC (column: YMC Triart C18 150×25 mm×5 um; mobile phase: [water (FA)-ACN]; gradient: 60% to 90% B in 10 min) to give tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)butyl)cyclopropyl)carbamate (400 mg, 79.4% yield) as a yellow oil. LCMS: 385.1, 387.1 [M+H] + .

[0332] Step 8: Preparation of tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)butyl)cyclopropyl)carbamate A mixture of tert-butyl (1-(3-((4-bromopyridin-2-yl)oxy)butyl)cyclopropyl)carbamate (280 mg, 0.73 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (245.32 mg, 0.73 mmol, 1 equiv.), Pd(dba) (66.55 mg, 0.073 mmol, 0.1 equiv.), Xantphos (84.10 mg, 0.15 mmol, 0.2 equiv.), and CsCO (710.33 mg, 2.18 mmol, 3 equiv.) in dioxane (5 mL) was heated and stirred at 90 °C for 1 h under a N atmosphere. The reaction mixture was then cooled to room temperature, filtered through a short pad of Celite, and rinsed with dioxane (10 mL). The combined filtrate was concentrated, and the resulting residue was purified by prep-TLC (PE / EA=2 / 1) to give tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)butyl)cyclopropyl)carbamate (250 mg, 48.2% yield) as a yellow solid. LCMS: 642.5 [M+H] + .

[0333] Step 9: Preparation of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (1-(3-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)butyl)cyclopropyl)carbamate (250 mg, 0.39 mmol, 1 equiv) in DCM (10 mL) was added DMAP (47.58 mg, 0.39 mmol, 1 equiv) and BocO (169.99 mg, 0.78 mmol, 0.18 mL, 2 equiv), and the mixture was stirred at 25° C. under a N atmosphere for 1 h. The mixture was then concentrated, and the resulting residue was purified by prep-TLC (PE / EA=2 / 1) to give tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 0.36 mmol, 90.0% purity) as a yellow solid. LCMS: 742.5 [M+H] + . Step 10: Preparation of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 0.40 mmol, 1 equiv.) and TBAF (1 M, 0.81 mL, 2 equiv.) in THF (6 mL) was stirred at 60° C. under a N atmosphere for 2 h. After the reaction was complete, the mixture was cooled to room temperature. The mixture was concentrated, and the resulting residue was purified by prep-TLC (PE / EA=1 / 1) to give tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (220 mg, 86.7% yield) as a yellow solid. LCMS: 628.4 [M+H] + .

[0334] Step 11: Preparation of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (220 mg, 0.35 mmol, 1 equiv.) in THF (3 mL) was added DMAP (21.41 mg, 0.17 mmol, 0.5 equiv.) and pyridine (138.59 mg, 1.75 mmol, 0.14 mL, 5 equiv.), followed by a solution of 4-nitrophenylcarbonochloridate (211.90 mg, 1.05 mmol, 3 equiv.) in DCM (3 mL). After the addition was complete, the mixture was stirred at 20° C. under a N atmosphere for 12 h. The mixture was concentrated, and the resulting residue was purified by prep-TLC (PE / EA=2 / 1) to give tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (250 mg, 89.9% yield) as a yellow solid. LCMS: 793.5 [M+H] + .

[0335] Step 12: (1R,3S)-3-(5-((2-((4-(1-aminocyclopropyl)butan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-((4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)butan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (250 mg, 0.32 mmol, 1 equiv) and TFA (3.07 g, 26.92 mmol, 2 mL, 85.40 equiv) in DCM (8 mL) was stirred at 20 °C under a N atmosphere for 2 h. After completion of the reaction, the volatiles are removed under reduced pressure to give crude (1R,3S)-3-(5-((2-((4-(1-aminocyclopropyl)butan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (200 mg) as a yellow oil, which was used in the next step without further purification. LCMS: 593.4 [M+H] + .

[0336] Step 13: (1'S,3'R,6'R,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one and (1'S,3'R,6'S,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one To a solution of (1R,3S)-3-(5-((2-((4-(1-aminocyclopropyl)butan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (150 mg, 0.25 mmol, 1 equiv.) in DMSO (40 mL) was added TEA (128.05 mg, 1.27 mmol, 0.17 mL, 5 equiv.), and the mixture was stirred at 100° C. under a N atmosphere for 0.5 h. The mixture was then cooled to room temperature and concentrated under high vacuum. The obtained crude product was purified by prep-TLC (PE / EA=0 / 1) to give (1'S,3'R,6'R,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (25 mg, 22.3% yield) as a yellow solid. Two isolated isomers were obtained: (1'S,3'R,6'S,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (30 mg, 0.066 mmol, 26.4% yield) as a yellow solid. LCMS: 454.5 [M+H] + .

[0337] Step 14: Preparation of (1'S,3'R,6'R,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (Compound 109) A solution of (1'S,3'R,6'R,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (25 mg, 0.055 mmol, 1 equiv) in formic acid (0.2 mL) was stirred at 100 °C under a N atmosphere for 0.5 h. The mixture was cooled to room temperature and concentrated to give a crude product, which was purified by reverse phase column (0.1% FA) to give (1'S,3'R,6'R,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (14.48 mg, 66.3% yield) as a white solid. LCMS: 398.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (br s, 1H), 8.99 - 8.81 (m, 1H), 8.30 - 8.16 (m, 1H), 7.75 (br d, J = 5.1 Hz, 1H), 7.61 - 7.09 (m, 1H), 6.46 - 6.37 (m, 1H), 6.33 - 6.26 (m, 1H), 6.26 - 6.25 (m, 1H), 6.10 - 5.86 (m, 1H), 5.07 - 4.90 (m, 1H), 4.89 - 4.23 (m, 1H), 3.24 (br s, 1H), 2.36 (br s, 1H), 2.12 - 1.86 (m, 4H), 1.81 - 1.46 (m, 5H), 1.31 - 1.15 (m, 3H), 0.65 - 0.47 (m, 4H) ppm.

