Carbamates for use as sarm1 inhibitors

Abstract

The present invention relates to carbamate compounds of formula (I), as further detailed herein, for use in inhibiting the SARM1 protein, as well as compositions comprising these compounds and methods of treatment by administration of the compounds and compositions.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480063570.7 (22) Application Date 2024.10.02 (30) Priority Data 63 / 588,208 2023.10.05 US 63 / 683,372 2024.08.15 US (85) PCT International Application Entering National Phase Date 2026.04.01 (86) PCT International Application Application Data PCT / US2024 / 049501 2024.10.02 (87) PCT International Application Publication Data WO2025 / 076017 EN 2025.04.10 (71) Applicant Genentech Corporation Address: California, USA (72) Inventors: Zeng Mingshuo, Zhu Bingyan, B.K.I. Chen, M.L. Dale Bell, L.J. Gazadeh, J.M. Grandner, S.A. Green, Liang Jun, R.T. Smith (74) Patent Agency: Beijing Kunrui Law Firm, 11494 Patent Attorney: Feng Xinqin (51) Int.Cl. C07D 413 / 08 (2006.01) C07D 413 / 14 (2006.01) C07D 498 / 10 (2006.01) A61P 25 / 28 (2006.01) A61K 31 / 4439 (2006.01) A61K 31 / 444 (2006.01) A61K 31 / 497 (2006.01) A61K 31 / 5377 (2006.01) (54) Invention Title: Carbamates as SARM1 Inhibitors (57) Abstract: This invention relates to carbamate compounds of formula (I) as further detailed herein, which are used to inhibit SARM1 protein, as well as compositions comprising these compounds and methods of treatment by administration of said compounds and compositions.Claims 13 pages, Description 119 pages, CN 121969615 A ​​2026.05.01 CN 1 21 96 96 15 A 1. A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: ring A is; or X1 is CR7 or N; X2 is CR4, CHR4 or N; X3 is absent, CH, CH2, NH or S; X4 is N, CH2, CH, NH, O or S; X5 is CR8; Y is absent, CR5R6 or CH2CH2, wherein R5 and R6 are independently H, OH, CN, halogenated, C1-6 alkyl or C1-6 cycloalkyl, or R5 and R6 together with the carbons they are bonded to form a C3-6 cycloalkyl; Z is CH or N; one of Q1 and Q2 is N. And the other is CR4; one of Q3 and Q4 is N and the other is CR4; or Q3 and Q4 are CR4; R1a is H or C1-6 alkyl; R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl and C1-6 alkyl substituted with C6-10 aryl or C1-6 haloalkoxy; wherein each aryl, heteroaryl, cycloalkyl and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl and C3-6 cycloalkyl; or R1a and R1b Together with the carbon atoms they are bonded to, they form a C3-6 cycloalkyl group; R2 is H, OH, CN, or a C1-6 alkyl group; R3 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl groups; R4 is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl; R7 and R8 are absent, or form a -CH2- bridge between the carbon atoms they are bonded to; indicates the connection point with the rest of the compound; and indicates a single or double bond. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is CR7; X2 is CHR4; X3 is absent or CH2; X4 is CH2 or O; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached.3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X1 is CR7; X2 is CHR4; X3 is absent; X4 is CH2; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached. 4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X1 is CR7; X2 is CHR4; X3 is CH2; X4 is O; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached. 5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R4 is H. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from [selected from] ... 8. The compound of claim 6, having formula (IV): (IV), or a pharmaceutically acceptable salt thereof. Claims 2 / 13 Page 3 CN 121969615 A ​​9. The compound of claim 6, having formula (V): or a pharmaceutically acceptable salt thereof. 10. The compound of claim 6, having formula (Va): (Va) or a pharmaceutically acceptable salt thereof. 11. The compound of claim 1, wherein ring A is [missing information], and the compound has formula (II): (II), or a pharmaceutically acceptable salt thereof. 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; and X4 is N. 13. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is CR4; X3 is NH; and X4 is N. 14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is N; X2 is CR4; X3 is CH; and X4 is N. 15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is CR4; X3 is S; and X4 is N. 16. The compound of any one of claims 13 to 15 or a pharmaceutically acceptable salt thereof, wherein R4 is H. 17. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is N; X2 is N; X3 is CH; and X4 is N.Claims 3 / 13, Page 4, CN 121969615, A: 18. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is S; and X4 is N. 19. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; and X4 is CH. 16. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from , , , , , , and . 20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R4 is H, halogenated, methyl, or C1-6 hydroxyalkyl. 21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R4 is H. 22. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from , , , , , , , , , and . 23. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from , , and . 24. The compound of claim 11, having formula (IIa): (IIa), or a pharmaceutically acceptable salt thereof. 25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R4 is H. 26. The compound of claim 11, having formula (IIb): (IIb), or a pharmaceutically acceptable salt thereof. 27. The compound of claim 11, having formula (IIc): (IIc), or a pharmaceutically acceptable salt thereof. 28. The compound of claim 11, having formula (IId): (IId), or a pharmaceutically acceptable salt thereof. 29. The compound of claim 11, having formula (IIe): (IIe), or a pharmaceutically acceptable salt thereof. 30. The compound of claim 11, having formula (IIf): (IIf), or a pharmaceutically acceptable salt thereof. 31. The compound of claim 11, having formula (IIg): (IIg), or a pharmaceutically acceptable salt thereof. 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is N. 33. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is CH.34. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R3 is H. 35. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R3 is methyl, phenyl, or pyridyl. 36. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein Y is absent. 37. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein Y is CH2CH2. 38. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein Y is CR5R6. 39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are independently AH, OH, CN, or halogenated. 40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are H. 41. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R5 is H and R6 is OH or CN. 42. The compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein R2 is H, OH, CN, or methyl. 43. The compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein R2 is H. 44. The compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, wherein R1a is H or methyl. 45. The compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, wherein R1a is H. 46. The compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, wherein R1a and R1b, together with the carbon atoms to which they are bonded, form a C3-6 cycloalkyl group. 47. The compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, wherein R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, and C1-6 alkyl substituted with C6-10 aryl or C1-6 haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, and C3-6 cycloalkyl.48. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted by one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, and C1-6 haloalkyl. 49. The compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein R1b is selected from [missing information - likely a specific group or group], wherein each R9 is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, and C3-6 cycloalkyl; and p is 0, 1, 2, 3, or 4. 50. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R1b is selected from claims 7 / 13, page 8, CN 121969615 A, , , , , , , , and, wherein p is 1 or 2. 51. The compound of claim 49 or 50 or a pharmaceutically acceptable salt thereof, wherein each R9 is independently selected from C1-6 alkyl, halogenated, and C1-6 haloalkyl. 52. The compound of claim 49 or 50 or a pharmaceutically acceptable salt thereof, wherein each R9 is independently selected from methyl, halogenated, and C1 haloalkyl. 53. The compound of claim 1, having formula (IIIa) or (IIIb): (IIIa) (IIIb), or a pharmaceutically acceptable salt thereof, wherein R6 is H, OH, or CN. 54. The compound according to claim 1, having formula (IVa) or (IVb): (IVa) (IVb ... 56. The compound according to claims 53 to 54 or a pharmaceutically acceptable salt thereof, wherein R1a is H and R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted by one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo and C1-6 haloalkyl.57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently halogenated. 58. The compound of claim 1, having a formula selected from: (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), or a pharmaceutically acceptable salt thereof. 59. The compound of claim 58 or a pharmaceutically acceptable salt thereof, wherein R4 is H. 60. The compound of claim 1, having a formula selected from: (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), or a pharmaceutically acceptable salt thereof. 61. The compound according to claim 1, having a formula selected from: (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6), or a pharmaceutically acceptable salt thereof. 62. The compound according to claim 1, having a formula selected from: (IId-1), (IId-2), (IId-3), (IId-4), (IId-5), (IId-6), or a pharmaceutically acceptable salt thereof. 63. The compound according to claim 1, having a formula selected from the following: (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIe-5), (IIe-6), or a pharmaceutically acceptable salt thereof. 64. The compound according to claim 1, having a formula selected from the following: (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIe-5), (IIe-6), or a pharmaceutically acceptable salt thereof. 65. The compound according to claim 1, having a formula selected from the following: (IIg-1), (IIg-2), (IIg-3), (IIg-4), (IIg-5), (IIg-6), or a pharmaceutically acceptable salt thereof.66. A compound or a pharmaceutically acceptable salt thereof, as provided in Table 1. 67. A pharmaceutical composition comprising: a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 66; and a pharmaceutically acceptable excipient. 68. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is formulated for oral administration. 69. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition is formulated for injection. 70. A method of treating or preventing axonal degeneration, the method comprising administering to an individual in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 66, or a pharmaceutical composition according to any one of claims 66 to 68. 71. The method of claim 70, wherein the individual is a person. 72. The method of claim 70 or 71, wherein the individual (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration. 73. A method for treating a neurodegenerative disease, the method comprising administering to an individual in need a therapeutically effective amount of a compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 66 to 68. 74. The method of claim 73, wherein the neurodegenerative disease is selected from ALS, CIPN, peripheral neuropathy, and MS. 75. The method of any one of claims 70 to 74, wherein the administration is via an oral route. 76. The method of any one of claims 70 to 74, wherein the administration is via injection. 77. A method for inhibiting SARM1, the method comprising contacting a biological sample with a therapeutically effective amount of a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 66 to 68. Claims 13 / 13 pages 14 CN 121969615 A ​​Carbamate used as a SARM1 inhibitor

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 588,208, filed October 5, 2023, and U.S. Provisional Patent Application No. 63 / 683,372, filed August 15, 2024, the entire contents of which are incorporated herein by reference.Technical Field

[0003] This invention relates to carbamate compounds of formula (I) as further detailed herein, for inhibiting the SARM1 (selective androgen receptor modulator 1) protein, compositions comprising these compounds, and methods of treatment by administration of said compounds and compositions. Background Art

[0004] Axon degeneration is a hallmark of several neurological disorders, including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (see, for example, Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 3482016, pp. 453-457 and Krauss et al., (2020) Trends Pharmacol. Sci.41, 281, each of which is cited herein by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. In the United States alone, the costs associated with these diseases currently exceed hundreds of billions of dollars annually. Because the incidence of many of these diseases and ailments increases with age, their incidence is rapidly increasing as demographics change.Summary of the Invention

[0005] In one aspect, this disclosure relates to a compound of formula (I):

[0006] (I),

[0007] or a pharmaceutically acceptable salt thereof,

[0008] wherein:

[0009] ring A is; or;

[0010] X1 is CR7 or N;

[0011] X2 is CR4, CHR4 or N;

[0012] X3 is absent, CH, CH2, NH or S; Specification 1 / 119 page 15 CN 121969615 A ​​

[0013] X4 is N, CH2, CH, NH, O or S;

[0014] X5 is CR8;

[0015] Y is absent, CR5R6 or CH2CH2, wherein R5 and R6 are independently H, OH, CN, halogenated, C1-6 alkyl or C1-6 cycloalkyl, or R5 R6 and the carbons bonded to them form a C3-6 cycloalkyl group;

[0016] Z is CH or N;

[0017] One of Q1 and Q2 is N and the other is CR4;

[0018] One of Q3 and Q4 is N and the other is CR4; or Q3 and Q4 are CR4;

[0019] R1a is H or a C1-6 alkyl group;

[0020] R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl and C1-6 substituted with C6-10 aryl or C1-6 haloalkoxy Alkyl; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, and C3-6 cycloalkyl; or

[0021] R1a and R1b together with the carbons to which they are bonded form a C3-6 cycloalkyl;

[0022] R2 is H, OH, CN, or C1-6 alkyl;

[0023] R3 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0024] R4 is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;

[0025] R7 and R8 The presence of -CH2- bridges between the carbon atoms to which they are connected;

[0026] indicates the connection point with the rest of the compound; and

[0027] indicates a single bond or a double bond.

[0028] Methods for preparing the compound and methods for using the compound to treat SARM1-mediated diseases and symptoms are also provided. Detailed Description

[0029] Definitions

[0030] The term "halogen" or "halo" refers to F, Cl, Br, or I. Additionally, terms such as "haloalkyl" mean including both monohaloalkyl and polyhaloalkyl.

[0031] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In one example, the alkyl group is one to eighteen carbon atoms (C1-18). In other examples, the alkyl group is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3.Examples of alkyl groups include methyl (Me, –CH3), ethyl (Et, –CH2CH3), 1-propyl (n-Pr, n-propyl, –CH2CH2CH3), 2-propyl (i-Pr, isopropyl, –CH(CH3)2), 1-butyl (n-Bu, n-butyl, –CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, –CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, –CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, –C(CH3)3), 1-pentyl (n-pentyl, –CH2CH2CH2CH2CH3), 2-pentyl (–CH(CH3) CH2CH2CH3), 3-pentyl (–CH(CH2CH3)2), 2-methyl-2-butyl (–C(CH3)2CH2CH3), 3-methyl-2-butyl (–CH(CH3)CH(CH3)2), 3-methyl-1-butyl (–CH2CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3) CH2CH3), 1-hexyl (–CH2CH2CH2CH2CH2CH3), 2-hexyl (–CH(CH3)CH2CH2CH2CH3), 3-hexyl (–CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (–CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (–CH(CH3)CH2CH(CH3)) 2) 3-Methyl-3-pentyl (–C(CH3)(CH2CH3)2), 2-Methyl-3-pentyl (–CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (–C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (–CH(CH3)C(CH3)3), 1-heptyl, and 1-octyl.

[0032] The terms “cyano” or “nitrile” refer to –C≡N or –CN.

[0033] The term “haloalkoxy” refers to –O-haloalkyl.

[0034] The term “hydroxyl” refers to –OH.

[0035] The term “hydroxyalkyl” refers to an alkyl group substituted with one hydroxyl group.

[0036] The term "aryl" refers to a carbocyclic aromatic group, whether or not fused with one or more groups, having a specified number of carbon atoms, or, if not specified, a maximum of 14 carbon atoms. One example includes an aryl group having 6 to 14 carbon atoms. Another example includes an aryl group having 6 to 10 carbon atoms.Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrene, naphthacenyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, etc. (see, for example, Lang's Handbook of Chemistry (Dean, JA, editor), 13th edition, Table 7-2

[1985] ). A specific aryl group is phenyl.

[0037] The term "cycloalkyl" refers to a saturated hydrocarbon cycloalkyl group. Cycloalkyl encompasses monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, and saturated ring systems. In one example, the cycloalkyl group has 3 to 12 carbon atoms (C3-12). In other examples, the cycloalkyl is C3-7, C3-8, C3-10, or C5-10. In other examples, the cycloalkyl group as a monocyclic ring is C3-8, C3-6, or C5-6. In another example, the cycloalkyl group as a bicyclic ring is C7-C12. In another embodiment, the cycloalkyl group as a spirocyclic system is C5-12. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridging bicyclic cycloalkyl groups include, but are not limited to, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Examples of spirocyclic alkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0038] The term “heteroaryl” refers to any monocyclic, bicyclic, or tricyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in one exemplary embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, editor), 13th edition, Tables 7-2

[1985] . This definition includes any bicyclic group in which any of the aforementioned heteroaryl rings is fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is attached to the remainder of the molecule. In one embodiment, a heteroaryl group comprises a 5- or 6-membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen.Exemplary heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxtriazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, tetraazinyl, tetrazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, and purine, as well as benzofused derivatives, such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazole, and indolyl.

[0039] In a particular embodiment, the heteroaryl group is attached at a carbon atom of the heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole rings; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole rings; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole rings; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0040] In some embodiments, the heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazole, 2-imidazoline, 3-imidazoline, pyrazole, pyrazole, 2-pyrazole, 3-pyrazole, piperidine, piperazine, indole, dihydroindole, 1H-indazole, at the 2 position of isoindole or isodihydroindole, at the 4 position of morpholine, and at the 9 position of carbazole or β-carbline.

[0041] "Fused" means any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with existing ring structures in the compounds of the present invention.

[0042] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0043] Unless otherwise indicated, the terms "compound(s) of the invention" and "compound(s) of the present invention" include formulas (I), (II), (III), (IV), (IIa) to (IIg), (IIIa) and (IIIb), (IVa) and (IVb), (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIc-1), (IIc-2), (IIc-3), (IIb-4), (IIc-5), (IIc-6), (IIc-1), (IIc-2), (IIc-3). (IIc-4), (IIc-5), (IIc-6), (IId-1), (IId-2), (IId-3), (IId-4), (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIf-1), (IIf-2), (IIf-3), (IIf-4), (IIf-5), (IIf-6), (IIg-1), (IIg-2), (IIg-3), (IIg-4), (IIg-5), and (IIg-6) compounds, as well as the compounds listed in this table, including their stereoisomers (including transisomers), geometric isomers, tautomers, isotopes, and salts (e.g., pharmaceutically acceptable salts).

[0044] Unless otherwise stated, the term “optionally substituted” means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range thereof) substituents used in the group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

[0045] As used herein, a wavy line “ " intersecting a bond in a chemical structure indicates the point of connection between an atom connected to a wavy bond in the chemical structure and the remainder of the molecule or the remainder of a molecular segment.

[0046] As used herein, “ " indicates a single or double bond in a chemical structure.

[0047] In some embodiments, it is generally described that a divalent group does not have a specific bonding configuration. It should be understood that, unless otherwise stated, the general description is intended to include both bonding structures.For example, unless otherwise specified, in groups R1-R2-R3, if group R2 is described as -CH2C(O)-, it should be understood that the group can be bonded as R1-CH2C(O)-R3 and R1-C(O)CH2-R3.

