CARBONYL-SUBSTITUTED DIAZAS PIROVER COMPOUNDS AND THEIR USE

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of the International Application No. PCT / CN2021 / 135427 filed on December 3, 2021, and the International Application No. PCT / CN2022 / 115162 filed on August 26, 2022.TECHNICAL FIELD

[0002] The present disclosure provides carbonyl substituted diazaspiro compounds that inhibit the interaction of menin with MLL and MLL fusion proteins, as further defined in the claims. The present disclosure also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and these compounds / compositions for use in the prevention or treatment of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.BACKGROUND

[0003] Rearrangement of the mixed lineage leukemia (MLL, also known as MLL1 or KMT2A) gene occurs in about 10% of acute leukemias, and is particularly prevalent in infant acute leukemias, accounting for up to ~70% of infant acute lymphocytic leukemia (ALL) cases (Issa, G. C. et al., Leukemia, 2021, 35, 2482). MLLr (MLL rearrangement) is also found in 85% of secondary acute myeloid (myelogeneous) leukemia (AML) cases that occur in patients treated with topoisomerase II inhibitors. More than 80 partner genes are implicated in MLL fusions, and six main partner genes make up about 80% of cases, which include AF4 (ALL-1 fused gene from chromosome 4), AF6, AF9, AF10, ENL (eleven-nineteen leukemia) and ELL (eleven-nineteen lysine-rich leukemia) (Meyer, C. et al., 2018, Leukemia, 32, 273). MLL translocations lead to the expression of MLL fusion proteins that enhance proliferation and block hematopoietic differentiation, ultimately driving the development of leukemia. MLLr leukemia is one of the high-risk types of leukemia with aggressive nature, resistance to therapy, and high frequency of early relapse, and with a 5-year survival rate of only approximately 35% (Marschalek, R. Br J Haematol. 2011, 152, 141). Therefore, there is huge unmet medical needs for MLLr leukemias. WO2020 / 045334A1, WO2019 / 060365A1 and WO2017 / 214367A1 relate to inhibitors of menin-MLL and thus exerting an anticancer effect.

[0004] The protein protein interaction (PPI) between menin and MLLr is critical to the pathogenesis of MLLr-driven leukemias by dysregulation of the HOXA and MEIS1 genes. On the other hand, recent studies revealed the importance of the menin-MLL1 wild-type (wt) interaction in AML with mutations in the nucleophosmin 1 (NPM1) gene. NPM1 mutation (NMP1c) is found in over 30% of AML patients with poor 5-year overall survival rate, and also associated with the upregulated expression of HOXA and MEIS1 genes (Kuhn, M. W. et al. Cancer Discov. 2016, 6, 1166). Menin inhibitors were reported to be able to block the interaction of menin with MLLr and MLL wt, and demonstrated potential use in the treatment of MLLr associated acute leukemias and NPM-mutated AML (Klossowski, S. et al. J Clin Invest. 2020, 130, 981).SUMMARY OF THE DISCLOSURE

[0005] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[0006] The present disclosure provides a compound of formula I: or pharmaceutically acceptable salt, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate thereof, wherein: X is F, Cl or CN; Y is N or CH; Z is selected from the group consisting of CH 2 , O, and S; R 1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl and 3-5 membered cycloalkyl ring, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C 1-6 alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo; 2) a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring, oxo and C 1-6 alkoxyl; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring and C 1-6 alkoxyl; R 2 and R 3 are each independently H or D; each R 4 is independently selected from the group consisting of halo, CN, OH, C 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, phenyl, C 1-6 alkyl, C 1-6 alkoxyl and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-10 membered heteroaryl ring or phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; R 5 is H or halo; a, b, c and d are each independently 1 or 2; n is 0 or 1; and m is 0, 1, 2 or 3; provided that R 4 , if present, substituted at any chemically permissible position(s) on the heterocyclyl except for the N atom adjacent to the attachment point of the heterocyclyl to the remaining structure of the compound.

[0007] The compound of formula I or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof as well as the specific compounds disclosed in the context of the present invention and covered by the scope of the compounds above are collectively called "the compound of the present disclosure".

[0008] The present disclosure also provides the compound of the present disclosure for use as a medicament.

[0009] The present disclosure also provides the compound of the present disclosure for use in the treatment or prevention of cancer or diabetes.

[0010] The present disclosure also provides a pharmaceutical composition, comprising the compound of the present disclosure, and optionally a pharmaceutically acceptable carrier.

[0011] The present disclosure also provides a kit for treating or preventing a cancer or diabetes, comprising a pharmaceutical composition of the present disclosure and an instruction for use.

[0012] Also disclosed herein is a method of in vitro inhibiting the interaction of menin with MLL and / or MLL fusion proteins, comprising contacting an effective amount of the compound of the present disclosure with menin.

[0013] The present disclosure also provides a combination, comprising the compound of the present disclosure and at least one additional therapeutic agent.

[0014] The present disclosure also provides a process for the preparation of the compound of the present disclosure, and intermediates for preparing the compound of the present disclosure.DETAILED DESCRIPTION OF THE DISCLOSURE Embodiments of the Disclosure - Part A

[0015] Embodiment 1. A compound of formula I: or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F, Cl or CN; Y is N or CH; Z is selected from the group consisting of CH 2 , O, and S; R 1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl and 3-5 membered cycloalkyl ring, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C 1-6 alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo; 2) a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring, oxo and C 1-6 alkoxyl; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring and C 1-6 alkoxyl; R 2 and R 3 are each independently H or D; each R 4 is independently selected from the group consisting of halo, CN, OH, C 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, phenyl, C 1-6 alkyl, C 1-6 alkoxyl and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-10 membered heteroaryl ring or phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; R 5 is H or halo; a, b, c and d are each independently 1 or 2; n is 0 or 1; and m is 0, 1, 2 or 3; provided that R 4 , if present, substituted at any chemically permissible position(s) on the heterocyclyl except for the N atom adjacent to the attachment point of the heterocyclyl to the remaining structure of the compound.

[0016] Embodiment 2. The compound according to the preceding Embodiment or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 5 is H.

[0017] Embodiment 3. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula II:

[0018] Preferably, the compound is of formula IIa: which preferably is more preferably is: wherein each p is dependently 0 or 1; q is 0, 1 or 2; R 4a is C 1-3 alkyl or halo; most preferably is: wherein each p is dependently 0 or 1; q is 0, 1 or 2; R 4a is C 1-3 alkyl or halo.

[0019] Embodiment 4. The compound according to any of the Embodiments 1 or 2 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula III:

[0020] Embodiment 5. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein X is F.

[0021] Embodiment 6. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein Z is CH 2 .

[0022] Embodiment 7. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each H.

[0023] Embodiment 8. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl and 3-5 membered cycloalkyl ring, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C 1-6 alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring with another ring heteroatoms selected from N, O and S, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo.

[0024] Embodiment 9. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-3 alkyl optionally substituted with one OH; preferably Ra is ethyl and Rb is iso-propyl; or R 1 is a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-3 alkyl and cyclopropyl; or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0025] Embodiment 10. The compound according to Embodiment 9 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-3 alkyl optionally substituted with one OH; preferably Ra is ethyl and Rb is iso-propyl; or R 1 is pyridyl, pyrimidinyl or pyrazolyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-3 alkyl and cyclopropyl; or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0026] Embodiment 11. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-3 alkyl, preferably Ra is ethyl and Rb is iso-propyl; or R 1 is a 6 membered heteroaryl or phenyl ring, substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0027] Embodiment 12. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra is ethyl and Rb is iso-propyl.

[0028] Embodiment 13. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is pyridyl, pyrimidinyl or phenyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0029] Embodiment 14. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is wherein A 1 or A 2 is N or CH; R 6 is selected from the group consisting of halo, CN and cyclopropyl; and R 7 is selected from the group consisting of H, halo, CN and cyclopropyl; preferably, R 1 is or R 1 is wherein A 3 is N or C substituted by halo, and R 8 is C 1-3 alkyl; preferably, R 1 is

[0030] Embodiment 15. The compound according to Embodiment 14 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula IIb':

[0031] Embodiment 16. The compound according to any one of Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-3 alkyl; preferably Ra is ethyl and Rb is iso-propyl; or R 1 is a 6 membered heteroaryl ring, substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0032] Embodiment 17. The compound according to Embodiment 16 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-3 alkyl; preferably Ra is ethyl and Rb is iso-propyl; or R 1 is pyridyl or pyrimidinyl, substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and cyclopropyl.

[0033] Embodiment 18. The compound according to any one of the preceding Embodiments 1-7 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of:

[0034] Embodiment 19. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1; and each of c and d is 1 or 2.

[0035] Embodiment 20. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: n is 0.

[0036] Embodiment 21. The compound according to any one of Embodiments 1-13 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein n is 0.

[0037] Embodiment 22. The compound according to any one of Embodiments 1-13 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein n is 1.

[0038] Embodiment 23. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

[0039] Embodiment 24. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1.

[0040] Embodiment 25. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of c and d is 2.

[0041] Embodiment 26. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: m is 1 or 2.

[0042] Embodiment 27. The compound according to any one of Embodiments 1-14 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1; each of c and d is 2; n is 0 or 1, preferably 0; and m is 0, 1 or 2.

[0043] Embodiment 28. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-6 alkylsulfonyl-; C 1-6 alkylsulfonylamino-; phenyl; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C 1-6 alkoxyl optionally substituted with 1, 2 or 3 halo; and cyclopropyl, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-6 membered heteroaryl ring, which is optionally substituted with 1, 2 or 3 C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl.

[0044] Embodiment 29. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-3 alkylsulfonyl-; C 1-3 alkylsulfonylamino-; phenyl; C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C 1-3 alkoxyl optionally substituted with 1, 2 or 3 halo; and cyclopropyl, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkyl, -C 1-3 alkyl-OH, C 1-3 alkoxyl-C 1-3 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-6 membered heteroaryl ring, which is optionally substituted with 1, 2 or 3 C 1-3 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl.

[0045] Embodiment 30. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is selected from the group consisting of:

[0046] Embodiment 31. The compound according to any one of Embodiments 1-3 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F; Z is CH 2 ; R 1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl optionally substituted by 1, 2 or 3 deuterium; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 C 1-6 alkyl; 2) a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl, CF 3 , 3-5 membered cycloalkyl ring, oxo and C 1-6 alkoxyl; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl, CF 3 , 3-5 membered cycloalkyl ring and C 1-6 alkoxyl; R 2 and R 3 are each H; each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-6 alkylsulfonyl-; C 1-6 alkylsulfonylamino-; phenyl; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C 1-6 alkoxyl optionally substituted with 1, 2 or 3 halo; and 3-6 membered cycloalkyl ring, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl; R 5 is H or halo; each of a and b is 1; each of c and d is 2; n is 0; and m is 0, 1 or 2; provided that R 4 , if present, substituted at any chemically permissible position(s) the heterocyclyl except for the N atom adjacent to the attachment point of the heterocyclyl to the remaining structure of the compound.

[0047] Embodiment 32. The compound according to Embodiment 31 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 5 is H.

[0048] Embodiment 33. The compound according to any one of Embodiments 31-32 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl or isopropyl.

[0049] Embodiment 34. The compound according to any one of Embodiments 31-32 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is a 5 or 6 membered heteroaryl ring or phenyl ring, wherein said heteroaryl ring is substituted with 1 or 2 substituents selected from the group consisting of halo, CN, C 1-3 alkyl, CF 3 , cyclopropyl, oxo and C 1-3 alkoxyl, wherein said phenyl ring is substituted with 1 or 2 substituents selected from the group consisting of halo, CN, C 1-3 alkyl, CF 3 , cyclopropyl, and C 1-3 alkoxyl.

[0050] Embodiment 35. The compound according to any one of Embodiments 31-32 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of:

[0051] Embodiment 36. The compound according to any one of Embodiments 31-35 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-3 alkylsulfonyl-; C 1-3 alkylsulfonylamino-; phenyl; C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C 1-3 alkoxyl optionally substituted with 1, 2 or 3 halo; and cyclopropyl; wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkyl and halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl.

[0052] Embodiment 37. The compound according to any one of Embodiments 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is selected from the group consisting of:

[0053] Embodiment 38. The compound according to any one of Embodiments 1-28 and 32-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo, CN, C 1-3 alkoxyl and cyclopropyl, or two adjacent R 4 , together with the carbon atoms to which they are attached, form cyclopropyl; and m is 1 or 2.

[0054] Embodiment 39. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN; C 1-6 alkoxyl; and cyclopropyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo; and R 4 ‴ is H.

[0055] Embodiment 40. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-6 alkyl optionally substituted with one halo; and C 1-6 alkoxyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C 1-6 alkyl; and R 4 ‴ is H.

[0056] Embodiment 41. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; C 1-3 alkyl optionally substituted with one halo; and C 1-3 alkoxyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C 1-3 alkyl; and R 4 ‴ is H.

[0057] Embodiment 42. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is

[0058] Embodiment 43. The compound according to any one of the Embodiments 39-42 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-3 alkyl optionally substituted with one halo; and C 1-3 alkoxyl.

[0059] Embodiment 44. The compound according to any one of Embodiments 39-42 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C 1-3 alkyl; and R 4 ‴ is H.

[0060] Embodiment 45. The compound according to any one of Embodiments 39-42 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of R 4 ' and R 4 ‴ is H; and R 4 " is C 1-3 alkyl substituted with one halo.

[0061] Embodiment 46. The compound according to any one of Embodiments 39-42 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 methyl; and R 4 ‴ is H.

[0062] Embodiment 47. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is wherein R 4 ‴ is H; and R 4 ' and R 4 " are independently selected from the group consisting of H; halo; C 1-6 alkyl optionally substituted with one halo; and C 1-6 alkoxyl; provided that one of R 4 ' and R 4 " is not H; or, R 4 ' and R 4 ", together with the carbon atoms to which they are attached, form a 3 or 5 membered cycloalkyl ring optionally substituted with 1 or 2 C 1-3 alkyl, or form a phenyl ring.

[0063] Embodiment 48. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is wherein R 4 ‴ is H; and R 4 ' and R 4 " are independently selected from the group consisting of H; halo; C 1-6 alkyl optionally substituted with one halo; and C 1-6 alkoxyl; provided that one of R 4 ' and R 4 " is not H; or, R 4 ' and R 4 ", together with the carbon atoms to which they are attached, form a 3 or 5 membered cycloalkyl ring optionally substituted with 1 or 2 C 1-3 alkyl.

[0064] Embodiment 49. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is wherein R 4 ' is H; and R 4 " and R 4 ‴ are independently C 1-3 alkyl.

[0065] Embodiment 50. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein one of R 4 ' and R 4 " is H; and the other is C 1-6 alkyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C 1-3 alkyl.

[0066] Embodiment 51. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ' is H; and R 4 " is C 1-6 alkyl substituted with one halo; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring.

[0067] Embodiment 52. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ' is H; and R 4 " is C 1-3 alkyl substituted with one F; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring.

[0068] Embodiment 53. The compound according to any one of Embodiments 1-27 and 31-36 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein each p is dependently 0 or 1; preferably both p are 0, or both p are 1; q is 0, 1 or 2; preferably q is 0 or 2; R 4a is C 1-3 alkyl, preferably methyl.

[0069] Embodiment 54. The compound according to Embodiment 53 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is

[0070] Embodiment 55. The compound according to Embodiment 1 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: Compound Nos. Structures Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Example 32 Example 33 Example 34 Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70 Example 71 Example 72 Example 73 Example 74 Example 75 Example 76 Example 77 Example 78 Example 79 Example 80 Example 81 Example 82 Example 83 Example 84 Example 85 Example 86 Example 87 Example 88 Example 89 Example 90 Example 91 Example 92 Example 93 Example 94 Example 95 Example 96 Example 97 Example 98a Example 98b Example 98c Example 98d Example 99a Example 99b Example 100a Example 100b Example 101 Example 102 Example 103 Example 104 Example 105 Example 106 Example 107

[0071] Embodiment 56. The compound of any one of the Embodiments 1-55, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use as a medicament.

[0072] Embodiment 57. The compound of any one of the Embodiments 1-55, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0073] Embodiment 58. The compound of any one of the Embodiments 1-55, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer or diabetes; preferably, the cancer is hematological tumor, e.g., selected from leukemia, lymphomas, myelomas (e.g., multiple myeloma), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and polycythemia vera; or solid tumor, e.g., selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma; more preferably, the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemias (AML), chronic myeloid leukemias (CML), acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemias (MLLr leukemia), MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, nucleophosmin (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia and MLL-ELL leukemia.

[0074] Embodiment 59. A pharmaceutical composition, comprising the compound of any one of the Embodiments 1-55, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0075] Embodiment 60. A combination, comprising the compound of any one of the Embodiments 1-55, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein said additional therapeutic agent preferably is an anti-neoplastic agent, e.g., a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.Embodiments of the Disclosure - Part B

[0076] Embodiment 1. A compound of formula I: or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F, Cl or CN; Y is N or CH; Z is selected from the group consisting of CH 2 , O, and S; R 1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl and 3-5 membered cycloalkyl ring, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, OH and C 1-6 alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo; 2) a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; R 2 and R 3 are each independently H or D; each R 4 is independently selected from the group consisting of halo, CN, OH, C 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, phenyl, C 1-6 alkyl, C 1-6 alkoxyl and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-10 membered heteroaryl ring or phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; R 5 is H or halo; a, b, c and d are each independently 1 or 2; n is 0 or 1; and m is 0, 1, 2 or 3.

[0077] Embodiment 2. The compound according to the preceding Embodiment or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo, CN, OH, C 1-6 alkylsulfonyl-, C 1-6 alkylsulfonylamino-, phenyl, C 1-6 alkyl and C 1-6 alkoxyl, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-10 membered heteroaryl ring or phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl.

[0078] Embodiment 3. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula II:

[0079] Preferably, the compound is of formula IIa: which preferably is more preferably is: wherein each p is dependently 0 or 1; q is 0, 1 or 2; R 4a is C 1-3 alkyl or halo; most preferably is: wherein each p is dependently 0 or 1; q is 0, 1 or 2; R 4a is C 1-3 alkyl or halo.

[0080] Embodiment 4. The compound according to any of the Embodiments 1 or 2 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula III:

[0081] Embodiment 5. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein X is F.

[0082] Embodiment 6. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein Z is CH 2 .

[0083] Embodiment 7. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently H.

[0084] Embodiment 8. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl and 3-5 membered cycloalkyl ring, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, OH and C 1-6 alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring with another ring heteroatoms selected from N, O and S, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl and halo.

[0085] Embodiment 9. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra and Rb are each C 1-6 alkyl, preferably Ra is ethyl and Rb is iso-propyl; or R 1 is a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring.

[0086] Embodiment 10. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is -(C=O)-NRaRb, wherein Ra is ethyl and Rb is iso-propyl.

[0087] Embodiment 11. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring.

[0088] Embodiment 12. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is wherein A 1 or A 2 is N or CH; R 6 is selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; and R 7 is selected from the group consisting of H, halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; preferably, R 1 is or or R 1 is wherein A 3 is N or C substituted by halo, and R 8 is C 1-6 alkyl; preferably, R 1 is

[0089] Embodiment 13. The compound according to Embodiment 12 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula IIb':

[0090] Embodiment 14. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1; and each of c and d is 1 or 2;

[0091] Embodiment 15. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, preferably 0.

[0092] Embodiment 16. The compound according to any one of the preceding Embodiments 1-15 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein n is 0.

[0093] Embodiment 17. The compound according to any one of the preceding Embodiments 1-15 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein n is 1.

[0094] Embodiment 18. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

[0095] Embodiment 19. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1.

[0096] Embodiment 20. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of c and d is 2.

[0097] Embodiment 21. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: m is 1 or 2.

[0098] Embodiment 22. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1; each of c and d is 2; n is 0 or 1, preferably 0; and m is 0, 1 or 2.

[0099] Embodiment 23. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-6 alkylsulfonyl-; C 1-6 alkylsulfonylamino-; phenyl; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; and C 1-6 alkoxyl optionally substituted with halo, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two R 4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 5-6 membered heteroaryl ring, which is optionally substituted with 1, 2 or 3 C 1-6 alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl.

[0100] Embodiment 24. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of: and

[0101] Embodiment 25. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of:

[0102] Embodiment 26. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is selected from the group consisting of:

[0103] Embodiment 27. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is selected from the group consisting of:

[0104] Embodiment 28. The compound according to any one of preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F; Z is CH 2 ; R 1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C 1-6 alkyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 C 1-6 alkyl; 2) a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and 3-5 membered cycloalkyl ring; R 2 and R 3 are each independently H; each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-6 alkylsulfonyl-; C 1-6 alkylsulfonylamino-; phenyl; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; and C 1-6 alkoxyl optionally substituted with 1, 2 or 3 halo; and 3-6 membered cycloalkyl ring, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl. R 5 is H or halo; each of a and b is 1; each of c and d is 2; n is 0; and m is 0, 1 or 2.

[0105] Embodiment 29. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 5 is H.

[0106] Embodiment 30. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R 4 is independently selected from the group consisting of halo; CN; OH; C 1-6 alkylsulfonyl-; C 1-6 alkylsulfonylamino-; phenyl; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; and C 1-6 alkoxyl optionally substituted with 1, 2 or 3 halo, wherein two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, and C 1-6 alkoxyl-C 1-6 alkyl-; or, two adjacent R 4 , together with the carbon atoms to which they are attached, optionally form a phenyl.

[0107] Embodiment 31. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is -(C=O)-NRaRb, and Ra and Rb are each independently selected from the group consisting of ethyl or isopropyl.

[0108] Embodiment 32. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is a 5 or 6 membered heteroaryl ring or phenyl, which is substituted with 1 or 2 substituents selected from the group consisting of halo, CN, C 1-6 alkyl and cyclopropyl.

[0109] Embodiment 33. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN; C 1-6 alkoxyl; and 3-6 membered cycloalkyl ring; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; and R 4 ‴ is H.

[0110] Embodiment 34. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN; C 1-6 alkoxyl; and cyclopropyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; and R 4 ‴ is H.

[0111] Embodiment 35. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN; and C 1-6 alkoxyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH, C 1-6 alkoxyl-C 1-6 alkyl- and halo; and R 4 ‴ is H.

[0112] Embodiment 36. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ', R 4 " and R 4 ‴ are independently selected from the group consisting of H; halo; CN; OH; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN; and C 1-6 alkoxyl.

[0113] Embodiment 37. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-6 alkyl, -C 1-6 alkyl-OH and C 1-6 alkoxyl-C 1-6 alkyl-; and R 4 ‴ is H.

[0114] Embodiment 38. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of R 4 ' and R 4 ‴ is H; and R 4 " is C 1-6 alkyl substituted with 1, 2 or 3 halo.

[0115] Embodiment 39. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halo; and R 4 ‴ is H.

[0116] Embodiment 40. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is

[0117] Embodiment 41. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is wherein R 4 ‴ is H; and R 4 ' and R 4 " are independently selected from the group consisting of H; halo; C 1-6 alkyl optionally substituted with 1, 2 or 3 halo; and C 1-6 alkoxyl; provided that one of R 4 ' and R 4 " is not H; or, R 4 ' and R 4 ", together with the carbon atoms to which they are attached, form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 C 1-3 alkyl.

[0118] Embodiment 42. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is wherein R 4 ' is H; and R 4 " and R 4 ‴ are independently C 1-3 alkyl.

[0119] Embodiment 43. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein one of R 4 ' and R 4 " is H; and the other is C 1-6 alkyl; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C 1-6 alkyl.

[0120] Embodiment 44. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ' is H; and R 4 " is C 1-6 alkyl substituted with 1 or 2 halo; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring, which is optionally substituted with 1 or 2 halo.

[0121] Embodiment 45. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R 4 ' is H; and R 4 " is C 1-6 alkyl substituted with 1, 2 or 3 halo; or R 4 ' and R 4 ", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring.

[0122] Embodiment 46. The compound according to any one of the preceding Embodiments or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein each p is dependently 0 or 1; preferably both p are 0, or both p are 1; q is 0, 1 or 2; preferably q is 0 or 2; R 4a is C 1-3 alkyl or halo; preferably R 4a is methyl or F.

[0123] Embodiment 47. The compound according to Embodiment 46 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is

[0124] Embodiment 48. The compound according to the Embodiment 1 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from Example 2 to Example 34 or Example 37 to Example 100.

[0125] Embodiment 49. The compound of any one of the Embodiments 1-48, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use as a medicament.

[0126] Embodiment 50. The compound of any one of the Embodiments 1-48, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer and other diseases mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0127] Embodiment 51. The compound of any one of the Embodiments 1-48, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer or diabetes; preferably, the cancer is hematological tumor, e.g., selected from leukemia, lymphomas, myelomas (e.g., multiple myeloma), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and polycythemia vera; or solid tumor, e.g., selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma; more preferably, the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemias (AML), chronic myeloid leukemias (CML), acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemias (MLLr leukemia), MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, nucleophosmin (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia and MLL-ELL leukemia.

[0128] Embodiment 52. A pharmaceutical composition, comprising the compound of any one of the Embodiments 1-48, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0129] Embodiment 53. A combination, comprising the compound of any one of the Embodiments 1-48, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein said additional therapeutic agent preferably is an anti-neoplastic agent, e.g., a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.Definitions

[0130] As used in the present disclosure, the following words, phrases and symbols have the meanings as set forth below, unless specified otherwise in the context.

[0131] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0132] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C 1-6 alkyl-OH is attached to the rest of the molecule through the alkyl.

[0133] The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon radical having 1-10 carbon atoms (C 1-10 ), preferably 1-6 carbon atoms (C 1-6 ), and more preferably 1-4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3 ). For example, "C 1-6 alkyl" refers to the alkyl having 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms. Examples of the alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

[0134] The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3 carbon-carbon double bonds (C=C) and having 2-10 carbon atoms (C 2-10 ), preferably 2-6 carbon atoms (C 2-6 ), more preferably 2-4 carbon atoms (C 2-4 ). For example, "C 2-6 alkenyl" refers to the alkenyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, which preferably contains 1 or 2 carbon-carbon double bonds; "C 2-4 alkenyl" refers to the alkenyl having 2-4 carbon atoms, which preferably contains 1 carbon-carbon double bond. Examples of the alkenyl include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment for the alkenyl may or may not be on the double bond.

[0135] The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3, carbon-carbon triple bonds (C≡C) and having 2-10 carbon atoms (C 2-10 ), preferably 2-6 carbon atoms (C 2-6 ), more preferably 2-4 carbon atoms (C 2-4 ). For example, "C 2-6 alkynyl" refers to the alkynyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, which preferably contains 1 or 2 carbon-carbon triple bonds; "C 2-4 alkynyl" refers to the alkynyl having 2-4 carbon atoms, which preferably contains 1 carbon-carbon triple bond. Examples of the alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment for the alkynyl may or may not be on the triple bond.

[0136] The term "halogen" or "halo" as used herein refers to fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro, most preferably fluoro.

[0137] The term "haloalkyl" as used herein refers to the alkyl as defined herein, in which one or more, for example 1, 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to the alkyl as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to the alkyl as defined herein, in which two or more, for example 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms may be different from each other. Examples of the haloalkyl include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CH 3 , and the like. Preferably haloalkyl is C 1-6 trifluoroalkyl, more preferably -CF 3 .

[0138] The term "alkyl substituted with 1, 2 or 3 ... halo" refers to the alkyl as defined herein, in which one or more, for example 1, 2 or 3 hydrogen atoms are replaced with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other, including, but being not limited to, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 F, -CF 2 CH 3 , and the like. Similarly, the term "alkyl substituted with 1, 2 or 3 ... CN" includes, but is not limited to, -CH 2 CN and -CH 2 CH 2 CN. The term "alkoxyl substituted with 1, 2 or 3 ... halo" includes, but is not limited to, -OCH 2 F, -OCHF 2 , -OCHF 3 , -OCH 2 CHF 3 .

[0139] The term "alkoxyl" as used herein refers to the group -O-alkyl, wherein the alkyl is as defined above. Examples of the alkoxyl include, but are not limited to, C 1-6 alkoxyl, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, and hexyloxy, including their isomers. Preferably alkoxyl is methoxy.

[0140] The term "cycloalkyl" as used herein refers to saturated cyclic hydrocarbon radical having 3-10 ring carbon atoms (C 3-10 ), such as 3-9 ring carbon atoms (C 3-9 ), 3-7 ring carbon atoms (C 3-7 ), 3-6 ring carbon atoms (C 3-6 ), 3-5 ring carbon atoms (C 3-5 ) or 5-6 ring carbon atoms (C 5-6 ), which may have one or more rings, e.g., 1 or 2 rings. For example, said cycloalkyl is monocyclic cycloalkyl, preferably monocyclic C 3-7 cycloalkyl, preferably monocyclic C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or monocyclic C 3-5 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl) ring. For example, said cycloalkyl is bicyclic cycloalkyl ring, preferably bicyclic C 5 -C 10 cycloalkyl ring. Bicyclic cycloalkyl include a fused ring, a bridged ring, or a spirocyclic ring.

[0141] The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring having 3-10 ring atoms (3-10 membered), such as 5-9 ring atoms (5-9 membered), 6-8 ring atoms (6-8 membered), 5-6 ring atoms (5-6 membered) or 7-9 ring atoms (7-9 membered), with one or more of, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, and the remaining ring atoms being carbon, and having one or more, for example 1, 2 or 3, preferably 1 or 2 rings, wherein the N or S heteroatom is optionally oxidized to various oxidation states. The point of attachment of heterocyclyl may be on N heteroatom or carbon atom. The ring(s) of the heterocyclyl also include(s) a fused ring, a bridged ring, or a spirocyclic ring. The ring(s) of the heterocyclyl may be saturated or contain(s) one or more, for example, one or two double bonds (i.e. partially unsaturated), but is (are) not fully conjugated, and not the heteroaryl as defined herein. For example, "5-9 membered heterocyclyl" refers to the monocyclic or bicyclic heterocyclyl having 5-9 ring atoms and containing 1, 2 or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O and S, preferably is saturated 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl. Examples of the heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, oxazinanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, azaspiro[3.5]nonanyl, or azaspiro[2.5]octanyl ring. Preferably, the heterocyclyl is morpholinyl or 3-oxa-6-azabicyclo[3.2.1]octanyl ring.

[0142] The term "aryl" as used herein refers to carbocyclic hydrocarbon radical having 6-14 carbon atoms (C 6-14 ), preferably 6-10 carbon atoms (C 6-10 ) and consisting of one ring or more fused rings, wherein at least one ring is aromatic. Examples of the aryl include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, or azulenyl ring, preferably phenyl or naphthalenyl ring, more preferably phenyl ring.