[0338] Step 14: Preparation of (1'S,3'R,6'S,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (compound 110) A solution of (1'S,3'R,6'S,Z)-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazolam-1(1,3)-cyclopentanacyclododecaphane]-11'-one (30.00 mg, 0.066 mmol, 1 equiv) in formic acid (0.2 mL) was stirred at 100 °C for 0.5 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated to give the crude product, which was purified by reverse phase column (0.1% FA) to give (1'S,3'R,6'S,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one (10.98 mg, 41.9% yield) as a white solid. LCMS: 398.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 9.02 - 8.83 (m, 1H), 8.22 (br d, J = 2.0 Hz, 1H), 7.72 (d, J = 5.5 Hz, 1H), 7.63 - 7.51 (m, 1H), 6.48 - 6.27 (m, 2H), 6.11 - 5.99 (m, 1H), 5.25 - 4.97 (m, 1H), 4.65 - 4.31 (m, 1H), 3.23 - 3.15 (m, 1H), 2.45 - 2.39 (m, 1H), 2.10 - 2.00 (m, 2H), 1.99 - 1.89 (m, 1H), 1.83 - 1.73 (m, 3H), 1.63 (br dd, J = 4.6, 7.6 Hz, 2H), 1.20 - 1.11 (m, 3H), 1.06 - 0.92 (m, 1H), 0.66 - 0.53 (m, 3H), 0.51 - 0.40 (m, 1H) ppm. Example 15: (1 1 S,1 3 R,6R,Z)-6-methyl-2 1H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 11) and (1 1 S,1 3 R,6S,Z)-6-Methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 12) [ka]

[0339] Step 1: Preparation of tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)carbamate A mixture of 4-((tert-butoxycarbonyl)amino)butanoic acid (5 g, 24.60 mmol, 1 equiv), HATU (14.03 g, 36.90 mmol, 1.5 equiv), DIEA (9.54 g, 73.81 mmol, 12.86 mL, 3 equiv), and N,O-dimethylhydroxylamine hydrochloride (3.60 g, 36.90 mmol, 1.5 equiv) in DMF (60 mL) was stirred at 25 °C for 12 h. The reaction mixture was then diluted with HO (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)carbamate (6 g, 99.0% yield). 1 HNMR (400 MHz, DMSO-d6) δ 6.84 - 6.82 (br t, J = 5.3 Hz, 1H), 3.64 (s, 3H), 3.07 (s, 3H), 2.95 - 2.92 (m, 2H), 2.69 (s, 9H), 2.37 - 2.34 (m, 2H), 1.62 - 1.55 (m, 2H), 1.37 (s, 9H) ppm.

[0340] Step 2: Preparation of tert-butyl (4-oxopentyl)carbamate To a solution of tert-butyl (4-(methoxy(methyl)amino)-4-oxobutyl)carbamate (1 g, 4.06 mmol, 1 equiv.) in THF (20 mL) at 0 °C under a N atmosphere, MeMgBr (3 M, 4.06 mL, 3 equiv.) was added slowly. After completion of the addition, the mixture was stirred at 0 °C under a N atmosphere for 1 h, and then the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (4-oxopentyl)carbamate (465 mg, 56.9% yield). 1 HNMR (400 MHz, DMSO-d6) δ 6.79 (m, 1H), 2.89 - 2.84 (m, 2H), 2.83 - 2.42 (t, J = 7.2 Hz, 2H), 2.06 (s, 3H), 1.57 - 1.50 (m, 2H), 1.37 (s, 9H) ppm.

[0341] Step 3: Preparation of tert-butyl (4-hydroxypentyl)carbamate To a solution of tert-butyl (4-oxopentyl)carbamate (465 mg, 2.31 mmol, 1 equiv.) in EtOH (10 mL) was added NaBH (174.82 mg, 4.62 mmol, 2 equiv.) portionwise at 0 °C under a N atmosphere. After completion of the addition, the mixture was stirred at 30 °C under a N atmosphere for 3 h. The reaction mixture was then quenched with saturated aqueous NH Cl (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (4-hydroxypentyl)carbamate (530 mg, 99.7% yield). 1HNMR (400 MHz, DMSO-d6) δ 6.75 (br d, J = 4.6 Hz, 1H), 4.35 - 4.31 (m, 1H), 3.58 - 3.52 (m, 1H), 2.90 - 2.85 (m, 2H), 1.37 (s, 11H), 1.31 - 1.14 (m, 2H), 1.11 - 0.99 (m, 3H) ppm.

[0342] Step 4: Preparation of tert-butyl (4-((4-bromopyridin-2-yl)oxy)pentyl)carbamate To a solution of tert-butyl (4-hydroxypentyl)carbamate (470 mg, 2.31 mmol, 1 equiv.) and 4-bromo-2-fluoro-pyridine (406.90 mg, 2.31 mmol, 1 equiv.) in THF (10 mL) was added t-BuOK (389.17 mg, 3.47 mmol, 1.5 equiv.) at 0 °C, and the mixture was warmed to 30 °C and stirred under a N atmosphere for 12 h. After the starting material was consumed, the reaction mixture was filtered through a pad of Celite and rinsed with THF (10 mL). The combined filtrate was concentrated under reduced pressure to give a residue that was purified by prep-TLC. The desired tert-butyl (4-((4-bromopyridin-2-yl)oxy)pentyl)carbamate (640 mg, 74.0% yield) was obtained. LCMS: 359.1, 361.1 [M+H] + .

[0343] Step 5: Preparation of tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentyl)carbamate A mixture of tert-butyl (4-((4-bromopyridin-2-yl)oxy)pentyl)carbamate (390 mg, 1.09 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (366.46 mg, 1.09 mmol, 1 equiv.), Xantphos (103.50 mg, 0.21 mmol, 0.2 equiv.), CsCO (1.06 g, 3.26 mmol, 3 equiv.), and Pd(dba) (99.41 mg, 0.11 mmol, 0.1 equiv.) in dioxane (5 mL) was stirred at 90 °C under a N atmosphere for 12 h. After the reaction was complete, the mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with ethyl acetate (30 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentyl)carbamate (450 mg, 67.3% yield). LCMS: 616.6 [M+H] + .

[0344] Step 6: Preparation of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (4-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)oxy)pentyl)carbamate (450 mg, 0.73 mmol, 1 equiv.) in THF (6 mL), BocO (478.36 mg, 2.19 mmol, 3 equiv.), TEA (332.69 mg, 3.29 mmol, 457.61 μL, 4.5 equiv.), and DMAP (133.89 mg, 1.10 mmol, 1.5 equiv.) were added at 0° C., and the mixture was then warmed to 50° C. and stirred for 12 hours under a N atmosphere. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (220 mg, 42.1% yield). LCMS: 716.5 [M+H] + .

[0345] Step 7: Preparation of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (220 mg, 0.31 mmol, 1 equiv.) in THF (4 mL) was added TBAF (1 M in THF, 0.8 mL, 2.6 equiv.), and the mixture was stirred at 60° C. for 2 hours under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=3 / 1) to give tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (145 mg, 78.4% yield). LCMS: 602.4 [M+H] + .