[0048] The term "pharmaceutically acceptable" means that the molecular entity and composition, when administered to animals (such as, for example, humans) as appropriate, do not produce adverse, allergic, or other adverse reactions.

[0049] The compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts formed with inorganic and organic acids that retain the bioavailability and properties of the free base and are not biologically or otherwise undesirable. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, dihydronaphthic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0050] The term "pharmaceutically acceptable base addition salt" includes salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific non-toxic organic alkaloids include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0051] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, benzenesulfonate, ethanesulfonate, malonate, sine, ascorbate, oleate, nicotinate, saccharin, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furonate or 3-furonate). Naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanesulfonate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothiocyanate (2-hydroxyethylsulfonate), 2-tris(methyl)benzenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, oxalate, malonate, methylbenzenesulfonate (2-m-benzenesulfonate), naphthalenesulfonate (2-naphthalenesulfonate), camphorsulfonate (camphor-10-sulfonate, e.g., (1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xyleneate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy- 1,1'-dinaphthylmethane-3,3'-dicarboxylic acid ester).

[0052] A "sterile" preparation is sterile or free of all live microorganisms and their spores.

[0053] The term "stereoisomer" refers to a compound having the same chemical composition but with different spatial arrangements of atoms or groups. Stereoisomers include diastereomers, enantiomers, conformational isomers, etc.

[0054] The term "chirality" refers to a molecule that does not overlap with its mirror-image counterpart, while the term "chirality" refers to a molecule that overlaps with its mirror-image counterpart.

[0055] The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0056] The term “enantiomer” refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0057] The stereochemical definitions and conventions used herein generally follow those of S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the symbol for the rotation of a compound with respect to plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally referred to as enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species.

[0058] The terms "tautomer" or "tautomeric form" refer to structural isomers with different energies that interconvert through a low energy barrier. For example, proton tautomers (also called proton-transformed tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions that occur through the recombination of some bonding electrons.

[0059] A “rotation-blocked isomer” is a stereoisomer resulting from the blocking of rotation around a single bond, wherein a sufficiently high rotational barrier is created by an energy difference due to steric strain or other actors, causing individual conformational isomers to separate.

[0060] The invention described herein also covers isotopically labeled compounds of the invention that are the same as those listed herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. All isotopes of any specific atom or element specified are covered within the scope of the compounds of the invention and their uses.Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Certain isotope-labeled compounds of the present invention (e.g., 3H and 14C-labeled compounds) can be used for the determination of compound and / or substrate tissue distribution. Tritium (3H) and carbon-14 (14C) isotopes are available due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or dose reduction requirements), and is therefore preferred in some cases. Positron emission isotopes (such as 15O, 13N, 11C, and 18F) can be used in positron emission tomography (PET) studies to examine the occupancy of substrate acceptors. The isotopically labeled compounds of this invention can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents according to a procedure similar to that disclosed in the examples below.

[0061] The compounds of the invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemic, diastereomer, or enantiomer as starting materials or intermediates. Mixtures of specific diastereomers can be separated or enriched with one or more specific diastereomers by chromatography or crystallization. Similarly, mixtures of enantiomers can be separated or enantiomerically enriched using the same techniques or other techniques known in the art. The asymmetric carbon or nitrogen atoms may each be in the R or S configuration, and both configurations are within the scope of this invention.

[0062] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are considered and included as compounds of the present invention. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, the stereoisomer is specified and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0063] “Subject,” “Individual,” or “Patient” refers to a vertebrate. In some embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), locomotives, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In some embodiments, the mammal is a human. In embodiments involving administration of the compound to a patient, the patient is typically a patient who needs it.

[0064] The terms “inhibition” and “reduction,” or any variations thereof, include any measurable reduction or complete inhibition to achieve the desired result.For example, the activity may be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof, compared to normal. Specification 6 / 119 pages 20 CN 121969615 A ​​

[0065] "Therapeuticly effective amount" means the amount of the compound of the present invention (such as compounds of formula (I), (II), (III) or (IV) or any other formula specified herein) or a pharmaceutically acceptable salt thereof, which (i) treats or prevents a particular disease, symptom or ailment, or (ii) alleviates, improves or eliminates one or more symptoms of a particular disease, symptom or ailment, and optionally (iii) prevents or delays the onset of one or more symptoms of a particular disease, symptom or ailment described herein.

[0066] “Treatment” (and its variants such as “treat” or “treating”) refers to a clinical intervention that attempts to alter the natural course of the treated individual or cells, and may be for prevention or in the course of clinicopathology. Expected therapeutic effects include preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, stabilizing (i.e., not worsening) the condition, slowing the rate of disease progression, improving or alleviating the condition, prolonging survival (compared to expected survival if treatment were not received), and alleviating or improving prognosis. In some embodiments, the compounds of the invention are used to delay the development of a disease or condition or to slow the progression of a disease or condition. Those requiring treatment include those who already have a condition or condition and those who are susceptible to a condition or condition (e.g., through gene mutations) or those who have a condition or condition to prevent.

[0067] As used herein, the term “therapeutic effect” encompasses therapeutic benefits and / or preventive benefits as described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0068] As used herein, the terms “co-administration,” “combination administration,” and their grammatical equivalents cover the administration of two or more formulations to an animal (including a human) such that both formulations and / or their metabolites are present in the animal. Co-administration includes simultaneous administration of a single composition, administration of a single composition at different times, or administration of a composition in which both formulations are present.

[0069] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds having the biological function of inhibiting a target protein by inhibiting the activity or expression of a protein such as SARM1.Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the preferred antagonists herein interact specifically with the target (e.g., bind), compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with the occurrence, growth, or spread of tumors.

[0070] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically rich atoms. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Isotope-labeled compounds (e.g., 3H and 14C-labeled compounds) can be used for the determination of compound or substrate tissue distribution. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are available due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or dose reduction requirements). In some embodiments, in the compounds of the present invention, one or more carbon atoms are replaced with 13C- or 14C-rich carbon. Positron emission tomography (PET) isotopes (such as 15O, 13N, 11C, and 18F) can be used in PET studies to examine substrate receptor occupancy. Isotope-labeled compounds can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents according to procedures similar to those disclosed in the embodiments or examples herein.

[0071] In particular, it is considered that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention described on page 7 / 119 of this specification, CN 121969615 A, may be used to produce or utilize any compound or composition of the invention.

[0072] Although this disclosure supports the definition of "or" only as an option and "and / or", the term "or" is used to mean "and / or" unless explicitly stated otherwise.

[0073] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of the error of the means or method used to determine that value.

[0074] As used herein, "a" or "an" means one or more unless explicitly stated otherwise. "Another" as used herein means at least a second or more.

[0075] The headings used herein are for compilation purposes only.

[0076] SARM1 Inhibitors

[0077] In one aspect, the present invention provides compounds capable of selectively binding to and / or regulating the SARM1 protein.

[0078] As described herein, one aspect of the invention comprises a compound of formula (I):

[0079] I,

[0080] or a pharmaceutically acceptable salt thereof;

[0081] wherein:

[0082] ring A is; or;

[0083] X1 is CR7 or N;

[0084] X2 is CR4, CHR4 or N;

[0085] X3 is absent, CH, CH2, NH or S;

[0086] X4 is N, CH2, CH, NH, O or S;

[0087] X5 is CR8;

[0088] Y is absent, CR5R6 or CH2CH2, wherein R5 and R6 are independently H, OH, CN, halogenated, C1-6 alkyl or C1-6 cycloalkyl, or R5 and R6 together with the carbons to which they are bonded form a C3-6 cycloalkyl;

[0089] Z is CH or N;

[0090] One of Q1 and Q2 is N and the other is CR4;

[0091] One of Q3 and Q4 is N and the other is CR4, or Q3 and Q4 are CR4;

[0092] R1a is H or C1-6 alkyl;

[0093] R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, bicyclo[1.1.1]pentan-1-yl and C1-6 substituted with C6-10 aryl or C1-6 haloalkoxy. Alkyl; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, and C3-6 cycloalkyl; or specification 8 / 119 page 22 CN 121969615 A ​​

[0094] R1a and R1b together with the carbons to which they are bonded form a C3-6 cycloalkyl;

[0095] R2 is H, OH, CN, or C1-6 alkyl;

[0096] R3 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0097] R4 is H, halo, cyano, C1-6 alkyl, C1-6 Halogenated alkyl or C1-6 hydroxyalkyl;

[0098] R7 and R8 are absent, or form a -CH2- bridge between the carbon atoms to which they are attached;

[0099] indicates the connection point with the rest of the compound; and

[0100] indicates a single bond or a double bond.

[0101] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, X1 is CR7; X2 is CHR4; X3 is absent or CH2; X4 is CH2 or O; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4 is H.

[0102] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, X1 is CR7; X2 is CHR4; X3 is absent; X4 is CH2; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4 is H.

[0103] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, X1 is CR7; X2 is CHR4; X3 is CH2; X4 is O; X5 is CR8; and R7 and R8 form a -CH2- bridge between the carbon atoms to which they are attached. In one such embodiment, R4 is H.

[0104] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is selected from

[0105] , , , and , wherein X1, X2, X3, X4, Q1, Q2, Q3 and Q4 are as defined above. In some such embodiments, X1 is C or N; X2 is CR4 or N; X3 is CH, NH or S; and X4 is N, CH, NH or S. In some embodiments, Q1 is N and Q2, Q3 and Q4 are CR4. In one such embodiment, R4 is H.

[0106] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is, and the compound has formula (II):

[0107] (II),

[0108] wherein Z, Y, X1, X2, X3, X4, R1a, R1b, R2 and R3 are as defined for formula (I).

[0109] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, X1 is C; X2 is N; X3 is NH; and X4 is N.

[0110] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, X1 is C; X2 is CR4; X3 is NH; and X4 is N, wherein R4 is as defined for formula (I). In one such embodiment, R4 is H.

[0111] In some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, X1 is N; X2 is CR4; X3 is CH; and X4 is N, wherein R4 is as defined for formula (I). In one such embodiment, R4 is H.

[0112] In some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, X1 is C; X2 is CR4; X3 is S; and X4 is N, wherein R4 is as defined for formula (I). In one such embodiment, R4 is H.

[0113] In some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, X1 is N; X2 is N; X3 is CH; and X4 is N.

[0114] In some embodiments of compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, X1 is C; X2 is N; X3 is S; and X4 is N.

[0115] In some embodiments of compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, X1 is C; X2 is N; X3 is NH; and X4 is CH.

[0116] In some embodiments of compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, ring A is selected from

[0117] , , , , , , , and. Wherein R4 is as defined for formula (I). In one such embodiment, R4 is H, a halogenated or C1-6 hydroxyalkyl. In one such embodiment, R4 is H.

[0118] In some embodiments of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, ring A is selected from

[0119] , , , , , , , , Specification 10 / 119 page 24 CN 121969615 A, and.

[0120] In some embodiments of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, ring A is selected from

[0121] , , , and.

[0122] In some embodiments of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, ring A is selected from, and.

[0123] According to some embodiments of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, the compounds have formula (IIa):

[0124] (IIa),

[0125] wherein Z, Y, R1a, R1b, R2, R3 and R4 are as defined for formula (I). In one such embodiment, R4 is H.

[0126] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IIb):

[0127] (IIb),

[0128] wherein Z, Y, R1a, R1b, R2 and R3 are as defined with respect to formula (I).

[0129] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IIc): Specification 11 / 119 pages 25 CN 121969615 A ​​

[0130] (IIc),

[0131] wherein Z, Y, R1a, R1b, R2 and R3 are as defined with respect to formula (I).

[0132] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IId):

[0133] (IId),

[0134] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula (I).

[0135] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IIe):

[0136] (IIe),

[0137] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula (I).

[0138] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IIf):

[0139] (IIf),

[0140] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula (I).

[0141] According to some embodiments of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, the compound has formula (IIg): Specification 12 / 119 page 26 CN 121969615 A ​​

[0142] (IIg),

[0143] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula (I).

[0144] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (III):

[0145] (III),

[0146] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula I.

[0147] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (IV):

[0148] (IV),

[0149] wherein Z, Y, R1a, R1b, R2 and R3 are as defined for formula I.

[0150] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (V)

[0151] (V)

[0152] wherein Z, Y, Q1, Q2, Q3, Q4, R1a, R1b, R2 and R3 are as defined herein.

[0153] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (Va)

[0154] (Va)

[0155] wherein Z, Y, Q3, Q4, R1a, R1b, R2 and R3 are as defined herein.

[0156] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), Z is N.

[0157] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), Z is CH.

[0158] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), R3 is H.

[0159] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or pharmaceutically acceptable salts thereof, R3 is methyl, phenyl, or pyridyl.

[0160] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or pharmaceutically acceptable salts thereof, Y is absent.

[0161] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or pharmaceutically acceptable salts thereof, Y is CH2CH2.

[0162] According to some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg) or pharmaceutically acceptable salts thereof, Y is CR5R6, wherein R5 and R6 are as defined for formula (I). In one such embodiment, R5 and R6 are independently H, OH, CN, or halogenated. In one such embodiment, R5 and R6 are H. In one such embodiment, R5 is H and R6 is OH or CN.

[0163] According to some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg) or pharmaceutically acceptable salts thereof, R2 is H, OH, CN, or methyl. In some such embodiments, R2 is H.

[0164] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), and (IIg), or pharmaceutically acceptable salts thereof, R1a is H or methyl. In some such embodiments, R1a is H.

[0165] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), and (IIg), or pharmaceutically acceptable salts thereof, R1a and R1b together with the carbon atoms to which they are bonded form a C3-6 cycloalkyl group.

[0166] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg) or pharmaceutically acceptable salts thereof, R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl and C1-6 alkyl substituted with C6-10 aryl or C1-6 haloalkoxy; wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl and C3-6 cycloalkyl.

[0167] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg) or pharmaceutically acceptable salts thereof, R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted by one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo and C1-6 haloalkyl.

[0168] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), and (IIg), or pharmaceutically acceptable salts thereof, R1b is selected from

[0169] , , , , , , , and , wherein each R9 is independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, and C3-6 cycloalkyl; and p is 0, 1, 2, 3, or 4. In some such embodiments, each R9 is independently selected from C1-6 alkyl, halo, and C1-6 haloalkyl. In some such embodiments, each R9 is independently selected from methyl, halo, and C1 haloalkyl.

[0170] In some embodiments of compounds of formula (I), (II), (III), (IV), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), and (IIg), or pharmaceutically acceptable salts thereof, R1b is selected from

[0171] , , , , , , , , , and, where p is 1 or 2. In some such embodiments, each R9 is independently selected from C1-6 alkyl, halogenated, and C1-6 haloalkyl. In some such embodiments, each R9 is independently selected from methyl, halogenated, and C1 haloalkyl.

[0172] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), R1b is selected from

[0173] , ...

[0174] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), or pharmaceutically acceptable salts thereof, R1b is selected from

[0175] , , , k, , and CF3.

[0176] According to some examples of compounds of formula (I), formula (II), formula (III), formula (IV), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), or pharmaceutically acceptable salts thereof, R1b is.

[0177] According to some embodiments of compounds of formula (I) or formula (III) or pharmaceutically acceptable salts thereof, the compounds have formula (IIIa) or formula (IIIb): Specification 17 / 119 Page 31 CN 121969615 A ​​

[0178] (IIIa)

[0179] (IIIb),

[0180] wherein R6 is H, OH or CN, and R1a and R1b are as defined for formula (I). In one such embodiment, R1a is H and R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted by one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo and C1-6 haloalkyl. In one such embodiment, each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently halogenated.

[0181] According to some embodiments of compounds of formula (I) or formula (IV) or pharmaceutically acceptable salts thereof, the compounds have formula (IVa) or formula (IVb):

[0182] (IVa)

[0183] (IVb),

[0184] wherein R6 is H, OH or CN, and R1a and R1b are as defined for formula (I).In one such embodiment, R1a is H and R1b is selected from C6-10 aryl, 5- to 10-membered heteroaryl and C1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C1-6 alkyl, halo and C1-6 haloalkyl. In one such embodiment, each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently halo.

[0185] According to some embodiments of compounds of formula (I) or formula (V), the compounds have formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf) Specification 18 / 119 pages 32 CN 121969615 A ​​

[0186] (Va) (Vb) (Vc) (Vd) (Ve) (Vf).

[0187] According to some embodiments of compounds of formula (I), formula (II), formula (IIa) or pharmaceutically acceptable salts thereof, the compounds have formula (IIa-1), formula (IIa-2), formula (IIa-3), formula (IIa-4), formula (IIa-5) or formula (IIa-6):

[0188] (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6),

[0189] wherein R1a, R1b and R4 are as defined for formula (I). In one such embodiment, R4 is H.

[0190] According to some embodiments of compounds of formula (I), formula (II), formula (IIb) or pharmaceutically acceptable salts thereof, the compounds have formula (IIb-1), formula (IIb-2), formula (IIb-3), formula (IIb-4), formula (IIb-5) or formula (IIb-6):

[0191] (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6),

[0192] wherein R1a and R1b are as defined for formula (I).

[0193] According to some embodiments of compounds of formula (I), formula (II), formula (IIc) or pharmaceutically acceptable salts thereof, the compounds have formula (IIc-1), formula (IIc-2), formula (IIc-3), formula (IIc-4), formula (IIc-5) or formula (IIc-6):

[0194] (IIc-1), (IIc-2), (IIc-3), (IIc-4), (IIc-5), (IIc-6),

[0195] wherein R1a and R1b are as defined for formula (I).