[0143] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic ring system having 5-12 ring atoms (5-12 membered), such as 5-10 ring atoms (5-10 membered), 5-9 ring atoms (5-9 membered), 8-10 ring atoms (8-10 membered), 5-6 ring atoms (5-6 membered), 5 ring atoms (5 membered) or 6 ring atoms (6 membered), wherein at least one ring is an 5 or 6 membered aromatic ring with one or more of, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, and the remaining ring atoms being carbon, and wherein the N or S heteroatom is optionally oxidized to various oxidation states. For example, the 5-10 membered heteroaryl is: 5-6 membered monocyclic heteroaryl, i.e. monocyclic aromatic hydrocarbon radical having 5 or 6 ring atoms (5 or 6 membered), with one or more of, for example 1, 2 or 3, preferably 1 or 2 of the ring atoms being ring heteroatoms independently selected from N, O, and S (preferably N), and the remaining ring atoms being carbon; preferably, monocyclic aromatic hydrocarbon radical having 6 ring atoms (6 membered), with 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O, and S, preferably N; or 8-10 membered bicyclic heteroaryl, i.e. bicyclic aromatic hydrocarbon radical having 8, 9, or 10 ring atoms (8, 9, or 10 membered), with one or more, for example, 1, 2, 3 or 4, preferably 1, 2 or 3 of the ring atoms are ring heteroatoms independently selected from N, O, and S (preferably N), and the remaining ring atoms being carbon, wherein at least one of the rings is aromatic.

[0144] Examples of the heteroaryl include, but are not limited to, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), pyridyl N-oxide, pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl), pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-5-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl), oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl (e.g., triazol-1-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, triazol-5-yl), tetrazolyl, triazinyl, thienyl, furyl, pyranyl, pyrrolyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl, imidazopyrrolyl, triazolopyridyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, tetrazolopyridyl, tetrahydropyrazolopyridyl, benzofuryl, benzoimidazolinyl, or indolyl. Preferably, the heteroaryl is pyrazolyl, triazolyl or pyrimidinyl ring, more preferably pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, triazol-1-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, triazol-5-yl.

[0145] The term "oxo" as used herein refers to the group =O.

[0146] The group "D" means hydrogen atom of the moiety is replaced with its isotope deuterium.

[0147] When a structure of a compound herein contains a bond represented by a wavy line ", it means a mixture of isomers in any ratio of the compound.

[0148] When a group carries a wavy line "" on a bond, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0149] As used herein, a bond through a ring means that a group having the bond is attached to the ring at any chemically permissible position of the ring, unless indicated otherwise.

[0150] The group wherein Z, n, m and R 4 are as defined in general formulas herein represents a heterocyclyl ring substituted by (R 4 ) m at any chemically permissible position (e.g. at Z, when Z is CH 2 ) of the ring. Preferably, in the present disclosure, the substiuation with R 4 is not occurred on the N atom adjacent to the attachment point of the group to the remaining structure of the compound.

[0151] The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur. For example, "optionally substituted with ..." encompasses both "unsubstituted" and "substituted with 1, 2, 3 or more" substituents as defined. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups do not include any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and / or inherently unstable.

[0152] The term "substituted" or "substituted with ..." as used herein, means that one or more hydrogens on the designated atom or group are replaced with one or more substituents independently selected from the indicated group of substituents, provided that the designated atom's normal valence is not exceeded. The term "substituted with 1, 2 or 3 ..." means that 1, 2 or 3 hydrogens on the designated atom or group are replaced with 1, 2 or 3 substituents independently selected from the indicated group of substituents, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e., =O), then 2 hydrogens on a single atom are replaced by the oxo. Combinations of substituents and / or variables are permissible only if such combinations result in a chemically correct and stable compound. A chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture.

[0153] It will be appreciated by a person skilled in the art that some of the compounds disclosed herein may contain one or more chiral centers or ring and therefore exist in two or more stereoisomers. The racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers and mixtures partially enriched with specific diastereomers when there are two chiral centers are within the scope of the present disclosure. It will be further appreciated by a person skilled in the art that the present disclosure includes all the individual stereoisomers (e.g. enantiomers, diastereoisomers, cis- or trans-isomers (e.g., configuration of substituents on bivalent cyclic saturated or partially saturated radicals), or atropisomers, whenever chemically possible), racemates of the compounds of the present disclosure, mixtures thereof, and, where appropriate, the individual tautomeric forms thereof.

[0154] The racemate or other mixtures of isomers can be used as such or can be resolved into their individual isomers. The resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separation of isomers are well known (e.g., cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971).

[0155] When a structure herein contains "(R)" and / or "(S)", it means that the chiral center of the compound marked by "(R)" or "(S)" is a single configuration in either R-configuration or S-configuration. Such R-configuration or S-configuration of the chiral center of the compound can also be represented by "" or "" merely in the structure. For example, the compounds of the present disclosure have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee (enantiomeric excess), or any values between those enumerated values), or have a diastereomeric purity of at least 60% de (diastereomeric excess) (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any values between those enumerated values).

[0156] The term "pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts formed by the compounds disclosed herein with an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate and the like; as well as with an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and salts with alkane-dicarboxylic acid of formula HOOC-(CH 2 ) n -COOH wherein n is 0-4, and the like. Also, "pharmaceutically acceptable salt" includes base addition salts formed by the compound of the present disclosure carrying an acidic moiety with pharmaceutically acceptable cations, for example, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0157] In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be produced from a base compound by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts. A person skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.

[0158] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), acetyl, trifluoroacetyl, phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include methoxymethyl, benzyl, benzyloxymethyl, methyl, triarylmethyl, acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, and tetrahydropyranyl. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 5th Edition, Wiley, New York, 2014.

[0159] The term "pharmaceutical combination" or "combination" as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents, e.g., kit or pharmaceutical composition. The term "fixed combination" means that the therapeutic agents, e.g. the compound of the present disclosure and an additional therapeutic agent, are both administered to a subject simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, e.g. the compound of the present disclosure and an additional therapeutic agent, are both administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of the subject.

[0160] The term "treating", "treat" or "treatment" in connection with a disease refers to administering one or more pharmaceutical substances, especially the compound of the present disclosure or a pharmaceutically acceptable salt thereof described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder. In some embodiments, the disease or disorder is cancer or diabetes.

[0161] The term "prevent" or "preventing" in connection with a disease refer to administering one or more pharmaceutical substances, especially the compound of the present disclosure to a subject that has a predisposition toward a disease or disorder, or has a risk of suffering from a disease or disorder, with the purpose to prevent or slow down the occurrence of the disease or disorder in the subject.

[0162] The term "effective amount" as used herein refers to an amount of the compound of the present disclosure effective to "treat" or "prevent" cancer or diabetes in a subject. The effective amount may cause any changes observable or measurable in a subject as described in the definition of "treating", "treat", "treatment", "preventing", or "prevent" above. For example, in the case of cancer, the effective amount can reduce the number of cancer or tumor cells; reduce the tumor size; inhibit or stop tumor cell infiltration into peripheral organs; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to reduce the symptoms of cancer. The term "effective amount" may also refer to an amount of the compound of the present disclosure effective to inhibit the interaction of menin with MLL and / or MLL fusion proteins.

[0163] The term "inhibition" or "inhibiting" indicates a decrease in the baseline activity of a biological activity or process.

[0164] The term "subject" as used herein means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. In some embodiments, the subject is a human.

[0165] The term "pharmaceutically acceptable" means that the substance following this term is useful in preparing a pharmaceutical composition and is generally safe, non-toxic, and neither biologically nor otherwise undesirable, especially for human pharmaceutical use.

[0166] The term "cancer" herein refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and / or ability to establish new growth at other sites. The term "cancer" includes, but is not limited to, hematological tumors and solid tumors, preferably is leukemia. The term "cancer" encompasses cancer of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary cancers, metastatic cancers, recurrent cancers, and refractory cancers. The term "cancer" includes, but is not limited to, leukemia, lymphomas, myelomas (e.g., multiple myeloma), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and polycythemia vera; prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma. The "leukemia" herein includes, but is not limited to, acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid (myelogeneous) leukemias (AML), chronic myeloid (myelogenous) leukemias (CML), acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemias (MLLr leukemia), MLL partial tandem duplicate leukemia (MLL-PTD leukemias), MLL amplified leukemias, MLL-positive leukemias, nucleophosmin (NPM)-mutated leukemia (NPM1-mutated leukemia, NPM1c leukemia), MOZ acute leukemia, NUP98 acute leukemia, and clathrin assembly lymphoid myeloid (CALM) acute leukemia; and MLL-AF4 (ALL-1 fused gene from chromosome 4) leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL (eleven-nineteen leukemia) leukemia and MLL-ELL (eleven-nineteen lysine-rich leukemia) leukemia.

[0167] All numerical ranges herein should be understood as disclosing each and every value within the range and each and every subset of values within the range, regardless of whether they are specifically disclosed otherwise. For example, when referring to any numerical range, it should be regarded as referring to each and every numerical value in the numerical range, for example, each and every integer in the numerical range. The present disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limit of the range.

[0168] Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by a person skilled in the art, to which the present disclosure pertains.Pharmaceutical Composition and Administration

[0169] The compound of the present disclosure (such as any of the compounds of the Examples herein) alone or in combination with one or more additional therapeutic agents can be formulated into a pharmaceutical composition. The pharmaceutical composition includes: (a) the compound of the present disclosure; (b) a pharmaceutically acceptable carrier (for example, one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0170] A pharmaceutically acceptable carrier refers to an excipient or adjuvant that is compatible with the active ingredient(s) in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the subject being treated. Suitable pharmaceutically acceptable carriers are disclosed in standard reference books in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy.), including one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., the compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0171] The compound of the present disclosure can be administered in various known manners, such as orally, parenterally, by inhalation, or by implantation. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.

[0172] The compound of the present disclosure may be administered in any convenient formulation, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.

[0173] In one example, the effective amount of the compound of the present disclosure administered parenterally per dose will be in the range of about 0.01 to 100 mg / kg, alternatively about 0.1 to 20 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the present disclosure.Indications and Treatment

[0174] The present disclosure relates to a compound provided herein for use in treating or preventing a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins, said use comprising administering to the subject in need thereof an effective amount of the compound of the present disclosure.

[0175] The present disclosure relates to a compound provided herein for use in treating or preventing cancer or diabetes, comprising administering to the subject in need thereof an effective amount of the compound of the present disclosure.

[0176] In one embodiment, the compound of the present disclosure is for use in the treatment or prevention of a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins.

[0177] In one embodiment, the compound of the present disclosure is for use in the treatment or prevention of cancer or diabetes.

[0178] In one embodiment, the compound of the present disclosure is for use in the treatment or prevention of hematological tumor, including but not limited to leukemia, lymphomas, myelomas (e.g., multiple myeloma), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and polycythemia vera; or solid tumor, including but not limited to prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

[0179] In one embodiment, the compound of the present disclosure is for use in the treatment or prevention of acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemias (AML), chronic myeloid leukemias (CML), acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemias (MLLr leukemia), MLL partial tandem duplicate leukemia (MLL-PTD leukemias), MLL amplified leukemias, MLL-positive leukemias, nucleophosmin (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, and clathrin assembly lymphoid myeloid (CALM) acute leukemia.Pharmaceutical Combination

[0180] The compound of the present disclosure may be used in combination with an additional therapeutic agent in the treatment of a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins. The additional therapeutic agent may be administered separately with the compound of the present disclosure or may be included with the compound of the present disclosure in a pharmaceutical composition according to the present disclosure, such as a fixed combination product. In some embodiments, the additional therapeutic agent is known or discovered to be effective in the treatment of a disease or disorder mediated by the interaction of menin with MLL and / or MLL fusion proteins or a compound that antagonizes another target associated with said particular disease. The combination may serve to increase efficacy, decrease one or more side effects, or decrease the required dose of the compound of the present disclosure.

[0181] In some embodiments, the compound of the present disclosure is administered in combination with an anti-neoplastic agent. The anti-neoplastic agents include, but are not limited to: radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents.General Synthetic Methods

[0182] Example compounds with general structure as A10 may be synthesized according to Scheme 1. Reaction between phenol A1 and 5-bromopyrimidine under basic conditions gave biaryl ether A2, which could be converted to N-oxide A3 in the presence of mCPBA. Subsequent reaction of the latter with chlorination reagent, like POCl 3 , readily afforded chloropyrimidine A4. Nucleophilic substitution reaction between chloride A4 and mono-protected spirodiamine A5 gave key intermediate A6. The following deprotection of A7, amide formation with N-protected cyclic amino acid A8, and N-deprotection afforded final compound A10.

[0183] Example compounds with structure as B4 may be synthesized according to Scheme 2. B1 could be prepared from appropriate phenol according to procedure similar to that for A6 as depicted in Scheme 1. Suzuki coupling reaction between B1 and (hetero)arylboronic acid afforded compound B3. Alternatively, a two-step route could be used to prepare B3, that is, B1 was converted to boronate B2 via palladium catalyzed boronylation reaction followed by Suzuki reaction of the latter with (hetero)aryl halide. Subsequent deprotection of B3, amidation with with N-protected cyclic amino acide A8, and final N-deprotection could afford compound B4.

[0184] Example compounds with general structure as C6 may be synthesized according to Scheme 3. Selective nucleophilic substitution reaction between mono-protected spirodiamine A5 and 3,5,6-trichloro-1,2,4-triazine C1 afforded triazine C2. The second nucleophilic substitution with phenol C3 gave monochoride C4. Removal of the chlorine atom under reductive conditions gave triazine C5. Again, subsequent deprotection, amidation with with N-protected cyclic amino acide A8, and final N-deprotection afforded compound C6.

[0185] Example compound with general structure as D1 in Scheme 4 could be prepared from chloride C4 in 3 steps, deprotection, amidation with with N-protected cyclic amino acide A8, and N-deprotection. Chloride C4 could also react with a neucleophile under basic conditions or with a bronic reagent in the presence of palladium catalyst to give intermediate D2, which, after deprotection, amidation with with N-protected cyclic amino acide A8, and N-deprotection, could afford example compound with general structure as D3 (Scheme 4).

[0186] Each embodiment described in the present disclosure and the features in each embodiment should be understood as being capable of combining with each other in any manner, and those technical solutions obtained by such combination(s) are all included in the scope of the present disclosure the same as if each and every technical solution obtained by such combination(s) were specifically and individually listed, unless the context clearly shows otherwise.

[0187] Various patents, patent applications, publications, and other references are cited or referred to herein. The discussion of those references is intended merely to summarize the assertions made therein. No admission is made that any such patents, patent applications, publications or references, or any portion thereof, are relevant material or prior art. The right to challenge the accuracy and pertinence of any assertion of such patents, patent applications, publications, and other references as relevant material or prior art is specifically reserved.EXAMPLES

[0188] The examples below are intended to illustrate the invention only, and should not be contorted to be limiting in any way.

[0189] Unless indicated otherwise, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS (mass spectrometry) data were measured by Agilent 6120B and / or Shimadzu LCMS2010. 1< H-NMR spectra were recorded on a nuclear magic resonance spectrometer operating at Bruker AVANCE NEO 400 MHz. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quarter), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Herz (Hz).

[0190] All reagents and starting materials, except intermediates as prepared below, used in this invention are commercially available or prepared according to the prior art.

[0191] All compound names except the reagents were generated by Chemdraw. If there is any inconsistency between the structure and the name of a compound given in this invention, the structure prevails, unless the context shows that the structure is incorrect and the name is right.

[0192] If there is any empty valence in any atom disclosed herein, the empty valence is the hydrogen atom which is omitted for convenience.

[0193] Isomers, if isolated from the same chromatagraphy separation condition in the following Examples, are named in the same sequence as they are eluted, unless specified otherwise.

[0194] In the following examples, the abbreviations below are used:List of Abbreviation

[0195] AbbreviationFull NameAcOHacetic acidBBr 3 boron tribromideCDCl 3 deuterated chloroformCs 2 CO 3 cesium carbonateDASTdiethylaminosulfur trifluorideDCMdichloromethaneDIADdiisopropyl azodicarboxylateDIPEAN,N-diisopropylethylamineDMFN,N-dimethylformamideDMSOdimethyl sulfoxideDPPAdiphenyl phosphoryl azideESIelectrospray ionizationEtOAcethyl acetatehhourHATUO-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHClhydrochlorideK 2 CO 3 potassium carbonateKOAcpotassium acetateLC / MSliquid chromatography-mass spectrometerLAHlithium aluminium hydrideLDAlithium diisopropylamidemCPBAmeta-chloroperbenzoic acidMeCNacetonitrileMeODdeuterated methanolmLmillilitermmolmillimoleMOMClchlormethyl methyl etherNa 2 SO 4 sodium sulfateNaBH 4 sodium borohydrideNaHsodium hydrideNaHCO 3 sodium bicarbonateNaOHsodium hydroxiden-BuLin-butyllithiumNCSN -chlorosuccinimideNMRnuclear magnetic resonancePctpercentagePd(AcO) 2 Palladium(II) acetatePd(dppf)Cl 2 1,1'-Bis(diphenylphosphino)ferrocene palladium(II)dichloridePd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladiumPEpetroleum etherpHpotential of hydrogenPMBCl4-methoxybenzylchloridePPh 3 triphenylphosphineprep-HPLCPreparation high performance liquid chromatographyprep-TLCpreparation thin layer chromatographyPOCl 3 Phosphoryl trichloridep-TSAp-toluenesulfonic acidrtroom temperaturesat.saturatedSFCsupercritical fluid chromatographyTBDPSCltert-butyl(chloro)diphenylsilaneTEAtriethylamineTFAtrifluoroacetic acidTHFtetrahydrofuranTMEDAN,N,N',N'-tetramethylethylenediamineXant-phos4,5-bis(diphenylphosphino)-9,9-dimethylxantheneZn(CN) 2 zinc cyanide Preparation of key intermediate Preparation of Intermediate 1, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0196] Step 1:

[0197] To a solution of 5-fluoro-2-methoxybenzoic acid (7.50 g, 44.1 mmol) and HATU (16.7 g, 44.0 mmol) in DMF (50 mL) was added ethyl(propan-2-yl)amine (15.4 g, 176 mmol) dropwise at 0 °C. The reaction mixture was warmed to room temperature gradually and stirred overnight. The reaction mixture was quenched with sat. NH 4 Cl solution (50 mL), extracted with EtOAc (100 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product N-ethyl-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (10.0 g, yield: 94.8%) as a light yellow solid. LC / MS (ESI) m / z: 240(M+H) +< .Step 2:

[0198] To a solution of N-ethyl-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (9.01 g, 37.6 mmol) in DCM (50 mL) was added BBr 3 (37.6 mL, 1.0 M in DCM) dropwise at -60 °C under N 2 atmosphere, the resulting mixture was stirred for 2 h at this temperature. Then the reaction mixture was quenched with cooled sat. NaHCO 3 at 0 °C, the mixture was extracted with DCM (100 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the desired product N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (4.01 g, yield: 47.2%) as a light yellow solid, which can be used in next step without further purification. LC / MS (ESI) m / z: 226(M+H) +< .Step 3:

[0199] To a mixture of N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (4.01 g, 17.7 mmol) in DMF (20 mL) was added 5-bromopyrimidine (3.40 g, 21.3 mmol) and Cs 2 CO 3 (11.6 g, 35.5 mmol). The reaction mixture was heated to 120 °C for 12 h. After cooled to room temperature, the mixture was quenched with sat. NH 4 Cl solution (50 mL), extracted with EtOAc (100 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to give the desired product N-ethyl-5-fluoro-N-(propan-2-yl)-2-(pyrimidin-5-yloxy)benzamide (1.99 g, yield: 37.1%) as a yellow oil. LC / MS (ESI) m / z: 304(M+H) +< .Step 4:

[0200] To a solution of N-ethyl-5-fluoro-N-(propan-2-yl)-2-(pyrimidin-5-yloxy)benzamide (1.99 g, 6.60 mmol) in DCM (20 mL) was added m-CPBA (3.41 g, 19.8 mmol) portionwise at 0 °C, then the resulting mixture was stirred for 10 h at rt. The reaction mixture was quenched with sat. NaHCO 3 , extracted with DCM (50 mL x 3), and the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 80%) to give the desired product 5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (0.901 g, yield: 42.8%) as a off-white solid. LC / MS (ESI) m / z: 320 (M+H) +< .Step 5:

[0201] To a solution of 5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (0.90 g, 2.8 mmol) and TEA (0.8 mL, 5.6 mmol) in CHCl 3 (10 mL) was added POCl 3 (0.80 mL, 8.4 mmol) dropwise at 0 °C. Then the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with sat.NaHCO 3 , and extracted with DCM (100 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (320 mg, yield: 33.6%) as a brown oil which can be used in next step without further purification. LC / MS (ESI) m / z: 338 / 340(M+H) +< .Step 6:

[0202] To a solution of 2-[(4-chloropyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (300 mg, 0.9 mmol) in MeCN (10 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (221 mg, 1.00 mmol) and K 2 CO 3 (246 mg, 1.80 mmol). The resulting mixture was heated to 80 °C for 5 h. After cooled to room temperature, the reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to give the desired product tert-butyl 2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan e-7-carboxylate (390 mg, yield: 83.2%) as a yellow solid. LC / MS (ESI) m / z: 528(M+H) +< .Step 7:

[0203] To a solution of tert-butyl 2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan e-7-carboxylate (200 mg, 0.4 mmol) in DCM (5 mL) was added TFA (2.0 mL) dropwise at room temperature, the resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated to give the crude product 2- 2-[(4-{2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benz amide (150 mg, yield: 92.5%) as a TFA salt which can be used in next step without further purification. LC / MS (ESI) m / z: 428(M+H) +< .

[0204] The following intermediates were prepared from the corresponding chemicals according to experimental procedure for Intermediate 1 (the major different chemicals used are listed in the column of starting material): IntermediateStructureStarting materialLCMS (ESI) m / zIntermediate 2 444 (M+H) +< Intermediate 3 426 (M+H) +< Intermediate 4 435 (M+H) +< Intermediate 5 Intermediate 41 430 (M+H) +< Intermediate 6 410 (M+H) +< Intermediate 7 414 (M+H) +< Intermediate 8 400 (M+H) +< Intermediate 9 442 (M+H) +< Intermediate 10 442 (M+H) +< Intermediate 11 442 (M+H) +< Intermediate 12 454 (M+H) +< Intermediate 13 Intermediate 22 240 (M+H) +< Preparation of Intermediate 14, 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide

[0205] Step 1:

[0206] To a solution of 5-fluoro-2-methoxybenzoic acid (1.00 g, 5.88 mmol) and HATU (2.28 g, 6.00 mmol) in DMF (10 mL) was added diisopropylamine (712 mg, 7.06 mmol) dropwise at 0 °C. The reaction mixture was warmed to room temperature gradually and stirred overnight. The reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, yield: 21.5 %) as a light yellow solid. LC / MS (ESI) m / z: 254(M+H) +< .Step 2:

[0207] To a solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (320 mg, 1.26 mmol) in DCM (10 mL) was added BBr 3 (3 mL, 1.0 M in DCM) dropwise at -60 °C under N 2 atmosphere, the resulting mixture was stirred for 2 h at this temperature. Then the reaction mixture was quenched with cooled MeOH at 0°C, the mixture was extracted with DCM (15 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE =0 ~ 20%) to afford the desired product N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (260 mg, yield: 86.3%) as a white solid, LC / MS (ESI) m / z: 240(M+H) +< .Preparation of Intermediate 15, (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid

[0208] Step 1:

[0209] To a solution of 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (200 mg, 0.82 mmol) in THF (5 mL) was added MeMgBr (1.2 mL, 1.23 mmol) dropwise at 0 °C under N 2 . The resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched with sat. NH 4 Cl solution (5 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 30%) to give the desired product 1-tert-butyl 2-methyl (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (180 mg, yield:80.2%) as a light yellow oil. LC / MS (ESI) m / z: 260(M+H) +< .Step 2:

[0210] To a solution of 1-tert-butyl 2-methyl (2S)-4-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (180 mg, 0.69 mmol) in MeOH (3 mL) and H 2 O (1 mL) was added NaOH (83 mg, 2.1 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h, The reaction mixture was adjusted the pH to 4-5 with 1.0 N HCl solution, diluted with H 2 O (10 mL), extracted with DCM (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the desired product (2S)-1-[(tert-butoxy)carbonyl]-4-hydroxy-4-methylpyrrolidine-2-carboxylic acid (150 mg, yield: 83.6%) as a off-white solid which can be used in next step directly without further purification. LC / MS (ESI) m / z: 190 (M-55) +< .Preparation of Intermediate 16, (2S,4R)-1-(tert-butoxycarbonyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid

[0211] Step 1:

[0212] To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.0 g, 4.0 mmol), TEA (0.83 g, 8.2 mmol) in DCM (15 mL) was added MsCl (0.50 g, 4.5 mmol) at 0°C under N 2 , the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water (30 mL), extracted with EtOAc (25 mL x 3). The combined organic phase was washed with brine (25 mL), and concentrated to give the crude product 1-tert-butyl 2-methyl (2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (1.1 g , yield: 83.4%) as a light yellow oil which was used in next step without further purification. LC / MS(ESI)m / z: 224(M-100+H) +< .Step 2:

[0213] To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (1.1 g, 3.4 mmol) in DMF (15 mL) was added NaSMe (230 mg, 4.0 mmol), the resulting mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE =10 ~ 25%) to afford the desired product (2S,4R)-1-tert-butyl 2-methyl 4-(methylthio)pyrrolidine-1,2-dicarboxylate (850 mg, yield: 90.7%) as a solid, 1H NMR (400 MHz, CDCl 3 ) δ 4.29 (dd, J = 23.9, 16.0 Hz, 1H), 3.97 (dd, J = 10.5, 7.0 Hz, 1H), 3.74 (s, 3H), 3.42 - 3.12 (m, 2H), 2.60 (dd, J = 13.0, 6.4 Hz, 1H), 2.12 (s, 3H), 1.99 - 1.88 (m, 1H), 1.47 - 1.40 (m, 9H).Step 3:

[0214] To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(methylthio)pyrrolidine-1,2-dicarboxylate (850 mg, 3.10 mmol) in DCM (20 mL) was added m-CPBA (1.1 g, 6.2 mmol) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (50 mL), washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE =5 ~ 25%) to afford the desired product (2S,4R)-1-tert-butyl 2-methyl 4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylate (500 mg , yield: 52.7 %) as light yellow solid, LC / MS(ESI)m / z: 330(M+Na) +< .Step 4:

[0215] To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-(methylsulfonyl)pyrrolidine-1,2-dicarboxylate (500 mg, 1.6 mmol) in EtOH (5 mL) was added NaOH aq. solution (2.0 mL, 2.0 N), and the resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated, and adjusted the pH to 2~3 with 1.0 N HCl solution, extracted with EtOAc (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (2S,4R)-1-(tert-butoxycarbonyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid (400 mg, yield: 83.8%) as light yellow oil which was used in next step without further purification, LC / MS(ESI)m / z: 316 (M+Na) +< .Preparation of Intermediate 17, (485,5S,7R)-6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanopyrazolo[3,4-c]pyr idine-5-carboxylic acid

[0216] Step 1:

[0217] To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.1 g, 3.8 mmol) in DCM (30 mL) was added Dess-Martin reagent (3.3 g, 7.7 mmol) at 0 °C, the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE= 5 ~ 20%) to give the desired product 2-tert-butyl 3-ethyl (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (800 mg , yield: 73.2%) as an oil, LC / MS(ESI)m / z: 184(M-100+H) +< .Step 2:

[0218] To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.2 g, 4.2 mmol) in toluene (10 mL) was added DMF-DMA (5 mL), the reaction mixture was heated to 120 °C for 24 h. The mixture was cooled to rt and the solvent was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 50% ~ 100%) to afford the desired product (1R,3S,4S)-2-tert-butyl 3-ethyl 5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylatee (500 mg, yield: 35.7%) as a light yellow solid, LC / MS(ESI)m / z: 283(M-55+H) +< .Step 3:

[0219] To a solution of (1R,3S,4S)-2-tert-butyl 3-ethyl 5-((dimethylamino)methylene)-6-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (300 mg, 0.9 mmol) and methylhydrazine solution (0.2 mL, 1.6 mmol) in MeCN (10 mL) was added HOAc (0.1 mL), the resulting mixture was stirred at 80 °C overnight. The reaction mixture was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 10 ~ 30%) to give the desired product 9-tert-butyl 8-ethyl 6-(tert-butyl) 5-ethyl (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methanopyrazolo[3,4-c]pyridine-5,6-dicarboxylate (150 mg, yield: 52%) as a white solid, LC / MS(ESI)m / z:322(M+H)+.Step 4:

[0220] To a solution of 6-(tert-butyl) 5-ethyl (4S,5S,7R)-1-methyl-1,4,5,7-tetrahydro-6H-4,7-methanopyrazolo[3,4-c]pyridine-5,6-dicarboxylate (150 mg, 0.5 mmol) in MeOH (8 mL) were added NaOH solution (3.0 mL, 2.0 N), the reaction mixture was stirred at 60 °C for 1h. The mixture was concentrated, and adjusted the pH to 2-3 with 1.0 N HCl, the mixture was extracted with EtOAc (20 mL x 3), the combined organic phase was dried, concentrated to give the crude product (4S,5S,7R)-6-(tert-butoxycarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanopyrazolo[3,4-c]pyr idine-5-carboxylic acid (80 mg, yield: 58.4%) as a yellow solid, LC / MS(ESI)m / z:294(M+H) +< .Preparation of Intermediate 18, (S)-N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-(1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-car bonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

[0221] Step 1:

[0222] To a solution of (S)-di-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in toluene (20 mL) was added DMF-DMA (2.8 mL, 24.7 mmol). The resulting mixture was heated to 105 °C for 6 h. The reaction mixture was cooled to rt and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE= 0~50%) to give the desired product di-tert-butyl 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate (2.0 g, yield: 84%) as an oil. LC-MS:m / z 341(M+H) +< .Step 2:

[0223] To a solution of di-tert-butyl 3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate (1.3 g, 3.8 mmol) in EtOH (10 mL) was added methylhydrazine solution (0.8 mL, 5.7 mmol), the resulting mixture was heated to 85 °C for 12 h in a sealed tube. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (EtOAc in PE= 0~100%) to give the desired product (S)-di-tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate (700 mg, yield: 57%) as a solid. LC-MS: m / z 324(M+H) +< .Step 3:

[0224] To a solution of (S)-di-tert-butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-4,5(1H)-dicarboxylate (300 mg, 0.93 mmol) in DCM (5 mL) at 0 °C was added TFA (2 mL) dropwise, and the resulting mixture was stirred at rt for 10 h. The reaction mixture was concentrated under reduced pressure to give the crude product (S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (240 mg, yield: 92%) as a light yellow oil which was used in next step without further purification. LC / MS (ESI) m / z: 168(M+H) +< .Step 4:

[0225] To a solution of (S)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (290 mg, 0.71 mmol) and TEA (0.09 mL, 0.71 mmol) in DCM (5 mL) was added Boc 2 O (170 mg, 0.71 mmol) dropwise at 0 °C, the resulting mixture was stirred 2 h at rt. The reaction mixture was diluted with H 2 O (5 mL), extracted with DCM (10 mL x 3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the desired crude product (S)-5-(tert-butoxycarbonyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-carboxylic acid (180 mg, yield: 94.6%) as a solid. LC / MS (ESI) m / z: 268(M+H) +< .