[0346] Step 8: Preparation of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (145 mg, 0.24 mmol, 1 equiv) in DCM (2 mL) was added pyridine (114.36 mg, 1.45 mmol, 0.12 mL, 6 equiv) and DMAP (14.72 mg, 0.12 mmol, 0.5 equiv), followed by a solution of 4-nitrophenyl carbonochloridate (242.84 mg, 1.20 mmol, 5 equiv) in DCM (2 mL) at 0 °C under N atmosphere. After the addition was complete, the mixture was warmed to 30 °C and stirred under N atmosphere for 12 h. The mixture was then cooled to room temperature, diluted with H2O (20 mL), and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate = 6 / 1) to give tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (150 mg, 81.2% yield). LCMS: 767.4 [M+H] + .

[0347] Step 9: Preparation of (1R,3S)-3-(5-((2-((5-aminopentan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of tert-butyl (2-((5-((tert-butoxycarbonyl)amino)pentan-2-yl)oxy)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (150 mg, 0.19 mmol, 1 equiv) in DCM (3 mL) was added TFA (914.90 mg, 8.02 mmol, 0.60 mL, 41.02 equiv) and the mixture was stirred at 30° C. under a N atmosphere for 12 h. The reaction mixture was then concentrated under reduced pressure to give the desired crude (1R,3S)-3-(5-((2-((5-aminopentan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg, 90.2% yield). LCMS: 567.4 [M+H] + .

[0348] Step 10: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-6-methyl-2 1 Preparation of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-((5-aminopentan-2-yl)oxy)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (100 mg, 0.18 mmol, 1 equiv.) in THF (20 mL) was added TEA (357.15 mg, 3.53 mmol, 0.49 mL, 20 equiv.), and the mixture was stirred at 20° C. under N atmosphere for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=1 / 1) to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-6-methyl-2 1H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (55 mg, 72.9% yield) was obtained. LCMS: 428.4 [M+H] + .

[0349] Step 11: (1 1 S,1 3 R,6R,Z)-6-methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 11) and (1 1 S,1 3 R,6S,Z)-6-Methyl-2 1 H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 12 (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-6-methyl-2 1 A solution of H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (55 mg, 0.128 mmol, 1 equiv.) in HCOOH (2 mL) was stirred at 100 °C under N atmosphere for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature and adjusted to pH = 10 with saturated NH₃·H₂O. The volatiles were then removed under reduced pressure. The resulting residue was purified by prep-TLC (dichloromethane:methanol = 10:1) and further purified by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO₂-MeOH (0.1% NH₃·H₂O)]; B%: 50%, isocratic elution mode) to give (1 1 S,1 3 R,6R,Z)-6-methyl-2 1H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (11.28 mg, 22.9% yield) and (1 1 S,1 3 R,6S,Z)-6-Methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (8.45 mg, 17.0% yield) was obtained. (1 1 S,1 3 R,6R,Z)-6-methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one LCMS: 372.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.15 - 12.01 (m, 1H), 8.93 - 8.82 (m, 1H), 7.72 (br d, J = 5.0 Hz, 1H), 6.85 - 6.65 (m, 1H), 6.43 - 6.38 (m, 1H), 6.33 - 6.24 (m, 1H), 6.02 - 5.92 (m, 1H), 5.16 - 4.94 (m, 1H), 3.01 - 2.75 (m, 2H), 2.09 - 1.93 (m, 2H), 1.83 - 1.73 (m, 4H), 1.56 - 1.42 (m, 3H), 1.28 - 1.19 (m, 6H) ppm. (1 1 S,1 3 R,6S,Z)-6-Methyl-2 1 H-5,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one LCMS: 372.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.19 - 12.00 (m, 1H), 8.99 - 8.78 (m, 1H), 7.80 - 7.68 (m, 1H), 6.95 - 6.71 (m, 1H), 6.47 - 6.36 (m, 1H), 6.32 - 6.21 (m, 1H), 6.02 - 5.94 (m, 1H), 4.95 - 4.84 (m, 1H), 3.23 - 3.15 (m, 2H), 2.09 - 1.93 (m, 2H), 1.86 - 1.71 (m, 4H), 1.53 - 1.44 (m, 3H), 1.24 (br d, J = 8.0 Hz, 6H) ppm. Example 16: (1 1 S,1 3 R,6R,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (compound 24) and (1 1 S,1 3 R,6S,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 Synthesis of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (compound 25) [ka]

[0350] Step 1: Preparation of tert-butyl (3-(2-hydroxypropyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of tert-butyl (3-(2-oxoethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1.27 g, 5.64 mmol, 1 equiv.) in THF (15 mL) was added MeMgBr (3 M, 11.27 mL, 6 equiv.) at −78° C., and the mixture was stirred at −78° C. for 6 h under a N atmosphere. After the aldehyde was consumed, the reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) at 0° C. and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-hydroxypropyl)bicyclo[1.1.1]pentan-1-yl)carbamate (900 mg, 66.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.93 (s, 1H), 3.86 - 3.81 (m, 1H), 2.65 (s, 1H), 1.94 - 1.93 (m, 6H), 1.70 - 1.69 (m, 2H), 1.44 (s, 9H), 1.25 - 1.19 (d, 3H) ppm.

[0351] Step 2: Preparation of tert-butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of tert-butyl (3-(2-hydroxypropyl)bicyclo[1.1.1]pentan-1-yl)carbamate (400 mg, 1.66 mmol, 1 equiv.) in DMF (20 mL), 4-bromo-2-chloro-6-(difluoromethyl)pyridine (602.79 mg, 2.49 mmol, 1.5 equiv.) and t-BuOK (371.98 mg, 3.32 mmol, 2 equiv.) were added, and the mixture was stirred at 20° C. under a N atmosphere for 8 hours. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate (350 mg, 47.2% yield) as a yellow oil. LCMS: 447.1 [M+H] + , 347.2 [M-Boc+H] + .

[0352] Step 3: Preparation of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-(2-((4-bromo-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate (320 mg, 0.715 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazole-5 A mixture of α-amine (289.79 mg, 0.859 mmol, 1.2 equiv.), Pd(dba) (65.51 mg, 0.072 mmol, 0.1 equiv.), Xantphos (82.79 mg, 0.143 mmol, 0.2 equiv.), and CsCO (699.26 mg, 2.15 mmol, 3 equiv.) in dioxane (20 mL) was stirred at 90 °C for 12 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate (360 mg, 53.6% yield) as a yellow oil. LCMS: 704.5 [M+H] + .