[0196] According to some embodiments of compounds of formula (I), formula (II), formula (IId) or pharmaceutically acceptable salts thereof, the compounds have formula (IId-1), formula (IId-2), formula (IId-3), formula (IId-4), formula (IId-5) or formula (IId-6):

[0197] (IId-1), (IId-2), (IId-3), (IId-4), (IId-5), (IId-6),

[0198] wherein R1a and R1b are as defined for formula (I).

[0199] According to some embodiments of compounds of formula (I), formula (II), formula (IIe) or pharmaceutically acceptable salts thereof, the compounds have formula (IIe-1), formula (IIe-2), formula (IIe-3), formula (IIe-4), formula (IIe-5) or formula (IIe-6):

[0200] (IIe-1), (IIe-2), (IIe-3), (IIe-4), (IIe-5), (IIe-6),

[0201] wherein R1a and R1b are as defined for formula (I).

[0202] According to some embodiments of compounds of formula (I), formula (II), formula (IIf) or pharmaceutically acceptable salts thereof, the compounds have formula (IIf-1), formula (IIf-2), formula (IIf-3), formula (IIf-4), formula (IIf-5) or formula (IIf-6):

[0203] (IIf-1), (IIf-2), (IIf-3), (IIf-4), (IIf-5), (IIf-6),

[0204] wherein R1a and R1b are as defined for formula (I).

[0205] According to some embodiments of compounds of formula (I), formula (II), formula (IIg), or pharmaceutically acceptable salts thereof, the compounds have formula (IIg-1), formula (IIg-2), formula (IIg-3), formula (IIg-4), formula (IIg-5), or formula (IIg-6):

[0206] (IIg-1), (IIg-2), (IIg-3), (IIg-4), (IIg-5), (IIg-6),

[0207] wherein R1a and R1b are as defined for formula (I).

[0208] According to some embodiments of compounds of formula (I), formula (II), formula (III), formula (IV), or pharmaceutically acceptable salts thereof, the compounds are selected from the compounds in Table 1 below or pharmaceutically acceptable salts thereof.

[0209] Table 1. Exemplary compounds of this disclosure. Salts of such compounds are also considered. See the preparation of such compounds in the Examples section. Compounds for which preparation details are not explicitly described in the examples can be prepared using methods generally known in the art, by modifying the preparation details of other compounds provided herein. Specification 22 / 119 pages 36 CN 121969615 A ​​

[0210] Specification 23 / 119 pages 37 CN 121969615 A ​​Specification 24 / 119 pages 38 CN 121969615 A ​​

[0211] The compounds of the present invention (e.g., compounds of formula (I), (II), (III), or (IV)) or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers defined, in terms of absolute stereochemical structure, as (R)- or (S)- forms of amino acids or as (D)- or (L)- forms. Therefore, the examples encompass all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein (page 25 / 119, 39 CN 121969615 A) contain an alkene double bond or other geometrically asymmetric center, it is intended to indicate that these compounds simultaneously contain both E and Z geometric isomers, unless otherwise stated. Similarly, it is intended to include all tautomer forms.

[0212] Embodiments of the present invention include all forms of rotational isomers and conformationally restricted states of the compounds of the present invention. Also included are hindered isomers, which are stereoisomers resulting from hindered rotation around a single bond, wherein a rotational barrier is formed due to an energy difference caused by steric strain or other effects, sufficient to separate various conformational isomers. For example, some compounds of the present invention may exist as mixtures of hindered isomers, or may be purified or enriched due to the presence of one hindered isomer.

[0213] In some embodiments, the compounds of formula (I), (II), (III), or (IV) are mixtures of hindered isomers. In other embodiments, the compounds of formula (I), (II), (III), or (IV) are substantially pure hindered isomers. In some embodiments, the compounds of formula (I), (II), (III), or (IV) are substantially pure R-h-h-h-isomers. In some other embodiments, the compounds of formula (I), formula (II), formula (III) or formula (IV) are substantially pure R-restricted transisomers.

[0214] Synthesis of SARM1 inhibitors

[0215] The compounds of this disclosure can be prepared by various methods described in the illustrative synthetic reaction schemes shown and described below.The starting materials and reagents used to prepare these compounds are generally available from commercial suppliers (such as Aldrich Chemical Co.) or prepared by methods known to those skilled in the art, according to the methods described in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Vol. 1–21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (eds.) Vol. 1–9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (eds.) Pergamon, Oxford 1984, Vol. 1–9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (eds.) Pergamon, Oxford 1996. Volumes 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods that can be used to synthesize the compounds of the present invention, and various modifications can be made to these synthetic reaction schemes in light of the disclosure contained herein, and suggestions are provided to those skilled in the art.

[0216] For illustrative purposes, the following reaction schemes provide pathways for synthesizing the compounds of the present invention and key intermediates. For detailed descriptions of each reaction step, please refer to the following example section. Those skilled in the art will understand that other synthetic routes can be used. Although certain specific starting materials and reagents are described in the process and discussed below, other starting materials and reagents can be substituted to provide various derivatives or reaction conditions. In addition, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art, according to the present disclosure.

[0217] If necessary, the starting materials and intermediates of the synthetic reaction schemes can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc.Such raw materials can be characterized using conventional methods, including physical constants and spectral data.

[0218] Unless otherwise stated, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, in a temperature range of about -78°C to about 150°C, more preferably in a temperature range of about 0°C to about 125°C, and most preferably and conveniently at about room temperature (or ambient temperature) or about 20°C.

[0219] Some of the compounds in the following embodiments have broadly defined substituents; however, those skilled in the art will readily recognize that the nature of the substituents can be varied to provide various compounds contemplated in the present invention. Furthermore, the reaction conditions are exemplary and are described on pages 26 / 119 of CN 121969615 A, and alternative conditions are well known. The reaction sequence in the following examples is not intended to limit the scope of the invention as described in the claims.

[0220] Those skilled in the art will recognize that the chemical reactions described herein can be readily applied to the preparation of other compounds of the present invention. For example, the synthesis of non-exemplary compounds according to the invention can be successfully achieved by modifications obvious to those skilled in the art, such as by appropriately protecting the interfering group, utilizing other suitable reagents known in the art, or by conventionally modifying the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of the invention.

[0221] Treatment methods using SARM1 inhibitors and uses of SARM1 inhibitors

[0222] This disclosure provides a variety of uses and applications of the compounds and / or compositions as described herein, for example, based on the activity and / or characteristics of the compounds and / or compositions as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, production, and / or other technical uses.

[0223] In one aspect, this disclosure provides a method comprising administering one or more compounds of formula (I) to an individual, for example, to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of formula (I) is a SARM1 inhibitor.

[0224] For example, in one aspect, this disclosure provides a method for treating or preventing axonal degeneration, the method comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one aspect, the individual is a person. In one aspect, the individual suffers from or is at risk of developing a condition characterized by axonal degeneration.

[0225] Another embodiment of this disclosure relates to a method for inhibiting SARM1 activity in an individual of need, the method comprising the step of administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0226] Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays, gene expression studies, and identification of biological targets.

[0227] In some embodiments, this disclosure relates to a method for treating axonal degeneration of a biological sample or inhibiting SARM1 in a biological sample, the method comprising the step of contacting the biological sample with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can be used, for example, as a method for inhibiting the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may be used as stabilizers to promote the survival of neurons in vitro.

[0228] In some embodiments, the compounds and / or pharmaceutical compositions of this disclosure inhibit the NAD enzyme activity of SARM1. Alternatively or additionally, in some embodiments, the compounds or pharmaceutical compositions of this disclosure alleviate one or more properties of neurodegeneration. In some embodiments, this disclosure provides a method of treating a neurodegenerative disease or disorder comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one aspect, neurodegenerative diseases are associated with axonal degeneration. In one aspect, neurodegenerative diseases are selected from amyotrophic lateral sclerosis (ALS), chemotherapy-induced peripheral neuropathy (CIPN), peripheral neuropathy, and multiple sclerosis (MS). Specification 27 / 119 pages 41 CN 121969615 A ​​

[0229] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may be used, for example, in medical practice. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may be used, for example, to treat, prevent, or improve axonal degeneration (e.g., one or more of its features or properties). In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may be used, for example, to inhibit axonal degeneration, including axonal degeneration due to reduction or depletion of NAD+.In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axonal damage due to degeneration at the distal axonal end.

[0230] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can be used, for example, as a method for inhibiting the degeneration of neurons or parts thereof in the peripheral nervous system. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can be used, for example, as a method for inhibiting or preventing the degeneration of neurons or parts thereof in the central nervous system. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are characterized by alleviating one or more symptoms or features of neurodegeneration when administered to an individual population. For example, in some embodiments, the associated symptoms or features can be selected from the degree, rate, and / or time of neuronal damage.

[0231] In some embodiments, this disclosure provides compounds that can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents according to this disclosure. The compounds provided in this disclosure also facilitate the study of SARM1 activity in biological and pathological phenomena and the comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo. In some embodiments, this disclosure provides assays for identifying and / or characterizing the compounds and / or compositions provided herein. In some embodiments, the provided assay utilizes specific reagents and / or systems (e.g., certain vector constructs and / or peptides) that can be used to determine SARM1 activity. For example, in some embodiments, the provided assay may utilize one or more labeled versions of SAM-TIR and / or TIR domains, for example, in which the SARM1 N-terminal self-inhibition domain is deleted.

[0232] In some embodiments, one or more compound and / or pharmaceutical compositions as described herein may be used as, for example, a method for inhibiting the degeneration of neurons derived from a subject. In some embodiments, one or more compound and / or pharmaceutical compositions as described herein may be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In some embodiments, one or more compound and / or pharmaceutical compositions as described herein may be used as stabilizers that promote the survival of neurons in vitro.

[0233] In some embodiments, one or more compound and / or pharmaceutical compositions as described herein may be used, for example, to affect biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers may be detected systemically or using samples from the subject's CSF, plasma, serum, and / or tissues. In some embodiments, one or more compound and / or compositions may be used to affect changes in the concentrations of NF-L and / or NF-H contained in the subject's CSF. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0234] In some embodiments, one or more biomarkers of neurodegeneration include: the concentration of NF-L in one or more of the subject's CSF, blood, and plasma samples; the concentration of NF-H in one or more of the subject's CSF, blood, and plasma samples; the concentration of ubiquitin C-terminal hydrolase L1 (UCH-L1) in one or more of the subject's CSF, blood, and plasma samples; the concentration of α-synuclein in one or more of the subject's CSF, blood, and plasma samples; the constitutive NAD+ level in the subject's neurons and / or axons; the constitutive cADPR level in the subject's neurons and / or axons; and albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, GFAP, hFABP, etc., in one or more of the subject's CSF, blood, plasma, skin biopsy, nerve biopsy, and brain biopsy samples. The levels of MCP-1, neurogranulin, NSE, sAPPα, sAPPβ, sTREM 2, phosphorylated tau, or total tau; and the levels of C-C motif chemokine ligand (CCL)2, CCL7, CCL12, colony-stimulating factor (CSF)1, or interleukin (IL)6 in one or more of the following samples from the subject: cerebrospinal fluid (CSF), blood, plasma, skin biopsy, nerve biopsy, and brain biopsy.

[0235] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may affect detectable changes in the levels of one or more neurodegenerative-related proteins in the subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, GFAP, hFABP, MCP-1, neurogranulin, NSE, sAPPα, sAPPβ, sTREM 2, phosphorylated tau, and / or total tau. In some embodiments, one or more compounds and / or compositions as described herein may affect changes in cytokines and / or chemokines (including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or 1l6).

[0236] In some embodiments, compounds and / or compositions as described herein may be administered to an individual suffering from one or more diseases, disorders, or conditions. In some embodiments, one or more diseases, disorders, or conditions are mediated by SARM1.

[0237] In some embodiments, neurodegenerative diseases or disorders include acute or chronic diseases or disorders of the peripheral nervous system (PNS), acute or chronic diseases or disorders of the central nervous system (CNS), or diseases associated with neurodegeneration.

[0238] In some embodiments, neurodegenerative diseases or disorders include acute diseases or disorders of the PNS. In some embodiments, acute diseases or disorders of the PNS are the result of mechanical injury, thermal injury, or injury caused by chemical agents or chemotherapy. In some embodiments, mechanical injury includes compressive or nerve crush injury or pressure injury. In some embodiments, compressive or nerve crush injury includes carpal tunnel syndrome, direct trauma, penetrating injury, contusion, fracture, or bone dislocation. In some embodiments, pressure injury includes pressure involving superficial nerves, pressure from a tumor, or increased intraocular pressure. In some embodiments, chemical agents or chemotherapy include cytotoxic anticancer agents, thalidomide, epothilone, taxane, vinca alkaloids, proteasome inhibitors, platinum-based drugs, or regoxetine. In some embodiments, epothilone is ixaprilone. In one embodiment, taxane is paclitaxel or docetaxel. In some embodiments, vinca alkaloids are vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, reoxetine is conjugated monomethylreoxetine E.

[0239] In some embodiments, neurodegenerative diseases or disorders include chronic diseases or disorders of PNS. In some embodiments, chronic diseases or disorders of PNS include systemic diseases, pain disorders, or metabolic diseases or disorders.

[0240] In some embodiments, chronic diseases or disorders of PNS include hereditary neuropathy, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathy, or other peripheral neuropathy.

[0241] In some embodiments, systemic diseases include diabetes, uremia, AIDS, leprosy, nutritional deficiencies, atherosclerosis, enteric neuropathy, axonal lesions, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis.

[0242] In some embodiments, pain disorders include chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasms, back pain, visceral pain, injury pain, toothache, neurogenic pain, neuropathic pain, neuritis, nerve damage, herpes zoster, herniated disc, ligament tear, or diabetes.

[0243] In some embodiments, metabolic diseases or disorders include diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lipid / glycolipid metabolism disorders, nutritional deficiencies, vitamin deficiencies, or mitochondrial disorders.

[0244] In some embodiments, neurodegenerative diseases or disorders include acute diseases or disorders of the CNS. In some embodiments, acute diseases or disorders of the CNS include ischemia, traumatic CNS injury, chemical agent injury, thermal injury, or viral encephalitis.

[0245] In some embodiments, ischemia includes cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritis anterior ischemic optic neuropathy.

[0246] In some embodiments, traumatic CNS injury includes spinal cord injury, TBI, mechanical injury to the head and / or spine, traumatic injury to the head and / or spine, blunt force injury, closed head injury, open head injury, exposure to concussion and / or explosive force, penetrating injury to the CNS, increased intraocular pressure, or injury from forces causing axonal degeneration, stretching, compression, or pure force.

[0247] In some embodiments, viral encephalitis includes enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, Lacrosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-related dementia).

[0248] In some embodiments, neurodegenerative diseases or disorders include chronic diseases or disorders of the CNS.

[0249] In some embodiments, chronic diseases or disorders of the CNS include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lewy Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher disease, Hunter syndrome, progressive multifocal leukoencephalopathy, Alexander disease, congenital myelination deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann syndrome, etc. - Pick's disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Peltozois-Metzbach disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, infectious spongiform encephalopathy, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globus leukodystrophy (Crape's disease), Bassen-Kornzweig syndrome. Syndrome), transverse myelitis, motor neuron disease, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic mild paraplegia, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenal medullary neuropathy, progressive supranuclear palsy (PSP), Friedrich ataxia, or spinal cord injury.

[0250] In some embodiments, chronic diseases or disorders of the CNS include optic nerve disorders, traumatic CNS injury, or metabolic diseases or disorders.

[0251] In some embodiments, optic nerve disorders include acute optic neuropathy (AON), hereditary or idiopathic retinal symptoms, Lieber's congenital amaurosis (LCA), Lieber's hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, extraretinal neuropathy, optic neuritis, optic degeneration associated with multiple sclerosis, Kerr's optic neuropathy, ischemic optic neuropathy, vitamin B12 deficiency, folic acid (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritis anterior ischemic optic neuropathy, exposure to ethanol or cyanide.

[0252] In some embodiments, traumatic CNS injury includes traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury, or chronic traumatic encephalopathy (CTE).

[0253] In some embodiments, metabolic diseases or disorders include diabetes, hypoglycemia, Basen-Kornzweig syndrome, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders.

[0254] In some embodiments, neurodegenerative diseases or disorders include diseases associated with neurodegeneration. In some embodiments, neurodegenerative diseases or disorders are caused by coagulation problems, inflammation, obesity, aging, stress, cancer, or diabetes.

[0255] In some embodiments, the symptom is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy. CIPN can be associated with a variety of drugs, such as, but not limited to, thalidomide, epothilone (e.g., ixaprazole), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin)).

[0256] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein may be used, for example, to treat one or more neurodegenerative diseases, disorders, or conditions selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein may be used, for example, to treat neuropathy or axonopathy associated with axonopathy. In some embodiments, neuropathy associated with axonopathy is a hereditary or congenital neuropathy or axonopathy. In some embodiments, neuropathy associated with axonopathy is caused by de novo mutation or somatic mutation. In some embodiments, neuropathy associated with axonopathy is selected from the list contained herein. In some embodiments, neuropathy or axonal lesions are associated with axonal degeneration (including, but not limited to, Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS).