[0226] The following intermediates were prepared from the corresponding chemicals according to experimental procedure for Intermediate 18 (the major different chemicals used are listed in the column of starting material): IntermediatesStructureStarting materialLCMS (ESI) m / zIntermediate 19 308 (M+H) +< Intermediate 20 344 (M+H) +< Intermediate 21 H 2 N-NH 2 H 2 O254 (M+H) +< Preparation of Intermediate 22, N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0227] Step 1:

[0228] To a stirred solution of 5-fluoro-2-methoxybenzoic acid (2.0 g, 11.7 mmol) and 2-[(propan-2-yl)amino]ethan-1-ol (1.5 mL, 13.6 mmol) in DCM (40 mL) at 0 °C were added DIPEA (2.56 mL, 15.5 mmol) and HATU (5.0 g, 13.1 mmol), then the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. NH 4 Cl solution, extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 5 ~ 50%) to give the desired product 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propan-2-yl)benzamide (2.5 g, yield: 83.3%) as a white solid. LC / MS (ESI) m / z: 256(M+H) +< .Step 2:

[0229] To a solution of 5-fluoro-N-(2-hydroxyethyl)-2-methoxy-N-(propan-2-yl)benzamide (2.5 g, 9.79 mmol) in DCM (100 mL) at 0 °C was added Dess-Martin reagent (4.5 g, 10.6 mmol), the resulting mixture was stirred at 25 °C for 10 h. The reaction mixture was poured into ice-water (50 mL), extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 5 ~ 30%) to give the desired product 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propan-2-yl)benzamide (2.2 g, yield: 88.7%) as a white solid. LC / MS (ESI) m / z: 254(M+H) +< .Step 3:

[0230] To a solution of 5-fluoro-2-methoxy-N-(2-oxoethyl)-N-(propan-2-yl)benzamide (2.2 g, 8.69 mmol) in DCM (50 mL) at -10 °C was added DAST (2.87 mL, 21.7 mmol) slowly, the reaction mixture was stirred at 25 °C for 5 h under N 2 atmosphere. The reaction mixture was poured into ice-water (50 mL), the mixture was extracted with EtOAc (50 mL x 3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 1 ~ 30%) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (350 mg, yield: 14.6%) as an oil. LC / MS (ESI) m / z: 276(M+H) +< .Step 4:

[0231] To a solution of N-(2,2-difluoroethyl)-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (350 mg, 1.27 mmol) in DCM (10 mL) at -60°C was added BBr 3 (3.4 mL, 3.40 mmol) dropwise under N 2 atmosphere, the resulting mixture was stirred for 2 h at -60 °C. The reaction mixture was quenched with ice sat. NaHCO 3 at 0 °C, extracted with DCM (100 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 1 ~ 20%) to give the desired product N-(2,2-difluoroethyl)-5-fluoro-2-hydroxy-N-(propan-2-yl)benzamide (300 mg, yield: 90.3%) as a white solid. LC / MS (ESI) m / z: 262(M+H) +< .Preparation of Intermediate 22-1, 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-(propan-2-yl)benzamide

[0232]

[0233] To a solution of 5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-methoxybenzamide (510 mg, 2.00 mmol) in DCM (10 mL) was added BBr 3 (4 mL, 1.0 M in DCM) dropwise at -40°C under N 2 atmosphere, the resulting mixture was stirred for 2 h at this temperature. Then the reaction mixture was quenched with cooled MeOH at -40°C slowly, and then diluted with DCM (50 mL). The organic layer was separated, washed with sat. NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain the desired product 5-fluoro-2-hydroxy-N-(2-hydroxyethyl)-N-isopropylbenzamide (330 mg, yield: 68.5%) as a yellow solid, which can be used in next step without further purification. LC / MS (ESI) m / z: 242(M+H) +< .Preparation of Intermediate 23, (6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid

[0234] Step 1:

[0235] To a solution of (2S)-1-[(tert-butoxy)carbonyl]-4-methylidenepyrrolidine-2-carboxylic acid (0.25 mL, 1.32 mmol) in DCM (5 mL) was added TMSCHN 2 (225.73 mg, 1.98 mmol) at room temperature, the resulting mixture was stirred for 2 h. The reaction mixture was quenched with AcOH (1.0 mL), then diluted with H 2 O (10 mL), extracted with DCM (10 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (300 mg, yield:89.48%) as a colorless oil, which was used in next step without further purification. LC / MS (ESI) m / z: 242(M+H) +< .Step 2:

[0236] To a stirred solution of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (400 mg) and NaI (82 mg, 0.54 mmol) in THF (10 mL) was added TMSCF3 (7.5 g, 53.05 mmol) at rt under N 2 , the resulting mixture was stirred in sealed tube at 65 °C for 12 h. The mixture was diluted with H 2 O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 5 ~ 30 %) to give the desired product (6S)-5-tert-butyl 6-methyl 1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (150 mg, yield: 29.5%) as a yellow oil; LCMS: ESI m / z 246(M+1) +< .Step 3:

[0237] To a solution of (6S)-5-tert-butyl 6-methyl 1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (200 mg, 0.68 mmol) in MeOH (3 mL) and H 2 O (1 mL) was added NaOH (80 mg, 2 mmol) at 0 °C, and the resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated, adjusted the pH to 2~3 with 1.0 N HCl, extracted with EtOAc (20 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (6S)-5-[(tert-butoxy)carbonyl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (150 mg, yield:74.8%) as an off-white solid which can be used in next step directly without further purification. LC / MS (ESI) m / z: 222 (M-55) +< .Preparation of Intermediate 24, (3S,5R)-2-(tert-butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

[0238] Step 1:

[0239] To a solution of methyl (1S)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-3-carboxylate (200 mg, 1.28 mmol) in DCE (5 mL) were added MeI (0.40 mL, 6.40 mmol), silver trifluoromethanesulfonate (1.60 g, 6.40 mmol) and 2,6-di-tert-butylpyridine (1.4 mL, 6.40 mmol). Then the reaction was stirred at 100 °C for 1 hour. The reaction mixture was cooled to rt, diluted with H 2 O (5 mL), extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (3S,SR)-2-tert-butyl 3-methyl 5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (150 mg, yield: 68%) as a yellow oil. LC / MS (ESI) m / z: 286 (M+1) +< .Step 2:

[0240] To a solution of (3S,SR)-2-tert-butyl 3-methyl 5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (200 mg, 1.17 mmol) in MeOH (3.0 mL) and H 2 O (1.0 mL) was added NaOH (200 mg, 5.00 mmol). Then the resulting mixture was stirred at 80°C for 1 h. Then the pH of reaction mixture was adjusted to 5 with 1.0 N HCl, extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product (3S,5R)-2-(tert-butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (150 mg, yield: 81%) as a white solid. LC / MS (ESI) m / z: 271 (M+1) +< .Preparation of Intermediate 25, (2S,4S)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid

[0241] Step 1:

[0242] To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (162 mg, 0.65 mmol) and TEA (0.20 mL, 1.3 mmol) in DCM (5 mL) was added MsCl (0.06 mL, 0.72 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with DCM (10 mL x 3), The combined organic phase was washed with water and brine, dried over with anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE =10 ~50%) to give the desired product (2S,4S)-1-tert-butyl 2-methyl 4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (160 mg, yield: 75%) as colorless oil. LC / MS (ESI) m / z: 323 (M+1) +< .Step 2:

[0243] To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (160 mg, 0.50 mmol) in MeOH (3.0 mL) and H 2 O (1.0 mL) was added NaOH (80 mg, 2.0 mmol), The resulting mixture was stirred at 20°C for 1 h under N 2 . Then the pH of reaction mixture was adjusted to 5 with 1.0 N HCl, extracted with EtAOc (15 mL x 3). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the crude product (2S,4S)-1-[(tert-butoxy)carbonyl]-4-methanesulfonamidopyrrolidine-2-carboxylic acid (130 mg, yield: 84%) as a solid. LC / MS (ESI) m / z: 309 (M+1) +< .

[0244] The following intermediate was prepared from the corresponding chemicals according to experimental procedure for Intermediate 25 (the major different chemicals used are listed in the column of starting material): IntermediateStructureStarting materialLCMS (ESI) m / zIntermediate 26 309 (M+H) +< Preparation of Intermediate 27, (2S,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-arboxylic acid

[0245] Step 1:

[0246] To a solution of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (301 mg, 2.07 mmol) in MeOH (5.0 mL) was added SOCl 2 (0.30 mL, 4.1 mmol). The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give the crude product (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (300 mg, yield: 91%) as a light yellow oil. LC / MS (ESI) m / z: 160 (M+1) +< .Step 2:

[0247] To a solution of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (300 mg, 1.88 mmol) in acetone (5.0 mL) and H 2 O (1.0 mL) at 0 °C were added TEA (0.52 mL, 3.7 mmol) and (Boc) 2 O (0.45 g, 2.07 mmol). The resulting mixture was stirred at 20 °C for 3 h, the reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with EtOAc (15 mL x 3), the combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude (2S,5S)-1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate (400 mg, yield: 81%) as a light yellow solid which can be used in next step directly, LC / MS (ESI) m / z: 260 (M+1) +< .Step 3:

[0248] To a solution of (2S,5S)-1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate (400 mg, 1.54 mmol) in DCM (10 mL) was added DAST (0.5 mL, 3.85 mmol) at -60 °C. The resulting mixture was stirred at rt for 16 h under N 2 . The reaction mixture was diluted with sat. NaHCO 3 solution (10 mL), extracted with DCM (15 mL x 3), The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude (2S,5R)-1-tert-butyl 2-methyl 5-fluoropiperidine-1,2-dicarboxylate (270 mg, yield: 67.2%) as a yellow oil which can be used in next step without further purification, LC / MS (ESI) m / z: 262 (M+H) +< .Step 4:

[0249] To a solution of 1-tert-butyl 2-methyl (2S,5R)-5-fluoropiperidine-1,2-dicarboxylate (270 mg, 1.01 mmol) in MeOH (3.0 mL) and H 2 O (1.0 mL) was added NaOH (120 mg, 3.0 mmol), The resulting mixture was stirred at rt for 1 h. Then the pH of reaction mixture was adjusted to 5 with 1N HCl, extracted with EtAOc (15 mL x 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product (25,5R)-1-(tert-butoxycarbonyl)-5-fluoropiperidine-2-carboxylic acid (130 mg, yield: 48%) as a solid which can be used in next step without further purification, LC / MS (ESI) m / z: 247 (M+H) +< .Preparation of Intermediate 28, (2S)-1-(tert-butoxycarbonyl)-4-(cyanomethyl)pyrrolidine-2-carboxylic acid

[0250] Step 1:

[0251] To a solution of diethyl (cyanomethyl)phosphonate (1.5 mL, 9.0 mmol) in THF (20 mL) was added LiHMDS (9.0 mL, 1.0 M in THF) at 0 °C, the resulting mixture was stirred for 1 h at 0°C, then (2S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.01 g, 8.22 mmol) in THF (10 mL) was added to the reaction mixture at same temperature. The reaction mixture was stirred for 16 h while warmed to rt, quenched with sat. NH 4 Cl solution (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic phase was dried over Na 2 SO 4 and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE=0 ~10%) to give the desired product 1-tert-butyl 2-methyl (2S,4Z)-4-(cyanomethylidene)pyrrolidine-1,2-dicarboxylate (900 mg, yield: 41.0%) as a yellow solid. LC / MS (ESI) m / z: 247 (M+H) +< .Step 2:

[0252] To a solution of 1-tert-butyl 2-methyl (2S)-4-(cyanomethylidene)pyrrolidine-1,2-dicarboxylate (900 mg, 3.38 mmol) in MeOH (5 mL) was added a slurry of Pd / C (90 mg, 10%) in EtOAc (10 mL). The resulting suspension was then stirred at rt for 16 h under a balloon of H 2 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the crude product (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (900 mg, yield: 99%) as a colorless oil which can be used in next step without further purification. LC / MS (ESI) m / z: 269(M+H) +< .Step 3:

[0253] To a solution of (2S)-1-tert-butyl 2-methyl 4-(cyanomethyl)pyrrolidine-1,2-dicarboxylate (650 mg, 2.29 mmol) in MeOH (5.0 mL) and H 2 O (1.0 mL) at 0 °C was added NaOH (200 mg, 5.00 mmol), the resulting mixture was heated to 65 °C for 1 h. The reaction mixture was cooled to room temperature, and adjusted the pH to 5 with 1.0 N HCl, the mixture was extracted with EtOAc (10 mL x 3), the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product (2S)-1-[(tert-butoxy)carbonyl]-4-(cyanomethyl)pyrrolidine-2-carboxylic acid (400 mg, yield: 47%) as a light yellow solid. LC / MS (ESI) m / z: 254(M+H) +< .Preparation of Intermediate 29, 4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0254]

[0255] To a stirred solution of 5-bromo-4-isopropylpyrimidine (1.00 g, 4.97 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.40 g, 5.47 mmol) in dioxane (10 mL) was added KOAc (1.50 g, 15.7 mmol) and Pd(dppf)Cl 2 (100 mg). The resulting mixture was heated to 110 °C for 12 h under N 2 atmosphere. After cooled to room temperature, the mixture was diluted with H 2 O (10 mL), extracted with EtOAc (30 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 ,filtered and concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to give the desired product 4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (610 mg, yield: 49%) as a white solid.LC / MS (ESI) m / z: 249 (M+H) +< .

[0256] The following intermediate was prepared from the corresponding chemicals according to experimental procedure for Intermediate 29 (the major different chemicals used are listed in the column of starting material): IntermediateStructureStaring materialLCMS (ESI) m / zIntermediate 30 246 (M+H) +< Preparation of Intermediate 31, 2-(4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yloxy)-5-fluorobenzoic acid

[0257] Step 1:

[0258] To a solution of 2-bromo-4-fluorophenol (3.01 g, 15.7 mmol) and 5-bromopyrimidine (2.75 g, 17.3 mmol) in DMF (30 mL) was added Cs 2 CO 3 (12.8 g, 39.3 mmol) at rt. The resulting mixture was heated to 120 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with sat. NH 4 Cl solution (50 mL), extracted with EtOAc (100 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE = 0~30%) to give the desired product 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.40 g, yield: 29.8 %) as a yellow solid; LCMS: ESI m / z 270(M+1) +< .Step 2:

[0259] To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.00 g, 3.70 mmol) and TEA (1.5 mL, 11 mmol) in MeOH (15 mL) was added Pd(dppf)Cl 2 (150 mg) at rt, The resulting mixture was stirred at 90 °C for 12 h under CO (70 psi) atmosphere. After cooled to rt, the solvent was concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (900 mg, yield: 92.7%) as a colorless oil. LC / MS (ESI) m / z: 249(M+H) +< .Step 3:

[0260] To a solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (900 mg, 3.63 mmol) in THF (20 ml) was added urea.H 2 O 2 (800 mg, 8.16 mmol) and TFAA (0.6 mL) at 0 °C under N 2 . The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with sat.NaHCO 3 , extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-ium-1-olate (830 mg, yield: 86.3%) as a yellow oil which can be used in next step directly without further purification. LCMS: ESI m / z 265(M+1) +< .Step 4:

[0261] To a solution of 5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-1-ium-1-olate (800 mg, 3.01 mmol) and DIPEA (5.6 mL, 34 mmol) in EtOAc (15 mL) was added POCl 3 (0.6 mL, 6.8 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h. The reaction mixture was quenched with sat. NaHCO 3 solution (20 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, yield: 93%) as a brown oil which can be used in next step directly without further purification. LCMS: ESI m / z 283(M+1) +< .Step 5:

[0262] To a solution of methyl 2-[(4-chloropyrimidin-5-yl)oxy]-5-fluorobenzoate (798 mg, 2.82 mmol) and DIPEA (5.3 mL, 32 mmol) in DMF (15 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (703 mg, 3.11 mmol) at rt. The resulting mixture was stirred at 65 °C for 3 h. After cooled to room temperature, the reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to give the desired product tert-butyl 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxy late (610 mg, yield: .45.5%) as a yellow solid, LCMS: ESI m / z 473 (M+1) +< .Step 6:

[0263] To a solution of tert-butyl 2-{5-[4-fluoro-2-(methoxycarbonyl)phenoxy]pyrimidin-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxy late (610 mg, 1.29 mmol) in MeOH (12 mL) and H 2 O (4.0 mL) was added NaOH (228 mg, 5.71 mmol) at 0 °C. the resulting mixture was stirred at rt for 1 h. Then the pH of mixture was adjusted to 5 with 1.0 N HCl, extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over with anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product 2-[(4-{7-[(tert-butoxy)carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluorobenzoi c acid (560 mg, yield:94.5%) as an off-white solid which can be used in next step without further purification. LC / MS (ESI) m / z:459 (M+H) +< .Step 7:

[0264] To a stirred solution of 2-[(4-{7-[(tert-butoxy) carbonyl]-2,7-diazaspiro [3.5] nonan-2-yl} pyrimidin-5-yl) oxy]-5-fluorobenzoic acid (200 mg, 0.44 mmol) and HATU (166 mg, 0.44 mmol) in DMF (4 mL) was added DIPEA (169 mg, 1.31 mmol). The resulting mixture was stirred for 10 minutes before 2-[(propan-2-yl) amino] ethan-1-ol (54 mg, 0.52 mmol) was added. The reaction mixture was stirred for 1 h at rt, and then diluted with H 2 O (10 mL), and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the desired product which was purified by Prep-TLC (MeOH in DCM = 9%) to give the desired product tert-butyl 2-(5- {4-fluoro-2- [(2-hydroxyethyl) (propan-2-yl) carbamoyl] phenoxy} pyrimidin-4-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (135 mg, yield: 56.9%) as a white solid. LCMS: ESI m / z 544 (M+1) +< .Step 8:

[0265] To a solution of tert-butyl 2-(5- {4-fluoro-2- [(2-hydroxyethyl) (propan-2-yl) carbamoyl] phenoxy} pyrimidin-4-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (50 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred for 1 h at rt. The resulting mixture was concentrated in vacuo to give the crude product 2-[(4-{2,7-diazaspiro [3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-5-fluoro-N-(2-hydroxyethyl)-N-(propan-2-yl)benzamide (40 mg, yield: 98%) as an oil which can be used directly in next step without further purification. LC / MS (ESI) m / z: 444(M+H) +< .Preparation of Intermediate 32, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(2-methoxyethyl )benzamide

[0266] Step 1:

[0267] To a solution of tert-butyl 2-(5-{4-fluoro-2-[(2-hydroxyethyl) (propan-2-yl) carbamoyl] phenoxy} pyrimidin-4-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (60 mg, 0.11 mmol ) in DMF (4 mL) was added NaH (7.0 mg, 0.17 mmol, 60%) at 0 °C. The reaction mixture was stirred for 10 min, and then MeI (31 mg, 0.22 mmol) was added. The resulting mixture was stirred at rt for 1 h, quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the desired product which was purified by Prep-TLC (MeOH in DCM =9%) to give the desired product tert-butyl 2-(5-{4-fluoro-2-[(2-methoxyethyl) (propan-2-yl) carbamoyl] phenoxy} pyrimidin-4-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (50 mg, yield: 81.2%) as a yellow solid. LCMS: ESI m / z 558 (M+1) +< .Step 2:

[0268] To a solution of tert-butyl 2-(5-{4-fluoro-2-[(2-methoxyethyl) (propan-2-yl) carbamoyl] phenoxy} pyrimidin-4-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (50 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo to give the crude product 2- [(4- {2,7-diazaspiro [3.5] nonan-2-yl} pyrimidin-5-yl) oxy]-5-fluoro-N-(2-methoxyethyl)-N-(propan-2-yl) benzamide (30 mg, yield: 73.5%) as a brown oil which can be used directly in next step without further purification. LC / MS (ESI) m / z: 458(M+H) +< .Preparation of Intermediate 33, 2-cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carbonitrile

[0269] Step 1:

[0270] To a solution of 3-bromo-4-hydroxybenzonitrile (1.01 g, 5.05 mmol) and cyclopropylboronic acid (520 mg, 6.06 mmol) in toluene (15 mL) were added PCy 3 (280 mg, 1 mmol), Pd(OAc) 2 (100 mg) and K 3 PO 4 (3.2 g, 15 mmol) at rt. The resulting mixture was stirred at 100 °C for 12 h under N 2 . The reaction mixture was cooled to rt, quenched with H 2 O (20 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 3-cyclopropyl-4-hydroxybenzonitrile (700 mg, yield: 82.8%) as a yellow oil. LC / MS (ESI) m / z: 158 (M-H) +< .Step 2:

[0271] To a solution of 3-cyclopropyl-4-hydroxybenzonitrile (700 mg, 4.39 mmol) and pyridine (1.12 g, 8.79 mmol) in THF (10 mL) was added Tf 2 O (1.1 mL, 6.59 mmol) at -5 °C under N 2 , the resulting mixture was stirred at 0 °C for 3 h. The reaction was quenched with sat. NaHCO 3 solution, extracted with DCM (30 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 80%) to give the desired product 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonate (1.01 g, yield: 74.2%) as an oil. LC / MS (ESI) m / z: 292 (M+H) +< .Step 3:

[0272] To a solution of 4-cyano-2-cyclopropylphenyl trifluoromethanesulfonate (300 mg, 1.03 mmol) and 5-fluoro-2-hydroxyphenylboronic acid (177 mg, 1.13 mmol) in dioxane (5.0 mL) and H 2 O (1.0 mL) were added Pd(dppf)Cl 2 (20 mg) and K 2 CO 3 (414 mg, 3.00 mmol), the resulting mixture was stirred at 100 °C for 10 h under N 2 atmosphere. The reaction mixture was cooled to rt, diluted with H 2 O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 50%) to give the desired product 2-cyclopropyl-5'-fluoro-2'-hydroxybiphenyl-4-carbonitrile (125 mg, yield: 47.7%) as a yellow solid. LC / MS (ESI) m / z: 254(M+H) +< .Preparation of Intermediate 34, 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzami de

[0273] Step 1:

[0274] To a stirred solution of trichloro-1,2,4-triazine (CAS 873-41-6, 0.88 g, 4.80 mmol) and TEA (1.39 mL, 9.99 mmol) in DCM (15 mL) was added tert-butyl 2,7-diazaspiro [3.5] nonane-7-carboxylate hydrochloride (1.05 g, 4.01 mmol) at 0 °C. The resulting mixture was stirred at rt for 12 h. The reaction mixture was quenched with H 2 O (20 mL), extracted with DCM (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give crude product which was purified by chromatography column on silica gel (EtOAc in PE=0 ~ 25%) to give the desired product tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (1.10 g, yield: 60.4%) as a white solid. LCMS: ESI m / z 374 (M+1) +< .Step 2:

[0275] To a stirred solution of tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (1.05 g, 2.81 mmol) and N-ethyl-5-fluoro-2-hydroxy-N-(propan-2-yl) benzamide (0.63 g, 2.81 mmol) in THF (12 mL) was added DBU (0.50 mL, 3.37 mmol) at rt. The resulting mixture was stirred at rt for 8 h. The reaction mixture was diluted with H 2 O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by chromatography column on silica gel (EtOAc in PE= 20%~50%) to obtain the desired product tert-butyl 2-(3-chloro-6- f 2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspir o[3.5]nonane-7-carboxylate (800 mg, yield: 50.6%) as a white solid. LCMS: ESI m / z 563 (M+1) +< .Step 3:

[0276] To a stirred solution of tert-butyl 2-(3-chloro-6-{2-[ethyl(propan-2-yl) carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (0.80 g, 1.42 mmol) in MeOH (10 mL) were added TEA (0.24 mL, 1.71 mmol) and a slurry of Pd / C (10%, 80 mg) in EtOAc (5 mL). The resulting suspension was vacuumed and refilled with hydrogen, stirred at rt for 8 h under balloon pressure of H 2 . The reaction mixture was filtered through a pad of celite, washed with MeOH (5 mL), the filtrate was concentrated to give the desired product tert-butyl 2-(6- {2-[ethyl (propan-2-yl) carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (750 mg, yield: 99.8%) as a white solid which can be used in next step without further purification. LCMS: ESI m / z 529 (M+1) +< .Step 4:

[0277] To a solution of tert-butyl 2-(6-{2-[ethyl(propan-2-yl) carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carboxylate (720 mg, 1.36 mmol) in DCM (10 mL) was added TFA (5 mL) at 0 °C. The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give the crude product 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl benzamide as a TFA salt (580 mg, yield: 99.4%) as a yellow oil which can be used directly in next step without further purification. LC / MS (ESI) m / z: 429 (M+H) +< .

[0278] The following intermediate was prepared from the corresponding chemicals according to experimental procedure for Intermediate 34 (the major different chemicals used are listed in the column of starting material): IntermediateStructureStarting materialLCMS (ESI) m / zIntermediate 35 Intermediate 14 443 (M+H) +< Intermediate 57 Intermediate 53 431 (M+H) +< Intermediate 60 Intermediate 54 433 (M+H) +< Intermediate 58 Intermediate 22-1 445 (M+H) +< Intermediate 59 Intermediate 22 465 (M+H) +< Intermediate 61 Intermediate 55 463 (M+H) +< Intermediate 62 Intermediate 56 449 (M+H) +< Preparation of Intermediate 36, 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane

[0279] Step 1:

[0280] To a solution of [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (605 mg, 3.93 mmol), 2-bromo-4-fluorophenol (500 mg, 2.62 mmol) in dioxane (10 mL) and H 2 O (2.0 mL) was added K 2 CO 3 (1.08 g, 7.85 mmol) and Pd(dppf)Cl 2 (192 mg, 0.26 mmol) at room temperature, the resulting mixture was stirred at 100 °C for 2 h under N 2 . The reaction mixture was cooled to rt, quenched with H 2 O (10 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to obtain the desired product 4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol (200 mg, yield: 34.7%) as a yellow solid. LC / MS (ESI) m / z: 221(M+H) +< .Step 2:

[0281] To a solution of tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.53 mmol) and 4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenol (118 mg, 0.53 mmol) in THF (5 mL) was added DBU (0.08 mL, 0.53 mmol) at room temperature, the resulting mixture was stirred overnight. The reaction mixture was diluted with H 2 O (10 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 40%) to obtain the desired product tert-butyl 2-(3-chloro-6-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane-7-carboxylate (120 mg, yield: 40.2%) as a light yellow solid. LC / MS (ESI) m / z: 558(M+H) +< .Step 3:

[0282] To a solution of tert-butyl 2-(3-chloro-6-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diaza spiro[3.5]nonane-7-carboxylate (120 mg, 0.22 mmol) and TEA (0.12 mL, 0.86 mmol) in EtOAc (3 mL) was added Pd / C (12 mg) at room temperature. The reaction mixture was vacuum and refilled with hydrogen, stirred at room temperature for 2 h under a balloon of H 2 . The reaction mixture was filtered through a pad of celite, the filtrate was concentrated to obtain the crude product tert-butyl 2-(6-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nona ne-7-carboxylate (60 mg, yield: 53.3%) as a yellow solid which can be used in next step without further purification. LC / MS (ESI) m / z: 524(M+H) +< .Step 4:

[0283] To a solution of tert-butyl 2-(6-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5] nonane-7-carboxylate (60 mg, 0.11 mmol) in DMF (2.0 mL) was added NCS (17 mg, 0.13 mmol) at 0°C, the resulting mixture was stirred for 3 h at same temperature. The reaction mixture was quenched with H 2 O (5 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 80%) to obtain the desired product tert-butyl 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane-7-carboxylate (40 mg, yield: 62.1 %) as a light yellow solid. LC / MS (ESI) m / z: 558(M+H) +< .Step 5:

[0284] To a solution of tert-butyl 2-(6-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diaza spiro[3.5]nonane-7-carboxylate (40 mg, 0.07 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) at room temperature, the resulting mixture was stirred for 1 h. The reaction mixture was concentrated to give the crude product 2-(6-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane (30 mg, yield: 91.4%) as a yellow oil which can be used in next step without further purification. LC / MS (ESI) m / z: 458(M+H) +< .Preparation of Intermediate 37, trans-1-(tert-butoxycarbonyl)-3-ethylpyrrolidine-2-carboxylic acid

[0285] Step 1:

[0286] To a mixture of methyl (2S)-pyrrolidine-2-carboxylate (2.01 g, 15.5 mmol) in DCM (30 mL) at 0 °C was added TEA (4.3 mL, 31 mmol) and NCS (2.30 g, 17.0 mmol) in small portions. The resulting mixture was stirring at rt for 3 h before pyridine (4.53 g, 35.6 mmol) was added slowly within 1 h, the reaction mixture was cooled to -20 °C, then CbzCl (5.81 g, 34.1 mmol) was added, the mixture was allowed to warm to room temperature gradually and stirred for 12 h. The reaction system was diluted with H 2 O (50 mL), extracted with DCM (50 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-benzyl 2-methyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (503 mg, yield:11.7%) as a yellow oil. LC / MS (ESI) m / z: 262(M+H) +< .Step 2:

[0287] To a solution of Me 2 S.CuBr (79 mg, 0.38 mmol) in THF (5.0 mL) at -40 °C was added vinylmagnesium bromide (2.8 mL, 1.0 M in THF) dropwise under N 2 . The resulting mixture was stirred for 1 h, a solution of 1-benzyl 2-methyl 4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (500 mg, 1.91 mmol) in THF (5.0 mL) was added dropwise, the reaction mixture was stirred for 4 h at this temperature. The mixture was quenched with sat. NH 4 Cl / NH 3 .H 2 O (8:1), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with sat. NH 4 Cl solution and dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product trans-1-benzyl 2-methyl -3-vinylpyrrolidine-1,2-dicarboxylate (505 mg, yield: 85.2%) as an oil. LC / MS (ESI) m / z: 292(M+H) +< .Step 3:

[0288] To a solution of trans-1-benzyl 2-methyl-3-vinylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol) and (Boc) 2 O (378 mg, 1.75 mmol) in MeOH (7.0 mL) was added Pd / C (10%, 50 mg) at rt, the resulting suspension was vacuum and refilled with hydrogen, stirred for 3 h under a balloon of H 2 . The reaction mixture was filtered through a pad of celite, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product trans-1-tert-butyl 2-methyl-3-ethylpyrrolidine-1,2-dicarboxylate (400 mg, yield: 86.1%) as a light-yellow oil. LC / MS (ESI) m / z: 202(M+H) +< .Step 4:

[0289] To a solution of trans-1-tert-butyl 2-methyl-3-ethylpyrrolidine-1,2-dicarboxylate (400 mg, 1.55 mmol) in MeOH (6.0 mL) and H 2 O (2.0 mL) at 0 °C was added NaOH (186 mg, 4.66 mmol), the resulting mixture was stirred at rt for 1 h, the reaction mixture was acidified with HCl solution (1.0 N) to pH=4~5, and extracted with EtOAc (15 mL x 3), the combined organic phase was dried over anhydrous over Na 2 SO 4 , filtered and concentrated to give the crude product trans-1-[(tert-butoxy)carbonyl]-3-ethylpyrrolidine-2-carboxylic acid (350 mg, yield: 87.9%) as white solid which can be used in next step without further purification. LC / MS (ESI) m / z: 188 (M+H) +< .Preparation of Intermediate 38, (2S,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid

[0290] Step 1:

[0291] To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (4.98 g, 20.4 mmol) in DCM (50 mL) were added imidazole (1.80 g, 26.5 mmol) and TBDPSCl (7.91 g, 30.6 mmol). The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with sat. NH 4 Cl solution (50 mL), extracted with DCM (100 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to give the desired product 1-tert-butyl 2-methyl (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (8.98 g, yield: 86.7%) as a colorless oil. LC / MS (ESI) m / z: 484(M+H) +< .Step 2:

[0292] To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (15.0 g, 31.0 mmol) in DCM (100 mL) was added HCl in dioxane (100 mL, 4.0 M) slowly at rt for 2 h. The resulting mixture was concentrated to give the crude product 1-tert-butyl 2-methyl (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (11.9 g, yield: 95.8%) as a white solid which was used in next step without further purification. LC / MS (ESI) m / z: 384(M+H) +< .Step 3:

[0293] To a solution of methyl (2S,4S)-4-[(tert-butyldiphenylsilyl)oxy]pyrrolidine-2-carboxylate (5.00 g, 13.0 mmol) in DCM (50 mL) at 0 °C was added TEA (3.3 mL, 23 mmol) and NCS (1.91 g, 14.3 mmol) in small portions, the resulting mixture was stirred at rt for 3 h before 2,6-lutidine (3 mL, 26.07 mmol) was added slowly within 1 h. The reaction mixture was cooled to -20 °C and CbzCl (4.70 g, 27.4 mmol) were added. The mixture was allowed to slowly warm to rt and stirred overnight. The reaction mixture was quenched with H 2 O (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-benzyl 2-methyl (4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.01 g, yield: 14.2%) as an oil. LC / MS (ESI) m / z: 516(M+H) +< .Step 4:

[0294] To a solution of CuBr.Me2S (480 mg, 2.33 mmol) in THF (5.0 mL) was added MeMgBr (2.9 mL, 1.0 M in THF) dropwise at -40 °C under N 2 , the mixture was stirred for 1 h at -40 °C before addition of a solution of 1-benzyl 2-methyl (4S)-4-[(tert-butyldiphenylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1 g, 1.94 mmol) in THF (10 mL). The resulting mixture was stirred for 1 h at -40 °C. The reaction mixture was quenched with sat. NH 4 Cl solution, extracted with EtOAc (20 mL x 3), the combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-benzyl 2-methyl (2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylate (300 mg, yield: 27.6%) as a yellow oil. LC / MS (ESI) m / z: 532(M+H) +< .Step 5:

[0295] To a solution of 1-benzyl 2-methyl (2S,3R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylpyrrolidine-1,2-dicarboxylate (300 mg, 0.56 mmol) in THF (5.0 mL) was added TBAF (0.85 mL, 1.0 M in THF). The resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with sat. NH 4 Cl solution (5 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 50%) to give the desired product 1-benzyl 2-methyl (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate (100 mg, yield: 60.4%) as a light yellow oil. LC / MS (ESI) m / z: 294 (M+H) +< .Step 6:

[0296] To a solution of 1-benzyl 2-methyl (2S,3R,4S)-4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate (100 mg, 0.34 mmol) in DCM (2.0 mL) was added DAST (0.07 mL, 0.51 mmol) at 0 °C under N 2 . The resulting mixture was stirred for 16 h at rt. The reaction mixture was quenched with sat. NaHCO 3 , extracted with DCM (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 40%) to give the desired product 1-benzyl 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (80 mg, yield: 75%) as a yellow oil; LCMS: ESI m / z 296(M+H) +< .Step 7:

[0297] To a solution of 1-benzyl 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc) 2 O (0.07 mL, 0.36 mmol) in MeOH (7.0 mL) was added Pd / C (10%, 15 mg) at rt, the resulting suspension was vacuum and refilled with hydrogen, stirred at rt for 3 h under H 2 balloon pressure. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-(tert-butyl) 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (60 mg, yield: 80%) as an oil. LC / MS (ESI) m / z: 206(M+H) +< .Step 8:

[0298] To a solution of 1-(tert-butyl) 2-methyl (2S,3R,4R)-4-fluoro-3-methylpyrrolidine-1,2-dicarboxylate (60 mg, 0.23 mmol) in MeOH (3 mL) and H 2 O (1 mL) was added NaOH (28 mg, 0.69 mmol) at 0°C. The resulting mixture was stirred for 4h at room temperature, the reaction mixture was concentrated, and adjusted the pH to 4~5 with 1.0 N HCl solution, extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (2S,3R,4R)-1-(tert-butoxycarbonyl)-4-fluoro-3-methylpyrrolidine-2-carboxylic acid (50 mg, yield: 83.5%) as an off-white solid which can be used in next step directly without further purification. LC / MS (ESI) m / z: 192 (M+1-56) +< .Preparation of Intermediate 39, (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid

[0299] Step 1:

[0300] To a solution of methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate (2.71 g, 18.6 mmol) in DCM (40 mL) was added imidazole (2.50 g, 37.2 mmol) and TBSCl (3.30 g, 22.3 mmol). The resulting mixture was stirred at rt for 16 h. The reaction mixture was washed with 10% aq. Na 2 CO 3 solution (50 mL), The aqueous layer was extracted with DCM (50 mL x 2), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, yield: 88.6%) as a light yellow oil which can be used in next step without further purification. LC / MS (ESI) m / z: 260(M+H)+.Step 2:

[0301] To a solution of methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-2-carboxylate (4.50 g, 17.3 mmol) in toluene (60 mL) at 0 °C was added H 2 O (20 mL) and sodium dichloroisocyanurate (3.60 g, 13.9 mmol), the resulting mixture was stirred for 16 h at 0 °C. The reaction mixture was filtered and concentrated to give the crude product methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, yield: 83.8%) as an oil which can be used in next step without further purification. LC / MS (ESI) m / z: 294 (M+H) +< .Step 3:

[0302] To a solution of methyl (2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-chloropyrrolidine-2-carboxylate (4.48 g, 15.3 mmol) in toluene (60 mL) at -10 °C was added TEA (6.4 mL, 46 mmol), the resulting mixture was stirred at rt overnight. The reaction mixture was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude intermediate methyl (3S)-3-[(tert-butyldimethylsilyl)oxy]-3,4-dihydro-2H-pyrrole-5-carboxylate (3.5 g) as a clear oil, the crude intermediate was dissolved into DCM (40 mL) and cooled to -10 °C, to this solution was added 2,6-lutidine (3.2 mL, 27 mmol) and CbzCl (2.80 g, 16.3 mmol) in small portions and stirred for 24 h at room temperature. Then ethylenediamine (0.25 mL, 3.7 mmol) was added to the mixture, and stirred for 15 min, the mixture was washed with citric acid solution (1.0 N, 30 mL) and aq. HCl (1.0 N, 25 mL) in turn, the organic phase was washed with water, NaHCO 3 solution (1.5 N) and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-benzyl 2-methyl (4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.51 g, yield: 26.7%) as a light yellow oil. LC / MS (ESI) m / z: 392(M+H) +< .Step 4:

[0303] To a solution of CuBr.Me 2 S (630 mg, 3.07 mmol) in THF (5.0 mL) was added EtMgBr (1.3 mL, 3.0 M in THF) dropwise at -40 °C under N 2 , the mixture was stirred for 1 h at -40 °C before a solution of 1-benzyl 2-methyl (4S)-4-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.00 g, 2.56 mmol) in THF (10 mL) was added. The resulting mixture was stirred for 1 h at -40 °C. The reaction mixture was quenched with sat. NH 4 Cl solution, extracted with EtOAc (20 mL x 3), the combined organic layer washed with brine and dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-benzyl 2-methyl (2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylate (200 mg, yield: 17.6%) as a light yellow oil. LC / MS (ESI) m / z: 422(M+H) +< .Step 5:

[0304] To a solution of 1-benzyl 2-methyl (2S,3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-3-ethylpyrrolidine-1,2-dicarboxylate (200 mg, 0.48 mmol) in THF (3.0 mL) was added TBAF (0.85 mL, 1.0 M in THF). The resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with sat. NH 4 Cl solution (5 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to give the desired product 1-benzyl 2-methyl (2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate (120 mg, yield: 78.2%) as a light yellow oil. LC / MS (ESI) m / z: 308 (M+H) +< .Step 6:

[0305] To a solution of 1-benzyl 2-methyl (2S,3R,4S)-3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate (120 mg, 0.39 mmol) in DCM (3.0 mL) was added DAST (0.07 mL, 0.51 mmol) at 0 °C under N 2 . The resulting mixture was stirred for 16 h at rt. The reaction mixture was quenched with sat. NaHCO 3 , extracted with DCM (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 40%) to give the desired product 1-benzyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (110 mg, yield: 86.6%) as a yellow oil; LCMS: ESI m / z 310(M+H) +< .Step 7:

[0306] To a solution of 1-benzyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (110 mg, 0.36 mmol) and (Boc) 2 O (78 mg, 0.36 mmol) in MeOH (2.0 mL) was added Pd / C (10%, 20 mg) at rt, the resulting suspension was vacuum and refilled with hydrogen, the mixture was stirred at rt for 3 h under a balloon of H 2 . The reaction mixture was filtered through a pad of celite, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-tert-butyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (90 mg, yield: 87%) as an oil. LC / MS (ESI) m / z: 276(M+H) +< .Step 8:

[0307] To a solution of 1-tert-butyl 2-methyl (2S,3R,4R)-3-ethyl-4-fluoropyrrolidine-1,2-dicarboxylate (90 mg, 0.38 mmol) in MeOH (3 mL) and H 2 O (1 mL) was added NaOH (65 mg, 1.63 mmol) at 0°C. The resulting mixture was stirred for 5h at room temperature, The reaction mixture was concentrated, and adjusted the pH to 4~5 with 1.0 N HCl solution, extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product (2S,3R,4R)-1-[(tert-butoxy)carbonyl]-3-ethyl-4-fluoropyrrolidine-2-carboxylic acid (70 mg, 78% yield) as a off-white solid which can be used in next step without further purification. LC / MS (ESI) m / z: 206 (M+1-56) +< .Preparation of Intermediate 40, (1-isopropyl-1H-pyrazol-5-yl)boronic acid

[0308]

[0309] To a solution of 1-(propan-2-yl)-1H-pyrazole (2.01 g, 18.2 mmol) in THF (40 mL) was added n-BuLi (11.0 mL, 27.5 mmol) at -70°C under N 2 , the mixture was stirred for 1 h at -70°C before triisopropyl borate (12.5 mL, 54.46 mmol) was added, the resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched with sat. NH 4 Cl solution at 0 °C, and adjusted the pH to 6 with 1.0 N HCl. The mixture was extracted with EtOAc (50 mL x 3), and the combined organic phase was washed with water and brine, dried over with anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (2 g, yield: 71%) as a white solid which can be used in next step without further purification. LC / MS (ESI) m / z: 523 (M+H) +< .Preparation of Intermediate 41, 5-fluoro-2-methoxybenzoic-3,4-d2 acid

[0310] Step 1:

[0311] To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate(500 mg, 2 mmol) in DMF (3 mL) was added NBS (464mg, 2.6 mmol) at rt, the resulting mixture was heated to 70 0< C for 4h. After cooled down to rt, water (5 mL) was added and extract with EtOAc (10 ml x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated give the crude product which was purified by column chromatography on silica gel (EtOAc in PE= 0 ~ 10%) to give the desired product methyl 3,4-dibromo-5-fluoro-2-hydroxybenzoate(410 mg, yield: 62.3%) as a white solid.1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H).Step 2:

[0312] To a solution of methyl 3,4-dibromo-5-fluoro-2-hydroxybenzoate (400 mg, 1.2 mmol) in DMF (5 mL) was added MeI (0.2 mL, 3.6 mmol) and K 2 CO 3 (843 mg, 6.1 mmol), the reaction mixture was stirred at r.t. for 5h, then water (10 mL) was added and extract with EtOAc (10 mL x 3). The combined organic layer was washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated give the crude product which was purified by column chromatography on silica gel (EtOAc in PE= 0 ~ 10%) to give the desired product methyl 3,4-dibromo-5-fluoro-2-methoxybenzoate(340 mg, yield: 81.5%) as a white solid. LC / MS (ESI) m / z: 417 (M+H) +< .Step 3:

[0313] To a solution of methyl 3,4-dibromo-5-fluoro-2-methoxybenzoate (340 mg, 0.99 mmol) in MeOD (5 mL) was added Pd / C (25 mg), the resulting mixture was stirred for 10h under D 2 atmosphere at 60 0< C. Filtered and concentrated to give the crude product methyl 5-fluoro-2-methoxybenzoate-3,4-d 2 (85 mg, yield: 45.9%) as a colorless oil which can be used in next step directly without further purification.LC / MS (ESI) m / z: 186 (M+H) +< .Step 4:

[0314] To a solution of methyl 5-fluoro-2-methoxybenzoate-3,4-d 2 (80 mg, 0.43 mmol) in MeOH / H 2 O (4 mL / 2mL) was added LiOH.H 2 O (72 mg, 1.72 mmol). The resulting mixture was stirred at rt for 2 h under N 2 atmosphere. Then the reaction mixture was diluted with H 2 O (50 mL), and adjusted the pH to 3-4, extracted with EtOAc (20 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product 5-fluoro-2-methoxybenzoic-3,4-d 2 acid (70 mg, yield: 94.6%) as a white solid. which was used in next step directly without further purification, LC / MS (ESI) m / z: 173 (M+H) +< .Preparation of Intermediate 42, 2- [(5- {2,7-diazaspiro [3.5] nonan-2-yl}-1,2,4-triazin-6-yl) oxy]-N-ethyl-5-fluoro-N-(propan-2-yl) benzamide

[0315] Step 1:

[0316] To a solution of 5-bromopyrimidine (1.01 g, 6.29 mmol) in THF (15 mL) was added cyclopropylmagnesium bromide (9.43 mL, 9.43 mmol, 1.0 M) dropwise at -20 °C under N 2 . The resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched with H 2 O (0.3 mL) followed by addition of DDQ (1.60 g, 6.92 mmol), the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with H 2 O (50 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by chromatography column on silica gel (EtOAc in PE= 0~10%) to give the desired product 5-bromo-4-cyclopropylpyrimidine (1.10 g, yield: 83.5%) as a white solid. LC / MS (ESI) m / z: 199 (M+H) +< .Step 2:

[0317] To a solution of 5-bromo-4-cyclopropylpyrimidine (200 mg, 1.00 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (188 mg, 1.21 mmol) in dioxane (5.0 mL) and H 2 O (1.0 mL) was added Pd(dppf)Cl 2 (20 mg) and K 2 CO 3 (347 mg, 2.51 mmol), the resulting mixture was stirred at 100 °C for 12 h under N 2 . The reaction mixture was cooled to rt, diluted with H 2 O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (200 mg, yield: 82.1%) as a light yellow solid. LC / MS (ESI) m / z: 231(M+H) +< .Step 3:

[0318] To a stirred solution of 2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenol (800 mg, 3.48 mmol) and tert-butyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.30 g, 3.48 mmol) in THF (20 mL) was added DBU (1.04 g, 6.90 mmol) at 0 °C. The resulting mixture was stirred at rt for 10 h. The reaction mixture was diluted with H 2 O (20 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by chromatography column on silica gel (EtOAc in PE= 10~50%) to obtain the desired product tert-butyl 2-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane-7-carboxylate (849 mg, yield: 43.2%) as a yellow solid. LCMS: ESI m / z 568 (M+1) +< .Step 4:

[0319] To a solution of tert-butyl 2-(3-chloro-6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5]nonane-7-carboxylate (300 mg, 0.53 mmol) and NaBH 4 (20 mg, 0.95 mmol) in THF (5 mL) was added TMEDA (220 mg, 0.53 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (30 mg) at room temperature, the resulting mixture was stirred overnight at rt. The reaction mixture was diluted with H 2 O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to obtain the desired product tert-butyl 2-{6-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3.5]non ane-7-carboxylate (250 mg, yield: 84.3%) as a light yellow solid. LC / MS (ESI) m / z: 534(M+H) +< .Step 5:

[0320] To a solution of tert-butyl 2-(6-(2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nona ne-7-carboxylate (600 mg, 1.12 mmol) in DCM (10 mL) was added TFA (5 mL) at 0°C. The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product 2- [(5- {2,7-diazaspiro [3.5] nonan-2-yl}-1,2,4-triazin-6-yl) oxy]-N-ethyl-5-fluoro-N-(propan-2-yl) benzamide (460 mg, yield: 90%) as a brown oil which can be used in next step without further purification. LC / MS (ESI) m / z: 434(M+H) +< .

[0321] The following intermediate was prepared from the corresponding chemicals according to experimental procedure for Intermediate 42: IntermediateStructureStaring materialsLCMS (ESI) m / zIntermediate 43 Intermediate 33 457 (M+H) +< Intermediate 44: Preparation of 2-(5-(4-fluoro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]no nane

[0322] Step 1:

[0323] To a solution of 5-fluoro-2-methoxybenzoic acid (4.01 g, 23.51 mmol) and DIEPA (5.8 mL, 35.33 mmol) in DCM (40 mL) was added HATU (13.4 g, 35.31 mmol) and NH 4 Cl (1.72 g, 31.82 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with Sat, NH 4 Cl solution, extracted with DCM (20 mL x 3), the combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 10~30%) to obtain the desired product 5-fluoro-2-methoxybenzamide (3.81 g, yield: 95.6%) as a white solid. LC / MS (ESI) m / z: 170(M+H) +< .Step 2:

[0324] A solution of 5-fluoro-2-methoxybenzamide (3.81 g, 22.52 mmol) in DMF-DMA (30.1 mL, 224.61 mmol) was heated to 100 °C overnight. the reaction mixture was concentrated under reduced pressure to give the crude product N-[(1E)-(dimethylamino)methylidene]-5-fluoro-2-methoxybenzamide (4.78 g, yield: 95.2%) as a colorless oil which can be used in next step directly without further purification. LC / MS (ESI) m / z 225(M+H) +< .Step 3:

[0325] To a solution of N-[(1E)-(dimethylamino)methylidene]-5-fluoro-2-methoxybenzamide (4.78 g, 21.41 mmol) in AcOH (30 mL) was added (propan-2-yl)hydrazine (1.61 g, 22.0 mmol). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, to the residue was added Sat NaHCO 3 solution (30 mL). Then the mixture was extracted with DCM (20 mL x 3), the combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0~40%) to obtain the desired product 5-(5-fluoro-2-methoxyphenyl)-1-(propan-2-yl)-1H-1,2,4-triazole (3.98 g, yield: 79.4%) as a light yellow solid .LC / MS (ESI) m / z: 236 (M+H) +< .Step 4:

[0326] To a solution of 5-(5-fluoro-2-methoxyphenyl)-1-(propan-2-yl)-1H-1,2,4-triazole (1 g, 4.25 mmol) in DCM (10 mL) was added BBr 3 (10 mL, 1 mol / L in DCM) dropwise at -60 °C under N 2 atmosphere, BBr 3 (10 mL, 1.0 M in DCM) dropwise at -60 °C under N 2 atmosphere, the resulting mixture was stirred for 2 h at this temperature. Then the reaction mixture was quenched with cooled sat. NaHCO 3 at 0°C, the mixture was extracted with DCM (30 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain desired product4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (700 mg, yield: 74.4%) as a yellow solid. LC / MS (ESI) m / z: 222 (M+H) +< .Step 5:

[0327] To a mixture of 4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenol (500 mg, 2.30 mmol) and Cs 2 CO 3 (2.21 g, 6.81 mmol) in DMF (10 mL) was added 5-bromopyrimidine (467 mg, 2.91 mmol). The reaction mixture was heated to 120 °C for 12 h. After cooled to room temperature, the mixture was quenched with sat. NH 4 Cl solution (50 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (MeOH in DCM = 0 ~ 4%) to obtain the desired product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (240 mg, yield: 35.5%) as a light yellow oil. LC / MS (ESI) m / z: 300 (M+H) +< .Step 6:

[0328] To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (240 mg, 0.81 mmol) in THF (10 mL) was added urea hydrogen peroxide (226 mg, 2.42 mmol) and TFAA (0.6 mL, 4.2 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 1 h under N 2 . The reaction mixture was washed with sat. aq. NaHCO 3 (30 mL) and sat. aq.Na 2 S 2 O 3 (30 mL), the water phase was extracted with DCM (15 mL x 3), the combined organic phase was washed with water and brine and dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain the crude product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-1-ium-1-olate (160 mg, yield: 63.3%) as a brown solid which was used in next step directly without further purification. LC / MS (ESI) m / z:254 (M+H) +< .Step 7:

[0329] To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-1-ium-1-olate (160 mg, 0.52 mmol) in EtOAc (10 mL) was added DIEPA (0.7 mL, 4.10 mmol) and POCl 3 (0.15 mL, 1.52 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with sat.NaHCO 3 , extracted with DCM (15 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product 4-chloro-5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, yield: 47.2%) as a brown oil which can be used in next step directly without further purification. LC / MS (ESI) m / z: 334(M+H) +< .Step 8:

[0330] To a solution of 4-chloro-5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidine (80 mg, 0.24 mmol) and K 2 CO 3 (132 mg, 0.96 mmol)) in MeCN (10 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (59.7 mg, 0.31 mmol). The resulting mixture was heated to 80 °C for 5 h. After cooled to room temperature, the reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with EtOAc (15 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 40%) to obtain the desired product tert-butyl tert-butyl 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carboxylate (30 mg, yield: 23.9%) as a white solid. LC / MS (ESI) m / z: 524 (M+H +< ).Step 9:

[0331] To a solution of tert-butyl 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carboxylate (30 mg, 0.06 mmol) in DCM (5 mL) was added TFA (2 mL) dropwise at room temperature, the resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated to give the crude product 2-(5-{4-fluoro-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]phenoxy}pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane (15 mg, yield: 61.8%) ) as a light yellow solid which can be used in next step directly without further purification. LC / MS (ESI) m / z: 213 (1 / 2 M+H +< ).Preparation of Intermediate 45, 2-(5-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane

[0332] Step 1:

[0333] To a solution of [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (686 mg, 4.46 mmol) and 5-(2-bromo-4-fluorophenoxy)pyrimidine (800 mg, 2.97 mmol) in dioxane (20 mL) and H 2 O (2.0 mL) was added K 2 CO 3 (1.2 g, 8.9 mmol) and Pd(dppf)Cl 2 (217 mg, 0.29 mmol) at rt, the resulting mixture was stirred at 100 °C for 2 h under N 2 . The reaction mixture was cooled to rt, quenched with H 2 O (5 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 50%) to give the desired product 5-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (602 mg, yield: 68%) as a yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.47 (s, 2H), 7.46 (s, 1H), 7.44 - 7.40 (m, 1H), 7.39 - 7.34 (m, 2H), 6.25 (d, J = 1.2 Hz, 1H), 4.39 - 4.31 (m, 1H), 1.29 (d, J = 6.4 Hz, 6H), LC / MS (ESI) m / z: 299(M+H) +< .Step 2:

[0334] To a solution of 5-{4-fluoro-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenoxy}pyrimidine (600 mg, 2.01 mmol) in DMF (10 mL) was added NCS (268 mg, 2.01 mmol) dropwise at room temperature, the resulting mixture was stirred for 3 h. The reaction mixture was quenched with H 2 O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 80%) to give the desired product 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (401 mg, yield: 65.7%) as a light yellow solid. 1< H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.48 (s, 2H), 7.63 (s, 1H), 7.55 - 7.40 (m, 3H), 4.34 - 4.25 (m, 1H), 1.28 (dd, J = 11.7, 6.5 Hz, 6H). LC / MS (ESI) m / z: 333(M+H) +< .Step 3:

[0335] To a solution of 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (150 mg, 0.45 mmol) in THF (5 mL) was added urea.H 2 O 2 (127 mg, 1.35 mmol) and TFAA (568 mg, 2.71 mmol) portion wise at 0 °C, the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with sat. NaHCO 3 , extracted with EtOAc (50 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (120 mg, yield: 76.3%) as a brown solid which can be used in next step without further purification. LC / MS (ESI) m / z: 349 (M+H) +< .Step 4:

[0336] To a solution of 5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-1-ium-1-olate (120 mg, 0.34 mmol) in EtOAc (3 mL) was added POCl 3 (0.10 mL, 1.0 mmol) and DIPEA (0.23 mL, 1.4 mmol) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. NaHCO 3 , extracted with DCM (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product 4-chloro-5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, yield: 87.1%) as a brown oil which can be used in next step without further purification. LC / MS (ESI) m / z: 367(M+H) +< .Step 5:

[0337] To a solution of 4-chloro-5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidine (110 mg, 0.30 mmol) in DMF (5 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (67 mg, 0.30 mmol) and K 2 CO 3 (124 mg, 0.89 mmol) at room temperature. The resulting reaction was stirred overnight at rt. The reaction mixture was quenched with H 2 O (5 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 50%) to give the desired tert-butyl 2-(5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspir o[3.5]nonane-7-carboxylate (100 mg, yield: 59.9%) as a white solid. LC / MS (ESI) m / z: 557(M+H) +< .Step 6:

[0338] To a solution of tert-butyl 2-(5-(2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carboxylate (100 mg, 0.18 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) dropwise at room temperature and the resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated to give the crude product 2-(5-{2-[4-chloro-1-(propan-2-yl)-1H-pyrazol-5-yl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspir o[3.5]nonane (60 mg, yield: 73%) as a light yellow syrup which can be used in next step directly without further purification. LC / MS (ESI) m / z: 457(M+H) +< .Preparation of Intermediate 46, Trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid

[0339]

[0340] Step 1: To a solution of 1-benzyl 2-methyl trans-3-ethenylpyrrolidine-1,2-dicarboxylate (1.30 g, 4.49 mmol, see Intermediate 37 for its synthesis), NaIO 4 (3.00 g, 13.48 mmol) and Potassium osmate dihydrate (0.17 g, 0.45 mmol) in MeOH (30 mL) and H 2 O (50 mL), the resulting mixture was stirred for 4 h at room temperature. Then the reaction mixture was diluted with H 2 O (20 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to obtain the desired product 1-benzyl 2-methyl trans-3-formylpyrrolidine-1,2-dicarboxylate (700 mg, 2.40 mmol, 53.48%) as a colorless oil. LC / MS (ESI) m / z: 292(M+H) +< Step 2:

[0341] To a solution of 1-benzyl 2-methyl trans-3-formylpyrrolidine-1,2-dicarboxylate (200 mg, 0.69 mmol) in MeOH (5 mL) at 0 0< C was added NaBH 4 (5 mg, 0.14 mmol) slowly. The resulting mixture was stirred at rt for 2 h. Then the reaction mixture was quenched with Sat. NH 4 Cl solution (5 mL), extracted with EtOAc (10 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product 1-benzyl 2-methyl trans-3-(hydroxymethyl) pyrrolidine-1,2-dicarboxylate (160 mg, 79.4%) as a light yellow oil. LC / MS (ESI) m / z: 294(M+H) +< .Step 3:

[0342] To a solution of 1-benzyl 2-methyl trans-3-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (160 mg, 0.55 mmol) in DCM (5 mL) was added DAST (132 mg, 0.82 mmol) at 0°C under N 2 . The resulting mixture was stirred for 16 h at rt. The reaction mixture was quenched with sat. NaHCO 3 , extracted with DCM (10 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to obtain the desired product 1-benzyl 2-methyl trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol, 49.6%) as a brown oil; LCMS: ESI m / z 296(M+H) +< .Step 4:

[0343] To a solution of 1-benzyl 2-methyl trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (80 mg, 0.27 mmol) and (Boc) 2 O (77 mg, 0.35 mmol) in MeOH (5 mL) was added Pd / C (10%, 20 mg) at rt, the resulting suspension was vacuum and refilled with hydrogen, the mixture was stirred at rt for 3 h under a balloon of H 2 . The reaction mixture was filtered through a pad of celite, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product 1-(tert-butyl) 2-methyl trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (50 mg, 70.6%) as an oil. LC / MS (ESI) m / z: 262(M+H) +< .Step 5:

[0344] To a solution of 1-(tert-butyl) 2-methyl trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (50 mg, 0.19 mmol) in MeOH (3 mL) and H 2 O (1 mL) was added NaOH (20 mg, 0.50 mmol) at 0°C. The resulting mixture was stirred for 5h at room temperature, The reaction mixture was concentrated, and adjusted the pH to 4~5 with 1.0 N HCl solution, extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product trans-1-(tert-butoxycarbonyl)-3-(fluoromethyl)pyrrolidine-2-carboxylic acid (40 mg, 85.2% yield) as a brown solid which can be used in next step without further purification. LC / MS (ESI) m / z: 248 (M+1-56) +< .Preparation of Intermediate 47, 5-(2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropylpicol inonitrile compound

[0345] Step 1:

[0346] To a solution of 6-bromo-2-chloropyridin-3-amine (2.30 g, 11.09 mmol) and Zn(CN) 2 (0.98 g, 8.32 mmol) in DMF (25 mL) was added Pd(PPh 3 ) 4 (0.38 g, 0.33 mmol) at rt. The resulting mixture was heated to 85°C for 12 h under N 2 atmosphere. The reaction mixture was quenched with Sat. NH 4 Cl solution, extracted with EtOAc (20 mL x 3), The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE =0~30%) to afford the desired product 5-amino-6-chloropyridine-2-carbonitrile (500 mg, yield: 29.4%) as a light-yellow solid, LC / MS (ESI) m / z: 154(M+H) +< .Step 2:

[0347] To a solution of 5-amino-6-chloropyridine-2-carbonitrile (2.71 g, 17.58 mmol), cyclopropylboronic acid (1.96 g, 22.86 mmol) and tricyclohexylphosphane (1.97 g, 7.03 mmol) in toluene (80 mL) and H 2 O (10 mL) was added Pd(AcO) 2 (40 mg, 0.18 mmol) and K 3 PO 4 (14.9 g, 70.33 mmol). The resulting mixture was stirred at 100 °C for 10 h under N 2 atmosphere. The reaction mixture was diluted with Sat. NH 4 Cl solution, extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE =5~30%) to afford the desired product 5-amino-6-cyclopropylpyridine-2-carbonitrile (1.12 g, yield: 40.1%) as a yellow solid. LC / MS (ESI) m / z: 160(M+H) +< .Step 3:

[0348] To a stirred solution of t-BuONO (2.53 mL, 21.11 mmol) and CuBr (4.04 g, 28.14 mmol) in MeCN (20 mL) at 70 °C was added a solution of 5-amino-6-cyclopropylpyridine-2-carbonitrile (1.12 g, 7.04 mmol) in MeCN (10 mL) dropwised. The resulting mixture was stirred at the same temperature for 1h. The reaction mixture was quenched with Sat. NH 4 Cl solution (30 mL), the mixture was extracted with EtOAc (20 mL x 3), the combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE =0~10%) to give the desired product 5-bromo-6-cyclopropylpyridine-2-carbonitrile (1 g, yield: 63.7%) as a yellow solid. LC / MS (ESI) m / z: 223(M+H) +< .Step 4:

[0349] To a solution of 5-bromo-6-cyclopropylpyridine-2-carbonitrile (1.00 g, 4.48 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (1.05 g, 6.72 mmol) in dioxane (10 mL) and H 2 O (2 mL) was added Pd(dppf)Cl 2 (50 mg) and Cs 2 CO 3 (4.38 g, 13.45 mmol), the resulting mixture was stirred at 100°C for 2 h under N 2 . The reaction mixture was cooled to rt, quenched with H 2 O (5 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel ( EtOAc in PE = 5 ~ 30%) to give the desired product 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carbonitrile (740 mg, yield: 64.9%) as a colorless oil. LC / MS (ESI) m / z: 255(M+H) +< .Step 5:

[0350] To a stirred solution of 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridine-2-carbonitrile (740 mg, 2.91 mmol) and tert-butyl 2-(dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (762 mg, 2.04 mmol, see Intermediate 34 for its synthesis) in THF (15 mL) was added DBU (0.65 mL, 4.37 mmol) at 0°C. The resulting mixture was stirred at rt for 10 h at rt. The reaction mixture was diluted with H 2 O (20 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography column on silica gel (EtOAc in PE= 0~50%) to afford the desired product tert-butyl 2-{3-chloro-6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-dia zaspiro[3.5]nonane-7-carboxylate (440 mg, yield: 25.5%) as a white solid. LCMS: ESI m / z 592(M+H) +< .Step 6:

[0351] To a solution of tert-butyl 2-{3-chloro-6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-dia zaspiro[3.5]nonane-7-carboxylate (600 mg, 1.01 mmol), [3-(dimethylamino)propyl]dimethylamine (263 mg, 2.03 mmol) in THF (15 mL) was added NaBH 4 (63 mg, 1.86 mmol) and Pd(dppf)Cl 2 (30 mg). The reaction mixture was stirred at rt for 12 h under N2 atmosphere, quenched with Sat. NH 4 Cl solution (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE= 0~40%) to obtain the desired product tert-butyl 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3. 5]nonane-7-carboxylate (240 mg, yield: 42.5%) as a white solid. LCMS: ESI m / z 558(M+H) +< .Step 7:

[0352] To a solution of tert-butyl 2-{6-[2-(6-cyano-2-cyclopropylpyridin-3-yl)-4-fluorophenoxy]-1,2,4-triazin-5-yl}-2,7-diazaspiro[3. 5]nonane-7-carboxylate (240 mg, 0.43 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) dropwise at room temperature and the resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated to give the crude product 5-(2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluorophenyl)-6-cyclopropylpicol inonitrile as a TFA salt (200 mg, yield: 75.1%) which can be used in next step directly without further purification. LC / MS (ESI) m / z: 458(M+H) +< .Preparation of Intermediate 48, 2-((3-chloro-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropy lbenzamide

[0353]

[0354] To a solution of tert-butyl 2-(3-chloro-6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3 .5]nonane-7-carboxylate (200 mg, 0.36 mmol, see Intermediate 34 for its synthesis) in DCM (5.0 mL) was added TFA (2.0 mL) dropwise at room temperature and the resulting mixture was stirred for 1 h at rt. The reaction mixture was concentrated to give the crude product 2-((3-chloro-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropy lbenzamide as a 2,2,2-trifluoroacetate salt (150 mg, yield: 74.4%) which can be used in next step directly without further purification. LC / MS (ESI) m / z: 463(M+H) +< .Preparation of Intermediate 49, rel-(2R,3R,4S)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid

[0355] Step 1:

[0356] To a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (21.5 mL, 84.24 mmol) and 1,4-dimethyl (2Z)-but-2-enedioate (10.6 mL, 84.24 mmol) in MeCN (150 mL) at 25°C was added LiF (2.66 g, 102.31 mmol), and the resulting mixture was stirred at 25°C for 18 h under N 2 atmosphere. The reaction mixture was then diluted with Sat. NH 4 Cl solution (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic phase was washed by water and brine sequentially, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product cis-3,4-dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (22.1 g, yield: 94.2%) as a light-yellow oil. 1< H NMR (400 MHz, CDCl 3 ) δ 7.31 - 7.23 (m, 5H), 3.66 (s, 8H), 3.33 - 3.28 (m, 2H), 3.17-3.12 (m, 2H), 2.77 - 2.67 (m, 2H), LC / MS (ESI) m / z: 278(M+H) +< .Step 2:

[0357] To a stirred solution of cis-dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (10.0 g, 36.06 mmol) in THF (50 mL) at 0°C was added LAH (4.5 g, 118.58 mmol) in small portions. The resulting mixture was stirred at 60°C for 18 h under N 2 atmosphere, and then quenched with water (4.5 mL), 15% NaOH solution (4.5 mL) and water (13.5 mL) dropwise. The mixture was filtered through celite and the filtrate was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with water and brine, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (MeOH in DCM =1 ~ 10%) to give the desired product cis-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (7.03 g, yield: 87.7%) as a colorless oil. LC / MS (ESI) m / z: 222(M+H) +< .Step 3:

[0358] To a stirred solution of cis-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol (4.00 g, 18.07 mmol) and Boc 2 O (4.95 g, 22.91 mmol) in MeOH (50 mL) were added TEA (1.49 g, 14.85 mmol) and 10% Pd / C (500 mg) at rt slowly. The resulting mixture was stirred at rt for 18 h under H 2 atmosphere, and then poured into water (200 mL). The mixture was extracted with EtOAc (200 mL x 3), and the combined organic phase was washed by water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to give the desired product tert-butyl cis-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (3.50 g, yield: 83.7%) as a colorless oil. LC / MS (ESI) m / z: 176(M+H-56) +< .Step 4:

[0359] To a stirred solution of cis-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (4.00 g, 17.29 mmol) and DIPEA (10.2 mL, 61.90 mmol) in DCM (50 mL) was added MsCl (4.05 mL, 52.38 mmol) at 0°C in 10min. The resulting mixture was stirred at 25°C for 18 h under N 2 atmosphere, quenched with Sat. NH 4 Cl solution (20 mL), and extracted with DCM (50 mL x 3). The combined organic phase was washed with water and brine, the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to give the desired product tert-butyl cis-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.81 g, yield: 86.6%) as a light yellow oil. LC / MS (ESI) m / z: 332(M+H-56) +< .Step 5:

[0360] To a stirred solution of tert-butyl cis-3,4-bis(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (5.81 g, 14.97 mmol) was added LiEt 3 BH (100 mL, 100 mmol) at 0°C in 30 min. The resulting mixture was stirred at 25°C for 12h under N 2 atmosphere, quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 10%) to give the desired product tert-butyl cis-3,4-dimethylpyrrolidine-1-carboxylate (1.50 g, yield: 50.3%) as a light-yellow oil. 1< H NMR (400 MHz, CDCl 3 ) δ 3.46-3.42 (m, 2H), 3.04-3.00 (m, 2H), 2.34 - 2.14 (m, 2H), 1.46 (s, 9H), 0.92 (d, J = 6.7 Hz, 6H).Step 6:

[0361] To a stirred solution of tert-butyl cis-3,4-dimethylpyrrolidine-1-carboxylate (300 mg, 1.51 mmol) in THF (3 mL) at -78°C was added s-BuLi (1.5 mL, 1.950 mmol) drop-wised in 30min. The resulting mixture was stirred for 3 h at the same temperature, then to it was bubbled with CO 2 for 1 h (maintain the inner temperature below -70°C). After warmed to room temperature, the mixture was quenched with 1N HCl to pH=5, and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product product rel-(2S,3S,4R)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-2-carboxylic acid (120 mg, yield: 32.8%) as a yellow semisolid which can be used in next step directly without further purification. LC / MS (ESI) m / z: 144(M+H-100) +< .Preparation of Intermediate 50, 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopenta[c]pyrrole-1-carboxylic acid

[0362] Step 1:

[0363] To a solution of tert-butyl cis-5-oxo-octahydrocyclopenta[c]pyrrole-2-carboxylate (5.00 g, 22.19 mmol) in THF (30 mL) at 0°C was added DAST (11.7 mL, 88.77 mmol) slowly, the reaction mixture was stirred at 25°C for 72h under N 2 atmosphere. The reaction mixture was quenched with Sat. NH 4 Cl solution (10 mL), the mixture was extracted with EtOAc (50 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 40%) to obtain the desired product tert-butyl cis-5,5-difluoro-octahydrocyclopenta[c]pyrrole-2-carboxylate (4 g, yield: 72.8%) as a light-yellow oil. LC / MS (ESI) m / z: 248(M+H) +< .Step 2:

[0364] To a solution of tert-butyl cis-5,5-difluoro-octahydrocyclopenta[c]pyrrole-2-carboxylate (3.21 g, 12.94 mmol) in THF (20 mL) at -78°C was added s-BuLi (29.8 mL, 38.82 mmol). After stirred at -78°C for 4h under N 2 atmosphere, the resulting mixture was stirred for 5h under CO 2 atmosphere at -78°C, and then allowed to return to rt gradually, and stirred for another 12h at rt. The mixture was quenched with 1N HCl solution , adjusted to pH of 4~5, and extracted with EtOAc (30 mL x 3). The combined organic layer was washed by brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford the crude product 2-[(tert-butoxy)carbonyl]-5,5-difluoro-octahydrocyclopenta[c]pyrrole-1-carboxylic acid (800 mg, yield: 21.2%) as a brown oil, which was used in next step without further purification. LC / MS (ESI) m / z: 292(M+H) +< .Preparation of Intermediate 51, trans-1-((benzyloxy)carbonyl)-3-(difluoromethyl)pyrrolidine-2-carboxylic acid

[0365] Step 1:

[0366] To a solution of 1-benzyl 2-methyl trans-3-ethenylpyrrolidine-1,2-dicarboxylate (1.30 g, 4.49 mmol, see Intermediate 37 for its synthesis), NaIO 4 (2.88g, 13.48 mmol) and potassium osmate dihydrate (170 mg, 0.45 mmol) in MeOH (30 mL) and H 2 O (50 mL), the resulting mixture was stirred for 4 h at room temperature. Then the reaction mixture was diluted with H 2 O (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to obtain the desired product 1-benzyl 2-methyl trans-3-formylpyrrolidine-1,2-dicarboxylate (700 mg, yield: 53.5%) as a yellow solid. LC / MS (ESI) m / z: 292(M+H) +< Step 2:

[0367] To DAST (5 mL) at 0°C was added a solid of 1-benzyl 2-methyl (2S,3S)-3-formylpyrrolidine-1,2-dicarboxylate (500 mg, 1.72 mmol), then the resulting mixture was stirred for 24 h at 40°C. The reaction mixture was diluted with DCM (50 mL), and washed with sat. NaHCO 3 . the organic phase was collected, and the water layer was extracted with DCM (20 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to obtain the desired product 1-benzyl 2-methyl trans-3-(fluoromethyl)pyrrolidine-1,2-dicarboxylate (300 mg, yield: 55.7%) as a yellow oil; LCMS: ESI m / z 314(M+H) +< .Step 3:

[0368] To a solution of 1-benzyl 2-methyl trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.96 mmol) in MeOH (5 mL) and H 2 O (2 mL) at 0°C was added NaOH (115 mg, 2.88 mmol). The resulting mixture was stirred for 2 h at room temperature, The reaction mixture was concentrated, and adjusted the pH to 4~5 with 1 N HCl solution, extracted with EtOAc (15 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product 1-benzyl 2-methyl trans-3-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (250 mg, yield: 82.2 %) as a brown solid, which was used in next step without further purification. LC / MS (ESI) m / z: 300 (M+1) +< .

[0369] The following intermediate was prepared from the corresponding chemicals according to experimental procedure for Intermediate 37 (the major different chemicals used are listed in the column of starting material): IntermediateStructureStarting materialLCMS (ESI) m / zIntermediate 52 290 (M+H) +< Preparation of Intermediate 53, N-(ethyl-1,1-d 2 )-5-fluoro-2-hydroxy-N-isopropylbenzamide

[0370] Step 1:

[0371] To a solution of N-isopropylacetamide (1 g, 9.89 mmol) in dry THF (10 mL) was added LiAlD 4 (620 mg, 14.83 mmol) at 0°C, the resulting mixture was stirred at 70°C for 24h. The reaction mixture was quenched with Sat. NH 4 Cl (10 mL), extracted with Et 2 O (20 mL x 3). The combined organic layer was washed with brine, then dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product N-(ethyl-1,1-d 2 )propan-2-amine (400 mg, yield: 45.4%) as a colorless liquid, which was used to next step without further purification. LC / MS (ESI) m / z: 90 (M+H) +< .Step 2:

[0372] To a solution of 5-fluoro-2-methoxybenzoic acid (700 mg, 4.11 mmol) and N-(ethyl-1,1-d2)propan-2-amine (400 mg, 4.49 mmol) in DMF (5 mL) was added HATU (2.03 g, 5.35 mmol) and DIPEA (1.06 g, 8.23 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature gradually and stirred overnight. The reaction mixture was quenched with sat. NH 4 Cl solution (10 mL), extracted with EtOAc (50 mL x 3), the combined organic phase was washed by water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 20%) to obtain the desired product N-(ethyl-1,1-d2)-5-fluoro-N-isopropyl-2-methoxybenzamide (400 mg, yield: 40.3%) as a white solid. LC / MS (ESI) m / z: 242(M+H) +< .Step 3:

[0373] To a solution of N-[(1,1-d2)ethyl]-5-fluoro-2-methoxy-N-(propan-2-yl)benzamide (400 mg, 1.66 mmol) in DCM (10 mL) was added BBr 3 (2.2 mL, 1.0 M in DCM) dropwise at -60°C under N 2 atmosphere, the resulting mixture was stirred for 7 h at this temperature. Then the reaction mixture was quenched with cooled sat. NaHCO 3 at 0°C, the mixture was extracted with DCM (30 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give desired product N-(ethyl-1,1-d 2 )-5-fluoro-2-hydroxy-N-isopropylbenzamide (270 mg, yield: 71.6%) as a light-yellow solid, which was used in next step without further purification. LC / MS (ESI) m / z: 228(M+H) +< .Preparation of Intermediate 54, 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol

[0374]

[0375] To a solution of 3-bromo-2-cyclopropylpyridine (250 mg, 1.26 mmol) and (5-fluoro-2-hydroxyphenyl)boronic acid (220 mg, 1.41 mmol) in dioxane (4.0 mL) and H 2 O (1.0 mL) was added Pd(dppf)Cl 2 (25 mg) and K 2 CO 3 (400 mg, 2.89 mmol), the resulting mixture was stirred at 100°C overnight under N 2 . The reaction mixture was cooled to rt, diluted with H 2 O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 10%) to obtain the desired product 2-(2-cyclopropylpyridin-3-yl)-4-fluorophenol (200 mg, yield:69.1%) as a yellow solid. LC / MS (ESI) m / z: 230(M+H) +< .Preparation of Intermediate 55, 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol

[0376] Step 1:

[0377] To a solution of 2-chloro-6-methoxypyridin-3-amine (2.5 g, 15.8 mmol), cyclopropylboronic acid (1.76 g, 20.5mmol) in toluene (20 mL) and H 2 O (4 mL) at rt was added K 3 PO 4 (13.4 g, 63.1 mmol), tricyclohexylphosphane (1.77 g, 6.31 mmol) and Pd(AcO) 2 (40 mg, 0.16 mmol). The resulting mixture was degassed with N 2 for three times and stirred at 100°C overnight under N 2 atmosphere.

[0378] The reaction mixture was cooled to rt, quenched with Sat. NH 4 Cl solution (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 10%) to obtain the desired product 2-cyclopropyl-6-methoxypyridin-3-amine (830 mg, yield: 32.1%) as a yellow solid. LC / MS (ESI) m / z: 164(M+H) +< .Step 2:

[0379] A suspension of tert-Butyl nitrite (1.82 mL, 15.2 mmol), CuBr (2.90 mg, 20.2 mmol) in MeCN (10 mL) was stirred at 70°C for 30min, then to this stirred mixture was added a solution of 2-cyclopropyl-6-methoxypyridin-3-amine (830 mg, 5.06 mmol) in MeCN (5 mL) dropwised. The resulting mixture was stirred at 70°C for another 1h. The reaction mixture was quenched with water (10 mL ), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed by water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (PE =100 %) to obtain the desired product 3-bromo-2-cyclopropyl-6-methoxypyridine (400 mg, yield: 34.7%) as a light-yellow oil. LC / MS (ESI) m / z: 229(M+H) +< .Step 3:

[0380] To a solution of 3-bromo-2-cyclopropyl-6-methoxypyridine (600 mg, 2.63 mmol) and (5-fluoro-2-hydroxyphenyl)boronicacid (615 mg, 3.95 mmol) in dioxane (16 mL) and H 2 O (4 mL) was added Cs 2 CO 3 (2.57g, 7.89 mmol) and Pd(dppf)Cl 2 (50 mg), the resulting mixture was stirred at 100°C overnight under N 2 atmosphere. The reaction mixture was cooled to rt, diluted with H 2 O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to obtain the desired product 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol (550 mg, yield: 80.6%) as a yellow solid. LC / MS (ESI) m / z: 260 [M+1]+.Preparation of Intermediate 56, 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)pyridin-2(1H)-one

[0381]

[0382] To a solution of 2-(2-cyclopropyl-6-methoxypyridin-3-yl)-4-fluorophenol (350 mg, 1.35 mmol, Intermediate 55 ) in HOAc (5 mL) was added 40% HBr solution (3 mL) at room temperature, and the resulting mixture was stirred overnight at 80°C. The reaction mixture was cooled to rt and concentrated. The residue was suspended in EtOAc (50 mL) and washed with sat NaHCO 3 (10 mL x 3), and brine, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product which was purified by silica gel column (EtOAc in PE=0~70% ) to obtain the desired product 6-cyclopropyl-5-(5-fluoro-2-hydroxyphenyl)-1,2-dihydropyridin-2-one (200 mg, yield: 60.4%) as a brown semi-solid, 1< H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 9.38 (s, 1H), 7.23 (d, J = 9.0 Hz, 1H), 7.02 - 6.92 (m, 2H), 6.89-6.85 (m, 1H), 6.21 (d, J = 8.9 Hz, 1H), 1.75-1.69 (m, 1H), 0.89-0.80 (m, 2H), 0.76-0.72 (m, 2H), LC / MS (ESI) m / z: 246(M+H) +< .Examples Example 2: Preparation of N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl} pyrimidin-5-yl)oxy]-N-(propan-2-yl)benzamide

[0383] Step 1:

[0384] To a solution of 2-[(4-{2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benz amide (Intermediate 1, 50 mg, 0.12 mmol) and (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (27 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (0.1 mL) and HATU (58 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred for 3 h at rt and quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (15 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (MeOH in DCM= 0 ~ 5%) to give the desired product tert-butyl(2S,4R)-2-[2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-d iazaspiro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (60 mg, yield: 79%) as a light yellow solid. LC / MS (ESI) m / z: 643(M+H) +< .Step 2:

[0385] To a solution of tert-butyl (2S,4R)-2-[2-(5-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}pyrimidin-4-yl)-2,7-diazaspiro [3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (60 mg, 0.1 mmol) in DCM (3 mL) was added TFA (1.0 mL). The resulting mixture was stirred for 1 h at rt, concentrated, the residue was purified by Prep-HPLC to afford the desired product N-ethyl-5-fluoro-2-[(4-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl} pyrimidin-5-yl)oxy]-N-(propan-2-yl)benzamide (35 mg, yield: 69%) as a white solid. 1< H NMR (400 MHz, CDCl 3 )δ 8.40 (d, J = 3.1 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.04 - 7.00 (m, 2H), 6.78 - 6.72 (m, 1H), 5.35 - 5.22 (m, 1H), 4.29 - 4.25 (m, 1H), 4.03 - 3.82 (m, 5H), 3.66 - 3.63 (m, 1H), 3.52 - 3.15 (m, 7H), 2.40 - 2.31 (m, 1H), 1.87 - 1.76 (m, 5H), 1.29 - 1.23 (m, 4H), 1.16 - 1.07 (m, 5H). LC / MS (ESI) m / z: 543(M+H) +< .