[0353] Step 4: Preparation of tert-butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(2-((4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-6-(difluoromethyl)pyridin-2-yl)oxy)propyl)bicyclo[1.1.1]pentan-1-yl)carbamate (360 mg, 0.511 mmol, 1 equiv) in DCM (20 mL) was added BocO (167.41 mg, 0.767 mmol, 1.5 equiv) and DMAP (62.47 mg, 0.511 mmol, 1 equiv), and the mixture was stirred at 20° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (255 mg, 62.0% yield) as a yellow oil. LCMS: 804.5 [M+H] + .

[0354] Step 5: Preparation of tert-butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (255 mg, 0.317 mmol, 1 equiv.) and TBAF (414.59 mg, 1.59 mmol, 5 equiv.) in THF (10 mL) was stirred at 20° C. for 8 hours. The reaction mixture was then concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give tert-butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (210 mg, 86.4% yield) as a yellow solid. LCMS: 690.3 [M+H] + .

[0355] Step 6: Preparation of (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate tert-Butyl (2-((1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (210 mg, 0.304 mmol, 1 To a solution of 4-nitrophenylcarbonylchloridate (184.08 mg, 0.913 mmol, 3 equiv.) in DCM (10 mL) was added pyridine (144.48 mg, 1.83 mmol, 6 equiv.) and DMAP (37.19 mg, 0.304 mmol, 1 equiv.), followed by a solution of 4-nitrophenylcarbonylchloridate (184.08 mg, 0.913 mmol, 3 equiv.) in DCM (10 mL), and the mixture was stirred at 45° C. for 16 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was treated with water (20 mL) and ethyl acetate (30 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl) carbonate (175 mg, 0.205 mmol, 67.2% yield) as a yellow oil. LCMS: 855.3 [M+H] + .

[0356] Step 7: Preparation of (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl)carbonate (175 mg, 0.205 mmol, 1 equiv) and TFA (116.70 mg, 1.02 mmol, 5 equiv) in DCM (3 mL) was stirred at 40° C. for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was concentrated in vacuo to afford (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (120 mg, 89.5% yield) as a yellow solid. LCMS: 655.3 [M+H] + .

[0357] Step 8: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-6-methyl-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one To a solution of (1R,3S)-3-(5-((2-((1-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-yl)oxy)-6-(difluoromethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (120 mg, 0.183 mmol, 1 equiv.) in THF (20 mL) was added DIEA (118.44 mg, 0.916 mmol, 0.16 mL, 5 equiv.) and the mixture was stirred at 80° C. under N atmosphere for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (petroleum ether / ethyl acetate=2:1) ​​to give (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (80 mg, 84.7% yield) was obtained as a yellow solid. LCMS: 516.3 [M+H] + .

[0358] Step 9: (1 1 S,1 3 R,6R,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one and (1 1 S,1 3 R,6S,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 Preparation of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-4 6 -(difluoromethyl)-6-methyl-2 1 A mixture of H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (80 mg, 0.155 mmol, 1 equiv.) in formic acid (2 mL) was heated and stirred at 100 °C for 1 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₃·H₂O)]; B%: 55%, isocratic elution mode) to give (1 1 S,1 3 R,6R,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (26.28 mg, 36.9% yield) as a white solid, and (1 1 S,1 3 R,6S,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one (29.37 mg, 41.2% yield) was obtained as a white solid. (1 1 S,1 3 R,6R,Z)-4 6 -(difluoromethyl)-6-methyl-2 1H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one LCMS: 460.2 [M+H] + , 482.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 11.98 (s, 1H), 8.69 (s, 1H), 7.44 (s, 1H), 6.79 - 6.51 (t, 1H), 6.41 (s, 1H), 6.22 (s , 1H), 5.87 (s, 1H), 5.19 - 5.18 (m, 1H), 4.23 - 4.20 (m, 1H), 3.32 -3.20 (m, 1H), 2.51 - 2.33 (m, 1H), 2.08 - 1.95 (m, 1H), 1.82 - 1.81 (m, 2H), 1.79 - 1.72 (m, 6H), 1.65 - 1.62 (m, 4H), 1.29 - 1.28 (d, J = 5.6, 3H) ppm. (1 1 S,1 3 R,6S,Z)-4 6 -(difluoromethyl)-6-methyl-2 1 H-5,11-Dioxa-3,9-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-8(1,3)-bicyclo[1.1.1]pentana-1(1,3)-cyclopentanacycloundecaphan-10-one LCMS: 460.2 [M+H] + , 482.2 [M+Na] + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.43 (s, 1H), 6.78 - 6.50 (m, 1H), 6.39 (s, 1H), 6.16 (s, 1H), 5.97 (s, 1H), 5.11 - 5.09 (m, 1H), 4.25 - 4.22 (m, 1H), 3.40 -3.24 (m, 1H), 2.50 - 2.44 (m, 1H), 1.90 - 1.88 (m, 5H), 1.86 - 1.84 (m, 4H), 1.75 - 1.73 (m, 3H), 1.65 - 1.63 (m, 1H), 1.27 - 1.24 (d, J = 5.6, 3H) ppm. Example 17: (1 1 S,1 3 R,5R,Z)-5-methyl-2 1 H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 71) and (1 1 S,1 3 R,5S,Z)-5-Methyl-2 1 Synthesis of H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (compound 72) [ka]

[0359] Step 1: Preparation of tert-butyl (3-(1-(4-bromopyridin-2-yl)ethoxy)propyl)carbamate To a solution of 1-(4-bromopyridin-2-yl)ethan-1-ol (800 mg, 3.96 mmol, 1 equiv.) in DMF (3 mL), NaH (316.73 mg, 7.92 mmol, 60% purity, 2 equiv.) was added, and the mixture was stirred at 0° C. under a nitrogen atmosphere for 2.5 hours. Then, tert-butyl (3-bromopropyl)carbamate (1.41 g, 5.94 mmol, 1.5 equiv.) was added at 0° C., and the mixture was kept stirring at 0° C. under a nitrogen atmosphere for 2.5 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give tert-butyl (3-(1-(4-bromopyridin-2-yl)ethoxy)propyl)carbamate (585 mg, 41.1% yield) as a white solid. LCMS: 359.1, 361.1 [M+H] + .