[0257] In some embodiments, one or more compounds or pharmaceutical compositions as described herein are characterized by alleviating one or more symptoms or features of neurodegeneration when administered to a subject population. For example, in some embodiments, the associated symptoms or features can be selected from the degree, rate, and / or timing of neuronal damage.In some embodiments, neuronal damage may be or includes axonal degeneration, synaptic loss, dendritic loss, loss of synaptic density, loss of dendritic branching, loss of axonal branching, loss of neuronal density, loss of myelin formation, loss of neuronal cell body, loss of synaptic enhancement, loss of action potential enhancement, loss of cytoskeleton stability, loss of axonal transport, loss of ion channel synthesis and renewal, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capacity, loss of axonal potential conduction, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal damage is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal damage is characterized by the presence of inclusion bodies, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal damage is characterized by the presence of stress granules. In some embodiments, neuronal damage is characterized by the intracellular activation of one or more members of the caspase family. In some embodiments, neuronal damage is characterized by the neuron undergoing programmed cell death (e.g., apoptosis, thermal apoptosis, ferroptosis, and / or necrosis) and / or inflammation.

[0258] In some embodiments, neurodegenerative or neurological diseases or disorders are associated with axonal degeneration, axonal injury, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, and axonal injury caused by leukoencephalopathy or leukodystrophy.In some embodiments, neurodegenerative or neurological diseases or disorders are selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelination reduction, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Perizoise-Metzbach disease, periventricular leukomalacia, glomerular leukodystrophy (Craper's disease), Waller's degeneration, optic neuritis, transverse myelitis, and amyotrophic lateral sclerosis. (Instructions for use, page 31 / 119, 45 CN 121969615 A) (ALS, Louis Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hunt syndrome, traumatic brain injury, radiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, glaucoma, Lieber's hereditary visual atrophy (neuropathy), Lieber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphovirus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Laros virus encephalitis, Bunyavirus encephalitis, childhood viral encephalitis, primary brain tumor. Charcot-Marie-Tooth disease, motor neuron disease, SMA, HSAN, adrenomellary neuropathy, PSP, Friedlich ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonal lesions, Guillain-Barré syndrome, AMAN, Creutzfeldt-Jakob disease, infectious spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial spastic paraplegia, French settlement disease, Strenpel-Lorland disease, and NASH.

[0259] In some embodiments, this disclosure provides SARM1 activity inhibitors for treating neurodegenerative or neurological diseases or disorders involving axonal degeneration or axonal lesions. This disclosure also provides methods for using SARM1 activity inhibitors to treat, prevent, or improve axonal degeneration, axonal lesions, and neurodegenerative or neurological diseases or disorders involving axonal degeneration.

[0260] In some embodiments, this disclosure provides methods for treating neurodegenerative or neurological diseases or disorders associated with axonal degeneration, axonal injury, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, and axonal injury caused by leukoencephalopathy or leukodystrophy.

[0261] In some embodiments, neuropathy and axonal lesions include any disease or condition involving neurons and / or supporting cells (such as glial cells, muscle cells, or fibroblasts), and particularly those involving axonal injury. Axonal injury may be caused by traumatic injury or by non-mechanical injury caused by disease, condition, or exposure to toxic molecules or drugs. The result of such injury may be axonal degeneration or dysfunction and loss of activity of functional neurons. Diseases and conditions that produce or are associated with such axonal injury belong to a large number of neuropathological diseases and conditions. Such neuropathy may include peripheral neuropathy, central neuropathy, and combinations thereof. Furthermore, peripheral neuropathy can result from diseases primarily affecting the central nervous system, while central nervous system manifestations can result from substantially peripheral or systemic diseases.

[0262] In some embodiments, peripheral neuropathy may involve damage to peripheral nerves and / or may be caused by neurological diseases or result from systemic diseases. Some such diseases may include diabetes, uremia, infectious diseases (such as AID or leprosy), nutritional deficiencies, vascular or collagen disorders (such as atherosclerosis), and autoimmune diseases (such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis polytuberculitis). In some embodiments, peripheral neuropathy is caused by traumatic (mechanical) injury to the nerves as well as chemical or thermal damage to the nerves. Symptoms of this type of peripheral neuropathy include compressive or nerve compression injuries, such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures, or bone dislocations; pressure involving superficial nerves (ulna, radius, or fibula), which may be due to prolonged use of crutches or staying in one position for too long, or tumors; intraneural hemorrhage; ischemia; exposure to cold or radiation, or certain drugs or toxic substances, such as herbicides or pesticides. In particular, nerve damage can be caused by chemical damage from cytotoxic anticancer agents, such as paclitaxel, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine. Typical symptoms of this type of peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling, or numbness), and pain in the arms, hands, legs, and / or feet. In some embodiments, the neuropathy is associated with mitochondrial dysfunction. (See page 46 of the specification 32 / 119, CN 121969615 A). This type of neurosis can manifest as a decrease in energy levels, specifically a decrease in NAD and ATP levels.

[0263] In some embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy, which includes a wide range of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, in particular, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders. A common feature of these diseases is peripheral nerve involvement caused by structural or functional changes in myelin sheath and axons due to metabolic pathway dysregulation.

[0264] In some embodiments, neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and external retinal neuropathy; optic neuritis and / or degeneration, including neuropathy associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathy, such as Ker's disease and Lieber's hereditary optic neuropathy; ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as Lieber's neuropathy as described above, neurodegenerative diseases caused by nutritional deficiencies (such as vitamin B12 or folic acid deficiency) and toxicities (such as those caused by ethanol or cyanide); neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiencies. Ischemic optic neuropathy also includes non-arteritis anterior ischemic optic neuropathy.

[0265] In some embodiments, neurodegenerative diseases associated with neuropathy or axonal lesions in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function, such as Parkinson's disease, motor neuron disease, and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases. Mechanical injuries, such as glaucoma or traumatic injuries to the head and spine, can also lead to nerve damage and degeneration of the brain and spinal cord. In addition, ischemia and stroke, as well as conditions such as nutritional deficiencies and chemical toxicity (such as with chemotherapeutic agents), can lead to central nervous system neuropathy.

[0266] In some embodiments, this disclosure provides methods for treating neuropathy or axonal lesions associated with axonal degeneration. In some such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of many neuropathy or axonopathy such as, for example, those that are hereditary or congenital, or associated with: Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS.Furthermore, neurodegenerative diseases not mentioned above, and subsets of such diseases, may also be treated using the methods of this disclosure. Such subsets of diseases may include Parkinson's disease or non-Parkinson's disease or Alzheimer's disease.

[0267] In some embodiments, the compound and / or pharmaceutical composition described herein is administered to an individual who has or is susceptible to a disease, disorder, or symptom as described herein; in some embodiments, such disease, disorder, or symptom is characterized by axonal degeneration, such as one of the symptoms mentioned herein.

[0268] In some embodiments, the individual administering the compound or pharmaceutical composition as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0269] In some embodiments, the provided method includes administering a compound of formula (I) to an individual in need. In some such embodiments, the individual is at risk of developing a symptom characterized by axonal degeneration. In some embodiments, the individual has a symptom characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a symptom characterized by axonal degeneration. In some embodiments, the provided method includes administering the composition as described herein to a population of individuals in need. In some embodiments, the population consists of individuals engaged in activities with a high probability of traumatic neuronal injury. In some embodiments, the population consists of athletes engaged in contact sports or other high-risk activities.

[0271] In some embodiments, the individual is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the individual is identified as being at risk of axonal degeneration, for example based on the individual's genotype, a diagnosis of a condition associated with axonal degeneration, and / or exposure to agents and / or conditions that induce axonal degeneration.

[0272] In some embodiments, the individual is at risk of developing a neurodegenerative disease. In some embodiments, the individual is an older person. In some embodiments, the individual is known to have genetic risk factors for neurodegeneration. In some embodiments, the individual has a family history of neurodegenerative disease. In some embodiments, the individual expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the individual comes from a population with a high incidence of neurodegeneration. In some embodiments, the individual has a hexanucleotide repeat amplification in open reading frame 72 of chromosome 9. In some embodiments, an individual has one or more copies of the ApoE4 allele.

[0273] In some embodiments, an individual administering a compound or pharmaceutical composition as described herein may be or includes an individual who has or is susceptible to a neurodegenerative disease, disorder, or condition. In some embodiments, a neurodegenerative disease, disorder, or condition may be or includes traumatic neuronal damage.In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussion and / or explosive force, or penetrating injury into a nerve-innervated area of ​​the brain cavity or body. In some embodiments, traumatic neuronal injury is a force that causes axonal degeneration, stretching, compression, or shearing.

[0274] In some embodiments, the individual is a subject engaged in an activity identified as a risk factor for neuronal degeneration, such as engaging in contact sports or occupations with a high chance of traumatic neuronal injury.

[0275] For example, the individual may be a patient receiving or being prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilone (e.g., ixaprazole), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0276] In some embodiments, the provided method includes administering a pharmaceutical composition as described herein to an individual or a group of individuals based on the presence or absence of one or more biomarkers. In some embodiments, the provided method further includes monitoring the levels of the biomarkers in the individual or group of individuals and adjusting the dosing regimen accordingly.

[0277] Dosage and Administration

[0278] The present invention provides pharmaceutical compositions or medicaments containing a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, and methods for preparing such compositions and medicaments using the compounds of the invention.

[0279] Thus, examples include a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Another example includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0280] In one instance, a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof having the desired purity can be formulated by mixing with a physiologically acceptable excipient, i.e., an excipient that is non-toxic to the recipient at a dosage and concentration in the dosage form at ambient temperature and appropriate pH. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is generally in the range of about 3 to about 8. In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is sterile. The compound of the present invention or a pharmaceutically acceptable salt thereof may be stored, for example, in the form of a solid or amorphous compound, a lyophilized formulation, or an aqueous solution.

[0281] The composition is formulated, measured, and administered in a manner consistent with good medical practice.Factors to be considered in this context include the specific condition to be treated, the severity of the condition, the specific patient to be treated, the individual patient's clinical symptoms, the cause of the condition, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to the practicing physician. The "therapeuticly effective amount" of the compound of the invention to be administered or a pharmaceutically acceptable salt thereof will be determined by such considerations and is the minimum amount required to inhibit SARM1 activity. Typically, this amount may be below the amount toxic to normal cells or the patient as a whole.

[0282] Depending on the method of administration, the pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways. Typically, articles for dispensing include containers in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include intervention protection components to prevent accidental contact with the contents of the package. Additionally, a label describing the contents of the container may be deposited on the container. Appropriate warnings may also be included on the label.

[0283] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include a semi-permeable matrix of a solid hydrophobic polymer containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, said matrix being in the form of a shaped article, such as a film or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactide, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0284] The dosage of the compound of the present invention or a pharmaceutically acceptable salt thereof for treating a human patient may be in the range of about 0.01 mg to about 1000 mg. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated, and the preferences and experience of the attending physician. A given dose can be administered once daily (QD), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic characteristics, including the absorption, distribution, metabolism, and excretion of the specific compound. Additionally, toxicity factors may influence the dosage and administration regimen. When administered orally, pills, capsules, or tablets can be taken daily or at a less frequent frequency within a specified time period. This regimen can be repeated for multiple treatment cycles.

[0285] A therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered by any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, or intralesional administration if local treatment is required. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0286] A therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered in any convenient form of administration, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0287] Conventional formulations are prepared by mixing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof with excipients. Suitable excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbate oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, such as ascorbic acid), colorants (e.g., inorganic pigments, such as iron oxide), and taste and / or odor modifiers, and are well known to those skilled in the art and detailed below, for example, Ansel, H.C., et al., Ansel's specification 35 / 119 pages 49 CN 121969615 A ​​Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R.C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005.The formulation may also contain one or more buffers, surfactants, lubricants, suspending agents, preservatives, opacifiers, flow aids, processing aids, sweeteners, flavoring agents, tasters, diluents, and other known additives to provide an aesthetically pleasing appearance of the pharmaceutical product (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to facilitate the production of the pharmaceutical product (i.e., the drug).

[0288] In some embodiments, the mixture of particles is processed by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and adding suitable excipients thereto, if necessary, to obtain a pharmaceutical formulation for oral administration. Suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose formulations, such as: for example, corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, a disintegrant may optionally be added. Disintegrants, by way of example only, include cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts such as sodium alginate.

[0289] In one embodiment, dosage forms, such as sugar-coated amygdalae and tablets, have one or more suitable coatings. In a particular embodiment, a concentrated sugar solution is used for the coating dosage form. The sugar solution may optionally contain additional components, such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes and / or pigments may also optionally be added to the coating for identification purposes. Additionally, dyes and / or pigments may optionally be used to characterize different combinations of doses of the active compound.

[0290] In some embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-in capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. In a particular embodiment, the push-in capsule contains the active ingredient mixed with one or more fillers. By way of example only, fillers include lactose, binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally stabilizers. In other embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. By way of example only, suitable liquids include one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be optionally added.

[0291] In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for buccal or sublingual administration. By way of example only, formulations suitable for buccal or sublingual administration include tablets, lozenges, or gels.In other embodiments, the compounds described herein are formulated into preparations for parenteral injection, including preparations suitable for bolus or continuous infusion. In certain embodiments, the preparations for injection are present in a unit dosage form (e.g., in an ampoule) or in a multi-dose container. Optionally, a preservative may be added to the injectable preparation. In other embodiments, the pharmaceutical composition is formulated as a sterile suspension, solution, or emulsion in an oily or aqueous solvent suitable for parenteral injection. Parenteral injection preparations may optionally contain formulations such as suspensions, stabilizers, and / or dispersants. In certain embodiments, pharmaceutical preparations for parenteral administration comprise an aqueous solution of the active compound in a water-soluble form. In further embodiments, suspensions of the compounds of the present invention or pharmaceutically acceptable salts thereof are prepared as suitable oily injectable suspensions. By way of example only, suitable lipophilic solvents or media for use in the pharmaceutical compositions described herein include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the aqueous injectable suspension contains substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of high-concentration solutions. Optionally, in other embodiments, the active ingredient may be in powder form for reconstitution with a suitable solvent (e.g., sterile, pyrogen-free water) prior to use.

[0292] In some embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. Suitable formulation depends on the chosen route of administration. Any pharmaceutically acceptable technique and excipient may be used as appropriate. Pharmaceutical compositions containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof are prepared in a conventional manner, by way of example only, through conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, encapsulation, coating, or compression processes.

[0293] The pharmaceutical composition comprises at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, described herein as the active ingredient. The active ingredient is in the form of a free acid or a free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds provided herein. Furthermore, the compounds described herein encompass both solvated and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds provided herein are also considered to be disclosed herein.Additionally, the pharmaceutical composition may optionally include other drugs or agents, excipients (such as preservatives), stabilizers, wetting agents or emulsifiers, solution promoters, salts for adjusting osmotic pressure, buffers, and / or other substances of therapeutic value.

[0294] A method of preparing a composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof comprises formulating a compound of the present invention or a pharmaceutically acceptable salt thereof with one or more inert pharmaceutically acceptable excipients to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein are in the form of liquid solutions or suspensions, suitable for use in a solid form in solution or suspension prior to use, or as emulsions. These compositions may also optionally contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0295] In some embodiments, pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof are illustratively available in liquid form, wherein the agent is present in solution, suspension, or both. Typically, when the composition is administered in solution or suspension form, a first portion of the agent is present in solution form, and a second portion of the agent is present in particulate form, in suspension form within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0296] In some embodiments, useful aqueous suspensions comprise one or more polymers as suspending agents. Useful polymers include water-soluble polymers, such as cellulose polymers (e.g., hydroxypropyl methylcellulose), and water-insoluble polymers, such as crosslinked carboxyl-containing polymers. Some pharmaceutical compositions described herein comprise mucosal adhesive polymers selected from, for example, carboxymethyl cellulose, carbomer (acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbofil, acrylic / butyl acrylate copolymer, sodium alginate, and dextran.

[0297] Useful pharmaceutical compositions may also optionally include a solubilizer to aid in the solubility of the compounds of the present invention or pharmaceutically acceptable salts thereof. The term "sorlubilizer" generally includes an agent that results in the formation of a micelle solution or a true solution of the pharmaceutical agent. Certain acceptable nonionic surfactants, such as polysorbate 80, can be used as solubilizers, such as ophthalmologically acceptable glycols, polyethylene glycols, such as polyethylene glycol 400, and glycol ethers.In addition, the available pharmaceutical compositions may optionally include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate / glucose, sodium bicarbonate, and ammonium chloride. The amounts of such acids, bases, and buffers required to maintain the pH of the composition within an acceptable range are included.

[0299] Additionally, the available compositions may optionally include one or more salts in amounts that allow the osmotic concentration of the composition to be within an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride ions, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0300] Other available pharmaceutical compositions may optionally include one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate and thimerosal; stable chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridine chloride.

[0301] Other available compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyethylene terephthalate and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octanol 10 and octanol 40.

[0302] Where desired, other available compositions include one or more antioxidants to enhance chemical stability. By way of example only, suitable antioxidants include ascorbic acid and sodium metabisulfite.

[0303] In some embodiments, the aqueous suspension composition is packaged in a single-dose container that is non-resealable after opening. Optionally, a multi-dose resealable container is used, in which case a preservative is typically included in the composition.

[0304] In optional embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery carriers or excipients that can be used herein. In some embodiments, organic solvents, such as N-methylpyrrolidone, are also used. In other embodiments, the compounds described herein are delivered using a sustained-release system, such as a semi-permeable matrix of a solid hydrophobic polymer containing a therapeutic agent. A variety of sustained-release materials are available herein. In some embodiments, the sustained-release capsule releases the compound for several weeks up to more than 100 days.

[0305] The present invention also provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary excipient.Veterinary excipients are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials that are inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or via any other intended route.