[0386] The following compounds were prepared from the appropriate intermediates or commercially available chemicals according to experimental procedure for Example 2: ExampleStructureStarting materials 1< H-NMR (400 MHz)LCMS (ESI) m / zExample 3 Intermediate 1 1< H NMR (400 MHz, CDCl 3 ) δ 8.51 - 8.35 (m, 1H), 8.23 (s, 0.6H), 7.83 (d, J = 6.2 Hz, 1H), 7.04 - 7.01 (m, 2H), 6.77 - 6.73 (m, 1H), 5.33 - 5.20 (m, 1H), 4.60 - 4.56 (m, 1H), 4.06 - 3.73 (m, 6H), 3.64 - 3.56 (m, 1H), 3.40 - 3.16 (m, 6H), 2.65 - 2.55 (m, 1H), 2.21 - 2.12 (m, 1H), 1.83 - 1.79 (m, 4H), 1.29 - 1.23 (m, 3H), 1.17 - 1.09 (m, 5H).543(M+H) +< and Example 4 Intermediate 1 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, J = 3.3 Hz, 1H), 7.81 - 7.80 (m, 1H), 7.04 - 7.00 (m, 2H), 6.79 - 6.74 (m, 1H), 4.03 - 3.83 (m, 6H), 3.68 - 3.64 (s, 1H), 3.51 - 3.30 (m, 6H), 2.77 (t, J = 10.8 Hz, 1H), 1.91 - 1.65 (m, 8H), 1.54 - 1.50 (m, 2H), 1.28 - 1.23 (m, 4H), 1.16 - 1.17 (m, 5H).539(M+H) +< and Example 5 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 8.28 (d, J = 8.6 Hz, 1H), 7.75-7.69 (m, 1H), 7.29 - 7.23 (m, 2H), 7.05-7.03 (m, 1H), 4.95 (s, 1H), 4.23-4.18 (m, 3H), 3.96-3.86 (m, 5H), 3.77 - 3.72 (m, 1H), 3.15-3.11 (m, 3H), 2.71-2.68 (m, 1H), 1.97-1.95 (m, 1H), 1.85 - 1.56 (m, 6H), 1.20-1.18 (m, 2H), 1.12-0.97 (m, 9H)541 (M+H) +< and Example 6 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.81-7.73 (m, 1H), 7.30 - 7.21 (m, 3H), 4.99 (d, J = 9.9 Hz, 1H), 4.30-4.18 (m, 4H), 3.91-3.84 (m, 1H), 3.73-3.68 (m, 1H), 3.49 - 3.29 (m, 5H), 3.15 (d, J = 5.0 Hz, 1H), 2.73-2.67 (m, 1H), 2.21-2.18 (m, 1H), 1.90-1.85 (m, 4H), 1.37 - 0.93 (m, 15H)551 (M+H) +< and Example 7 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 8.59 (s, 1H), 8.35 (d, J = 4.9 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.35 - 7.24 (m, 2H), 7.08-7.07 (m, 1H), 5.57 (s, 1H), 4.62-4.57 (m, 2H), 4.01-3.92 (m, 4H), 3.81 - 3.69 (m, 1H), 3.28 - 3.11 (m, 5H), 2.12 - 2.07 (m, 1H), 1.91-1.70 (mz, 6H), 1.21 - 0.98 (m, 10H)541(M+H) +< and Example 8 Intermediate 1 1< H NMR (400 MHz, CDCl 3 ) δ 8.40 - 8.39 (m, 1H), 7.80 (d, J = 3.9 Hz, 1H), 7.03-6.99 (m, 2H), 6.73 - 6.71 (m, 1H), 4.21 (s, 1H), 4.03-3.95 (m, 2H), 3.92 - 3.81 (m, 4H), 3.64 - 3.50 (m, 4H), 3.37-3.28 (m, 1H), 3.20-3.17 (m, 1H), 3.05-2.98(m, 1H), 2.37-2.31 (m, 3H), 1.80 - 1.73 (m, 4H), 1.28-1.22 (m, 5H), 1.14 (d, J = 6.4 Hz, 4H)and Example 9 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.28 (s, 1H), 7.81-7.78 (m, 1H), 7.21-7.17 (m, 2H), 6.98-6.94 (m, 1H), 4.41 - 4.37 (m, 1H), 4.06 - 3.88 (m, 5H), 3.57 - 3.44 (m, 6H), 3.08 (d, J = 5.2 Hz, 1H), 2.63-2.41 (m, 1H), 1.93-1.78 (m, 6H), 1.32 - 1.08 (m, 14H)551 (M+H) +< and Example 10 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.27 (d, J = 5.4 Hz, 1H), 7.80-7.77 (m, 1H), 7.22-7.16 (m, 2H), 6.99 - 6.96 (m, 1H), 6.51 (t, J = 74.1 Hz, 1H), 5.03 (s, 1H), 4.73 (t, J = 8.6 Hz, 1H), 4.07 - 3.85 (m, 5H), 3.85 - 3.33 (m, 8H), 3.31-3.20 (m, 1H), 2.66-2.60 (m, 1H), 2.19 - 2.16 (m, 1H), 1.86 - 1.80 (m, 4H), 1.32 - 1.03 (m, 9H)591 (M+H)+and Example 11 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 8.28 (d, J = 8.7 Hz, 1H), 7.74-7.68 (m, 1H), 7.32 - 7.24 (m, 2H), 7.09 - 7.02 (m, 1H), 4.63-4.61 (m, 1H), 4.40-4.31 (m, 1H), 3.94 - 3.69 (m, 6H), 3.44-3.40 (m, 6H), 3.25 - 3.22 (m, 2H), 2.56 (s, 1H), 1.81 - 1.64 (m, 6H), 1.21 - 1.03 (m, 9H), 0.64-0.49 (m, 2H)567 (M+H)+and Example 12 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.22-7.16 (m, 2H), 7.01-6.97 (m, 1H), 4.65 - 4.48 (m, 2H), 4.33-4.29 (m, 1H), 4.11 - 3.88 (m, 5H), 3.58 - 3.49 (m, 5H), 3.36-3.34 (m, 1H), 3.11-3.03 (m, 1H), 2.45 - 2.30 (m, 1H), 1.99 - 1.67 (m, 6H), 1.34 - 1.12 (m, 9H)575 (M+H)+and Example 13 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 8.64 (s, 1H), 8.31 (d, J = 6.2 Hz, 1H), 7.78-7.72 (m, 1H), 7.32 - 7.20 (m, 2H), 7.11-7.04 (m, 1H), 4.91 (d, J = 8.0 Hz, 1H), 3.97-3.87 (m, 4H), 3.76 - 3.73 (m, 1H), 3.44-3.41 (m, 2H), 3.30-3.27 (m, 3H), 3.23-3.19 (m, 3H), 3.13-3.12 (m, 1H), 2.82-2.76 (m, 1H), 2.04-2.00 (m, 1H), 1.75-1.68 (m, 4H), 1.20 - 0.88 (m, 12H)581(M+H) +< andIntermediate 24 Example 14 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26 (d, J = 5.8 Hz, 1H), 7.79-7.76 (m, 1H), 7.20 - 7.17 (m, 2H), 6.99-6.98 (m, 1H), 4.41-4.38 (m, 1H), 3.99-3.93 (m, 5H), 3.59-3.51 (m, 3H), 3.45-3.42 (m, 2H), 3.19 - 3.16 (m, 1H), 2.93-2.90 (m, 1H), 2.42 - 2.35 (m, 1H), 1.85-1.80 (m, 5H), 1.32 - 1.10 (m, 15H)555 (M+H) +< andIntermediate 15 Example 15 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.21-7.16 (m, 2H), 7.05 - 6.95 (m, 1H), 4.17 (t, J = 7.4 Hz, 1H), 4.10 - 3.84 (m, 5H), 3.82 - 3.75 (m, 1H), 3.65 - 3.45 (m, 6H), 3.41 - 3.33 (m, 1H), 3.22-3.18 (m, 1H), 2.97 (s, 3H), 2.57 - 2.46 (m, 1H), 2.18 - 2.08 (m, 1H), 1.86-1.78 (m, 4H), 1.34 - 1.06 (m, 10H)603(M+H) +< andIntermediate 16 Example 16 Intermediate 1 1< H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 3.7 Hz, 1H), 7.82 (s, 1H), 7.04-7.00 (m, 2H), 6.76-6.72 (m, 1H), 5.59-5.49 (m, 1H), 4.08-3.98 (m, 4H), 3.97 - 3.79 (m, 3H), 3.70 - 3.41 (m, 5H), 3.37 - 3.26 (m, 1H), 3.20-3.13 (m, 2H), 3.07-3.04 (m, 1H), 2.95 (s, 3H), 2.36 - 2.23 (m, 1H), 1.81-1.72 (m, 2H), 1.33 - 1.07 (m, 11H)618(M+H) +< andIntermediate 25 Example 18 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 8.28-8.26 (m, 1H), 7.80-7.77 (m, 1H), 7.23 - 7.16 (m, 2H), 7.01 - 6.93 (m, 1H), 4.61 (t, J = 8.1 Hz, 1H), 4.12 - 4.09 (m, 3H), 3.98 - 3.88 (m, 3H), 3.58-3.51 (m, 7H), 3.38 - 3.31 (m, 2H), 3.28 - 3.24 (m, 2H), 2.44-2.40 (m, 1H), 2.22-2.16 (m, 1H), 1.85-1.80 (m, 4H), 1.32 - 1.09 (m, 10H)618(M+H) +< andIntermediate 26 Example 17 Intermediate 4 and 1< H NMR (400 MHz, DMSO) δ 8.39 (d, J = 6.7 Hz, 1H), 8.01-7.97 (m, 1H), 7.92 (dd, J = 12.4, 2.1 Hz, 1H), 7.8-7.84 (m, 1H), 7.06-7.00 (m, 1H), 5.32-5.18 (m, 1H), 4.10 (t, J = 7.8 Hz, 1H), 3.90-3.88 (m, 2H), 3.83 - 3.72 (m, 3H), 3.40-3.38 (m, 5H), 3.17-3.04 (m, 2H), 2.99-2.90 (m, 1H), 2.17 - 1.91 (m, 3H), 1.72-1.61 (m, 4H), 1.24-1.10 (m, 9H)550(M+H) +< Example 19 Intermediate 2 and 1< H NMR (400 MHz, DMSO) δ 8.33 (d, J = 8.5 Hz, 1H), 8..14 (s, 0.4H), 7.87-7.82 (m, 1H), 7.48 - 7.41 (m, 2H), 7.00-6.93 (m, 1H), 5.42-5.28 (m, 1H), 4.43 (t, J = 8.2 Hz, 1H), 3.99 - 3.72 (m, 5H), 3.45-3.39 (m, 4H), 3.25-3.20 (m, 4H), 2.43-2.39 (m, 1H), 2.09-2.00 (m, 1H), 1.83 - 1.62 (m, 4H), 1.24 - 1.00 (m, 9H)559(M+H) +< Example 20 Intermediate 3 1< H NMR (400 MHz, MeOD) δ 8.26 (d, J = 8.0 Hz, 1H), 7.77-7.69 (m, 1H), 7.18 (t, J = 8.2 Hz, 2H), 6.96-6.93 (m, 1H), 5.33-5.20 (m, 1H), 4.25 - 4.17 (m, 1H), 4.00 (br, 4H), 3.57-3.52 (m, 6H), 3.25-3.22 (m, 1H), 3.13-3.04 (m, 1H), 2.84-2.72 (m, 1H), 2.45-2.34 (m, 1H), 1.95-1.78 (m, 5H), 1.25-1.16 (m, 4H), 0.64 (d, J = 6.9 Hz, 4H)541(M+H) +< Example 21 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.22-7.16 (m, 2H), 700-6.97 (m, 1H), 4.06 (br, 2H), 3.99 - 3.83 (m, 4H), 3.61 - 3.44 (m, 5H), 3.41- 3.34 (m, 1H), 3.27-3.15 (m, 1H), 3.18 - 3.08 (m, 1H), 2.88-2.76 (m, 1H), 2.22-2.16 (m, 1H), 1.90 - 1.56 (m, 7H), 1.31 (d, J = 6.7 Hz, 2H), 1.23 (t, J = 7.0 Hz, 2H), 1.20 - 1.10 (m, 6H).525(M+H) +< and Example 22 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.27-8.25 (m, 1H), 7.78-7.74 (m, 1H), 7.21-7.16 (m, 2H), 7.00-6.96 (m, 1H), 4.06 (br, 2H), 4.00 - 3.82 (m, 3H), 3.64 - 3.46 (m, 5H), 3.29-3.34 (m, 1H), 2.95-2.84 (m, 2H), 2.18-2.13 (m, 1H), 1.99-1.89 (m, 3H), 1.81 (br, 4H), 1.44 (s, 3H), 1.34 - 1.28 (m, 2H), 1.24 (t, J = 7.0 Hz, 2H), 1.20 - 1.07 (m, 6H)539(M+H) +< and Example 23 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.24 - 7.14 (m, 2H), 7.01-6.97 (m, 1H), 4.28-4.16 (m, 1H), 4.10-4.03 (m, 2H), 4.00-3.95 (m, 2H), 3.91 - 3.88 (m, 1H), 3.59-3.46 (m, 5H), 3.42-3.33 (m, 1H), 3.13-3.07 (m, 1H), 2.44-2.25 (m, 1H), 1.90-1.75 (m, 5H), 1.47 - 1.28 (m, 4H), 1.23 (t, J = 6.9 Hz, 3H), 1.19 - 1.03 (m, 6H)587(M+H) +< andIntermediate 23 Example 24 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26-8.24 (m, 1H), 7.77-7.73 (m, 1H), 7.20-7.16 (m, 2H), 7.03-6.97 (m, 1H), 4.25-4.14 (m, 1H), 4.06 (s, 2H), 4.10-3.98 (m, 2H), 3.90-3.86 (m, 1H), 3.58-3.51 (m, 5H), 3.40-3.35 (m, 1H), 3.27-3.23 (m, 1H), 3.13-3.07 (m, 1H), 2.44-2.25 (m, 1H), 1.86-1.74 (m, 5H), 1.45-1.30 (m, 4H), 1.25-1.22 (t, J = 6.9 Hz, 3H), 1.20 - 1.07 (m, 6H)587(M+H) +< andIntermediate 23 Example 25 Intermediate 1 1< H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 7.81 (s, 1H), 7.04-7.00 (m, 2H), 6.77-6.71 (m, 1H), 4.50-4.38 (m, 1H), 4.10 - 3.80 (m, 5H), 3.63 - 3.18 (m, 9H), 2.72-2.68 (m, 1H), 2.30-2.26 (m, 1H), 1.85-1.73 (m, 6H), 1.29 - 1.12 (m, 10H)557(M+H) +< andIntermediate 27 Example 26 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.25 - 7.14 (m, 2H), 7.05-6.97 (m, 1H), 4.14 - 3.94 (m, 5H), 3.95-3.88 (m, 2H), 3.78-3.75 (m, 1H), 3.64-3.57 (m, 2H), 3.52-3.42 (m, 4H), 3.40 - 3.32 (m, 2H), 3.27-3.25 (m, 1H), 2.95-2.93 (m, 2H), 1.84-1.76 (m, 4H), 1.34 - 1.14 (m, 9H)541(M+H) +< and Example 28 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26 (d, J = 6.4 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.22 - 7.17 (m, 2H), 6.99 - 6.97 (m, 1H), 5.03 (s, 1H), 4.25-4.21 (m, 1H), 4.04 - 3.94 (m, 4H), 3.92 - 3.88 (m, 1H), 3.78 (s, 1H), 3.76 (s, 3H), 3.62 (s, 1H), 3.55 - 3.50 (m, 1H), 3.38-3.37 (m, 2H), 3.28 - 3.12 (m, 2H),2.03-1.93 (m, 4H), 1.32 - 1.09 (m, 9H)577(M+H) +< andIntermediate 18 Example 29 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.25 (d, J = 6.3 Hz, 1H), 7.78-7.74 (m, 1H), 7.21 - 7.16 (m, 2H), 6.99- 6.96 (m, 1H), 4.03 (s, 2H), 3.98 - 3.85 (m, 3H), 3.59 - 3.48 (m, 4H), 3.39 - 3.33 (m, 1H), 2.90 - 2.84 (m, 1H), 2.82 - 2.75 (m, 1H), 2.15 - 2.10 (m, 2H), 1.94 - 1.84 (m, 2H), 1.80 (s, 5H), 1.39 (s, 3H), 1.32 - 1.08 (m, 9H)539(M+H) +< and Example 30 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26-8.24 (m, 1H), 7.77-7.73 (m, 1H), 7.22 - 7.15 (m, 2H), 7.04 - 6.95 (m, 1H), 4.33 - 4.27 (m, 1H), 4.16 - 3.94 (m, 4H), 3.93 - 3.83 (m, 1H), 3.62 - 3.47 (m, 3H), 3.43-3.93 (m, 2H), 2.75-2.74 (m, 1H), 2.67-2.59 (m, 1H), 1.80-1.75 (m, 5H), 1.52-1.48 (m, 1H), 1.33 - 1.14 (m, 9H), 1.11-1.08 (m, 1H), 0.65-0.63 (m, 1H), 0.41-0.37 (m, 1H)537(M+H) +< and Example 31 Intermediate 5 and 1< H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 7.80 -7.76 (m, 1H), 7.22-7.18 (m, 1H), 5.57-5.39 (m, 1H), 4.94 - 4.88 (m, 1H), 4.19 k-3.98 (m, 4H), 3.95-3.84 (m, 1H), 3.74 - 3.46 (m, 7H), 3.43 -3.33 (m, 1H), 2.95 - 2.82 (m, 1H), 2.29--2.12 (m, 1H), 1.94 - 1.79 (m, 4H), 1.33 - 1.11 (m, 9H).545(M+H) +< Example 32 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26-8.24 (m, 1H), 7.77-7.73 (m, 1H), 7.21-7.16 (m, 2H), 6.99-6.98 (m, 1H), 4.05-3.88 (m, 5H), 3.73 - 3.67 (m, 1H), 3.57-3.45 (m, 5H), 3.39-3.35 (m, 1H), 2.99-2.95 (m, 1H), 2.24-2.20 (m, 1H), 1.82-1.75 (m, 4H), 1.70-1.63 (m, 1H), 1.49 - 1.44 (m, 1H), 1.33 - 1.13 (m, 9H), 1.11-1.08 (m, 1H), 0.49 (t, J = 5.3 Hz, 2H)537(M+H) +< and Example 33 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 8.29 (d, J = 8.4 Hz, 1H), 7.75-7.68 (m, 1H), 7.32 - 7.12 (m, 7H), 7.11-7.04 (m, 1H), 5.38 (s, 1H), 4.33 (d, J = 14.3 Hz, 1H), 4.09 - 4.05 (m, 2H), 4.00 - 3.80 (m, 4H), 3.77- 3.66 (m, 4H), 1.86 - 1.65 (m, 4H), 1.27-1.19 (m, 3H), 1.12 - 1.09 (m, 5H), 1.06 - 1.04 (m, 2H)573(M+H) +< and Example 34 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.50 (br, 1H), 7.82-7.73 (m, 1H), 7.31 - 7.26 (m, 3H), 4.45-4.42 (m, 1H), 3.91-3.84 (m, 1H), 3.77- 3.58 (m, 5H), 3.49-3.46 (s, 2H), 3.43-3.40 (m, 2H), 2.03-1.99 (m, 2H), 1.89-1.88 (m, 4H), 1.38-1.36 (m, 1H), 1.33-1.31 (m, 2H), 1.25-1.04 (m, 9H), 1.03-0.99 (m, 1H), 0.58 (m 1H).537(M+H) +< and Example 36 (reference) Intermediate 6 1< H NMR (400 MHz, MeOD) δ 8.29-8.29 (m, 1H), 7.82-7.79 (m, 1H), 7.46-7.42 (m, 1H), 7.40 - 7.34 (m, 1H), 7.27-7.23 (m, 1H), 6.95 - 6.88 (m, 1H), 5.40-5.27 (m, 1H), 4.69 - 4.41 (m, 3H), 4.12-4.07 (m, 2H), 4.00 - 3.86 (m, 3H), 3.63-3.50 (m, 6H), 2.69 - 2.52 (m, 1H), 2.07-2.01 (m, 1H), 1.97-1.81 (m, 5H), 1.26 (t, J = 6.9 Hz, 3H), 1.17 (d, J = 6.4 Hz, 5H), 1.08 (t, J = 7.0 Hz, 1H)525(M+H) +< and Example 37 Intermediate 7 1< H NMR (400 MHz, MeOD) δ 8.28-8.25 (m, 1H), 7.82 - 7.73 (m, 1H), 7.23 - 7.14 (m, 2H), 7.03 - 6.96 (m, 1H), 5.35- 5.22 (m, 1H), 4.30 - 4.12 (m, 4H), 4.10 - 4.03 (m, 1H), 3.91 - 3.83 (m, 1H), 3.78 - 3.56 (m, 3H), 3.55 - 3.45 (m, 2H), 3.25 - 3.19 (m, 1H), 3.14-3.05 (m, 1H), 2.39-2.37 (m, 1H), 2.28-2.20 (m, 1H), 2.17-2.12 (m, 1H), 2.04-1.92 (m, 1H), 1.34 - 1.14 (m, 9H), 1.11-1.08 (m, 1H)529(M+H) +< and Example 38 Intermediate 8 1< H NMR (400 MHz, MeOD) δ 8.27-8.25 (m, 1H), 7.80-7.75 (m, 1H), 7.21-7.17 (m, 2H), 6.97-6.96 (m, 1H), 5.33-5.19 (m, 1H), 4.51 - 4.44 (m, 4H), 4.41-4.37 (m, 2H), 4.22 - 4.10 (m, 2H), 3.90-3.86 (m, 2H), 3.54 - 3.49 (m, 1H), 3.40-3.38 (m, 1H), 3.22 - 3.02 (m, 2H), 2.35 - 2.24 (m, 1H), 2.00-1.90 (m, 1H), 1.32 - 1.09 (m, 9H)515(M+H) +< and Example 40 Intermediate 1 1HNMR (400 MHz, DMSO) δ8.29-8.27 (m, 1H), 7.76-7.69 (m, 1H), 7.31 - 7.24 (m, 2H), 7.10 - 7.00 (m, 1H), 4.32-4.31 (m, 1H), 3.97 (s, 2H), 3.90-3.88 (m, 2H), 3.76 - 3.73 (m, 1H), 3.25-3.19 (m, 5H), 2.98-2.92 (m, 2H), 2.59 (s, 2H), 2.13-2.04 (m, 1H), 1.77 (s, 1H), 1.69 (s, 3H), 1.54 (s, 1H), 1.19 (s, 2H), 1.12-1.09 (m, 5H), 1.05-1.03 (m, 2H), 1.01-0.97 (m, 1H), 0.77 (d, J = 7.0 Hz, 3H).539(M+H) +< and Example 41 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.27 - 8.26 (m, 1H), 7.79 - 7.75 (s, 1H), 7.21- 7.16 (m, 2H), 7.02-6.92 (m, 1H), 4.13-4.08 (m, 2H), 4.02-3.97 (m, 2H), 3.93 - 3.88 (m, 1H), 3.74-3.65 (m, 2H), 3.52-3.46 (m, 4H), 3.25-3.20 (m,, 2H), 3.09-2.99 (m, 1H), 2.30 - 2.21 (m, 1H), 2.03- 2.00 (m, 1H), 1.89-1.78 (m, 4H), 1.60-1.52 (m, 1H), 1.27-1.21 (m, 3H), 1.20-1.10 (m, 9H)539(M+H) +< and Example 42 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.28 - 8.27 (m, 1H), 7.82 - 7.74 (m, 1H), 7.39 - 7.31 (m, 1H), 7.23 - 7.13 (m, 2H), 7.05 - 6.93 (m, 1H), 5.36 (s, 1H), 4.50 - 4.47 (m, 1H), 4.32 - 4.24 (m, 1H), 4.11 - 3.87 (m, 6H), 3.85 - 3.79 (m, 2H), 3.66 - 3.62 (m, 1H), 3.55 - 3.45 (m, 1H), 3.44 - 3.33 (m, 2H), 2.01 - 1.75 (m, 4H), 1.39 - 1.07 (m, 12H), 0.65 - 0.61 (m, 2H), 0.29 - 0.35 (m, 2H).539(M+H) +< andIntermediate 19 Example 43 Intermediate 44 and 1< H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.39-7.35 (m, 2H), 7.07-7.05 (m, 1H), 5.35-5.21 (m, 1H), 4.59 - 4.54 (m, 1H), 4.27 - 4.22 (m, 1H), 3.85 (s, 4H), 3.53-3.48 (m, 4H), 3.28-3.24 (m, 1H), 3.16-3.07 (m, 1H), 2.45-2.36 (m, 1H), 1.99 - 1.70 (m, 5H), 1.44 (d, J = 6.6 Hz, 6H)539(M+H) +< Example 44 Intermediate 1 1< H NMR (400 MHz, DMSO) δ 8.29-8.27 (m, 1H), 7.76 - 7.69 (m, 1H), 7.37 - 7.25 (m, 8H), 7.10 - 7.03 (m, 1H), 5.39 (s, 1H), 5.26 (s, 2H), 4.22 - 4.19 (m, 1H), 3.99-3.84 (m, 5H), 3.77 - 3.65 (m, 3H), 3.55-3.45 (m, 3H), 1.88 - 1.61 (m, 4H), 1.23 - 0.99 (m, 10H)653(M+H) +< andIntermediate 20 Example 45 Intermediate 14 1< H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.79 (s, 1H), 7.25-7.21 (m, 2H), 7.00-6.97 (m, 1H), 6.35-6.06 (m, 1H), 5.35-5.22 (m, 1H), 4.58 (s, 1H), 4.30 - 4.22 (m, 1H), 4.10 - 3.92 (m, 5H), 3.85 - 3.65 (m, 2H), 3.57-3.51 (m, 4H), 3.16-3.09 (m, 1H), 2.49-2.38 (m, 1H), 1.88-1.78 (m, 4H), 1.35-1.34 (m, 1H), 1.17 (s, 6H)579(M+H) +< and Example 46 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.41 - 8.34 (m, 1H), 7.93 - 7.85 (m, 1H), 7.19 - 7.13 (m, 2H), 6.86 - 6.82 (m, 1H), 5.38 - 5.24 (m, 1H), 4.58 - 4.44 (m, 1H), 4.04 - 3.99 (m, 2H), 3.98-3.93 (m, 1H), 3.84 - 3.73 (m, 6H), 3.55 - 3.45 (m, 1H), 3.43 - 3.34 (m, 1H), 3.25 - 3.15 (m, 2H), 2.45 - 2.38 (m, 1H), 2.08 - 1.90 (m, 1H), 1.78 (br, 4H), 1.33 - 1.12 (m, 9H)543(M+H) +< and Example 47 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26 - 8.25 (m, 1H), 7.78 - 7.74 (m, 1H), 7.21 - 7.15 (m, 2H), 7.01 - 6.95 (m, 1H), 4.15 - 4.03 (m, 3H), 3.98--3.95 (m, 2H), 3.93 - 3.86 (m, 1H), 3.59 - 3.45 (m, 5H), 3.39 - 3.28 (d, J = 6.8 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.17 - 2.09 (m, 1H), 1.82 - 1.77 (m, 5H), 1.32 - 1.28 (m, 3H), 1.26 - 1.11 (m, 9H), 1.05 (d, J = 6.6 Hz, 6H)539(M+H) +< and Example 48 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.26 - 8.24 (m, 1H), 7.77 - 7.74 (m, 1H), 7.31 - 7.25 (m, 4H), 7.21 - 7.15 (m, 3H), 7.00 - 6.95 (m, 1H), 4.26 - 4.21 (m, 1H), 4.10 - 4.06 (m, 2H), 3.98 - 3.96 (m, 2H), 3.91 - 3.85 (m, 1H), 3.65 - 3.62 (m, 1H), 3.58 - 3.55 (m, 1H), 3.53 - 3.47 (m, 4H), 2.81 - 2.75 (m, 1H), 2.36-2.28(m, 1H), 2.20-2.14 (m, 1H), 1.84-1.79 (m, 4H), 1.30 (d, J = 6.6 Hz, 2H), 1.26 - 1.08 (m, 9H)601(M+H) +< and Example 49 Intermediate 31 and1H NMR (400 MHz, MeOD) δ 8.26-8.25 (m, 1H), 7.78-7.75 (m, 1H), 7.22-7.18 (m, 2H), 7.00-6.97 (m, 1H), 5.34-5.21 (m, 1H), 4.25 -4.22 (m, 1H), 4.11-3.98 (m, 3H), 3.93-3.88 (m, 1H), 3.78-3.76 (m, 1H), 3.67 - 3.66 (m, 1H), 3.56 - 3.53 (m, 5H), 3.47 - 3.45 (m, 1H), 3.36-3.34 (m, 1H), 3.24-3.23 (m, 1H), 3.15-3.06 (m, 1H), 2.47 - 2.35 (m, 1H), 1.87-1.83 (m, 4H), 1.33 - 1.28 (m, 3H), 1.19-1.13 (m, 4H).559(M+H) +< Example 50 Intermediate 32 and1HNMR (400 MHz, DMSO) δ 8.30-8.27 (m, 1H), 7.75-7.67 (m, 1H), 7.31-7.25 (m, 2H), 7.05-6.98 (m, 1H), 5.32-5.18 (m, 1H), 4.09- 4.05(m, 1H), 3.93 - 3.74 (m, 5H), 3.49-3.43(m, 6H), 3.13-2.87 (m, 4H), 2.19-1.66 (m, 7H), 1.40 - 1.19 (m, 3H), 1.10-1.03 (m, 5H)573(M+H) +< Example 51 Intermediate 10 1< H NMR (400 MHz, DMSO) δ 8.31-8.27 (m, 1H), 7.79-7.69 (m, 1H), 7.36-7.28 (m, 2H), 7.09-7.05 (m, 1H), 5.31-5.17 (m, 1H), 4.07 - 3.87 (m, 6H), 3.69 - 3.64 (m, 1H), 3.53-3.42 (m, 6H), 3.23 - 3.02 (m, 5H), 2.95 - 2.85 (m, 1H), 2.16 - 1.91 (m, 2H), 1.75- 1.65 (m, 4H), 1.24- 1.08 (m, 3H)557(M+H) +< and Example 52 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.30 (s, 1H), 7.78-7.74 (m, 1H), 7.25 - 7.16 (m, 2H), 7.07-7.01 (m, 1H), 4.42 - 4.31 (m, 2H), 4.14-4.12 (m, 2H), 4.03-4.01 (m, 2H), 3.981 - 3.85 (m, 1H), 3.63-3.49 (m, 5H), 3.41 - 3.32 (m, 2H), 3.29 - 3.23 (m, 1H), 2.88 - 2.79 (m, 1H), 1.87-1.81 (m, 4H), 1.32-1.08 (m, 9H)543(M+H) +< and Example 53 Intermediate 9 and 1< H NMR (400 MHz, MeOD) δ 8.30 - 8.23 (m, 1H), 7.84 - 7.71 (m, 1H), 7.26 - 7.14 (m, 2H), 7.04 - 6.94 (m, 1H), 5.37 - 5.19 (m, 1H), 4.68 - 4.46 (m, 1H), 4.26 - 4.21 (m, 1H), 4.18 - 3.88 (m, 5H), 3.81 - 3.42 (m, 9H), 3.26 - 3.21 (m, 1H), 3.15 - 3.05 (m, 1H), 2.48 - 2.34 (m, 1H), 1.92 - 1.73 (m, 5H), 1.39 - 1.22 (m, 3H)557(M+H) +< Example 54 Intermediate 1 1< H NMR (400 MHz, MeOD) δ 8.29 - 8.28 (m, 1H), 7.82 - 7.81 (m, 1H), 7.80 - 7.72 (m, 1H), 7.23 - 7.17 (m, 2H), 7.00 - 6.94 (m, 1H), 5.71 (s, 1H), 4.59 - 4.55 (m, 2H), 4.38 - 4.35 (m, 1H), 4.14 - 3.77 (m, 7H), 3.69 - 3.48 (m, 3H), 2.02 - 1.93 (m, 2H), 1.87 - 1.77 (m, 2H), 1.36 - 1.18 (m, 9H).563(M+H) +< andIntermediate 21 Example 58 Intermediate 45 and1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.81 (s, 1H), 7.62 (s, 1H), 7.36 - 7.30 (m, 1H), 7.26 - 7.22 (m, 1H), 7.07 - 7.02 (m, 1H), 5.38 - 5.18 (m, 1H), 4.41 - 4.32 (m, 1H), 4.27 - 4.19 (m, 1H), 3.92- 3.81 (m, 4H), 3.60 - 3.43 (m, 4H), 3.28 - 3.19 (m, 1H), 3.16 - 3.08 (m, 1H), 2.46 - 2.34 (m, 1H), 2.03 - 1.86 (m, 1H), 1.84 - 1.69 (m, 4H), 1.45 - 1.40 (m, 3H), 1.35 (d, J = 6.6 Hz, 3H)572(M+H) +< Example 59 Intermediate 12 1< H NMR (400 MHz, MeOD) δ 8.28 (s, 1H), 7.81 (s, 1H), 7.32 - 7.21 (m, 2H), 7.02 - 6.98 (m, 1H), 5.50 - 5.35 (m, 1H), 4.77 - 4.73 (m, 1H), 4.64 - 4.61 (m, 1H), 4.07 - 3.99 (m, 4H), 3.88 - 3.85 (m, 1H), 3.75 - 3.68 (m, 2H), 3.63 - 3.59 (m, 3H), 3.57 - 3.55 (m, 1H), 3.51 - 3.46 (m, 3H), 2.82 - 2.72 (m, 1H), 2.21 - 1.96 (m, 4H), 1.91 - 1.79 (m, 6H)569(M+H) +< and Example 27: Preparation of 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)ox y)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0387] Step 1:

[0388] To a solution of 2-(4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yloxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (Intermediate 1, 280 mg, 0.53 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (277 mg, 0.60 mmol) in DMF (5 mL) was added DIPEA (0.8 mL, 3.5 mmol) and HATU (266 mg, 0.70 mmol) at 0 °C. Then the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. NH 4 Cl solution, extracted with EtOAc (20 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 30%) to give the desired product tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (180 mg, yield: 80%) as a white solid. LCMS: m / z 641 (M+H) +< Step 2:

[0389] To a solution of tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (180 mg, 0.28 mmol) and DIPEA (72 mg,0.56 mmol) in DCM (10 mL) was added MsCl (0.10 mL,0.42 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with sat. NH 4 Cl solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE=0 ~ 20%) to give the desired product tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carbonyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (150 mg, yield: 80%) as a white solid. LCMS: m / z 719 (M+H) +< Step 3:

[0390] To a solution of tert-butyl (2S,4S)-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3. 5]nonane-7-carbonyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (150 mg, 0.21 mmol) in DMF (5 mL) was added NaCN (20 mg, 0.40 mmol) at 0°C. The mixture was stirred at 100°C for 10 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (EtOAc in PE=0 ~ 20%) to give the desired product tert-butyl (2S,4R)-4-cyano-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz aspiro[3.5]nonane-7-carbonyl)pyrrolidine-1-carboxylate (60 mg, yield: 45%) as a yellow solid. LCMS: m / z 650 (M+H) +< Step 4:

[0391] To a solution of tert-butyl (2S,4R)-4-cyano-2-(2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz aspiro[3.5]nonane-7-carbonyl)pyrrolidine-1-carboxylate (60 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1.0 mL) at 0 °C. The reaction mixture was stirred for 1 h at rt and concentrated under reduced pressure to give the crude product which was purified by Prep-HPLC to afford the desired product 2-((4-(7-((2S,4R)-4-cyanopyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)ox y)-N-ethyl-5-fluoro-N-isopropylbenzamide (20 mg, yield: 30%) as a white solid. 1< H NMR (400 MHz, MeOD) δ 8.26-8.25 (m, 1H), 7.78-7.74 (m, 1H), 7.21 - 7.15 (m, 2H), 7.00 - 6.96 (m, 1H), 4.20-4.16 (m, 1H), 4.06 - 3.87 (m, 5H), 3.58 - 3.46 (m, 5H), 3.39-3.36 (m, 1H), 3.27-3.26 (m, 1H), 3.15- 2.91 (m, 2H), 2.40 - 2.17 (m, 1H), 1.84-1.78 (m, 4H), 1.32 - 1.09 (m, 10H). LCMS: m / z 550 (M+H) +< .Example 39: Preparation of N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro [3.5] nonan-2-yl}-1,2,4-triazin-6-yl) oxy]-N-(propan-2-yl) benzamide

[0392] Step 1:

[0393] To a stirred solution of (2S,4R)-1-[(tert-butoxy) carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (381 mg, 1.63 mmol) and HATU (517 mg, 1.36 mmol) in DMF (15 mL) was added DIPEA (0.68 mL, 4.1 mmol). The reaction mixture was stirred at rt for 10 min before addition of 2- [(5-{2,7-diazaspiro [3.5] nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl) benzamide (583 mg, 1.36 mmol), the resulting mixture was stirred for another 1 h at rt. The reaction mixture was quenched with H 2 O (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by chromatography column on silica gel ( MeOH in DCM= 0 ~5%) to give the desired product tert-butyl (2S,4R)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazas piro[3.5]nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (650 mg, yield: 74.2%) as a white solid. LCMS: ESI m / z 644 (M+H) +< .Step 2:

[0394] To a solution of tert-butyl (2S,4R)-2-[2-(6-{2-[ethyl(propan-2-yl) carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro [3.5] nonane-7-carbonyl]-4-fluoropyrrolidine-1-carboxylate (500 mg, 0.78 mmol) in DCM (10 mL) was added TFA (5 mL) at rt. The reaction mixture was stirred for 1 h at rt. The resulting mixture was concentrated, the residue was purified with Prep-HPLC (0.1% formic acid in CH 3 CN) to afford desired product N-ethyl-5-fluoro-2-[(5-{7-[(2S,4R)-4-fluoropyrrolidine-2-carbonyl]-2,7-diazaspiro [3.5] nonan-2-yl}-1,2,4-triazin-6-yl) oxy]-N-(propan-2-yl) benzamide (315 mg, yield: 74.6%) as a white solid. 1< H NMR (400 MHz, MeOD) δ 8.59 (d, J = 6.6 Hz, 1H), 7.46-7.43 (m, 1H), 7.35 - 7.22 (m, 2H), 5.56-5.43 (m, 1H), 4.98 - 4.93 (m, 1H), 4.54 (s, 2H), 4.13 (s, 2H), 3.87-3.80 (m, 1H), 3.71-3.51 (m, 7H), 3.17 (m, 1H), 2.95-2.85 (m, 1H), 2.29-2.14 (m, 1H), 1.97 - 1.90 (m, 4H), 1.25 - 0.87 (m, 9H), LC / MS (ESI) m / z: 544(M+H) +< .