[0360] Step 2: Preparation of tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethoxy)propyl)carbamate A mixture of tert-butyl (3-(1-(4-bromopyridin-2-yl)ethoxy)propyl)carbamate (620 mg, 1.73 mmol, 1 equiv.), 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (640.84 mg, 1.90 mmol, 1.1 equiv.), Pd(dba) (158.03 mg, 0.172 mmol, 0.1 equiv.), Xantphos (199.71 mg, 0.345 mmol, 0.2 equiv.), and CsCO (1.69 g, 5.18 mmol, 3 equiv.) in dioxane (20 mL) was stirred at 90 °C for 12 h under a N atmosphere. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethoxy)propyl)carbamate (1.1 g, 93.1% yield) as a yellow oil. LCMS: 616.4 [M+H] + .

[0361] Step 3: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (3-(1-(4-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)pyridin-2-yl)ethoxy)propyl)carbamate (1.13 g, 1.83 mmol, 1 equiv.) in DCM (20 mL) was added BocO (1.20 g, 5.50 mmol, 1.26 mL, 3 equiv.), DIEA (711.35 mg, 5.50 mmol, 3 equiv.), and DMAP (112.07 mg, 0.917 mmol, 0.5 equiv.), and the mixture was stirred at 20 °C under a N atmosphere for 12 h. The volatiles were then removed under reduced pressure, and the remaining residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (1.0 g, 1.40 mmol, 76.1% yield) as a yellow solid. LCMS: 716.5 [M+H] + .

[0362] Step 4: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate A solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (1.0 g, 1.40 mmol, 1 equiv.) and TBAF (1 M, 13.97 mL, 10 equiv.) in THF (2 mL) was stirred at 40° C. under a N atmosphere for 2 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The desired tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (820 mg, 1.36 mmol, 97.6% yield) was obtained as a colorless oil. LCMS: 602.3 [M+H] + .

[0363] Step 5: Preparation of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate To a solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (400 mg, 0.664 mmol, 1 equiv.) in DCM (15 mL) was added pyridine (315.47 mg, 3.99 mmol, 6 equiv.), 4-nitrophenyl carbonochloridate (803.88 mg, 3.99 mmol, 6 equiv.), and DMAP (40.60 mg, 0.332 mmol, 0.5 equiv.), and the mixture was stirred at 50° C. for 16 h under a N atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, and the volatiles were removed. The remaining residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (TFA as additive) to give tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 0.391 mmol, 58.8% yield) as a yellow oil. LCMS: 767.4 [M+H] + .

[0364] Step 6: Preparation of (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of tert-butyl (2-(1-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)pyridin-4-yl)(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (270 mg, 0.352 mmol, 1 equiv) and TFA (401.5 mg, 3.52 mmol, 10 equiv) in DCM (5 mL) was stirred at 20 °C under a N atmosphere for 3 h. The volatiles were then removed under reduced pressure to give the desired crude (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (190 mg, 95.2% yield) as a yellow solid. LCMS: 567.3 [M+H] + .

[0365] Step 7: (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-5-methyl-2 1 Preparation of H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one To a solution of (1R,3S)-3-(5-((2-(1-(3-aminopropoxy)ethyl)pyridin-4-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (180 mg, 0.317 mmol, 1 equiv.) in THF (50 mL) was added DIEA (410.55 mg, 3.18 mmol, 10 equiv.) and the mixture was stirred at 100° C. under N atmosphere for 3 h. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give (1 1 S,1 3 R,Z)-2 1-(tert-butyl)-5-methyl-2 1 H-6,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (135 mg, 87.5% yield) was obtained as a pale yellow oil. LCMS: 428.3 [M+H] + .

[0366] Step 8: (1 1 S,1 3 R,Z)-5-Methyl-2 1 Preparation of H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (1 1 S,1 3 R,Z)-2 1 -(tert-butyl)-5-methyl-2 1 A solution of H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (120 mg, 0.28 mmol, 1 equiv.) in HCOOH (2 mL) was stirred at 25 °C under a N atmosphere for 3 h. After completion of the reaction, the reaction mixture was concentrated to give (1 1 S,1 3 R,Z)-5-Methyl-2 1 H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (50 mg, 0.134 mmol, 48.0% yield, 100% purity) was obtained as a pale yellow oil, which was used in the next step without further purification. LCMS: 372.2 [M+H] + .

[0367] Step 9: (1 1 S,1 3 R,5R,Z)-5-methyl-2 1 H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one and (11 S,1 3 R,5S,Z)-5-Methyl-2 1 Preparation of H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one The resulting residue was purified using an SFC column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH / ACN]; B%: 45%, isocratic elution mode) to give (1 1 S,1 3 R,5R,Z)-5-methyl-2 1 H-6,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (19.83 mg, 39.3% yield, 99.0% purity) and (1 1 S,1 3 R,5S,Z)-5-Methyl-2 1 H-6,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one (14.65 mg, 0.039 mmol, 29.0% yield, 99.0% purity) was obtained as a white solid. (1 1 S,1 3 R,5R,Z)-5-methyl-2 1 H-6,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one: LCMS: 372.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.09 - 12.06 (m, 1H), 8.96 (s, 1H) 8.03- 8.02 (m, 1H), 6.99 (s, 1H), 6.72 - 6.66 (m, 1H), 5.94 (s, 1H), 5.06 (s, 1H), 4.28 - 4.25 (m, 1H), 3.33 - 3.28 (m, 1H), 3.27 - 3.20 (m, 3H), 2.51 - 2.50 (m, 1H), 1.79 - 1.77 (m, 1H), 1.76 - 1.74 (m, 1H), 1.73 - 1.64 (m, 1H), 1.63 - 1.26 (m, 6H),1.25 - 0.85 (m, 3H) ppm. (1 1 S,1 3 R,5S,Z)-5-Methyl-2 1 H-6,12-Dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one: LCMS: 372.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.14 - 12.13 (m, 1H), 8.93 - 8.83 (m, 1H), 8.03 - 8.02 (m, 1H), 7.00 (s, 1H), 6.83 - 6.65 (m, 2H), 5.94 (s, 1H), 507 - 4.99 (m, 1H), 4.29 (s, 1H), 3.49 - 3.26 (m, 1H), 3.24 - 3.23 (m, 2H), 2.87 (s, 1H), 2.50 (s, 1H), 2.08 - 2.04 (m, 1H), 2.02 - 1.75 (m, 7H), 1.73 - 1.26 (m, 3H) ppm. Example 18: (1 1 S,1 3 R,7 1 R,7 3 S,Z)-2 1Synthesis of H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one (compound 108) [ka]

[0368] Step 1: Preparation of tert-butyl ((1r,3r)-3-(((4-bromopyridin-2-yl)oxy)methyl)cyclobutyl)carbamate To a solution of 4-bromo-2-fluoro-pyridine (1.05 g, 5.96 mmol, 1.2 equiv.) and tert-butyl ((1r,3r)-3-(hydroxymethyl)cyclobutyl)carbamate (1 g, 4.97 mmol, 1 equiv.) in THF (15 mL) was added tBuOK (836.31 mg, 7.45 mmol, 1.5 equiv.) and the mixture was stirred under N atmosphere at 25° C. for 2 h. After the starting material was consumed, the mixture was poured into HO (30 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give 1.6 g of tert-butyl ((1r,3r)-3-(((4-bromopyridin-2-yl)oxy)methyl)cyclobutyl)carbamate as...