[0306] Articles

[0307] In another embodiment of the invention, an article, or “kit,” is provided that contains raw materials for treating the diseases and conditions described above. In one embodiment, the kit comprises a container containing the compounds of the invention or pharmaceutically acceptable salts thereof. The kit may also include a label or instruction manual on or associated with the container. The term “instruction manual” is used to refer to the instructions typically included in the commercial packaging of a therapeutic product, which contains information relating to the indications, usage, dosage, administration, contraindications, and / or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. Containers can be formed from a variety of materials such as glass or plastic. The container may contain the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a formulation thereof, which is effective in treating the symptoms, and may have a sterile inlet (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is a compound of the present invention or a pharmaceutically acceptable salt thereof. Optionally or additionally, the article may also include a second container containing a pharmaceutical diluent, such as water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextran solution. It may further include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0308] In another embodiment, the kit is suitable for delivering the compound of the present invention or a pharmaceutically acceptable salt thereof in a solid oral form, such as tablets or capsules. Such kits may include a number of unit doses. An example of such kits is "blister packaging". Blister packaging is well known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals.

[0309] Examples

[0310] The following examples illustrate the preparation and biological evaluation of compounds within the scope of this invention. These examples and preparations are provided to enable those skilled in the art to better understand and practice the invention. They should not be considered as limiting the scope of the invention, but merely as illustrations and representations.

[0311] Abbreviations

[0312] The abbreviations used in the following examples may include: Specification 39 / 119 page 53 CN 121969615 A ​​

[0313]

[0314] Analytical Procedures

[0315] Chiral Analysis Separation Methods: The chiral analysis separation methods (e.g., supercritical fluid chromatography (SFC) and high performance liquid chromatography (HPLC)) used in the following synthetic examples are summarized in the table below. Specification 40 / 119 page 54 CN 121969615 A ​​

[0316] Specification 41 / 119 page 55 CN 121969615 A ​​

[0317] LCMS Analysis Methods

[0318] Agilent 10-min: The experiments were conducted using an Agilent 1290 UHPLC coupled with an Agilent MSD (6140) mass spectrometer system, which used ESI as the ion source. LC separation was performed using a Phenomenex XB-C18, 1.7 mm, 50 × 2.1 mm column at a flow rate of 0.4 ml / min. Mobile phase A (MPA) was water with 0.1% FA, and mobile phase B (MPB) was acetonitrile with 0.1% FA. The gradient started at 2% MPB over 7 minutes and ended at 98% MPB (see manual page 42 / 119, page 56, CN 121969615 A), held at 98% B for 1.5 minutes, and then equilibrated for 1.5 minutes. The LC column temperature was 40 °C. UV absorbance was acquired using a DAD detector, and full scan mass spectrometry was applied in all experiments.

[0319] Agilent 30-min: Experiments were performed using an Agilent 1290 HPLC coupled with an Agilent MSD (6140) mass spectrometer system, which used ESI as the ion source. LC separations were performed on an Agilent Zorbax Eclipse XDB-C18, 3.5 μm, 100 × 3.0 mm column at a flow rate of 0.7 mL / min. Mobile phase A (MPA) was water with 0.1% FA, and mobile phase B (MPB) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min, held at 98% B for 2.5 min, and then equilibrated for 1.5 min. The LC column temperature was 40 °C. UV absorbance was acquired using a DAD detector, and full scan mass spectrometry was applied in all experiments.

[0320] Thermo qE 10-min: Samples were analyzed on a Dionex Ultimate 3000 coupled with a Thermo Scientific Q Exactive HRMS system using ESI as the ionization source. LC separation was performed on a Phenomenex XB-C18, 1.7 μm, 50 × 2.1 mm column at a flow rate of 0.4 ml / min. MPA (mobile phase A) was water with 0.1% FA, and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 7 min, held at 98% MPB for 1.5 min, and then equilibrated for 1.5 min. The LC column temperature was 40 °C. UV absorbance was acquired using a DAD detector, and full scan mass spectrometry was applied in all experiments.

[0321] Thermo qE 30-min: Samples were analyzed on a Dionex Ultimate 3000 coupled with a Thermo Scientific Q Exactive HRMS system using ESI as the ionization source. LC separations were performed on an Agilent Zorbax Eclipse XDB-C18, 3.5 μm, 100 × 3.0 mm column at a flow rate of 0.7 ml / min. MPA (mobile phase A) was water with 0.1% FA, and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min, held at 98% B for 2.5 min, and then equilibrated for 1.5 min. The LC column temperature was 40 °C. UV absorbance was acquired using a DAD detector, and full scan mass spectrometry was applied in all experiments.

[0322] Experimental Procedure

[0323] Intermediate 1: 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0324]

[0325] Step 1: Synthesis of 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0326]

[0327] A mixture of 3,5-dibromo-1H-pyrazole (50.0 g, 221 mmol) and K2CO3 (91.8 g, 664 mmol) in MeCN (350 mL) was stirred at 25 °C for 0.5 h under a nitrogen atmosphere. Then SEM-Cl (40.6 g, 244 mmol, 43.1 mL) was added dropwise at 25 °C and then stirred for 16 h.The mixture was refluxed at 80 °C for 3.5 h. LCMS showed complete depletion of the starting material. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (50.5 g, 142 mmol, 64.1% yield) was given as a colorless oil. LCMS: (ESI, m / z) [M+H]+ = 357, RT = 0.640 min. 1H NMR: (400 MHz, CDCl3) δ ppm -0.04 - 0.12 (m, 9 H) 0.87 - 0.98 (m, 2 H) 3.56 - 3.73 (m, 2 H) 5.44 (s, 2 H) 6.38 (s, 1 H). Instructions for Use, Page 43 / 119, No. 57, CN 121969615 A ​​

[0328] Step 2: Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (INT-1)

[0329]

[0330] Pd(dppf)Cl2 (20.6 g, 28.1 mmol) was added to a mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (200 g, 562 mmol), pyridin-4-ylorganoboronic acid (75.9 g, 617 mmol) and K2CO3 (233 g, 1.68 mol) in dioxane (1000 mL) and H2O (400 mL). The reaction mixture was stirred at 100 °C for 45 minutes under a nitrogen atmosphere. LCMS showed complete depletion of the starting material. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (500 mL) and brine (800 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (800 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1). INT-1 was given as a yellow solid (260 g, 734 mmol, 43.6% yield). LCMS: (ESI, m / z) [M+H]+ = 355, RT = 0.468 min.1H NMR: (400 MHz, CDCl3) δ ppm -0.05 - 0.09 (m, 9 H) 0.86 - 1.06 (m, 2 H) 3.62 - 3.91 (m, 2 H) 5.36 - 5.63 (m, 2 H) 6.52 - 6.80 (m, 1 H) 7.53 - 7.72 (m, 2 H) 8.62 - 8.79 (m, 2 H).

[0331] Intermediate 2: 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one

[0332]

[0333] Step 1: Synthesis of 3-amino-1-(4-chloro-3-fluoro-phenyl)propane-1-ol

[0334]

[0335] LiAlH4 (4.11 g, 108.31 mmol) was added fractionally to a solution of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propionitrile (10.7 g, 54.15 mmol) in THF at 0°C under a nitrogen atmosphere. After stirring at 0°C for 0.5 hours, the resulting mixture was stirred at 60°C for 3 hours. After cooling to 0°C, the reaction was quenched by adding water (4.1 mL), 15% NaOH solution (4.1 mL), and water (8.2 mL). The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 13% to 43% FA in water) to give 3-amino-1-(4-chloro-3-fluoro-phenyl)propane-1-ol (4.5 g, 41% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+ = 204.1

[0336] Step 2: Synthesis specification of 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one (INT-2) 44 / 119 pages 58 CN 121969615 A ​​

[0337]

[0338] CDI (5.16 g, 31.82 mmol) was added fractionally to a solution of 3-amino-1-(4-chloro-3-fluoro-phenyl)propane-1-ol (4.3 g, 21.2 mmol) and DIPEA (11.08 mL, 63.64 mmol) in DCM (120 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by rapid column chromatography (SiO2, 5% methanol in dichloromethane) to give 6-(4-chloro-3-fluoro-phenyl)-1,3-oxazinan-2-one as a white solid (intermediate 2, 2.35 g, 48% yield).1H NMR (CDCl3, 400 MHz): δ 7.41 (t, J = 8.0Hz, 1H), 7.23-7.17 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 5.32- 5.26 (m, 1H) , 3.49 - 3.30 (m, 2H) , 2.25 - 2.16 (m, 1H) , 2.06 - 1.93 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 230.1

[0339] Examples 1a and 1b

[0340]

[0341] Step 1: Synthesis of 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-1-(4-chloro-3-fluorophenyl)propane-1-ol)

[0342]

[0343] DIPEA (4.4 mL, 25.2 mmol) and 3-amino-1-(4-chloro-3-fluorophenyl)propane-1-ol (3.4 g, 8.4 mmol) were added to a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (3 g, 8.4 mmol) in n-BuOH (20 mL). 8.4 mmol). The reaction mixture was stirred at 120 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by rapid column chromatography (SiO2, 90% ethyl acetate in petroleum ether) to give 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-1-(4-chloro-3-fluorophenyl)propane-1-ol (3.5 g, 87% yield) as a yellow solid.LCMS: (ESI, m / z) [M+H]+ = 479.0

[0344] Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol

[0345]

[0346] 3-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-1-(4-chloro-3-fluorophenyl)propane-1-ol (6.0 g, 12.5 mmol), pyridin-4-organoboronic acid (1.8 g, 15 mmol) were prepared. A mixture of K₂CO₃ (5.2 g, 37.51 mmol) and Pd(dppf)Cl₂ (915 mg, 1.25 mmol) in 1,4-dioxane (80 mL) and H₂O (16 mL) was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 80% ethyl acetate in petroleum ether) to give 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol (3.1 g, 52% yield) as a brown solid.

[0347] Step 3: Synthesis of 6-(4-chloro-3-fluoro-phenyl)-3-[5-(4-pyridinyl)-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1,3-oxazinane-2-one

[0348]

[0349] CDI (2.1 g, 12.97 mmol) was added to a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol (3.1 g, 6.48 mmol), DIPEA (4.3 mL, 25.94 mmol) and DMAP (158 mg, 1.3 mmol) in DMF (80 mL). The reaction was stirred at 100°C for 16 hours under a nitrogen atmosphere.After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 3% methanol in dichloromethane) to give 6-(4-chloro-3-fluoro-phenyl)-3-[5-(4-pyridyl)-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1,3-oxazinyl-2-one (2 g, 61% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+ = 478.1

[0350] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one

[0351]

[0352] A solution of 6-(4-chloro-3-fluorophenyl)-3-[5-(4-pyridinyl)-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1,3-oxazin-2-one (2 g, 3.97 mmol) in 5% TFA / HFIP (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in MeOH (50 mL). Adjust the pH of the mixture to 8 with saturated NaHCO3 solution. Filter the mixture and concentrate the filtrate. Dilute the residue with water (10 mL) and extract with ethyl acetate (50 mL x 2). Dry the combined organic layers over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by reversed-phase chromatography (acetonitrile: 25% to 55% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one (800 mg, 54% yield) as a white solid.LCMS: (ESI, m / z) [M+ H]+ = 374.0

[0353] Step 5: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 1a and 1b)

[0354]

[0355] 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (850 mg, 1 μm) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 μm), supercritical CO2 / EtOH + 0.1% NH4OH = 45 / 55; 80 mL / min) 0.47 mmol) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 1a, peak 1, Rt = 2.186 min, 209 mg, 25% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 1b, peak 2, Rt = 2.807 min, 258 mg, 30% yield), both of which are white solids. Example 1a: H NMR (DMSO-d6, 400 MHz): δ 8.67 (d, J=4.8 Hz, 2H), 7.90 (d, J=4.8 Hz, 2H), 7.69 (t, J=8.0 Hz, 1H), 7 .57 (d, J = 10.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 10.4 Hz, 1H), 4.22-4.19 (m, 1H), 4.03-3.97 (m, 1H) , 2.45- 2.40 (m, 1H) , 2.37 - 2.26 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 374.0

[0357] Example 1b: 1H NMR (DMSO‑d6, 400 MHz): δ 8.67 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 4.8 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 10.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 4.22 – 4.19 (m , 1H) , 4.03 -3.97 (m, 1H), 2.45 -2.40 (s, 1H), 2.37 -2.25 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 374.0

[0358] Examples 2a and 2b

[0359]

[0360] Step 1: Synthesis of 6-phenyl-1,3-oxazinan-2-one

[0361] Specification 47 / 119 pages 61 CN 121969615 A ​​

[0362] CDI (1.07 g, 6.61 mmol) was added to a solution of 3-amino-1-phenylpropane-1-ol (1.0 g, 6.61 mmol) in DCM (125 mL). The reaction was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction was quenched with H₂O (30 mL), and the resulting solution was extracted with DCM (30 x 3 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 90% ethyl acetate in petroleum ether) to give 6-phenyl-1,3-oxazinan-2-one (676 mg, 52% yield) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.38-7.26 (m, 5H), 5.73 (s, 1H), 5.37-5.34 (m, 1H), 3.50-3.46 (m, 1H), 3.41-3.36 (m, 1H) , 2.15-2.11 (m, 1H), 2.10-2.08 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 178.1

[0363] Step 2: Synthesis of 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one

[0364]

[0365] DMEDA (0.06 mL, 0.56 mmol) and CuI (108 mg, 0.56 mmol) were added to a mixture of 6-phenyl-1,3-oxazinane-2-one (500 mg, 2.82 mmol) and 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridine (1100 mg, 1.70 mmol) in 1,4-dioxane (25 mL). mmol), K2CO3 (1.17 g, 8.47 mmol). The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 35% ethyl acetate in petroleum ether) to give 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (380 mg, 28% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.71 (s, 2H), 7.63 (d, J = 5.2 Hz, 2H), 7.45-7.33 (m, 5H), 7.16 (s, 1H), 5.47 – 5.44 (m, 1H), 5.37 (s, 2H), 4.16-4.12 (m, 1H), 3.98-3.97 (m, 1H), 3.77-3.73 (m, 2H), 2.45-2.42 (m, 1H), 2.35-2.32 (m, 1H) , 0.97 (t, J = 8.0 Hz, 2H), 0.06 (s, 9H).LCMS: (ESI, m / z) [M+H]+ = 451.6

[0366] Step 3: Synthesis of 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

[0367]

[0368] A solution of 6-phenyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (150 mg, 0.33 mmol) in 5% TFA / HFIP (10 mL, 6.49 mmol) was stirred at room temperature for 3 hours. The mixture was concentrated and saturated NaHCO3 (6 mL) was added. The mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with water (5 mL) and brine (3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 3% methanol in dichloromethane) to give 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazine as a white solid (90 mg, 84% yield). LCMS: (ESI, m / z) [M+H]+ = 320.9

[0369] Step 4: Chiral separation of 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 2a and 2b)

[0370]

[0371] 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (90 mg, 0.28 mmol) was separated by chiral SFC (Chiralcel OD (250 mm x 30 mm, 5 μm), supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to give (R)-6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one as a white solid. (S)-6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 2a, peak 1, Rt = 2.872 min, 18.5 mg, 20% yield) and (S)-6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one as a white solid (Example 2b, peak 2, Rt = 3.860 min, 13.8 mg, 15% yield).

[0372] Example 2a: 1H NMR (DMSO-d6, 400 MHz): δ 13.33 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.46-7.40 (m, 5H), 7.16 (s, 1H), 5.59-5.55 (m, 1H), 3.98-3.87 (m, 2H), 2.42-2.38 (m, 1H), 2.32-2.25 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 321.0

[0373] Example 2b: 1H NMR (DMSO-d6, 400 MHz): δ 13.35 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.46-7.38 (m, 5H), 7.16 (s, 1H), 5.58-5.56 (m, 1H), 3.99-3.87 (m, 2H), 2.41-2.27 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 321.0

[0374] Examples 3a and 3b

[0375]

[0376] Steps 1 to 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

[0377]

[0378] The general procedure described for the preparation of 6-phenyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 2a and 2b) was performed by step 2 In this study, 6-(4-chloro-3-fluorophenyl)-1,3-oxazin-2-one was prepared by replacing 6-phenyl-1,3-oxazin-2-one.LCMS: (ESI, m / z) [M+H]+ = 372.9

[0379] Step 3: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 5 and 6) Instructions 49 / 119 pages 63 CN 121969615 A ​​

[0380]

[0381] By chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 μm), supercritical CO2 / i-PrOH + 0.1% NH4OH = 40 / 60; 80 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (290 mg, 0.78 mmol) were separated at a rate of mL / min to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 3a, peak 1, Rt = 2.359 min, 58 mg, 20% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 3b, peak 2, Rt = 3.850 min, 35 mg, 12% yield) as white solids.