[0395] The following compounds were prepared from the appropriate intermediates or commercially available chemicals according to experimental procedure for Example 39: ExampleStructureStarting materials 1< H-NMR (400 MHz)LCMS (ESI) m / zExample 55 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.40 (m, 1H), 7.30 - 7.25 (m, 1H), 7.22 - 7.20 (m, 1H), 4.45 (br, 2H), 4.05 - 4.01 (m, 3H), 3.84 - 3.81 (m, 1H), 3.66 - 3.45 (m, 6H), 3.21 - 3.19 (m, 1H), 2.95 - 2.92 (m, 1H), 1.94 - 1.85 (m, 4H), 1.55 - 1.53 (m, 2H), 1.22 - 1.07 (m, 7H), 0.82 - 0.80 (m, 2H), 0.67 - 0.65 (m, 1H), 0.39 - 0.38 (m, 1H)538(M+H) +< and Example 56 Intermediate 35 1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.45-7.41 (m, 1H), 7.35-7.28 (m, 2H), 5.32-5.18 (m, 1H), 4.33 -4.31 (m, 2H), 4.09-4.08 (m, 2H), 3.94-3.89 (m, 3H), 3.57-3.55 (m, 4H), 2.96-2.87 (m, 2H), 1.76 - 1.70 (m, 6H), 1.41 (d, J = 5.9 Hz, 3H), 1.29 (d, J = 5.9 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H), 0.65 (d, J = 3.9 Hz, 3H)558(M+H) +< and Example 57 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.42 - 7.40 (m, 1H), 7.32 - 7.28 (m, 1H), 7.22 - 7.20 (m, 1H), 4.60 - 4.58 (m, 1H), 4.48 - 4.45 (m, 2H), 4.03 - 3.98 (m, 2H), 3.84 - 3.80 (m, 2H), 3.72 - 3.70 (m, 1H), 3.67 - 3.60 (m, 3H), 3.52 - 3.48 (m, 3H), 3.02 - 2.95 (m, 1H), 2.27 - 2.23 (m, 1H), 1.99 - 1.85 (m, 4H), 1.56 - 1.52 (m, 1H), 1.23 - 1.15 (m, 9H), 0.86 - 0.80 (m, 3H)540(M+H) +< and Example 60 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43 - 7.40 (m, 1H), 7.31 - 7.29 (m, 1H), 7.23 - 7.20 (m, 1H), 4.70 - 4.67 (m, 1H), 4.60 - 4.56 (m, 1H), 4.50 - 4.40 (m, 2H), 4.03 - 3.98 (m, 2H), 3.84 - 3.80 (m, 1H), 3.67 - 3.61 (m, 1H), 3.56 - 3.50 (m, 4H), 2.83 - 2.77 (m, 1H), 2.37 - 2.32 (m, 1H), 2.13 - 2.09 (m, 2H), 1.94 - 1.87 (m, 4H), 1.33 - 1.29 (m, 2H), 1.21 - 1.12 (m, 9H), 0.81 - 0.79 (m, 2H)540(M+H) +< and Example 61 Intermediate 34 1< H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 7.26-7..25 (m, 1H), 7.17 - 7.11 (m, 1H), 7.02-6.99 (m, 1H), 4.51-4.27 (m, 2H), 4.06 - 3.82 (m, 4H), 3.54-3.40 (m, 4H), 3.14-3.10 (m, 2H), 2.97 - 2.91 (m, 1H), 2.60-2.53 (m, 1H), 2.47 - 2.33 (m, 3H), 1.89-1.81 (m, 5H), 1.58-1.49 (m, 2H), 1.16 - 0.78 (m, 9H)565(M+H) +< andIntermediate 28 Example 62 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.54-7.50 (m, 1H), 7.37 - 7.28 (m, 1H), 7.32 - 7.28 (m, 1H), 5.35-5.22 (m, 1H), 4.28-4.16 (m, 2H), 3.89 (br, 3H), 3.60 - 3.48 (m, 5H), 3.19-3.07 (m, 1H), 2.48-2.34 (m, 1H), 2.02 - 1.74 (m, 6H), 1.10-1.02 (m, 3H), 0.82-0.72 (m, 1H).549(M+H) +< and Example 63 Intermediate 34 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.29-7.28 (m, 1H), 7.17 - 7.12 (m, 1H), 7.06 - 6.98 (m, 1H), 5.05-5.03 (m, 1H), 4.57 - 4.30 (m, 2H), 3.96-3.85 (m, 4H), 3.54 - 3.13 (m, 7H), 2.83-2.81 (m, 1H), 2.38-2.36 (m, 1H), 1.90-1.81 (m, 5H), 1.19 - 0.76 (m, 13H)540(M+H) +< and Example 64 Intermediate 35 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.42-7.38 (m, 1H), 7.28-7.23 (m, 1H), 7.18 -7.16(m, 1H), 4.51- 4.43 (m, 2H), 4.04 - 3.97 (m, 2H), 3.79 - 3.74 (m, 1H), 3.67-3.48 (m, 6H), 3.17-3.13 (m, 1H), 2.97-2.91 (m, 1H), 2.27-2.20 (m, 1H), 1.96 - 1.84 (m, 5H), 1.54-1.48 ( m, 4H), 1.40-1.38 (m, 3H), 1.15 (t, J = 5.9 Hz, 6H), 0.75 (d, J = 6.4 Hz, 3H)554(M+H) +< and Example 65 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.39 (m, 1H), 7.30 - 7.26 (m, 1H), 7.22 - 7.20 (m, 1H), 4.48 - 4.41 (m, 2H), 4.09 - 3.97 (m, 3H), 3.86 - 3.8 (m, 2H), 3.78 - 3.66 (m, 1H), 3.52 - 3.44 (m, 3H), 3.31 - 3.26 (m, 2H), 2.91 - 2.89 (m, 1H), 1.94 - 1.85 (m, 4H), 1.75 - 1.71 (m, 2H), 1.25 - 1.14 (m, 9H), 1.09 - 1.05 (m, 1H), 0.95 - 0.93 (m, 3H), 0.81 - 0.78 (m, 2H)554(M+H) +< and Example 66 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.25 (m, 1H), 7.22 - 7.20 (m, 1H), 4.48- 4.42 (m, 2H), 4.04 - 3.92 (m, 4H), 3.85 - 3.79 (m, 1H), 3.76 - 3.65 (m, 1H), 3.52 - 3.44 (m, 3H), 3.26 - 3.21 (m, 1H), 3.13 - 3.05 (m, 1H), 3.01 - 2.95 (m, 1H), 1.95 - 1.76 (m, 6H), 1.27 - 1.13 (m, 9H), 1.09 - 1.05 (m, 1H), 0.97 - 0.95 (m, 3H), 0.81 - 0.78 (m, 2H)554(M+H) +< and Example 67 Intermediate 43 1H NMR (400 MHz, MeOD) δ 8.33-8.29 (m, 1H), 7.53 - 7.51 (m, 2H), 7.31 - 7.25 (m, 3H), 7.21 - 7.17 (m, 1H), 5.48 - 5.35 (m, 1H), 4.69 - 4.65 (m, 1H), 4.01 - 3.95 (m, 1H), 3.87 - 3.85 (m, 2H), 3.50 - 3.43 (m, 7H), 2.77 - 2.70 (m, 1H), 2.18 - 2.09 (m, 1H), 1.75 - 1.66 (m, 5H), 0.93 - 0.86 (m, 1H), 0.70 - 0.61 (m, 3H)572(M+H)+and Example 68 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43-7.40 (m, 1H), 7.32 - 7.21 (m, 2H), 4.45-4.43 (m, 3H), 4.05-4.02 (m, 2H), 3.85 - 3.72 (m, 3H), 3.56-3.52 (m, 4H), 3.24-3.21 (m, 2H), 1.98-1.85 (m, 5H), 1.76-1.74 (m, 1H), 1.22 - 1.14 (m, 13H), 0.81-0.78 (m, 2H).566(M+H) +< and Example 69 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.45 (s, 2H), 7.56-7.53 (m, 1H), 7.38 - 7.31 (m, 2H), 4.69 (d, J = 7.4 Hz, 1H), 4.26-4.23 (m, 1H), 4.00-3.97 (m, 3H), 3.76-3.73 (m, 1H), 3.57 - 3.44 (m, 4H), 3.34-3.33 (m, 1H), 2.88 (s, 1H), 2.37-2.32 (m, 1H), 1.86 - 1.82 (m, 6H), 1.11 - 0.95 (m, 6H), 0.83-0.80 (s, 1H)545(M+H)+and Example 70 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.42 - 7.40 (m, 1H), 7.31 - 7.20 (m, 2H), 4.58 (s, 4H), 4.47-4.45 (s, 2H), 4.02-4.00 (m, 2H), 3.84 - 3.79 (m, 1H), 3.57-3.48 (m, 4H), 3.37-3.35 (m, 1H), 2.20-2.18 (m, 1H), 2.06 - 2.01 (m, 1H), 1.96 - 1.84 (m, 4H), 1.76 - 1.62 (m, 2H), 1.46 - 1.41 (m, 1H), 1.22 - 1.13 (m, 6H), 1.09 - 1.00 (m, 4H), 0.81-0.78 (m, 2H)554(M+H) +< andIntermediate 37 Example 71 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.45 - 7.29 (m, 1H), 7.32 - 7.20 (m, 2H), 4.58 (s, 4H), 4.46 - 4.41 (m, 2H), 4.03-4.00 (d, J = 14.4 Hz, 2H), 3.86 - 3.80 (m, 1H), 3.59 - 3.45 (m, 4H), 3.40 - 3.35 (m, 1H), 2.28- 2.24 (m, 1H), 2.15-2.10 (m, 1H), 1.7-1.93 (m, 2H), 1.90 - 1.83 (m, 3H), 1.75 - 1.67 (m, 1H), 1.54 - 1.46 (m, 1H), 1.22 - 1.12 (m, 6H), 1.09 - 1.01 (m, 4H), 0.84 - 0.76 (m, 2H)554(M+H) +< andIntermediate 37Example 72 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.54-7.50 (m, 1H), 7.37 - 7.28 (m, 2H), 4.17-4.09 (m, 2H), 3.89 (s, 3H), 3.62 - 3.48 (m, 4H), 2.38 (t, J = 8.6 Hz, 1H), 2.15 - 2.10 (m, 1H), 1.92-1.88 (m, 1H), 1.85-1.76 (m, 7H), 1.10 - 1.01 (m, 6H), 0.77 (s, 1H)545 (M+H)+and Example 73 Intermediate 35 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.42-7.38(m, 1H), 7.28-7.23 (m, 1H), 7.18-7.16 (m, 1H), 4.52-4.41 (m, 2H), 4.10 - 3.98 (m, 3H), 3.77-3.74(m, 1H), 3.56 - 3.51 (m, 5H), 3.28 - 3.25 (m, 1H), 2.40 - 2.35 (m, 1H), 2.12 -2.10 (m, 1H), 1.94-1.83 (m, 6H), 1.51 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.4 Hz, 3H)554(M+H) +< and Example 74 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.20 (m, 2H), 4.45 (s, 2H), 4.00-3.98 (m, 3H), 3.85-3.79 (m, 1H), 3.68-3.48 (m, 5H), 3.44-3.40 (m, 1H), 3.19 - 3.16 (m, 1H), 2.70-2.63 (m, 3H), 2.01-1.79 (m, 7H), 1.68-1.64 (m, 2H), 1.49-1.47 (m, 1H), 1.28 - 1.05 (m, 7H), 0.81 (d, J = 4.7 Hz, 2H)566(M+H) +< and Example 75 Intermediate 36 1< H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.59 (s, 1H), 7.58 - 7.54 (m, 1H), 7.44 - 7.39 (m, 1H), 7.27 - 7.24 (m, 1H), 5.45 - 5.33 (m, 1H), 4.63 - 4.58 (m, 1H), 4.28 - 4.21 (m, 1H), 4.16 - 4.12 (m, 2H), 3.96 - 3.94 (m, 2H), 3.72 - 3.67 (m, 1H), 3.57 - 3.45 (m, 4H), 3.39 - 3.36 (m, 1H), 2.72 - 2.63 (m, 1H), 2.15 - 2.03 (m, 1H), 1.92 - 1.81 (m, 4H), 1.38 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H)573(M+H) +< and Example 76 Intermediate 35 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.42 - 7.39 (m, 1H), 7.29 - 7.23 (m, 1H), 7.19 - 7.16 (m, 1H), 4.53 - 4.45 (m, 3H), 4.05 - 3.99 (m, 2H), 3.81 - 3.66 (m, 3H), 3.58 - 3.48 (m, 3H), 3.42 - 3.37 (m, 1H), 3.18 - 3.15 (m, 1H), 2.80 - 2.79 (m, 1H), 2.33 - 2.25 (m, 1H), 1.92 - 1.86 (m, 4H), 1.78 - 1.74 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 5.6 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 0.95 - 0.91 (m, 3H), 0.75 (d, J = 6.4 Hz, 3H)554(M+H) +< and Example 77 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.89 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.54 - 7.50 (m, 1H), 7.37 - 7.28 (m, 2H), 4.19 - 4.15 (m, 1H), 3.91 - 3.88 (m, 3H), 3.70 - 3.62 (m, 3H), 3.57-3.53 (m, 1H), 3.48 - 3.45 (m, 1H), 3.20 - 3.12 (m, 1H), 3.00 - 2.94 (m, 1H), 2.27 - 2.21(m, 1H), 2.01 - 1.94 (m, 1H), 1.86 - 1.77 (m, 5H), 1.57 - 1.49 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.10 - 1.02 (m, 3H), 0.80 - 0.76 (m, 1H)545(M+H)+and Example 78 Intermediate 43 1H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 7.54-7.49 (m, 2H), 7.31 - 7.25 (m, 3H), 7.20 - 7.17 (m, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.92 (m, 1H), 3.89 - 3.84 (m, 2H), 3.69 - 3.54 (m, 3H), 3.52 - 3.42 (m, 2H), 3.24 - 3.16 (m, 1H), 2.95 - 2.91 (m, 1H), 1.84 - 1.80 (m, 2H), 1.76 - 1.70 (m, 2H), 1.68 - 1.64 (m, 1H), 1.56 - 1.52 (m, 2H), 0.94 - 0.85 (m, 1H), 0.72 - 0.61 (m, 4H), 0.44 - 0.37 (m, 1H)566(M+H)+and Example 79 Intermediate 43 1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 7.54 - 7.52 (m, 2H), 7.31 - 7.25 (m, 3H), 7.21 - 7.17 (m, 1H), 4.58 (, 1H), 4.00 - 3.95 (m, 1H), 3.88 - 3.85 (m, 2H), 3.78 - 3.7 (m, 2H), 3.60 - 3.53 (m, 2H), 3.43 - 3.39 (m, 1H), 3.20 - 3.15 (m, 1H), 3.05 - 2.99 (m, 1H), 2.28 - 2.21 (m, 1H), 2.03 - 1.93 (m, 1H), 1.83 - 1.70 (m, 4H), 1.68 - 1.63 (m, 1H), 1.59 - 1.52 (m, 1H), 1.22 - 1.14 (m, 3H), 0.92 - 0.88 (m, 1H), 0.70 - 0.60 (m, 3H)568(M+H)+and Example 80 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.54 - 7.51 (m, 1H), 7.37 - 7.29 (m, 1H), 7.32 - 7.29 (m, 1H), 4.69 (s, 1H), 3.92-3.90 (m, 3H), 3.65 - 3.47 (m, 6H), 3.40-3.37 (m, 1H), 1.89 - 1.81 (m, 7H), 1.09 - 1.03 (m, 4H), 0.78-0.75 (m, 1H), 0.57-0.55 (m, 1H)543(M+H)+and Example 81 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.54-7.50 (m, 1H), 7.37 - 7.33 (m, 1H), 7.32 - 7.28 (m, 1H), 4.19-4.15 (m, 1H), 3.90-3.87 (m, 4H), 3.66 - 3.47 (m, 4H), 3.36 - 3.33 (m, 1H), 2.89-2.85 (m, 1H), 1.85 - 1.78 (m, 5H), 1.55-1.52 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.14-1.08 (m, 9H), 0.79-0.75 (m, 1H)571(M+H) +< and Example 82 Intermediate 42 1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.54 - 7.50 (m, 1H), 7.37 - 7.33 (m, 1H), 7.32 - 7.29 (m, 1H), 4.19-4.15 (m, 1H), 3.90 (br, 3H), 3.82 - 3.79 (m, 1H), 3.60 - 3.47 (m, 4H), 3.38-3.34 (m, 1H), 2.38 - 2.65 (m, 1H), 2.59 - 2.54 (m, 2H), 1.93-1.91 (m, 1H), 1.84 - 1.77 (m, 7H), 1.67 - 1.60 (m, 2H), 1.49 - 1.44 (m, 1H), 1.13 - 1.01 (m, 3H), 0.80-0.76 (s, 1H).571(M+H) +< and Example 83 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.39 (m, 1H), 7.31 - 7.25 (m, 1H), 7.22 - 7.20 (m, 1H), 5.12-4.96 (m, 1H), 4.47-4.42 (m, 2H), 4.02 - 3.98 (m, 2H), 3.91 (d, J = 9.8 Hz, 1H), 3.84 - 3.79 (m, 1H), 3.74-3.70 (m, 1H), 3.61-3.48 (m, 3H), 3.44 - 3.34 (m, 1H), 3.18 - 3.06 (m, 3H), 2.35-2.37 (m, 1H), 1.93 - 1.85 (m, 4H), 1.22 - 1.05 (m, 10H), 0.82 - 0.80 (m, 2H)544(M+H) +< andIntermediate 38Example 84 Intermediate 34 1< H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 7.28 (d, J = 4.6 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.05-6.99 (m, 1H), 4.50 - 4.29 (m, 3H), 3.95-3.79 (m, 5H), 3.62-3.51 (m, 5H), 3.33 (s, 3H), 3.21-3.16 (m, 2H), 3.01 - 2.93 (m, 1H), 1.95 - 1.91 (m, 2H), 1.92-1.84 (m, 5H), 1.15-1.03 (m, 7H), 0.80-0.76 (s, 2H)556(M+H) +< and Example 85 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.44-7.41 (m, 1H), 7.33-7.27 (m, 6H), 5.43 (s, 1H), 4.52 - 4.43 (m, 3H), 4.17-4.14 (m, 1H), 4.09-4.00 (m, 4H), 3.86-3.80 (m, 2H), 3.52-3.48 (m, 1H), 2.05-1.91 (m, 5H), 1.30-1.28 (m, 1H), 1.22 - 1.14 (m, 6H), 1.08 (t, J = 7.0 Hz, 1H), 0.82 (d, J = 5.6 Hz, 2H)574(M+H) +< and Example 86 Intermediate 34 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.39 (m, 1H), 7.31 - 7.20 (m, 2H), 5.25-5.11 (m, 1H), 4.46-4.42 (m, 2H), 4.02 - 3.90 (m, 3H), 3.85 - 3.79 (m, 1H), 3.71 - 3.48 (m, 5H), 3.23 - 3.09 (m, 3H), 2.30 - 2.21 (m, 1H), 1.91-1.86 (m, 4H), 1.61 - 1.47 (m, 2H), 1.22 - 1.13 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 1.03 - 1.00 (m, 3H), 0.81 - 0.78 (m, 2H)572(M+H) +< andIntermediate 39 Example 87 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43-7.38 (m, 1H), 7.12 - 7.20 (m, 2H), 4.68-4.64 (m, 1H), 4.46-4.44 (m, 2H), 4.03-4.01 (m, 2H), 3.84 - 3.80 (m, 1H), 3.71-3.69 (m, 1H), 3.49-3.49 (m, 5H), 3.16-3.12 (m, 1H), 2.93 - 2.88 (m, 1H), 2.70 - 2.67 (m, 1H), 2.50-2.48 (m, 1H), 1.92-1.88 (m, 4H), 1.54-1.45 (m, 1H), 1.21 - 1.09 (m, 11H), 0.81-0.79 (m, 2H)540(M+H) +< and Example 88 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.44 - 7.38 (m, 1H), 7.31 - 7.25 (m, 1H), 7.24 - 7.18 (m, 1H), 4.58 - 4.55 (m, 2H), 4.52 - 4.38 (m, 3H), 4.06 - 4.00 (m, 3H), 3.84 - 3.80 (m, 1H), 3.65 - 3.48 (m, 4H), 3.23 - 3.19 (m, 1H), 2.97 - 2.90 (m, 1H), 2.66 - 2.62 (m, 1H), 1.98 - 1.83 (m, 5H), 1.69 - 1.63 (m, 1H), 1.29 - 1.27 (m, 1H), 1.22 - 1.13 (m, 6H), 1.09 - 1.04 (m, 1H), 0.14 - 0.78 (m, 2H)558(M+H) +< andintermediate 46 Example 89 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43 - 7.38 (m, 1H), 7.31 - 7.25 (m, 1H), 7.23 - 7.20 (m, 1H), 4.61 - 4.55 (m, 2H), 4.52 - 4.45 (m, 3H), 4.27 - 4.22 (m, 1H), 4.01 - 3.98 (m, 2H), 3.85-3.80 (m, 1H), 3.67 - 3.48 (m, 4H), 3.23 - 3.18 (m, 1H), 3.13-3.08 (m, 1H), 2.69 - 2.65 (m, 1H), 2.06-2.02 (m, 1H), 1.93 - 1.87 (m, 4H), 1.79 - 1.70 (m, 1H), 1.28 - 1.27 (m, 1H), 1.22 - 1.20 (m, 2H), 1.17-1.13 (m, 4H), 1.09 - 1.04 (m, 1H), 0.81 - 0.78 (m, 2H)558(M+H) +< andIntermediate 46 Example 90 Intermediate 47 1< H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.71 - 7.52 (m, 3H), 7.34 - 7.25 (m, 2H), 4.06 - 3.97 (m, 2H), 3.90 - 3.85 (m, 2H), 3.68 - 3.43 (m, 6H), 2.79 - 2.59 (m, 3H), 2.07- 1.94 (m, 1H), 1.80-1.66 (m, 9H), 1.50-1.42 (m, 1H), 0.99-0.92 (m, 3H), 0.72-0.52 (m, 1H)595(M+H) +< and Example 91 Intermediate 48 1< H NMR (400 MHz, MeOD) δ 7.45 - 7.39 (m, 1H), 7.31 - 7.20 (m, 2H), 4.48 (s, 2H), 4.05 (s, 3H), 3.85 - 3.78 (m, 1H), 3.64 - 3.48 (m, 5H), 3.21 - 3.13 (m, 2H), 2.93 (d, J = 10.4 Hz, 1H), 1.94 - 1.93 (m, 2H), 1.86 - 1.84 (m, 2H), 1.56 - 1.52 (m, 2H), 1.24 - 1.07 (m, 7H), 0.88 (s, 2H), 0.67 - 0.63 (m, 1H), 0.39-0.37 (m, 1H).573(M+H) +< and Example 92 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 7.44-7.29 (m 1H), 7.31 - 7.20 (m, 2H), 4.48-4.46 (m, 3H), 4.04-4.00 (m, 2H), 3.85-3.80 (m, 1H), 3.59 - 3.50 (m, 5H), 3.05-3.00 (m, 1H), 2.42 (s, 2H), 1.95 - 1.89 (m, 4H), 1.420- 1.35 (m, 1H), 1.22 - 1.04 (m, 14H), 0.84-0.80 (s, 2H)554(M+H) +< andIntermediate 49 Example 93 Intermediate 34 1< H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.20 (m, 2H), 4.48 - 4.40 (m, 2H), 4.19-4.177 (m, 1H), 4.02-3.99 (m, 2H), 3.84-3.79 (m, 2H), 3.51-3.45 (m, 5H), 2.84-2.80 (m, 1H), 2.35-2.29 (m, 2H), 1.95-1.87 (m, 4H), 1.21 - 1.00 (m, 14H), 0.80 (d, J = 5.0 Hz, 2H)554(M+H) +< andIntermediate 49 Example 94 Intermediate 47 1< H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.68 - 7.55 (m, 3H), 7.36 - 7.25 (m, 2H), 4.38 - 4.35 (m, 1H), 4.02 - 3.90 (m, 3H), 3.61 - 3.42 (m, 6H), 3.18 - 3.16 (m, 1H), 1.83 - 1.72 (m, 7H), 1.33 - 1.28 (m, 1H), 0.99-0.85 (m, 4H), 0.49-0.45 (m, 1H)567(M+H) +< and Example 95 Intermediate 47 1< H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 7.68 - 7.53 (m, 3H), 7.37 - 7.27 (m, 2H), 4.42 (s, 1H), 4.06 - 4.04 (m, 1H), 3.95 - 3.90 (m, 3H), 3.76-3.71 (m, 1H), 3.64-3.42 (m, 4H), 3.24 - 3.21 (m, 1H), 1.94 - 1.74 (m, 7H), 1.20 - 1.14 (m, 6H), 1.03 - 0.90 (m, 3H), 0.71-0.47 (m, 1H).595(M+H) +< and Example 96 Intermediate 43 1< H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.55-7.50 (m, 2H), 7.31 - 7.25 (m, 3H), 7.22-7.19 (m, 1H), 5.49 (s, 1H), 4.54-4.51 (m, 1H), 4.13-4.07 (m, 1H), 4.03-3.94 (m, 1H), 3.89-3.86 (m, 2H), 3.72 - 3.54 (m, 4H), 3.50-3.39 (m, 7H), 2.24-2.18 (m, 1H), 1.91-1.82 (m, 5H), 1.69-1.61 (m, 1H), 0.94-0.85 (m, 1H), 0.72 - 0.60 (m, 3H)584(M+H) +< and Example 97 Intermediate 43 1< H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 7.54-7.50 (m, 2H), 7.31 - 7.25 (m, 3H), 7.20-7.19 (m, 1H), 4.02 - 3.93 (m, 1H), 3.86 (s, 2H), 3.74 (d, J = 5.0 Hz, 1H), 3.67 - 3.55 (m, 2H), 3.43 - 3.40 (m, 2H), 3.35-3.33 (m, 1H), 2.68 - 2.61 (m, 1H), 2.56 - 2.43 (m, 2H), 1.81 - 1.59 (m, 11H), 0.91 - 0.87 (m, 3H), 0.71-0.64 (m, 2H)595(M+H) +< and Example 101 Intermediate 47 1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.71 - 7.52 (m, 3H), 7.36 - 7.25 (m, 2H), 4.64 (s, 1H), 4.14 (br, 1H), 4.05 - 3.87 (m, 3H), 3.82 - 3.67 (m, 1H), 3.64 - 3.32 (m, 9H), 2.31 - 2.20 (m, 1H), 2.03 - 1.73 (m, 6H), 1.05 - 0.85 (m, 3H), 0.70 - 0.55 (m, 1H).585(M+H) +< and Example 102 Intermediate 57 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43-7.38 (m, 1H), 7.31-7.20 (m, 2H), 4.50 - 4.32 (m, 3H), 4.11 - 3.91 (m, 2H), 3.85-3.78 (m, 1H), 3.72 - 3.45 (m, 5H), 3.01 - 2.94 (m, 1H), 2.91 - 2.80 (m, 1H), 2.78 - 2.67 (m, 1H), 2.11-2.01 (m, 1H), 1.97 - 1.79 (m, 6H), 1.77 - 1.65 (m, 2H), 1.59 - 1.50 (m, 1H), 1.21 - 1.10 (m, 6H), 1.06 (s, 1H), 0.80 (d, J = 5.4 Hz, 2H).568(M+H) +< and Example 103 Intermediate 60 1H NMR (400 MHz, MeOD) δ 8.38 (d, J = 4.2 Hz, 1H), 8.33 (s, 1H), 7.53 - 7.48 (m, 2H), 7.31 - 7.12 (m, 3H), 4.35 (d, J = 4.5 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.90 - 3.83 (m, 2H), 3.78 - 3.74 (m, 1H), 3.63 - 3.37 (m, 5H), 3.00 - 2.93 (m, 1H), 2.90 - 2.81 (m, 1H), 2.79 - 2.69 (m, 1H), 2.11 - 2.03 (m, 1H), 1.90 - 1.71 (m, 9H), 1.59 - 1.53 (m, 1H), 0.97 - 0.81 (m, 3H), 0.59 - 0.50 (m, 1H).570(M+H) +< and Example 104 Intermediate 58 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.37 (m, 1H) 7.34 - 7.23 (m, 2H), 4.49-4.40 (m, 2H), 4.31 - 4.26 (m, 1H), 4.06 - 3.98 (m, 2H), 3.85 - 3.79 (m, 1H), 3.74-3.65 (m, 2H), 3.64 - 3.47 (m, 7H), 2.95 - 2.78 (m, 2H), 2.76 - 2.67 (m, 1H), 2.11 - 2.06 (m, 1H), 1.99 - 1.81 (m, 7H), 1.73 - 1.68 (m, 2H), 1.56-1.62 (m, 1H), 1.24 (d, J = 6.8 Hz, 1H), 1.17 - 1.12 (m, 2H), 0.83 - 0.74 (m, 2H).582(M+H) +< and Example 105 Intermediate 59 1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.41 (s, 1H), 7.43-7.40 (m, 1H), 7.34 - 7.25 (m, 2H), 6.31-6.00 (m, 1H), 4.49 - 4.38 (m, 3H), 4.05 - 3.99 (m, 2H), 3.95-3.88 (m, 1H), 3.67 - 3.48 (m, 6H), 3.05-3.01 (m, 1H), 2.91 - 2.75 (m, 2H), 2.15 - 2.05 (m, 2H), 1.96 - 1.84 (m, 7H), 1.76 - 1.68 (m, 2H), 1.59-1.54 (m, 1H), 1.24 - 1.09 (m, 3H), 0.86 - 0.78 (m, 2H).602(M+H) +< and Example 106 Intermediate 62 1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.47-7.44 (m, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 6.34 (d, J = 9.2 Hz, 1H), 4.61 - 4.58 (m, 1H), 4.45 (d, J = 4.6 Hz, 1H), 4.25 - 4.13 (m, 2H), 3.97 - 3.91 (m, 2H), 3.68 - 3.43 (m, 4H), 3.05-3.01 (m, 1H), 2.93 - 2.85 (m, 1H), 2.80-2.73 (m, 1H), 2.16 - 2.06 (m, 1H), 1.92 - 1.68 (m, 9H), 1.59 - 1.53 (m, 1H), 0.92 - 0.69 (m, 4H).586(M+H) +< and Example 107 Intermediate 61 1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.53 - 7.47 (m, 1H), 7.35-7.33 (m, 1H), 7.27 - 7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.55 - 6.51 (m, 1H), 4.51- 4.46 (m, 1H), 4.08 - 4.00 (m, 1H), 3.92 - 3.82 (m, 5H), 3.77 - 3.48 (m, 5H), 3.41 - 3.34 (m, 1H), 3.10 - 3.03 (m, 1H), 2.95 - 2.86 (m, 1H), 2.81 - 2.74 (m, 1H), 2.21 - 2.06 (m, 1H), 1.94 - 1.56 (m, 10H), 1.02 - 0.72 (m, 3H), 0.48 - 0.30 (m, 1H).600(M+H) +< and Example 98: Preparation of 2-((5-(7-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2, 4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0396] Step 1:

[0397] To a solution of 2-((5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenza mide (100 mg, 0.23 mmo, Intermediate 34 ) and 2-(tert-butoxycarbonyl)-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carboxylic acid (67.9 mg, 0.23 mmol, Intermediate 50 ) in DMF (3 mL) was added DIPEA (50 mg, 0.39 mmol) and HATU (133 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred for 3 h at rt and quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (15 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated, the residue was purified by column chromatography on silica gel (MeOH in DCM= 0 ~ 5%) to give the desired product tert-butyl -1-(2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]no nane-7-carbonyl)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (40 mg, yield:24.4%) as a light yellow solid. LC / MS (ESI) m / z: 702 (M+H) +< .Step 2:

[0398] To a solution of tert-butyl -1-(2-(6-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]no nane-7-carbonyl)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (150 mg, 0.21 mmol) in DCM (10 mL) was added TFA (4 mL). The resulting mixture was stirred for 1 h at rt, and concentrated. The residue was diluted with EtOAc (20 mL), and the pH was adjusted to 9 with sat. NaHCO 3 solution. The organic phase was collected, and dried with anhydrous Na 2 SO 4 , filtered and concentrated. The resulting crude product was purified by Prep-HPLC to obtain the desired product 2-((5-(7-5,5-difluorooctahydrocyclopenta[c]pyrrole-1-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2, 4-triazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (90 mg, yield: 69.9%) as a white solid, which was submitted to SFC chiral separation to give four isomers. (Two conditions were used. The first condition gave the pure isomer 3 and isomer 4 respectively and a mixture of isomers 1 and 2. The latter was then submitted to the second condition to afford pure isomer 1 and isomer 2 respectively)

[0399] Example 98a: isomer 1 (9.8 mg, yield: 10.8%) as a white solid, (SFC condition: SHIMADZA PREP SPLUTION SFC, Column: ChiralPak IH, 250×21.1um, I.D., 5um; Mobile phase: A for CO 2 and B for EtOH+0.1%NH 3 H 2 O, Gradient: B 17%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254nm, Cycle-time: 18 min, Eluted time: 3.5 h. retention time: 8.39 min); 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.20 (m, 2H), 4.48-4.42 (m, 2H), 4.03-3.97 (m, 3H), 3.84 - 3.75 (m, 1H), 3.64 - 3.48 (m, 5H), 3.13-3.06 (m, 2H), 2.96 - 2.87 (m, 3H), 2.34-2.26 (m, 1H), 2.06-1.81 (m, 7H), 1.23 - 1.14 (m, 6H), 1.06 (d, J = 7.1 Hz, 1H), 0.82-0.79 (m, 2H), LC / MS (ESI) m / z: 602 (M+H) +< .

[0400] Example 98b: isomer 2, (16.3 mg, yield: 18.1%) as a white solid, (SFC condition: SHIMADZA PREP SPLUTION SFC, Column: ChiralPak IH, 250×21.1um, I.D., 5um; Mobile phase: A for CO 2 and B for EtOH+0.1%NH 3 H 2 O, Gradient: B 17%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °< C, Wavelength: 254nm, Cycle-time: 18 min, Eluted time: 3.5 h. retention time: 11.09 min); 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.20 (m, 2H), 4.48 - 4.38 (m, 2H), 4.03 - 4.00 (m, 2H), 3.91 (d, J = 3.9 Hz, 1H), 3.85-3.80 (m, 1H), 3.69 - 3.45 (m, 5H), 3.40 - 3.35 (m, 1H), 3.27-3.20 (m, 1H), 2.80 - 2.66 (m, 3H), 2.45 - 2.37 (m, 1H), 2.33-2.24 (m, 1H), 2.20-2.07 (m, 1H), 1.97 - 1.82 (m, 5H), 1.22 - 1.14 (m, 6H), 1.06 (d, J = 7.1 Hz, 1H), 0.82-0.78 (m, 2H), LC / MS (ESI) m / z: 602 (M+H) +< .