Claims

1. Compounds of formula (I), their tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives: 【Chemistry 105】 wherein, in formula (I): A is a substituted or unsubstituted amide or a 5- to 12-membered aromatic ring, wherein the 5- to 12-membered aromatic ring optionally contains one or more heteroatoms and one, two, three, or four R Ａ１ where each R Ａ１ are independently hydrogen, —C(═O)R Ａ２ , C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, Halo, C １ ~C ５ Haloalkyl, C １ ~C ５ alkoxy, and —CN, and each R Ａ２ are independently hydrogen, hydroxyl, C １ ~C ５ Alkyl, C １ ~C ５ Alkoxy, C １ ~C ５ Haloalkyl, C ２ ~C ５ alkenyl, and C ２ ~C ５ alkynyl; B is N, N ＋ -O － , and C.R. ０ where R ０ is hydrogen, halo, -CN, C １ ~C ５ Alkyl, C １ ~C ５ Haloalkyl, C １ ~C ５ Alkoxy, and C ３ ~C ５ cycloalkyl; R １ is hydrogen, halo, -CN, and C １ ~C ５ alkyl, or R １ and Y, together with the carbon atom to which they are attached, form a 5- to 6-membered aromatic ring, wherein the aromatic ring optionally contains 1 to 3 heteroatoms; X and Y are independently N, N ＋ -O － , or CR ２ where each R ２ are independently hydrogen, haloalkyl, C １ ~C ５ Alkyl, C １ ~C ５ Alkoxy, and C ３ ~C ５ cycloalkyl; Q is absent or -WC(R ３ ) (R ４ )—, where R ３ and R ４ are independently hydrogen, deuterium, C １ ~C ５ Alkyl, C １ ~C ５ haloalkyl, and halo; or R ３ and R ４ together with the carbon atom to which they are attached form a carbonyl group or a 3- to 6-membered cycloalkyl, and W is absent or is alkylene, —C(═O)—R ６ -, -O-, -R ６ -O-, -O-R ６ -, -N(R ７ )-, -NH-C(=O)-, -C(=O)-N(R ６ )-, -S-, -S(=O) ２ -, -P(R ７ ) ２ -, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R Ｂ and each R ６ is independent, C １ ~C ５ alkylene, 3- to 6-membered heterocycle, and 3- to 6-membered cycloalkyl; ７ are independently hydrogen, oxo, and C １ ~C ５ alkyl, and each R Ｂ are independently hydrogen, oxo, halo, and C １ ~C ５ alkyl; L is absent or a linker 1 to 10 carbon atoms in length, where one or more of the carbon atoms is an oxo, C １ ~C ５ Haloalkyl, halo, deuterium, or C １ ~C ５ and optionally substituted with alkyl, and one or more carbon atoms are selected from the group consisting of 3- to 6-membered bridged cycloalkyl, 3- to 7-membered fused cycloalkyl, alkenyl, —O—, —N(R ８ )-, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted by 1, 2, 3, or 4 R ９ and each R ８ are independently hydrogen and C １ ~C ５ alkyl, and each R ９ are independently hydrogen, oxo, and C １ ~C ５ alkyl; and R １０ and R １１ are independently selected from hydrogen, halo, and C １ ~C ５ alkyl; However, the compound of formula (I) is the following: (1 １ S, 1 ３ R, Z)-2 １ H-12-oxa-3,6,10-triaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 １ S, 1 ３ R, Z)-2 １ H-12-oxa-3,6,10-triaza-4(3,5)-pyridina-2(5,3)-pyrazola-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, (1 １ S, 1 ３ R, Z)-2 １ H-12-oxa-3,6,10-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclododecaphane-5,11-dione, or (1 １ S, 1 ３ R, Z)-2 １ H-13-oxa-3,6,11-triaza-2(5,3)-pyrazola-4(1,3)-benzena-1(1,3)-cyclopentanacyclotridecaphane-5,12-dione At least one entity that is not.

2. The at least one entity is a compound of formula (II), its tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives: 【Chemistry 106】 2. At least one entity according to claim 1 selected from:

3. The at least one entity is a compound of formula (III), its tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives: 【Chemistry 107】 2. At least one entity according to claim 1 selected from:

4. The at least one entity is a compound of formula (IV), its tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives: 【Chemistry 108】 2. At least one entity according to claim 1 selected from:

5. The at least one entity is a compound of formula (V), its tautomers, stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, hydrates, and deuterated derivatives: 【Chemistry 109】 2. At least one entity according to claim 1 selected from:

6. A is, 【Chemical 110】 5. At least one entity according to any one of claims 1, 2, or 4, wherein

7. 10. At least one entity according to any one of claims 1, 2, or 4, wherein A is selected from a 5-membered aromatic ring and a 6-membered aromatic ring, wherein the 5-membered aromatic ring and the 6-membered aromatic ring optionally contain one or more heteroatoms.

8. 8. At least one entity according to claim 7, wherein the five-membered and six-membered aromatic rings contain one or more heteroatoms.

9. A is, 【Chemistry 111】 9. At least one entity according to claim 8 selected from:

10. At least one R Ａ１ is C １ ~C ５ 9. At least one entity of any one of claims 1, 2, 4, 7, or 8 is alkoxy.

11. At least one R Ａ１ 9. At least one entity according to any one of claims 1, 2, 4, 7, or 8, wherein is hydrogen.

12. At least one R Ａ１ is C １ ~C ５ 10. At least one entity according to any one of claims 1, 2, 4, 7, or 8, which is alkyl.