[0382] Example 3a: 1H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.74-7.66 (m, 3H), 7.55-7.36 (m, 2H), 7.14 (s, 1H), 5.62-5.59 (m, 1H), 3.99-3.85 (m, 2H), 2.44-2.40 (m, 1H), 2.27-2.23 (m, 1H).LCMS: (ESI, m / z) [M+H]+ =372.9

[0383] Example 3b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.37 (br s, 1H), 8.66‑8.64 (m, 2H), 7.75‑7.67 (m, 3H), 7.56 ‑ 7.34 (m, 2H) , 7.14 (s, 1H) , 5.63 ‑ 5.59 (m, 1H) , 4.05 ‑ 4.01 (m , 1H) , 3.91 ‑ 3.87 (m , 1H) , 2.45 ‑ 2.40 (m , 1H) , 2.27- 2.24 (m, 1H). LCMS: (ESI, m / z) [M+H]+ =373.0

[0384] Examples 4a and 4b

[0385]

[0386] Step 1: Synthesis of 1-(6-fluoropyridin-3-yl)but-3-en-1-ol

[0387]

[0388] Allyl magnesium bromide (1 M, 55.16 mL, 55.16 mmol) was slowly added to a solution of 6-fluoronicotinaldehyde (6 g, 47.9 mmol) in THF (60 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 hours. The reaction was quenched with saturated NH4Cl (50 mL) solution and extracted with ethyl acetate (60 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 25% ethyl acetate in petroleum ether) to give 1-(6-fluoropyridin-3-yl)but-3-en-1-ol (4 g, 50% yield) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.20 (s, 1H), 7.86-7.81 (m, 1H), 6.94 (dd, J = 8.4, 3.2 Hz, 1H), 5.84-5.75 (m, 1H), 5.23-5.18 (m, 2H), 4.82 (t, J = 6.4 Hz, 1H), 2.57-2.47 (m, 2H), 2.16 (s, 1H).LCMS: (ESI, m / z) [M+H]+ = 168.1 Specification 50 / 119 pages 64 CN 121969615 A ​​

[0389] Step 2: Synthesis of 5-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine

[0390]

[0391] Imidazole (4.9 g, 71.7 mmol) and tert-butylchlorodimethylsilane (5.4 g, 35.8 mmol) were added to a solution of 1-(6-fluoropyridin-3-yl)but-3-en-1-ol (4.0 g, 23.9 mmol) in DCM (60 mL). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 5% ethyl acetate in petroleum ether) to give 5-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine (6 g, 89% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.11 (d , J = 2.0 Hz, 1H) , 7.78 ‑ 7.74 (m, 1H) , 6.90 (dd , J = 2.8, 8.4 Hz, 1H) , 5.77 ‑ 5.68 (m, 1H) , 5.06 ‑ 4.97 (m, 2H) , 4.75 (t, J = 6.0 Hz, 1H) , 2.49 ‑ 2.37 (m, 2H) , 0.88 (s, 9H) , 0.07 (s, 3H) , ‑0.10 (s, 3H). LCMS: (ESI, m / z) [M+H]+ = 282.1

[0392] Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propionaldehyde

[0393]

[0394] K2O5O4 (654 mg, 1.78 mmol) and NaIO4 (13.3 g, 62.1 mmol) were added fractionally to a solution of 5-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-2-fluoropyridine (5.0 g, 17.7 mmol) in THF (100 mL) and water (100 mL) at 0 °C. The reaction was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was extracted with ethyl acetate (200 mL).The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15% ethyl acetate in petroleum ether) to give 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propionaldehyde (2.9 g, 58% yield), a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 9.79 (t, J = 1.6 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.83-7.78 (m, 1H), 6.93 (dd, J = 8.4, 2.8 Hz , 1H) , 5.31 ‑ 5.28 (m, 1H) , 2.94 ‑ 2.88 (m, 1H) , 2.70 ‑ 2.66 (m, 1H) , 0.86 (s, 9H) , 0.08 (s, 3H) , ‑0.11 (s, 3H). LCMS: (ESI, m / z) [M+H]+ = 284.1

[0395] Step 4: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine

[0396]

[0397] 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propanal (1.2 g, 4.23 mmol) in DCE (20 mL). (Instructions 51 / 119 pages 65 CN 121969615 A) Methyl(1,2,4-triazol-5-amine) (1.18 g, 4.06 mmol) and AcOH (0.24 mL, 4.23 mmol). After stirring at room temperature for 30 min, NaBH(OAc)3 (1.35 g, 6.35 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (540 mg, 23% yield), which was a yellow oil. LCMS: (ESI, m / z) [M+H]+ = 559.2

[0398] Step 5: Synthesis of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol

[0399]

[0400] TBAF (1 M, 1.18 mL in THF) was added to a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (440 mg, 0.79 mmol) in THF (5 mL). 1.18 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 90% ethyl acetate in petroleum ether) to give 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol (310 mg, 89% yield) as a yellow solid.LCMS: (ESI, m / z) [M+H]+ = 445.2

[0401] Step 6: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one

[0402]

[0403] DIEA (0.42 mL, 2.56 mmol) and CDI (311) were added to a solution of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)propane-1-ol (285 mg, 0.64 mmol) in DMF (3 mL). The reaction mixture was prepared by stirring at room temperature for 3 hours and then at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 100% ethyl acetate in petroleum ether) to give 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one (260 mg, 86% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H] + = 471.1

[0404] Step 7: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one, page 52 / 119, CN 121969615 A ​​

[0405]

[0406] The solution of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (250 mg, 0.53 mmol) in 5% TFA / HFIP (8 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL) and a saturated NaHCO3 solution (20 mL) was added. The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by reversed-phase chromatography (acetonitrile: 0% to 30% FA in water) to give 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (130 mg, 72% yield) as a white solid. LCMS: (ESI, m / z) [M+ H]+ = 340.9

[0407] Step 8: Chiral separation of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 4a and 4b)

[0408]

[0409] 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (130 μm) was separated by chiral SFC (Chiralpak IG (250 × 30 mm, 10 μm), supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) (mg) to obtain 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 4a, peak 1, Rt = 3.211 min, 32 mg, 25% yield) and 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 4b, peak 2, Rt = 4.506 min, 32 mg, 25% yield), both of which are white solids. Example 4a: H NMR (DMSO-d6, 400 MHz): δ 13.88 (br s, 1H), 8.68 (d, J=6.0 Hz, 2H), 8.38 (d, J=1.6 Hz, 1H), 8.20-8.11 (m, 1H) , 7.90 (d , J = 6.0 Hz, 2H) , 7.30 (dd, J = 8.4, 2.4 Hz, 1H) , 5.78 ‑ 5.75 (m, 1H) , 4.28 ‑ 4.21 (m, 1H) , 4.06 ‑ 3.96 (m, 1H) , 2.46-2.38 (m, 2H).LCMS: (ESI, m / z) [M+H]+ = 340.9

[0411] Example 4b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.88 (br s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.38 (d, J = 1.6 Hz, 1H) , 8.20 ‑ 8.11 (m, 1H) , 7.90 (d , J = 6.0 Hz, 2H) , 7.30 (dd, J = 8.4, 2.4 Hz, 1H) , 5.78 ‑ 5.74 (m, 1H) , 4.28 ‑ 4.20 (m, 1H) , 4.06- 3.97 (m, 1H), 2.46 - 2.38 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 340.9

[0412] Examples 5a and 5b Specification 53 / 119 pages 67 CN 121969615 A ​​

[0413]

[0414] Step 1: Synthesis of 3-amino-1-(3,4-difluorophenyl)propane-1-ol

[0415]

[0416] Under a nitrogen atmosphere at 0°C, LiAlH4 (2.5 M, 33.12 mL, 82.81 mmol) was added dropwise to a solution of 3-(3,4-difluorophenyl)-3-oxo-propionitrile (5.0 g, 27.6 mmol) in tetrahydrofuran (100 mL). After addition, the mixture was stirred at 60°C for 3 hours under a nitrogen atmosphere. After cooling to 0°C, the reaction was quenched with H₂O (3.2 mL), 15% NaOH aqueous solution (3.2 mL), and H₂O (9.6 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give 3-amino-1-(3,4-difluorophenyl)propane-1-ol (5 g crude product), which was used directly in the next step without further purification.LCMS: (ESI, m / z) [M+H]+ = 188.1

[0417] Steps 2 to 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one

[0418]

[0419] The general procedure described for the preparation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 1a / 1b and 2a / 2b) was performed by using 3- The amino-1-(3,4-difluorophenyl)propane-1-ol was used to replace 3-amino-1-(4-chloro-3-fluorophenyl)propane-1-ol to prepare 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinyl-2-one. LCMS: (ESI, m / z) [M+H]+ = 357.9

[0420] Step 6: Chiral separation of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 5a and 5b)

[0421]

[0422] 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (322 mg, 0.90 μL) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 µm), supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) mmol), to obtain 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 5a, peak 1, Rt = 1.942 min, 108 mg, 34% yield) and 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 5b, peak 2, Rt = 2.931 min, 121 mg, 37% yield), both of which are white solids.Example 5a: H NMR (DMSO-d6, 400 MHz): δ 13.83 (s, 1H), 8.67 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.64-7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.38 - 7.32 (m, 1H), 5.69 - 5.64 (m, 1H), 4.27 - 4.20 (m, 1H), 4.06 - 3.96 (m, 1H), 2.46 - 2.28 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 357.9

[0424] Example 5b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.86 (br s, 1H), 8.68 (d, J = 5.6 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.64-7.57 (m, 1H), 7.56-7.49 (m, 1H), 7.38-7.32 (m, 1H), 5.69-5.64 (m, 1H), 4.28-4.20 (m, 1H) , 4.06-3.96 (m, 1H), 2.46–2.28 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 358.0

[0425] Examples 6a and 6b

[0426]

[0427] Step 1: Synthesis of 3-amino-1-(4-fluorophenyl)propane-1-ol

[0428]

[0429] LiAlH4 (2.5 M, 36.78 mL, 91.94 mmol in THF) was added dropwise to a mixture of 3-(4-fluorophenyl)-3-oxopropionitrile (5.0 g, 30.65 mmol) in THF (120 mL) at 0 °C under a nitrogen atmosphere. After the addition, the reaction was stirred at 60 °C for 48 h. After cooling to 0°C, the reaction was quenched with H2O (3.5 mL), 15% NaOH aqueous solution (3.5 mL), and H2O (10 mL). The mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-1-(4-fluorophenyl)propane-1-ol (3 g crude product), which was used directly in the next step without purification.LCMS: (ESI, m / z) [M+H]+ = 170.3

[0430] Steps 2 to 5: Synthesis of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one

[0431]

[0432] The general procedure described for the preparation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one (Examples 1a / 1b and 2a / 2b) was used to prepare 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinan-2-one by replacing 3-amino-1-(4-chloro-3-fluorophenyl)propane-1-ol in step 1. (Specification 55 / 119) Page 69 CN 121969615 A ​​Fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one. LCMS: (ESI, m / z) [M+H]+ = 339.9

[0433] Step 6: Chiral separation of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 6a and 6b)

[0434]

[0435] 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (200 mg, 0.59 μg / min) was separated by chiral SFC (Phenomenex Cellulose-2 (250 mm x 30 mm, 10 µm), supercritical CO2 / EtOH + 0.1% NH4OH = 44 / 56; 150 mL / min). mmol) to obtain 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 6a, peak 1, Rt = 2.273 min, 58 mg, 29% yield) and 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 6b, peak 2, Rt = 2.807 min, 57 mg, 28% yield), both of which are white solids.Example 6a: H NMR (DMSO-d6, 400 MHz): δ 13.81 (s, 1H), 8.68 (d, J = 3.6 Hz, 2H), 7.90 (d, J = 6.0 Hz, 2H), 7.59-7.48 (m, 2H), 7.33-7.24 (m, 2H), 5.67 (dd, J = 10.8, 2.8 Hz, 1H), 4.28-4.17 (m, 1H), 4.07-3.96 (m, 1H), 2.46-2.27 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 339.9

[0437] Example 6b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.85 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 7.90 (d, J = 4.8 Hz, 2H) , 7.60 ‑ 7.49 (m, 2H) , 7.33 ‑ 7.24 (m, 2H) , 5.67 (dd , J = 10.8, 2.8 Hz, 1H) , 4.28 ‑ 4.17 (m , 1H) , 4.07 ‑ 3.95 (m , 1H) , 2.47- 2.24 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 339.9

[0438] Examples 7a and 7b

[0439]

[0440] Steps 1 to 7: Synthesis of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one

[0441]

[0442] The general procedure described for the preparation of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Examples 4a and 4b) was performed by step 1 In this paper, 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1, 2,4-triazol-5-yl)-1,3-oxazin-2-one is prepared by replacing 6-fluoronicotinaldehyde with 6-chloro-5-pyridin-3-aldehyde. (See specification 56 / 119, page 70, CN 121969615 A)LCMS: (ESI, m / z) [M+H]+ = 374.9

[0443] Step 8: Chiral separation of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one (Examples 7a and 7b)

[0444]

[0445] 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazinane-2-one (Examples 7a and 7b) was separated by chiral SFC (Chiralcel OJ (250 mm x 30 mm, 10 µm), supercritical CO2 / i-PrOH + 0.1% NH4OH = 40 / 60; 80 mL / min). 1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (400 mg) was used to give 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 7a, peak 1, Rt = 1.581 min, 95.3 mg, 24% yield) and 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1,3-oxazin-2-one (Example 7b, peak 2, Rt = 2.434 min, 99.9 mg, 25% yield) as white solids. Example 7a: H NMR (DMSO-d6, 400 MHz): δ 13.90 (br s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 8.44 (d, J = 1.6 Hz), 8.15 (dd, J = 8.0, 1.6 Hz, 1H) , 7.90 (d , J = 6.4 Hz, 2H) , 5.81 ‑ 5.78 (m , 1H) , 4.27 ‑ 4.22 (m , 1H) , 4.04 ‑ 3.95 (m , 1H) , 2.54 ‑ 2.50 (m, 1H) , 2.42- 2.34 (m, 1H).LCMS: (ESI, m / z) [M+H] = 374.9

[0447] Example 7b: 1H NMR: (DMSO‑d6, 400 MHz) δ 13.91 (br s, 1H), 8.67 (d, J = 6.0 Hz, 2H), 8.44 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.0, 1.6 Hz,, 1H), 7.90 (d, J = 6.4 Hz, 2H), 5.81-5.78 (m, 1H), 4.27-4.22 (m, 1H), 4.05-3.95 (m, 1H) , 2.54–2.50 (m, 1H), 2.45–2.34 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 374.9

[0448] Examples 8a and 8b

[0449]

[0450] Step 1: Synthesis of 3-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propionitrile 57 / 119 pages 71 CN 121969615 A ​​

[0451]

[0452] n-BuLi (58.5 mL, 146.25 mmol) was added dropwise to a solution of acetonitrile (7.6 mL, 146.25 mmol) in THF (150 mL) at -78 °C under a nitrogen atmosphere. After stirring at -78°C for 20 minutes, a solution of methyl 6-(trifluoromethyl)pyridin-3-carboxylate (15.0 g, 73.12 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 15% EE in petroleum ether (25% ethanol in ethyl acetate)) to give 3-oxo-3-[6-(trifluoromethyl)-3-pyridyl]propionitrile (7.1 g, 45% yield) as a yellow oil. H NMR (DMSO-d6, 400 MHz): δ 8.93 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H).

[0454] Step 2: Synthesis of 3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propionitrile

[0455]

[0456] Sodium borohydride (3.3 g, 86.39 mmol) was added to a solution of 3-oxo-3-[6-(trifluoromethyl)-3-pyridinyl]propionitrile (3.7 g, 17.28 mmol) in MeOH (60 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and concentrated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propionitrile (3.5 g, 94% yield), which was a yellow oil and used directly in the next step without further purification.

[0457] 1H NMR (CDCl3, 400 MHz): δ 8.74 (d, J = 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 5.22 (t, J = 6.0 Hz, 1H), 2.90–2.78 (m, 2H).

[0458] Step 3: Synthesis of 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propane-1-ol

[0459]

[0460] LiAlH4 (2.5 M, 12.2 mL, 30.44 mmol) was added dropwise to a mixture of 3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propionitrile (3.5 g, 15.22 mmol) in THF (70 mL) at 0 °C. The reaction was stirred at 60 °C for 3 hours under a nitrogen atmosphere. After cooling to 0 °C, the reaction was quenched with water (1.5 mL), 15% NaOH aqueous solution (1.5 mL), and water (5 mL). The mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propane-1-ol (3.3 g crude product), which was a yellow oil and used directly in the next step without further purification.

[0461] H NMR (DMSO-d6, 400 MHz): δ 8.71 (s, 1H), 8.02 (dd, J=8.0 Hz, 1H), 7.88-7.85 (m, 1H), 4.88 (t, J=6.4 Hz, 1H), 2.71 - 2.60 (m, 2H), 1.74 - 1.65 (m, 2H).

[0462] Steps 4 to 7: Synthesis of 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one

[0463]

[0464] 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one was prepared by replacing 3-amino-1-(4-chloro-3-fluoro-phenyl)propane-1-ol with 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propane-1-ol in step 1 using the general procedure described for the preparation of 1a / 1b.