[0401] Example 98c: isomer 3, (8.8 mg, yield: 9.7%) as a white solid, (SFC condition: SHIMADZA PREP SPLUTION SFC, Column: ChiralPak CIG, 250×21.1um, I.D., 5um; Mobile phase: A for CO 2 and B for IPA+0.1%NH 3 H 2 O, Gradient: B 50%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254nm, Cycle-time: 45min, Eluted time:5 h. retention time: 12.61min);1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.21 (m, 2H), 4.49 - 4.41 (m, 2H), 4.13 (d, J = 7.0 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.85-3.79 (m, 1H), 3.72-3.48 (m, 5H), 3.17 - 3.13 (m, 2H), 3.02 - 2.90 (m, 3H), 2.36-2.27 (m, 1H), 2.03-1.84 (m, 7H), 1.23 - 1.12 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 0.81 (d, J = 5.1 Hz, 2H). LC / MS (ESI) m / z: 602 (M+H) +< . Example 98d: isomer 4, (20.1 mg, yield: 22.3%) as a white solid, (SFC condition: SHIMADZA PREP SPLUTION SFC, Column: ChiralPak CIG, 250×21.1um, I.D., 5um; Mobile phase: A for CO 2 and B for IPA+0.1%NH 3 H 2 O, Gradient: B 50%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254nm, Cycle-time: 45min, Eluted time:5 h. retention time: 28.06 min); 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.18 (m, 2H), 4.47- 4.30 (m, 2H), 4.02-3.98 (m, 3H), 3.84-3.80 (m, 1H), 3.62-3.42 (m, 6H), 3.25 - 3.20 (m, 1H), 2.85-2.74 (m, 3H), 2.48-2.40 (m, 1H), 2.36-2.25 (m, 1H), 2.17-2.16 (m, 1H), 2.03 - 1.86 (m, 5H), 1.22 - 1.11 (m, 6H), 1.06 (d, J = 7.1 Hz, 1H), 0.81 (d, J = 5.2 Hz, 2H), HNMR, LC / MS (ESI) m / z: 602 (M+H) +< .Example 99: Preparation of 2-((5-(7-(trans-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triaz in-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0402] Step 1:

[0403] To a solution of trans-1-[(benzyloxy)carbonyl]-3-(difluoromethyl)pyrrolidine-2-carboxylic acid (250 mg, 0.83 mmol, Intermediate 51 ) and 2-[(5-{2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)ben zamide(357 mg, 0.83 mmol, Intermediate 34 ) in DMF (5 mL) was added HATU (476 mg, 1.25 mmol) and DIPEA (323 mg, 2.51 mmol) at room temperature. The resulting mixture was stirred for 3 h at rt and quenched with sat. NH 4 Cl solution (10 mL), and extracted with EtOAc (20 mL x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH in DCM= 0 ~ 5%) to give the desired product benzyl trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylate (200 mg, yield: 33.7%) as a off-white solid, LC / MS (ESI) m / z: 710 (M+H) -< .Step 2:

[0404] To a solution of benzyl trans-3-(difluoromethyl)-2-[2-(6-{2-[ethyl(propan-2-yl)carbamoyl]-4-fluorophenoxy}-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]pyrrolidine-1-carboxylate (200 mg, 0.28 mmol) in MeOH (10 mL) was added Pd / C (30 mg, 10% Palladium on activated charcoal) at rt, The reaction mixture was stirred at rt for 5 h under H 2 atmosphere (balloon). The reaction mixture was filtered and concentrated. The resulting crude product was purified by Prep-HPLC to obtain the desired product 2-[(5-{7-[trans-3-(difluoromethyl)pyrrolidine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-tria zin-6-yl)oxy]-N-ethyl-5-fluoro-N-(propan-2-yl)benzamide (30 mg, yield: 36.9%) as a white solid. which was separated by SFC to give two isomers. (SFC conditions: Waters Thar 80 preparative SFC, Column: ChiralCel, 250×21.1um, I.D., 5um; Mobile phase: A for CO 2 and B for MeOH+0.1%NH 3 H 2 O, Gradient: B 40%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254nm, Cycle-time: 5 min, Eluted time:2 h. retention time: 5.5 min for 99a, and 7.8 min for 99b)Example 99a:

[0405] 2-((5-(7-((2S,3S)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-tr iazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (35.3 mg, yield: 21.4%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.19 (m, 2H), 6.10-5.81 (m, 1H), 4.48 - 4.41 (m, 2H), 4.14 (d, J = 5.4 Hz, 1H), 4.04 - 3.97 (m, 2H), 3.84 - 3.80 (m, 1H), 3.71 - 3.47 (m, 5H), 3.25-3.11 (m, 2H), 2.94 - 2.78 (m, 2H), 2.06 - 1.81 (m, 6H), 1.22 - 1.12 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 0.81 (d, J = 4.9 Hz, 2H). LC / MS (ESI) m / z: 576 (M+H) +< .Example 99b:

[0406] 2-((5-(7-((2R,3R)-3-(difluoromethyl)pyrrolidine-2-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-t riazin-6-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (36.8 mg, yield: 22.9%) as a white solid. 1< H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.38 (m, 1H), 7.31 - 7.19 (m, 2H), 6.11-5.82 (m, 1H), 4.48-4.39 (m, 2H), 4.17 (d, J = 5.2 Hz, 1H), 4.02-3.96 (m, 2H), 3.85-3.79 (m, 1H), 3.72 - 3.48 (m, 5H), 3.24 - 3.11 (m, 2H), 2.97-2.81 (m, 2H), 2.05 - 1.84 (m, 6H), 1.22 - 1.13 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 0.87 - 0.74 (m, 2H). LC / MS (ESI) m / z: 576 (M+H) +< .

[0407] The following compounds were prepared from the appropriate intermediates or commercially available chemicals according to experimental procedure for Example 99: ExampleStructureStarting materials1H-NMR (400 MHz)LCMS (ESI) m / zExample 100a Intermediate 52 and 1< H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.43-7.39 (m, 1H), 7.31 - 7.20 (m, 2H), 4.55-4.44 (m, 3H), 4.05-3.99 (m, 2H), 3.86-3.79 (m, 2H), 3.59 - 3.35 (m, 5H), 3.27 - 3.20 (m, 1H), 2.19-2.12 (m, 1H), 2.03 - 1.85 (m, 5H), 1.68-1.63 (m, 1H), 1.21 - 1.13 (m, 6H), 1.07 (t, J = 7.1 Hz, 1H), 0.91 - 0.81 (m, 4H), 0.68-0.61 (m, 2H), 0.27 (s, 2H).566(M+H) +< Example 100b Intermediate 52 and 1< H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.43-7.40 (m, 1H), 7.31-7.20 (m, 2H), 4.50 - 4.38 (m, 2H), 4.05-3.96 (m, 3H), 3.84-3.75 (m, 2H), 3.59 - 3.45 (m, 3H), 3.23 - 3.02 (m, 3H), 2.04 - 1.71 (m, 6H), 1.54-1.45 (m, 1H), 1.22 - 1.14 (m, 6H), 1.07 (t, J = 7.0 Hz, 1H), 0.88 - 0.82 (m, 4H), 0.60 - 0.49 (m, 2H), 0.19 (s, 2H).566(M+H) +< Pharmacological Examples

[0408] SNDX-5613 used in the following assays was either sourced from MCE, cat. No. HY-136175, or prepared according to procedures reported in WO2017214367.1. Menin-MLL1 inhibition assay

[0409] 1x assay buffer (Tris 7.5 50 mM, NaCl 50 mM, DTT 1 mM, Tween-20 0.01%) was prepared and test compounds solution (10 mM in DMSO, Sigma, Cat. No. 34869) were transferred to assay plate (384-well plate, Perkin Elmer, Cat. No. 6007279) by Echo. The final fraction of DMSO is 1%. 20 nM of Menin protein (Menin (2-610) isform2, ChemPartner, Cat. No.2020111101) in 1x assay buffer was added to prepare 2x enzyme solution. Then 10 nM of MLL-peptide (Ac-SRWRFPARPGTGRR-Ahx-Ahx-K(FAM)-NH 2 , GL Biochem (Shanghai), Cat. No. 833831 / 202009220104) in 1x assay buffer was added to prepare 2x substrate solution. 10 µL of 2x enzyme solution was transferred to assay plate or 10 µL of 1x assay buffer for low control group. 10 µL of 2x substrate solution was added to each well to start reaction. mP data on Envision (Ex480 / Em535(s), Em535(p)) was collected.

[0410] Compound potencies were determined by first calculating % inhibition at each compound concentration according to equation 1: Inhibition % = Max − Signal / Max − Min * 100

[0411] IC 50 values of the compounds of the present disclosure was obtained by using equation 2 and showed in the following Table 1: Y=Bottom + (Top-Bottom) / (1+(IC50 / X)*HillSlope), where Y is %inhibition and X is compound concentration (Equation 2)

[0412] The test results of the compounds of the present disclosure were shown in Table 1.2. Cell proliferation assay

[0413] RPMI1640 (from Invitrogen, Cat. No. 11875-093; Lot. No. 2327411) IMDM (from Invitrogen, Cat. No. 12440-053; Lot. No. 2192731) FBS (from Gibco, Cat. No. 10099141C, Lot. No. 2233792CP) Penicillin-Streptomycin solution (from Invitrogen, Cat. No. 15140-122, Lot. No. 2321118) Glutamax (from Invitrogen, Cat. No. 35050-061; Lot. No. 2248972) 0.25%Trypsine-EDTA (from Invitrogen, Cat. No. 25200-072; Lot. No. 2276876) Staurosporine (from Selleck, Cat. No. S1421, Lot. No. # S142106) DMSO (from Sigma, Cat. No. 276855-1L, Lot. No. 276855-1L) Cell Line Vendor Cat# Lot. No Description Growth properties Complete medium Seeding Density Incubation time MV-4-11ATCCCRL-9591583522301leukemia, biphenotypic B myelomonocyticsuspensionIMDM+ 10%FBS75004 DaysMOLM-13Addex BioC0003003126132leukemia, acute myeloidsuspensionRPMI1640+ 20%FBS300012 DaysOCI-AML-3DSMZACC-58210leukemia, acute myeloidsupensionRPMI 1640+ 20%FBS60005 DaysHL-60ATCCCCL-2405036502leukemia, acute promyelocyticsuspensionIMDM+ 20%FBS40004 Days

[0414] The antiproliferative activity of test compounds was assessed in human leukemia cell lines. The cell line MV4-11, MOLM13 and OCI-AML3, which expresses the MLL fusion protein MLL-AF4, MLL-AF9 and carry the NPM1c gene mutation, respectively, were tested. HL-60 was used as a control cell line containing two MLL wildtype alleles in order to exclude compounds that display general cytotoxic effect. MV4-11 cells were cultured in IMDM supplemented with 10% FBS, MOLM13 and OCI-AML3 cells were cultured in RPMI1640 supplemented with 20% FBS, and HL-60 cells were cultured in IMDM supplemented with 20% FBS. Corresponding cells (MV4-11, MOLM13, OCI-AML3 or HL-60 cell line) were seeded in 100 uL medium per well in 96-well plate (white wall with clear bottom, tissue culture treated, Corning, Cat. No. CLS3903; Lot.No.30419025). Plates were placed in the CO 2 incubator overnight. Compounds solution (2 mM starting, 4-fold serial dilution) were prepared and added to the wells containing 100 µL of the culture medium with HPD300 according to the plate map and centrifuged at 1000 rpm for 1 minute (200-fold dilution totally). MV4-11, MOLM13, OCI-AML3 and HL-60 cells were incubated with the compounds for 4, 12, 5 and 4 days, respectively, under 5% CO 2 at 37°C, respectively. 100 µL of CellTiter-Glo reagent (Promega, Cat. No. G7573, Lot. No. 0000416710) was added to the assay plate by Multidrop Combi instrument, contents were mixed for 10 minutes on an orbital shaker to induce cell lysis. After incubation at room temperature for 10 mins, clear bottom with white back seal was pasted and luminescence with Envision was read.

[0415] The test results of the compounds of the present disclosure were shown in Table 1. Table 1. Biological data CompoundsBiochemical assayCell antiproliferation assayMenin-MLL1 IC50 (nM)MV-4-11 IC50 (nM)OCI-AML3 IC50 (nM)MOLM13 IC50 (nM)HL-60 IC50 (nM)HL-60 (Pct of inhibition at 10 µM)SNDX-56133.48.074.721.6797098.9%Example 24.320.3102.062.4>10000-30.1%Example 320.9329.2Example 45.033.1Example 57.0440.0Example 66.033.8Example 77.5219.8Example 85.5331.7Example 912.940.7Example 108.3238.5Example 116.3128.3Example 124.768.2Example 1316.7Example 149.2Example 1555.2Example 1622.3Example 1725.3316.6Example 1813.5Example 195.040.2Example 2010.1267.1Example 215.842.2Example 224.9134.4Example 238.7127.1Example 248.0102.1Example 258.4232.5Example 2610.2647.2Example 2718.4419.9Example 285.2107.4Example 297.0271.4Example 304.733.8Example 316.741.0Example 326.575.4Example 334.519.3Example 344.118.0>10000-12.2%Example 364.066.0Example 3715.4Example 383.369.0Example 394.243.0>10000-24.9%Example 405.426.2Example 413.67.731.423.7>10000-22.2%Example 425.593.5Example 434.8169.7Example 443.930.7Example 453.436.1Example 467.7494.5Example 473.715.9>10000-10.6%Example 4811.4144.3Example 493.657.3>10000-8.4%Example 504.4120.1Example 514.3221.0Example 5221.0Example 5310.9786.1Example 544.3582.3Example 552.314.2186.261.9>10000-5.0%Example 563.716.8132.268.3>10000-12.2%Example 575.313.0143.957.8>10000-16.4%Example 583.527.1>10000-4.5%Example 595.5158.6Example 604.540.1>10000-8.4%Example 616.1153.3Example 623.439.5>10000-9.1%Example 633.543.4Example 641.99.620.2>1000011.2%Example 653.115.157.0>10000-3.7%Example 6611.0308.0Example 672.820.561.1>1000023.8%Example 684.113.868.346.1>1000014.1%Example 694.456.4Example 704.69.552.749.5>100001.0%Example 7116.01252.4Example 725.556.3Example 734.122.0Example 744.65.630.914.9>100007.9%Example 755.840.6Example 763.716.7Example 773.417.3>1000017.5%Example 782.96.528.114.2>1000040.0%Example 799.95.925.915.6>1000033.8%Example 804.339.0>100000.0%Example 813.97.725.516.6>1000021.4%Example 824.25.611.212.3>1000022.3%Example 833.651.0Example 845.120.067.160.9>1000015.1%Example 855.576.7>10000-2.8%Example 863.676.0281.6199.3>1000010.8%Example 874.941.6Example 883.224.2101.968.6>1000011.4%Example 8924.01006.0Example 902.82.66.1Example 917.3248.0Example 928.018.8Example 9324.8457.0Example 943.411.8Example 952.55.5Example 964.05.6Example 974.42.3Example 98a5.4333.4Example 98b22.02643Example 98c44.5Example 98d2.329.5Example 99a5.446.4Example 99b43.01934.0Example 100a2.76.9Example 100b11.7284.5Example 1016.06.8Example 1025.44.6Example 1034.41.5Example 1044.526.7Example 1054.017.1Example 1062.09.4Example 1072.42.4 3. Liver microsome stability study

[0416] Studies were carried out in liver microsomes (Corning, 0.5 mg / mL). Stock solutions were prepared at 10 mM in DMSO for the test compounds. Aliquots of the stock solutions were diluted to 0.5 mM with acetonitrile, and then further diluted upon the addition of liver microsomes / buffer to 1.5 µM. An aliquot of 30 µL of 1.5 µM solutions was mixed with 15 µL of 6 mM NADPH and the final concentration of NADPH was 2 mM, which had been pre-warmed to 37°C. Test compounds and Ketanserin final concentrations were 1 µM. The plates were kept in a 37°C water bath for the duration of the experiment. At each time point (0, 5, 15, 30, 45 minutes), 135 µL of acetonitrile was added into corresponding wells. After the final time point was quenched by acetonitrile, the assay plates were shaken at the vibrator (IKA, MTS 2 / 4) for 10 min (600 rpm / min) and then centrifuged at 5,594 g for 15 min (Thermo Multifuge × 3R). Aliquots of the supernatant were taken, diluted 1:1 into distilled water, and analyzed by LC-MS / MS. The peak area response ratio to internal standard (PARR) of the compounds at 5, 15, 30, 45 minutes was compared to the PARR at time 0 to determine the percent of test compound remaining at each time point. Half-lives were calculated using Excel software, fitting to a single-phase exponential decay equation. Table 2. Human liver microsome stabilityCompoundsHuman liver microsome T1 / 2 (min)SNDX-561312Example 2292Example 3860Example 3994Example 55159Example 57105Example 60119Example 6286Example 63125Example 6567Example 69154Example 72158Example 7781Example 8468Example 8766 4. hERG inhibition study

[0417] The inhibition effects of the test compounds on hERG were carried out in CHO-hERG cells (cell density: 21.5 × 10 ~ 6 / mL). 10 µL compound mother liquor was added to 20 µL DMSO solution, and then continuously diluted to 6 concentrations by 3-fold. The compound solution (4 uL) of six different concentrations were added to the extracellular solution (996 uL) and diluted to the final concentration to be tested (250-fold dilution totally). The highest test concentration was 40.00 µM, followed by 40.0, 13.3, 4.4, 1.48, 0.49 and 0.16 µM. The content of DMSO in the final test concentration did not exceed 0.2%, at which DMSO had no effect on the hERG potassium channel. The high impedance sealing of single cell and the formation of whole cell model were all completed automatically by Qpatch instrument. Table 3. hERG inhibition dataCompoundshERG (µM)SNDX-56139.6Example 2> 40Example 55>40Example 57>40Example 60>40Example 68>40Example 74>40Example 77>40Example 8229.4 Example 85.5331.7Example 912.940.7Example 108.3238.5Example 116.3128.3Example 124.768.2Example 1316.7Example 149.2Example 1555.2Example 1622.3Example 1725.3316.6Example 1813.5Example 195.040.2Example 2010.1267.1Example 215.842.2Example 224.9134.4Example 238.7127.1Example 248.0102.1Example 258.4232.5Example 2610.2647.2Example 2718.4419.9Example 285.2107.4Example 297.0271.4Example 304.733.8Example 316.741.0Example 326.575.4Example 334.519.3Example 344.118.0>10000-12.2%Example 364.066.0Example 3715.4Example 383.369.0Example 394.243.0>10000-24.9%Example 405.426.2Example 413.67.731.423.7>10000-22.2%Example 425.593.5Example 434.8169.7Example 443.930.7Example 453.436.1Example 467.7494.5Example 473.715.9>10000-10.6%Example 4811.4144.3Example 493.657.3>10000-8.4%Example 504.4120.1Example 514.3221.0Example 5221.0Example 5310.9786.1Example 544.3582.3Example 552.314.2186.261.9>10000-5.0%Example 563.716.8132.268.3>10000-12.2%Example 575.313.0143.957.8>10000-16.4%Example 583.527.1>10000-4.5%Example 595.5158.6Example 604.540.1>10000-8.4%Example 616.1153.3Example 623.439.5>10000-9.1%Example 633.543.4Example 641.99.620.2>1000011.2%Example 653.115.157.0>10000-3.7%Example 6611.0308.0Example 672.820.561.1>1000023.8%Example 684.113.868.346.1>1000014.1%Example 694.456.4Example 704.69.552.749.5>100001.0%Example 7116.01252.4Example 725.556.3Example 734.122.0Example 744.65.630.914.9>100007.9%Example 755.840.6Example 763.716.7Example 773.417.3>1000017.5%Example 782.96.528.114.2>1000040.0%Example 799.95.925.915.6>1000033.8%Example 804.339.0>100000.0%Example 813.97.725.516.6>1000021.4%Example 824.25.611.212.3>1000022.3%Example 833.651.0Example 845.120.067.160.9>1000015.1%Example 855.576.7>10000-2.8%Example 863.676.0281.6199.3>1000010.8%Example 874.941.6Example 883.224.2101.968.6>1000011.4%Example 8924.01006.0Example 902.82.66.1Example 917.3248.0Example 928.018.8Example 9324.8457.0Example 943.411.8Example 952.55.5Example 964.05.6Example 974.42.3Example 98a5.4333.4Example 98b22.02643Example 98c44.5Example 98d2.329.5Example 99a5.446.4Example 99b43.01934.0Example 100a2.76.9Example 100b11.7284.5Example 1016.06.8Example 1025.44.6Example 1034.41.5Example 1044.526.7Example 1054.017.1Example 1062.09.4Example 1072.42.4 3. Liver microsome stability study

[0418] Studies were carried out in liver microsomes (Corning, 0.5 mg / mL). Stock solutions were prepared at 10 mM in DMSO for the test compounds. Aliquots of the stock solutions were diluted to 0.5 mM with acetonitrile, and then further diluted upon the addition of liver microsomes / buffer to 1.5 µM. An aliquot of 30 µL of 1.5 µM solutions was mixed with 15 µL of 6 mM NADPH and the final concentration of NADPH was 2 mM, which had been pre-warmed to 37°C. Test compounds and Ketanserin final concentrations were 1 µM. The plates were kept in a 37°C water bath for the duration of the experiment. At each time point (0, 5, 15, 30, 45 minutes), 135 µL of acetonitrile was added into corresponding wells. After the final time point was quenched by acetonitrile, the assay plates were shaken at the vibrator (IKA, MTS 2 / 4) for 10 min (600 rpm / min) and then centrifuged at 5,594 g for 15 min (Thermo Multifuge × 3R). Aliquots of the supernatant were taken, diluted 1:1 into distilled water, and analyzed by LC-MS / MS. The peak area response ratio to internal standard (PARR) of the compounds at 5, 15, 30, 45 minutes was compared to the PARR at time 0 to determine the percent of test compound remaining at each time point. Half-lives were calculated using Excel software, fitting to a single-phase exponential decay equation. Table 2. Human liver microsome stabilityCompoundsHuman liver microsome T1 / 2 (min)SNDX-561312Example 2292Example 3860Example 3994Example 55159Example 57105Example 60119Example 6286Example 63125Example 6567Example 69154Example 72158Example 7781Example 8468Example 8766 4. hERG inhibition study

[0419] The inhibition effects of the test compounds on hERG were carried out in CHO-hERG cells (cell density: 21.5 × 10 ~ 6 / mL). 10 µL compound mother liquor was added to 20 µ L DMSO solution, and then continuously diluted to 6 concentrations by 3-fold. The compound solution (4 uL) of six different concentrations were added to the extracellular solution (996 uL) and diluted to the final concentration to be tested (250-fold dilution totally). The highest test concentration was 40.00 µM, followed by 40.0, 13.3, 4.4, 1.48, 0.49 and 0.16 µM. The content of DMSO in the final test concentration did not exceed 0.2%, at which DMSO had no effect on the hERG potassium channel. The high impedance sealing of single cell and the formation of whole cell model were all completed automatically by Qpatch instrument. Table 3. hERG inhibition dataCompoundshERG (µM)SNDX-56139.6Example 2> 40Example 55>40Example 57>40Example 60>40Example 68>40Example 74>40Example 77>40Example 8229.4

Claims

1. A compound of formula I: or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F, Cl or CN; preferably, X is F; Y is N or CH; Z is selected from the group consisting of CH2, O, and S; R1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C1-6alkyl and 3-5 membered cycloalkyl ring, wherein the C1-6alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halo, OH and C1-6alkoxyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-6alkyl and halo; 2) a 5-6 membered heteroaryl ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring, oxo and C1-6alkoxyl; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo and CN, 3-5 membered cycloalkyl ring and C1-6alkoxyl; R2 and R3 are each independently H or D; preferably, R2 and R3 are each H; each R4 is independently selected from the group consisting of halo, CN, OH, C1-6alkylsulfonyl-, C1-6alkylsulfonylamino-, phenyl, C1-6alkyl, C1-6alkoxyl and 3-6 membered cycloalkyl ring, wherein the alkyl or alkoxyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; wherein two adjacent R4, together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-6alkyl, -C1-6alkyl-OH, C1-6alkoxyl-C1-6alkyl- and halo; or, two R4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; or, two adjacent R4, together with the carbon atoms to which they are attached, optionally form a 5-10 membered heteroaryl ring or phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-6alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; R5 is H or halo; preferably, R5 is H; a, b, c and d are each independently 1 or 2; n is 0 or 1; and m is 0, 1, 2 or 3; provided that R4, if present, substituted at any chemically permissible position(s) the heterocyclyl except for the N atom adjacent to the attachment point of the heterocyclyl to the remaining structure of the compound.

2. The compound according to claim 1 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula II:

3. The compound according to claim 1 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is of formula III:

4. The compound according to any one of the preceding claims or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein Z is CH2.

5. The compound according to any one of the preceding claims or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: R1 is wherein A1 or A2 is N or CH; R6 is selected from the group consisting of halo, CN and cyclopropyl; and R7 is selected from the group consisting of H, halo, CN and cyclopropyl; preferably, R1 is or R1 is wherein A3 is N or C substituted by halo, and R8 is C1-3alkyl; preferably, R1 is or, R1 is selected from the group consisting of:

6. The compound according to any one of the preceding claims or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each of a and b is 1; each of c and d is 2; n is 0 or 1, preferably 0; and m is 0, 1 or 2.

7. The compound according to any one of the preceding claims or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: each R4 is independently selected from the group consisting of halo; CN; OH; C1-6alkylsulfonyl-; C1-6alkylsulfonylamino-; phenyl; C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C1-6alkoxyl optionally substituted with 1, 2 or 3 halo; and cyclopropyl, wherein two adjacent R4, together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-6alkyl, -C1-6alkyl-OH, C1-6alkoxyl-C1-6alkyl- and halo; or, two R4 attached to the same carbon atom together with said carbon atom optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 halo; or, two adjacent R4, together with the carbon atoms to which they are attached, optionally form a 5-6 membered heteroaryl ring, which is optionally substituted with 1, 2 or 3 C1-6alkyl, wherein the alkyl is optionally substituted with one 3-6 membered cycloalkyl ring or phenyl; or, two adjacent R4, together with the carbon atoms to which they are attached, optionally form a phenyl.

8. The compound according to any one of the preceding claims or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: the moiety is selected from the group consisting of:

9. The compound according to any one of claims 1 to 2 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein: X is F; Z is CH2; R1 is selected from the group consisting of: 1) -(C=O)-NRaRb, wherein: Ra and Rb are each independently selected from the group consisting of C1-6alkyl optionally substituted by 1, 2 or 3 deuterium; or Ra and Rb, together with the nitrogen atom to which they are attached, form a 5-6 membered monocyclic or 7-9 membered bicyclic heterocyclyl ring, which is optionally substituted with 1, 2 or 3 C1-6alkyl; 2) a 5-6 membered heteroaryl ring substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C1-6alkyl, CF3, 3-5 membered cycloalkyl ring, oxo and C1-6alkoxyl; 3) phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN, C1-6alkyl, CF3, 3-5 membered cycloalkyl ring and C1-6alkoxyl; R2 and R3 are each H; each R4 is independently selected from the group consisting of halo; CN; OH; C1-6alkylsulfonyl-; C1-6alkylsulfonylamino-; phenyl; C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, CN and OH; C1-6alkoxyl optionally substituted with 1, 2 or 3 halo; and 3-6 membered cycloalkyl ring, wherein two adjacent R4, together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-6alkyl and halo; or, two adjacent R4, together with the carbon atoms to which they are attached, optionally form a phenyl; R5 is H or halo; preferably, R5 is H; each of a and b is 1; each of c and d is 2; n is 0; and m is 0, 1 or 2; provided that R4, if present, substituted at any chemically permissible position(s) the heterocyclyl except for the N atom adjacent to the attachment point of the heterocyclyl to the remaining structure of the compound.

10. The compound according to any one of claims 1-6 and 9 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the moiety is wherein R4', R4" and R4‴ are independently selected from the group consisting of H; halo; CN; OH; C1-6alkyl optionally substituted with one halo; and C1-6alkoxyl or R4' and R4", together with the carbon atoms to which they are attached, optionally form a 3-6 membered cycloalkyl ring, which is optionally substituted with 1 or 2 C1-6alkyl; and R4‴ is H; or, the moiety is wherein R4‴ is H; and R4' and R4" are independently selected from the group consisting of H; halo; C1-6alkyl optionally substituted with one halo; and C1-6alkoxyl; provided that one of R4' and R4" is not H; or, R4' and R4", together with the carbon atoms to which they are attached, form a 3 or 5 membered cycloalkyl ring optionally substituted with 1 or 2 C1-3alkyl, or form a phenyl ring; or, the moiety is wherein R4' is H; and R4" is C1-6alkyl substituted with one halo; or R4' and R4", together with the carbon atoms to which they are attached, optionally form a 3 or 5 membered cycloalkyl ring; or, the moiety is wherein each p is dependently 0 or 1; preferably both p are 0, or both p are 1; q is 0, 1 or 2; preferably q is 0 or 2; R4a is C1-3alkyl, preferably methyl.

11. The compound according to claim 1 or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: Compound Nos.StructuresExample 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Example 32 Example 33 Example 34 Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70 Example 71 Example 72 Example 73 Example 74 Example 75 Example 76 Example 77 Example 78 Example 79 Example 80 Example 81 Example 82 Example 83 Example 84 Example 85 Example 86 Example 87 Example 88 Example 89 Example 90 Example 91 Example 92 Example 93 Example 94 Example 95 Example 96 Example 97 Example 98a Example 98b Example 98c Example 98d Example 99a Example 99b Example 100a Example 100b Example 101 Example 102 Example 103 Example 104 Example 105 Example 106 Example 107 12. The compound of any one of the claims 1-11, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use as a medicament.

13. The compound of any one of the claims 1-11, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer or diabetes; preferably, the cancer is hematological tumor, e.g., selected from leukemia, lymphomas, myelomas (e.g., multiple myeloma), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and polycythemia vera; or solid tumor, e.g., selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma; more preferably, the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemias (AML), chronic myeloid leukemias (CML), acute lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed lineage leukemia (MLL), MLL-rearranged leukemias (MLLr leukemia), MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, nucleophosmin (NPM)-mutated leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, MLL-AF4 leukemia, MLL-AF6 leukemia, MLL-AF9 leukemia, MLL-AF10 leukemia, MLL-ENL leukemia and MLL-ELL leukemia.

14. A pharmaceutical composition, comprising the compound of any one of the claims 1-11, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

15. A combination, comprising the compound of any one of the claims 1-11, or a stereoisomer, a racemate, a tautomer, a hydrate or a solvate, or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein said additional therapeutic agent preferably is an antineoplastic agent, e.g., a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.