13. At least one R Ａ１ 9. At least one entity according to any one of claims 1, 2, 4, 7, or 8, wherein is halo.

14. At least one R Ａ１ is C １ ~C ５ 10. At least one entity according to any one of claims 1, 2, 4, 7, or 8 is haloalkyl.

15. At least one R Ａ１ 9. At least one entity of any one of claims 1, 2, 4, 7, or 8, wherein is -CN.

16. At least one R Ａ１ -C(=O)-R Ａ２ 9. At least one entity according to any one of claims 1, 2, 4, 7, or 8, wherein

17. R Ａ２ is C １ ~C ５ 17. At least one entity of claim 16 which is alkoxy.

18. R Ａ２ is C １ ~C ５ 17. At least one entity of claim 16 which is alkyl.

19. R Ａ２ 17. At least one entity according to claim 16, wherein is hydrogen.

20. R Ａ２ 17. At least one entity according to claim 16, wherein is hydroxyl.

21. R Ａ２ is C １ ~C ５ 17. At least one entity of claim 16 which is haloalkyl.

22. R Ａ２ is C ２ ~C ５ 17. At least one entity of claim 16 which is alkynyl.

23. B is N or N ＋ -O － 23. At least one entity according to any one of claims 1, 4, 5, or 7-22, wherein

24. B is CR ０ 23. At least one entity according to any one of claims 1, 4, 5, or 7-22, wherein

25. R ０ 25. At least one entity according to claim 24, wherein is hydrogen.

26. R ０ 25. At least one entity according to claim 24, wherein is halo.

27. R ０ 25. At least one entity of claim 24, wherein is -CN.

28. R ０ is C １ ~C ５ 25. At least one entity of claim 24 which is alkyl.

29. R ０ is C １ ~C ５ 25. At least one entity of claim 24 which is haloalkyl.

30. R ０ is C １ ~C ５ 25. At least one entity of claim 24 which is alkoxy.

31. R ０ is C １ ~C ５ 25. At least one entity of claim 24 which is cycloalkyl.

32. R １ 32. At least one entity according to any one of claims 1 to 31, wherein is hydrogen.

33. R １ 32. At least one entity according to any one of claims 1 to 31, wherein is halo.

34. R １ is independently selected from F, Cl, I, and Br.

35. R １ is C １ ~C ５ 32. At least one entity according to any one of claims 1 to 31 which is alkyl.

36. R １ But -CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , and -CH ２ -CH ２ -CH ３ 36. At least one entity according to claim 35 selected from:

37. R １ and Y, together with the carbon atom to which they are attached, form a 5- to 6-membered aromatic ring, wherein the 5- to 6-membered aromatic ring optionally contains one or more heteroatoms.

38. 38. At least one entity according to claim 37, wherein the 5- to 6-membered aromatic ring contains 1 to 3 heteroatoms.

39. Y is N or N ＋ -O － 37. At least one entity according to any one of claims 1 to 36,

40. Y is CR ２ 37. At least one entity according to any one of claims 1 to 36,

41. X is N or N ＋ -O － 41. At least one entity according to any one of claims 37 to 40, wherein

42. 42. At least one entity according to claim 41, wherein X is N.

43. X is CR ２ 41. At least one entity according to any one of claims 37 to 40, wherein

44. R ２ are independently hydrogen, halo, haloalkyl, C １ ~C ５ Alkyl, C １ ~C ５ Alkoxy, and C ３ ~C ５ 44. At least one entity according to claim 40 or 43 selected from cycloalkyl.

45. At least one R ２ are independently hydrogen, —CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , -CH ２ -CH ２ -CH ３ , 【Chemistry 112】 45. At least one entity according to claim 44 selected from:

46. At least one R ２ But hydrogen, 【Chemistry 113】 45. At least one entity according to claim 44, wherein:

47. At least one R ２ is C １ ~C ５ 45. At least one entity of claim 44 which is alkoxy.

48. At least one R ２ is a halo selected from F, Cl, Br, and I.

49. 49. At least one entity according to any one of claims 1 or 5 to 48, wherein Q is absent.

50. Q is -W-C(R ３ ) (R ４ )-.

51. R ３ and R ４ are independently hydrogen, deuterium, C １ ~C ５ Alkyl, C １ ~C ５ 51. At least one entity of claim 50 selected from haloalkyl, and halo.

52. R ３ or R ４ 51. At least one entity according to claim 50, wherein at least one of is hydrogen.

53. R ３ and R ４ and together with the carbon atom to which they are attached form a carbonyl group or a 3- to 6-membered cycloalkyl.

54. 54. At least one entity according to any one of claims 50 to 53, wherein W is absent.

55. W independently represents alkylene, —C(═O)—R ６ -, -O-, -R ６ -O-, -O-R ６ -, -N(R ７ )-, -NH-C(=O)-, -C(=O)-N(R ６ ) -, -S(=O) ２ -, -P(R ７ ) ２ -, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle, wherein the alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycle are selected from 1, 2, 3, 4, or 5 R Ｂ 54. At least one entity according to any one of claims 50 to 53, optionally substituted with:

56. R ６ but, 【Chemistry 114】 56. At least one entity according to claim 55 selected from:

57. R ６ But -CH ２ -, -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ - and -CH ２ -CH ２ -CH ２ -CH ２ - At least one entity according to claim 55 selected from:

58. W is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered cycloalkyl and the 3- to 6-membered heterocycle are selected from the group consisting of 1, 2, 3, or 4 R Ｂ 56. At least one entity of claim 55, optionally substituted with

59. W is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered cycloalkyl and the 3- to 6-membered heterocycle are selected from the group consisting of 1, 2, 3, or 4 R Ｂ 59. At least one entity of claim 58, substituted with:

60. W is, 【Chemical 115】 56. At least one entity according to claim 55 selected from:

61. At least one R Ｂ are independently hydrogen, oxo, —CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , and -CH ２ -CH ２ -CH ３ 61. At least one entity according to any one of claims 55 or 58 to 60 selected from:

62. 62. At least one entity according to any one of claims 1 to 61, wherein L is absent.

63. L is a linker 1 to 10 carbon atoms in length, where one or more of the carbon atoms of L is oxo, C １ ~C ５ Haloalkyl, halo, deuterium, or C １ ~C ５ and one or more carbon atoms of L are optionally substituted with a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, an alkenyl, —O—, —S—, —S(═O) ２ -, -N(R ８ ), a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are optionally substituted by 1, 2, 3, or 4 R ９ 62. At least one entity according to any one of claims 1 to 61, optionally substituted with:

64. 64. At least one entity according to claim 63, wherein L is a linker of 1 to 5 carbon atoms in length.