[0465] LCMS: (ESI, m / z) [M+H]+ = 391.0

[0466] Step 8: Chiral separation of 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (Examples 8a and 8b)

[0467]

[0468] 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6- ... (trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (127 mg, 0.33 mmol) was used to give 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (Example 8a, peak 1, Rt = 0.976 min, 40 mg, 31% yield) and 3-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (Example 8b, peak 2, Rt = 1.415 min, 38 mg, 30% yield) as white solids. Example 8a: H NMR (DMSO-d6, 400 MHz): δ 13.96 (s, 1H), 8.91 (s, 1H), 8.68 (d, J = 6.0 Hz, 2H), 8.22 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H) , 7.90 (d , J = 5.2 Hz, 2H) , 5.88 ‑ 5.86 (m , 1H) , 4.25 ‑ 4.20 (m , 1H) , 4.08 ‑ 4.00 (m, 1H) , 2.56 ‑ 2.34 (m, 2H).LCMS: (ESI, m / z) [M+H]+ = 391.0

[0470] Example 8b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.89 (s, 1H) , 8.91 (s, 1H) , 8.68 (d, J = 6.0 Hz, 2H) , 8.22 (d, J = 8.8 Hz, 1H) , 8.03 (d, J = 8.0 Hz, 1H) , 7.90 (d , J = 6.0 Hz, 2H) , 5.88 ‑ 5.86 (m , 1H) , 4.27 ‑ 4.22 (m , 1H) , 4.08 ‑ 4.00 (m, 1H) , 2.56–2.34 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 391.0

[0471] Examples 9a and 9b

[0472] Specification 59 / 119 pages 73 CN 121969615 A ​​

[0473] Step 1: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine

[0474]

[0475] 3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propionaldehyde (3 g, 10.5 mmol) was added to DCE (30 mL) and MeOH (30 mL) 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine (3.1 g, 10.5 mmol) and AcOH (60 μL, 1.06 mmol) were added to the solution. The reaction mixture was stirred at 70 °C for 2 hours, and then NaBH(OAc)3 (2 g, 31.7 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 40% ethyl acetate in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (3.6 g, 61% yield), which was a yellow oil.

[0476] LCMS: (ESI, m / z) [M+H]+ = 558.3 ​​

[0477] Step 2: Synthesis of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol

[0478]

[0479] TBAF (1 m, 8 mL, 8 mmol in THF) was added to a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (3 g, 5.3 mmol) in THF (30 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 80% ethyl acetate in petroleum ether) to give 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol (2.1 g, 88% yield), a brown oil.

[0480] LCMS: (ESI, m / z) [M+H]+ = 444.2

[0481] Step 3: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Instructions for Synthesis, 60 / 119 pages, 74 CN 121969615 A)

[0482]

[0483] Add DIPEA to a solution of 1-(6-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol (1.6 g, 3.76 mmol) in DMF (17 mL). (2.5 mL, 15.06 mmol), CDI (1.8 g, 11.29 mmol), and DMAP (91 mg, 0.75 mmol). The reaction was stirred at room temperature for 1 hour and then heated at 100 °C for 16 hours. Ethyl acetate (150 mL) was added, and the organic layer was washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 80% ethyl acetate in petroleum ether) to give 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (1.3 g, 74% yield) as a yellow solid.

[0484] LCMS: (ESI, m / z) [M+H]+ = 470.2

[0485] Step 4: Synthesis of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0486]

[0487] A solution of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (800 mg, 1.7 mmol) in 15% TFA / HFIP (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was redissolved in ethyl acetate (20 mL) and washed with NaHCO3 solution (20 mL). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The crude product was purified by reversed-phase chromatography (acetonitrile: 20% to 50% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (500 mg, 86% yield) as a white solid.

[0488] Step 5: Chiral separation of 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 9a and 9b)

[0489]

[0490] 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (500 mg, 1.47 μm) was separated by chiral SFC (Chiralcel SS (250 mm x 25 mm, 10 μm), supercritical CO2 / MeOH + 0.1% NH4OH = 55 / 45; 80 mL / min) mmol) to obtain 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 9a, peak 1, Rt = 3.268 min, 195.1 mg, 38% yield) and 6-(6-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 9b, peak 2, Rt = 4.010 min, 201.6 mg, 39% yield), both of which are white solids.

[0491] Example 9a: 1H NMR (DMSO-d6, 400 MHz): δ 13.34 (br s, 1H), 8.66-8.61 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H), 8.16-8.10 (m, 1H), 7.76-7.71 (m, 2H), 7.29 (dd, J = 2.8, 8.8 Hz, 1H), 7.14 (s, 1H), 5.71-5.64 (m, 1H), 4.10-4.00 (m, 1H), 3.96 - 3.84 (m, 1H), 2.47 - 2.28 (m, 2H).LCMS: (ESI, m / z) [M+H]+ = 339.9

[0492] Example 9b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.56 (br s, 1H), 8.66‑8.61 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H) , 8.17 ‑ 8.09 (m, 1H) , 7.76 ‑ 7.70 (m, 2H) , 7.29 (dd, J = 2.8, 8.4 Hz, 1H) , 7.14 (s, 1H) , 5.72 ‑ 5.62 (m, 1H) , 4.12 ‑ 3.99 (m, 1H) , 3.96–3.84 (m, 1H), 2.47–2.30 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 340.0

[0493] Examples 10a and 10b

[0494]

[0495] Step 1: Synthesis of tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)

[0496]

[0497] Ditert-butyl dicarbonate (6.6 mL, 28.9 mmol) and triethylamine (10.0 mL, 72.1 mmol) were added to a solution of 3-amino-1-(3,4-difluorophenyl)propane-1-ol (4.5 g, 24.0 mmol) in DCM (90 mL). The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 50% ethyl acetate in petroleum ether) to give tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)carbamate (1.5 g, 23% yield), which was a brown oil. H NMR (DMSO-d6, 400 MHz): δ 7.37-7.31 (m, 2H), 7.17-7.12 (m, 1H), 6.77 (s, 1H), 5.39 (d, J = 4.8 Hz, 1H), 4.59- 4.52 (m, 1H) , 3.01 - 2.91 (m, 2H) , 1.70 - 1.62 (m, 2H) , 1.36 (s, 9H).

[0499] Step 2: Synthesis of 6-(3,4-difluorophenyl)-1,3-oxazinane-2-one

[0500]

[0501] Under a nitrogen atmosphere at 0°C, tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)carbamate (1.72 g, 5.99 mmol) was added to a solution of NaH (60% in mineral oil, 359 mg, 8.98 mmol) in anhydrous DMF (25 mL). After stirring at 0°C for 0.5 hours, the mixture was warmed to room temperature for 2 hours. The reaction mixture was quenched and concentrated with saturated NH4Cl solution (10 mL). The residue was purified by rapid column chromatography (SiO2, 0% to 15% ethyl acetate in petroleum ether) to give 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one (720 mg, 49% yield) as a yellow oil.

[0502] 1H NMR (CDCl3, 400 MHz): δ 7.24–7.13 (m, 3H), 6.98 (s, 1H), 5.32–5.20 (m, 1H), 3.48–3.35 (m, 2H), 2.20–2.10 (m, 1H), 2.08–1.94 (m, 1H).

[0503] Step 3: Synthesis of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one

[0504]

[0505] DMEDA (0.1 mL, 0.6 mmol), K2CO3 (1.4 g, 10.1 mmol), and CuI (120 mg, 3.8 mol) were added to a mixture of 6-(3,4-difluorophenyl)-1,3-oxazinane-2-one (670 mg, 3.1 mmol), 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (1.3 g, 3.8 mol) in 1,4-dioxane (15 mL). (0.6 mmol). The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 0% to 30% ethyl acetate in petroleum ether) to give 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (870 mg, 53% yield) as a white solid.

[0506] LCMS: (ESI, m / z) [M+H]+ = 487.2

[0507] Step 4: Synthesis of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0508]

[0509] A solution of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (620 mg, 1.3 mmol) in 5% TFA / HFIP (28 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and saturated NaHCO3 (6 mL) was added. The mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with water (5 mL) and brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (450 mg, 71% yield) as a white solid, which was used directly in the next step without further purification.

[0510] LCMS: (ESI, m / z) [M+H]+ = 357.1

[0511] Step 5: Chiral separation of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinyl-2-one (Examples 10a and 10b) (Instructions for reference 63 / 119, page 77, CN 121969615 A)

[0512]

[0513] Separation of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinyl-2-one by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 μm), supercritical CO2 / i-PrOH + 0.1% NH4OH = 40 / 60; 80 mL / min) 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (450 mg, 1.26 mmol) was prepared as a white solid to give 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 10a, peak 1, Rt = 1,485 min, 122 mg, 27% yield) and 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 10b, peak 2, Rt = 2,426 min, 132 mg, 29% yield) as a white solid. Example 10a: H NMR (DMSO-d6, 400 MHz): δ = 13.35 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.60-7.48 (m, 2H) , 7.35 ‑ 7.29 (m, 1H) , 7.16 (s, 1H) , 5.61 ‑ 5.52 (m, 1H) , 4.08 ‑ 3.98 (m, 1H) , 3.94 ‑ 3.830 (m, 1H) , 2.44 ‑ 2.35 (m, 1H) , 2.33- 2.20 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 357.1

[0515] Example 10b: 1H NMR (DMSO-d6, 400 MHz): δ = 13.34 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.60–7.48 (m, 2H), 7.35–7.29 (m, 1H), 7.15 (s, 1H), 5.61–5.52 (m, 1H), 4.08–3.98 (m, 1H), 3.94–3.83 (m, 1H), 2.44–2.35 (m, 1H), 2.33–2.20 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 357.1

[0516] Examples 11a and 11b

[0517]

[0518] Step 1: Synthesis of 6-(4-fluorophenyl)-1,3-oxazinan-2-one

[0519]

[0520] CDI (1.44 g, 8.87 mmol) was added to a solution of 3-amino-1-(4-fluorophenyl)propane-1-ol (1.0 g, 5.91 mmol) and DIPEA (3.09 mL, 17.73 mmol) in THF (40 mL). The mixture was stirred at room temperature for 2 hours and then stirred at 60 °C for 16 hours. The mixture was concentrated and the residue was purified by reversed-phase chromatography (acetonitrile: 18% to 48% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-fluorophenyl)-1,3-oxazin-2-one (260 mg, 19% yield) as a white solid. H NMR (CDCl3, 400 MHz): δ 7.41-7.33 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 5.65 (s, 1H), 5.33 (dd, J = 2.8, 10.4 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.45 - 3.37 (m, 1H), 2.26 - 2.17 (m, 1H), 2.14 - 2.05 (m, 1H).

[0522] LCMS: (ESI, m / z) [M+H]+ = 196.1

[0523] Step 2: Synthesis of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one

[0524]

[0525] 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (400 mg, 1.13 mmol), 6-(4-fluorophenyl)-1,3-oxazinane-2-one (220 mg, 1.13 mmol) were added to 1,4-dioxane (6 mL). DMDACH (0.02 mL, 0.23 mmol), CuI (43 mg, 0.23 mmol), and K2CO3 (468 mg, 3.39 mmol) were added to the mixture. The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 50% EE in petroleum ether (ethyl acetate / ethanol = 3 / 1)) to give 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 38% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.74-8.68 (m, 2H), 7.63-7.57 (m, 2H), 7.47-7.37 (m, 2H), 7.15-7.07 (m, 3H), 5.33 (dd , J = 2.8, 10.0 Hz, 1H) , 5.37 (s, 2 H) , 4.22 ‑ 4.14 (m, 1H) , 4.03‑3.91 (m, 1H) , 3.75 (t, J = 8.4 Hz, 2H) , 2.49 ‑ 2.39 (m , 1H) , 2.36 - 2.24 (m, 1H), 1.00 - 0.94 (m, 2H), 0.03 - 0.00 (m, 9H).

[0527] Step 3: Synthesis of 6-(4-fluorophenyl)-3-[3-(4-pyridinyl)-1H-pyrazol-5-yl]-1,3-oxazinan-2-one

[0528]

[0529] A mixture of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 0.43 mmol) in 5% TFA / HFIP solution (6 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and adjusted to pH = 8 with saturated NaHCO3 solution. The organic phase was separated and the aqueous phase was extracted with DCM (5 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 29% to 59% / 0.05% NH₄OH in water + 10 mM NH₄HCO₃) to give 6-(4-fluorophenyl)-3-[3-(4-pyridyl)-1H-pyrazol-5-yl]-1,3-oxazinane-2-one (80 mg, 55% yield) as a white solid.

[0530] LCMS: (ESI, m / z) [M+H]+ = 339.1

[0531] Step 4: Chiral separation of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 11a and 11b) (Instructions for reference 65 / 119, page 79, CN 121969615 A)

[0532]

[0533] Separation of 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 11a and 11b) by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 μm); supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (80 mg, 0.24 mmol) was prepared to give the desired product 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 11a, 24.0 mg, peak 1, Rt = 1.860 min, 29% yield) and the desired product 6-(4-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 11b, 20.1 mg, peak 2, Rt = 2.556 min, 24% yield) as white solids.Example 11a: H NMR (DMSO-d6, 400 MHz): δ 8.63 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.52 (dd, J = 5.6, 8.4 Hz, 2H), 7 .27 (t , J = 8.8 Hz , 2H) , 7.13 (s, 1H) , 5.60 ‑ 5.52 (m, 1H) , 4.02 ‑ 3.96 (m, 1H) , 3.94 ‑ 3.84 (m, 1H) , 2.40 ‑ 2.22 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 338.9

[0535] Example 11b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.34 (s, 1H), 8.63 (d, J = 5.2 Hz, 2H), 7.73 (d, J = 5.2 Hz, 2H) , 7.55 ‑ 7.48 (m, 2H) , 7.27 (t, J = 8.8 Hz, 2H) , 7.16 (s, 1H) , 5.60 ‑ 5.52 (m, 1H) , 4.03 ‑ 3.94 (m, 1H) , 3.92 ‑ 3.82 (m, 1H) , 2.40 -2.22 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 339.1

[0536] Examples 12a and 12b

[0537]

[0538] Step 1: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine

[0539]

[0540] 3-(pyridin-4-yl)-1-((2-)-(tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propanal (1.64 g, 5.16 mmol) in a solution of 3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propanal (1.64 g, 5.16 mmol) in DCE (15 mL) and MeOH (15 mL) was added to a solution of 3-(tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propanal (1.64 g, 5.16 mmol) in DCE (15 mL) and MeOH (15 mL). (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine (1.5 g, 5.16 mmol l) and AcOH (34 mg, instructions 66 / 119 pages 80 CN 121969615 A ​​0.52 mmol).After stirring at room temperature for 30 minutes, NaBH3CN (974 mg, 15.49 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated at 50 °C for 16 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 solution (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 0% to 20% ethyl acetate in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-amine (900 mg, 29% yield) as a yellow oil.

[0541] LCMS: (ESI, m / z) [M+H]+ = 592.2

[0542] Step 2: Synthesis of 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol

[0543]

[0544] TBAF (1 M, 2.3 mL in THF) was added to a solution of N-(3-((tert-butyldimethylsilyl)oxy)-3-(6-chloro-5-fluoropyridin-3-yl)propyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (900 mg, 1.52 mmol) in THF (10 mL). 2.3 mmol). The reaction was stirred at room temperature for 2 hours, and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 80% ethyl acetate in 0-petroleum ether) to give 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol (570 mg, 78% yield) as a yellow solid.

[0545] LCMS: (ESI, m / z) [M+H]+ = 478.1

[0546] Step 3: Synthesis of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one

[0547]

[0548] DIPEA (0.77 mL, 4.69 mmol) and CDI were added to a solution of 1-(6-chloro-5-fluoropyridin-3-yl)-3-((3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)amino)propane-1-ol (560 mg, 1.17 mmol) in DMF (6 mL). (570 mg, 3.51 mmol) and DMAP (29 mg, 0.23 mmol). The reaction was stirred at room temperature for 1 hour, then stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 60% to 70% ethyl acetate in petroleum ether) to give 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (460 mg, 78% yield) as a yellow solid.

[0549] LCMS: (ESI, m / z) [M+H]+ = 504.1 Specification 67 / 119 pages 81 CN 121969615 A ​​

[0550] Step 4: Synthesis of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0551]

[0552] A solution of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (460 mg, 0.91 mmol) in 10% TFA / HFIP (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then NaHCO3 solution (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3).The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (acetonitrile: 31% to 61% / 0.05% NH₄OH in water) to give 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 58% yield) as a white solid.

[0553] Step 5: Chiral separation of 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 12a and 12b)

[0554]

[0555] 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 5 μm), supercritical CO2 / EtOH + 0.1% NH4OH = 50 / 50; 50 mL / min) to obtain 6-(6-chloro-5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one, both of which were white solids. 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 12a, peak 1, Rt = 2.390 min, 59.5 mg, 29% yield) and 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 12b, peak 2, Rt = 3.177 min, 66.2 mg, 33% yield). Example 12a: H NMR (DMSO-d6, 400 MHz): δ 13.36 (br s, 1H), 8.64 (d, J=6.0 Hz, 2H), 8.42 (d, J=1.6 Hz, 1H), 8.14-8.10 (m, 1H) , 7.73 (d , J = 6.0 Hz, 2H) , 7.15 (br s , 1H) , 5.73 ‑ 5.69 (m , 1H) , 4.10 – 3.98 (m , 1H) , 3.94 ‑ 3.85 (m, 1H) , 2.47 ‑ 2.41 (m, 1H) , 2.39 - 2.28 (m, 1H). LCMS: (ESI, m / z) [M+H ]+ = 374.0.Example 12b: H NMR (DMSO-d6, 400 MHz): δ 13.35 (br s, 1H), 8.64 (d, J=6.0 Hz, 2H), 8.42 (d, J=1.6 Hz, 1H), 8.14-8.10 (m, 1H) , 7.73 (d , J = 6.0 Hz, 2H) , 7.14 (br s , 1H) , 5.74 ‑ 5.70 (m , 1H) , 4.10 ‑ 3.99 (m , 1H) , 3.95 ‑ 3.85 (m, 1H) , 2.45 ‑ 2.40 (m, 1H) , 2.39–2.28 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 374.0.