65. One or more carbon atoms of L may be oxo, C １ ~C ５ Haloalkyl, halo, deuterium, or C １ ~C ５ 65. At least one entity according to claim 63 or 64, which is substituted with alkyl.

66. One or more carbon atoms of L may be oxo, C １ ~C ５ Haloalkyl, halo, or C １ ~C ５ 65. At least one entity according to claim 63 or 64, which is substituted with alkyl.

67. One or more carbon atoms of L may be C １ ~C ５ 65. At least one entity of claim 63 or claim 64, optionally substituted with alkyl.

68. One or more carbon atoms of L may be —CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , or -CH ２ -CH ２ -CH ３ 68. At least one entity of claim 67, optionally substituted with:

69. 66. At least one entity according to claim 65, wherein one or more carbon atoms of L are optionally substituted with deuterium.

70. One or more carbon atoms of L is selected from the group consisting of a 3- to 6-membered bridged cycloalkyl, a 3- to 7-membered fused cycloalkyl, an alkenyl, —O—, —S—, —S(═O) ２ -, -N(R ８ ), a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are each substituted with 1, 2, 3, or 4 R ９ 70. At least one entity according to any one of claims 63 to 69, optionally substituted with:

71. At least one R ８ are independently hydrogen, —CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , and -CH ２ -CH ２ -CH ３ 71. At least one entity according to claim 70 selected from:

72. The 3- to 6-membered heterocycle, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered bridged cycloalkyl are each independently selected from the group consisting of 1, 2, 3, or 4 R ９ 71. At least one entity of claim 70, substituted with:

73. At least one R ９ are independently hydrogen, halo, oxo, -CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , and -CH ２ -CH ２ -CH ３ 73. At least one entity according to claim 72 selected from:

74. The 3- to 6-membered bridged cycloalkyl, the 3- to 6-membered cycloalkyl, and the 3- to 6-membered heterocycle are independently: 【Chemistry 116】 71. At least one entity according to claim 70 selected from:

75. L is: 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 62. At least one entity according to any one of claims 1 to 61 selected from:

76. The at least one entity: (1 １ S, 1 ３ R,9S,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9R,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,7 １ R,7 ３ S, Z)-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1'S,3'R,6'R,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one, (1'S,3'R,6'S,Z)-6'-methylspiro[cyclopropane-1,9'-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphane]-11'-one, (1 １ S, 1 ３ R,7 １ S, 7 ３ S,6R,Z)-6-methyl-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,7 １ R,7 ３ R,6R,Z)-6-methyl-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,7 １ S, 7 ３ R,6S,Z)-6-methyl-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,7 １ R,7 ３ S,6S,Z)-6-methyl-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,6S,9S,Z)-6,9-dimethyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,6S,9R,Z)-6,9-dimethyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-5,5-difluoro-9-methyl-2 １ H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-8,8-difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-8,8-difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one-6,6-d ２ , (1 １ S, 1 ３ R,9S,E)-2 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,E)-2 ４ ,8,8-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-7,7-difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,Z)-1 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R, 1 ４ S,9S,Z)-1 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,Z)-1 ４ ,8,8-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R, 1 ４ S,9S,Z)-1 ４ ,8,8-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,7 １ S, 7 ３ R, E)-1 ４ , 2 ４ -difluoro-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R, 1 ４ S, 7 １ R,7 ３ S, E)-1 ４ , 2 ４ -difluoro-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,9S,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,E)-2 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,7 １ R,7 ３ S, Z)-2 １ H-5,10-dioxa-3,8-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,7 １ R, 73S, E)-2 ４ -Fluoro-2 １ H-5,10-dioxa-3,8-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ R, 1 ３ S, 1 ４ R,9S,E)-1 ４ , 2 ４ -difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R, 14S, 9S, E)-1 ４ , 2 ４ -difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,E)-1 ４ , 2 ４ ,8,8-tetrafluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R, 1 ４ S,9S,E)-1 ４ , 2 ４ ,8,8-tetrafluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyrimidina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,Z)-1 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,E)-1 ４ , 2 ４ -difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(2,6)-pyrazina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,E)-2 ４ ,7,7-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, and (1 １ S, 1 ３ R,9S,E)-2 ４ -fluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyrimidina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one 2. At least one entity according to claim 1 selected from:

77. The at least one entity: (1 １ S, 1 ３ R,9S,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9R,Z)-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,7 １ R,7 ３ S,6S,Z)-6-methyl-2 １ H-5,10-dioxa-3,8-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentana-7(1,3)-cyclobutanacyclodecaphan-9-one, (1 １ S, 1 ３ R,9S,Z)-5,5-difluoro-9-methyl-2 １ H-12-oxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-8,8-difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ S, 1 ３ R,9S,Z)-8,8-difluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one-6,6-d ２ , (1 １ S, 1 ３ R,9S,E)-2 ４ ,8,8-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, (1 １ R, 1 ３ S, 1 ４ R,9S,Z)-1 ４ ,8,8-trifluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one, and (1 １ R, 1 ３ S, 1 ４ R,9S,E)-1 ４ , 2 ４ ,8,8-tetrafluoro-9-methyl-2 １ H-5,12-dioxa-3,10-diaza-4(4,2)-pyridina-2(3,5)-pyrazola-1(1,3)-cyclopentanacyclododecaphan-11-one 2. At least one entity according to claim 1 selected from:

78. A pharmaceutical composition comprising at least one entity according to any one of claims 1 to 77 and at least one pharmaceutically acceptable carrier or excipient.

79. 79. A method of treating a disease or condition in a subject that is at least partially modulated by CDK2, the method comprising administering to said subject in need thereof at least one entity according to any one of claims 1 to 77 or a pharmaceutical composition according to claim 78.

80. 79. A method of inhibiting CDK2 in a patient, the method comprising administering to said patient at least one entity according to any one of claims 1 to 77 or a pharmaceutical composition according to claim 78.

81. 79. A method of treating a disease or disorder segregated with CDK2 in a patient, the method comprising administering to the patient at least one entity according to any one of claims 1 to 77 or a pharmaceutical composition according to claim 78, wherein the disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

82. 82. The method of any one of claims 79 to 81, wherein the disease, disorder, or condition is cancer.

83. 83. The method of claim 82, wherein the cancer is selected from breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, small intestine cancer, pancreatic cancer, liver cancer, kidney cancer, head and neck cancer, skin cancer, bone cancer, thyroid cancer, peritoneal cancer, and brain cancer.

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