[0558] Examples 13a and 13b Specification 68 / 119 pages 82 CN 121969615 A ​​

[0559]

[0560] Step 1: Synthesis of tert-butyl (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)carbamate

[0561]

[0562] Boc2O (5.5 mL, 24.0 mmol) was added to a solution of 3-amino-1-(6-(trifluoromethyl)pyridin-3-yl)propane-1-ol (4.4 g crude, 20.0 mmol) and TEA (6.07 g, 60.0 mmol) in DCM (90 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 35% ethyl acetate in petroleum ether) to give tert-butyl (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)carbamate (1.05 g, 16% yield) as a yellow oil. H NMR (DMSO-d6, 400 MHz): δ 8.71 (s, 1H), 8.00 (dd, J=1.2, 8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 6.80 (t, J=5.2 Hz, 1H), 5.62 (d, J = 4.4 Hz, 1H), 4.75 (q, J = 5.6 Hz, 1H), 3.12-2.85 (m, 2H), 1.76 (q, J = 7.20 Hz, 2H), 1.36 (s, 9H).

[0564] Step 2: Synthesis of 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one

[0565]

[0566] NaH (60% of mineral oil, 150 mg, 3.8 mmol) was added to a solution of (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)carbamate tert-butyl ester (800 mg, 2.5 mmol) in DMF (12 mL) under a nitrogen atmosphere at 0 °C. After stirring at 0 °C for 15 minutes, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 5% methanol in dichloromethane) to give 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (200 mg, 33% yield) as a yellow oil. H NMR (DMSO-d6, 400 MHz): δ 8.81 (d, J=1.60 Hz, 1H), 8.10 (dd, J=8.0, 2.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.48 (s, 1H) , 5.56 (dd, J = 10.4, 2.4 Hz, 1H) , 3.32 ‑ 3.26 (m, 1H) , 3.24 ‑ 3.14 (m, 1H) , 2.30 ‑ 2.17 (m, 1H) , 2.05 ‑ 1.90 (m, 1H).

[0568] Step 3: Synthesis of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinane-2-one

[0569]

[0570] DMEDA (0.04 mL) was added to a solution of 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinane-2-one (290 mg, 1.2 mmol) and 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)pyridine (459 mg, 1.3 mmol) in 1,4-dioxane (6 mL). 0.4 mmol), K2CO3 (488 mg, 3.5 mmol), and CuI (67 mg, 0.4 mmol). The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 14% EE in petroleum ether (25% ethanol in ethyl acetate)) to give 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (220 mg, 36% yield) as a yellow solid. H NMR (DMSO-d6, 400 MHz): δ 8.88 (s, 1H), 8.73-8.66 (m, 2H), 8.18 (dd, J=8.4, 2.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H) , 7.72-7.60 (m, 2H), 7.02 (s, 1H), 5.81 (dd, J = 10.4, 2.4 Hz, 1H), 5.45 (s, 2H), 4.12-4.00 (m, 1H), 3.95-3.88 (m, 1H) , 3.63 (t, J = 8.0 Hz, 2H) , 2.55 ‑ 2.50 (m, 1H) , 2.40 ‑ 2.27 (m, 1H) , 0.84 (t, J = 8.0 Hz, 2H) , ‑0.06 (s, 9H).

[0572] Step 4: Synthesis of 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one

[0573]

[0574] A solution of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (220 mg, 0.4 mmol) in 5% TFA / HFIP (5 mL) was stirred at room temperature for 16 hours. The mixture was adjusted to pH 7 with saturated NaHCO3 solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 28% to 58% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to give 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (90 mg, 55% yield) as a yellow solid.

[0575] Step 5: Chiral separation of 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (Examples 13a and 13b)

[0576] Specification 70 / 119 pages 84 CN 121969615 A ​​

[0577] 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (110 mg, 0.3 mmol) to give 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (13a, peak 1, Rt = 2.403 min, 44.4 mg, 40% yield) and 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazin-2-one (13b, peak 2, Rt = 3.029 min, 201.6 mg, 39% yield), both of which were white solids.Example 13a: H NMR (DMSO-d6, 400 MHz): δ 13.39 (s, 1H), 8.89 (s, 1H), 8.64 (d, J=4.8 Hz, 2H), 8.20 (d, J=8.0 Hz, 1H) , 8.01 (d , J = 8.0 Hz , 1H) , 7.73 (d , J = 5.6 Hz, 2H) , 7.17 (s, 1H) , 5.82 ‑ 5.78 (m, 1H) , 4.10 ‑ 4.00 (m, 1 H) 3.99 ‑ 3.85 (m, 1H) , 2.62 - 2.54 (m, 1H), 2.40 - 2.27 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 390.1

[0579] Example 13b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.38 (s, 1H), 8.89 (s, 1H), 8.64 (d, J = 4.8 Hz, 2 H) , 8.19 (d , J = 8.0 Hz , 1H) , 8.01 (d , J = 8.0 Hz , 1H) , 7.73 (d, J = 5.6 Hz, 2H) , 7.17 (s, 1H) , 5.82 ‑ 5.78 (m, 1H) , 4.10 ‑ 4.00 (m, 1H) , 3.99 - 3.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.40 - 2.27 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 390.1

[0580] Examples 14a and 14b

[0581]

[0582] Step 1: Synthesis of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine

[0583]

[0584] Pd(PPh3)2Cl2 (394 mg, 0.56 mmol) and LiCl (476 mg, 11.23 mmol) were added to a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol (2.0 g, 5.62 mmol) in DMF (30 mL) and 4-(tributyltinyl)pyridazine (3.1 g, 8.42 mmol).The resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was passed through a diatomaceous earth mat and washed with ethyl acetate (50 mL) as per the instructions (page 71 / 119, CN 121969615 A). The organic layer was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 20% ethyl acetate in petroleum ether) to give 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine (600 mg, 30% yield) as a yellow solid. 1H NMR (DMSO‑d6, 400 MHz): δ 9.56‑9.48 (m, 1H), 9.40‑9.39 (m, 1H), 7.97‑7.95 (m, 1H), 7.17 (s, 1H), 5.56 (s, 2H), 3.62 (t, J = 8.4 Hz, 2H), 0.83 (t, J = 8.4 Hz, 2H), -0.07(s, 9H).

[0585] Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0586]

[0587] DMEDA (0.03 mL, 0.28 mmol), CuI (54 mg, 0.28 mmol) and K2CO3 were added to a mixture of 6-(4-chloro-3-fluorophenyl)-1,3-oxazin-2-one (355 mg, 1.55 mmol) and 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine (500 mg, 1.41 mmol) in 1,4-dioxane (10 mL). (583 mg, 4.22 mmol). The resulting mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 15% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (220 mg, 31% yield) as a white solid.

[0588] Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0589]

[0590] A solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (300 mg, 0.60 mmol) in 5% TFA / HFIP (21 mL) was incubated at room temperature for 8 hours. The mixture was concentrated and adjusted to pH = 8 with NaHCO3 (20 mL), and then ethyl acetate (15 mL) was added. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 3% methanol in dichloromethane) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (200 mg, 90% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+ = 374.0

[0591] Step 4: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 14a and 14b) (Instructions 72 / 119 pages 86 CN 121969615 A)

[0592]

[0593] Separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one by chiral SFC (Chiralcel IG (250 mm x 30 mm, 10 μm), supercritical CO2 / i-PrOH + 0.1% NH4OH = 60 / 40; 80 mL / min) 3-Oxazinan-2-one (200 mg, 0.54 mmol) was used to give crude product 160 mg peak 1 and 50 mg peak 2. Peak 1 was purified by reversed-phase chromatography (acetonitrile: 28–58% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one as a white solid (Example 14a, Rt = 2.711 min, 16.9 mg, 8% yield).Peak 2 was purified by reversed-phase chromatography (acetonitrile: 27% to 57% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one as a white solid (Example 14b, Rt = 3.600 min, 17.2 mg, 8% yield). Example 14a: H NMR (DMSO-d6, 400 MHz): δ 9.64 (s, 1H), 9.27 (d, J = 5.6 Hz, 1H), 8.03-7.94 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.0 Hz, 1H) , 7.35 (d, J = 8.4 Hz, 1H) , 7.26 (s, 1H) , 5.62 (d, J = 9.6 Hz, 1H) , 4.00 ‑ 3.92 (m, 1H) , 3.95 ‑ 3.86 (m, 1H) , 2.45 - 2.38 (m, 1H), 2.33 - 2.23 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 374.0

[0595] Example 14b: 1H NMR (DMSO‑d6, 400 MHz): δ 9.64 (s, 1H), 9.27 (d, J = 4.8 Hz, 1H), 7.99‑7.98 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H) , 7.55 - 7.52 (m, 1H) , 7.34 (d, J = 9.6 Hz, 1H) , 7.26 (s, 1H) , 5.61 (d, J = 8.4 Hz, 1H) , 4.02 - 3.95 (m, 1H) , 3.94 - 3.86 (m, 1H), 2.45 - 2.40 (m, 1H), 2.33 - 2.23 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 373.9

[0596] Examples 15a and 15b

[0597]

[0598] Step 1: Synthesis of ethyl 3,5-dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate 73 / 119 pages 87 CN 121969615 A ​​

[0599]

[0600] NaH (60% of mineral oil, 0.8 g, 20.14 mmol) was added dropwise to a solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (5.0 g, 16.78 mmol) in DMF (50 mL) at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 minutes, SEM-Cl (3.56 mL, 20.14 mmol) was added dropwise. The reaction was stirred at room temperature for 4 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 20% ethyl acetate in petroleum ether) to give ethyl 3,5-dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (6.2 g, 86% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 5.51 (s, 2H) , 4.37 (q, J = 6.8 Hz, 2H) , 3.65 (t, J = 8.0 Hz, 2H) , (t, J = 7.2 Hz, 3H) , 0.96 - 0.87 (m, 2H), 0.02 (s, 9H).

[0601] Step 2: Synthesis of (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)methanol

[0602]

[0603] Under nitrogen atmosphere at -78°C, DIBAL-H (49.04 mL, 49.04 mmol) was added dropwise to a solution of ethyl 3,5-dibromo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (10.5 g, 24.52 mmol) in THF (100 mL). The mixture was stirred at -78°C for 30 minutes under nitrogen atmosphere, and then warmed to room temperature and stirred for 16 hours. The mixture was quenched with saturated Rochelle salt solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to give (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol (6.0 g, 63% yield) as a yellow oil. ¹H NMR: (CDCl₃, 400 MHz): δ 5.45 (s, 2H), 4.52 (s, 2H), 3.63 (t, J = 8.4 Hz, 2H), 0.92 (t, J = 8.0 Hz, 2H), -0.01 (s, 9H).

[0604] Step 3: Synthesis of 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0605]

[0606] TBSCl (3.3 g, 22.14 mmol) was added to a solution of (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)methanol (5.7 g, 14.76 mmol) and imidazole (1.5 g, 22.14 mmol) in DCM (60 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to give 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.2 g, 95% yield) as a yellow oil.LCMS: (ESI, m / z) [M+H]+ = 240.1

[0607] Step 4: Synthesis of 4-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)pyridine

[0608]

[0609] At room temperature, 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (6.7 g, 13.39 mmol), potassium carbonate (5.6 g, 40.17 mmol) and pyridine-4-yl organoboronic acid (1.81 g, 14.73 mmol) were added to 1,4-dioxane (50 mL) and water (10 mL). Pd(dppf)Cl2 (0.98 g, 1.34 mmol) was added to the solution. The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to give 4-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (2.7 g, 40% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+ = 498.2

[0610] Step 5: Synthesis of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one

[0611]

[0612] At room temperature, 4-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (1.19 g, 2.4 mmol) and 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (500 mg, 2.18 mmol) were synthesized. K₃PO₄ (1.39 g, 6.53 mmol), DMEDA (0.07 mL, 0.65 mmol), and CuI (124 mg, 0.65 mmol) were added to a solution of 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 30% ethyl acetate (25% ethanol) in petroleum ether) to give a yellow oily substance 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (360 mg, 26% yield). ¹H NMR (DMSO-d⁶, 400 MHz): δ 8.74 (d, J = 6.0 Hz, 2H), 7.69 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 12.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.64–5.61 (m, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 3.85–3.77 (m, 1H). 3.73 ‑ 3.65 (m, 1H) , 3.55 (t, J = 8.0 Hz, 2H) , 2.45 ‑ 2.40 (m, 1H) , 2.31 ‑ 2.18 (m, 1H) , 0.80 (t, J = 8.4 Hz, 2H) , 0.76 (s, 9H), -0.08 (s, 15H).

[0613] Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0614]

[0615] 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(4-chloro-3-fluorophenyl)-1,3-oxazin-2-one (160 mg, 0.25 mmol) was reacted in a solution of 2 M HCl in 1,4-dioxane (3 mL) for 1 hour at room temperature. The reaction was concentrated and a saturated NaHCO3 solution (3 mL) was added. After stirring at room temperature for 30 minutes, the solution was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 35% ethyl acetate (25% ethanol) in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (64 mg, 64% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+ = 403.0

[0616] Step 7: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 15a and 15b)

[0617]

[0618] by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 μm); Supercritical CO2 / i-PrOH + 0.1% NH4OH = 50 / 50; 80 mL / min) Separation of 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (86 mg, 0.21 mmol) as a white solid to obtain 6-(4-chloro-3-fluorophenyl)-3-(4-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 15a, peak 1, Rt = 3.010 min, 32 mg, 37%) (Yield) and 6-(4-chloro-3-fluoro-phenyl)-3-[4-(hydroxymethyl)-3-(4-pyridinyl)-1H-pyrazol-5-yl]-1,3-oxazinane-2-one (Example 15b, peak 2, Rt = 4.514 min, 36 mg, 42% yield).

[0619] Example 15a: 1H NMR (DMSO-d6, 400 MHz): δ 13.46 (s, 1H), 8.69 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.58–7.54 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H). 8.4 Hz, 1H), 5.67-5.64 (m, 1H), 4.93 (s, 1H), 4.39 (s, 2H), 3.87-3.80 (m, 1H), 3.70-3.60 (m, 1H), 2 .42 ‑ 2 .27 (m , 2H).LCMS: (ESI, m / z) [M+H] + = 403.0

[0620] Example 15b: 1H NMR: (DMSO-d6, 400 MHz): δ 13.45 (s, 1H), 8.70 (d, J = 6.0 Hz, 2H), 7.80-7.70 (m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 5.67-5.64 (m, 1H), 4.92 (s, 1H), 4.39 (s, 2H), 3.87-3.83 (m, 1H), 3.69-3.67 (m, 1H), 2.42–2.27 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 403.1

[0621] Examples 16a and 16b

[0622]

[0623] Step 1: Synthesis of 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0624]

[0625] SEM-Cl (2.2 mL, 12.8 mmol) was added dropwise to a solution of 3,5-dibromo-4-methyl-1H-pyrazole (2.8 g, 11.6 mmol) and K2CO3 (4.8 g, 35.0 mmol) in MeCN (40 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by rapid column chromatography (SiO2, 5% ethyl acetate in petroleum ether) to give a crude product, which was then purified by reversed-phase chromatography (acetonitrile: 68% to 98% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5 g, 35% yield) as a brown oil. H NMR (CDCl3, 400 MHz): δ 5.42 (s, 2H), 3.61 (t, J = 8.0 Hz, 2H), 2.02 (s, 3H), 0.91 (t, J = 8.4 Hz, 2H), -0.01 (s, 9H).

[0627] Step 2: Synthesis of 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)pyridine

[0628]

[0629] K2CO3 (1.5 g, 10.5 mmol) and Pd(dppf)Cl2 (256 mg, 0.35 mmol) were added to a solution of 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.3 g, 3.5 mmol) and pyridine-4-yl organoboronic acid (431 mg, 3.5 mmol) in 1,4-dioxane (15 mL) and water (3 mL). (Instructions 77 / 119 pages 91 CN 121969615 A ​​mmol). The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate (30 mL) was added. The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 20% ethyl acetate in petroleum ether) to give 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (460 mg, 35% yield) as a colorless oil.

[0630] LCMS: (ESI, m / z) [M+H]+ = 368.0

[0631] Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

[0632]

[0633] 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (460 mg, 1.25 mmol), 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (430 mg, 1.87 mmol) and K2O3 (517 mg, 3.75 mmol) were added to 1 DMEDA (22 mg, 0.25 mmol) and CuI (47 mg, 0.25 mmol) were added to a solution of 4-dioxane (5 mL). The reaction was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 60% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (260 mg, 40% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.75 (d, J = 5.6 Hz, 2H), 7.51-7.43 (m, 3H), 7.31-7.27 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.53 ‑ 5.46 (m, 1H) , 5.28 (s, 2H) , 3.99 ‑ 3.88 (m, 1H) , 3.85 ‑ 3.79 (m, 1H) , 3.76 ‑ 3.68 (m, 2H) , 2.48 ‑ 2.25 (m, 2H) , 2.03 (s, 3H) , 1.01 - 0.91 (m, 2H) , 0.01 (s, 9H).

[0635] LCMS: (ESI, m / z) [M+H]+ = 517.1

[0636] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0637]

[0638] A solution of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (220 mg, 0.42 mmol) in dioxane in 2 M HCl (6 mL, 12 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and ethyl acetate (20 mL) was added. The mixture was adjusted to pH 8 with saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 33% to 63% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (140 mg, 85% yield) as a white solid.

[0639] Step 5: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 16a and 16b)

[0640]

[0641] 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (140 mg, 0.37 mmol) was separated by chiral SFC (Chiralcel ID (250 mm x 25 mm, 10 μm), supercritical CO2 / IPA + 0.1% NH4OH = 55 / 45; 80 mL / min) to obtain 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (140 mg, 0.37 mmol) as a white solid. (4-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 16a, peak 1, Rt = 4.173 min, 50.8 mg, 34% yield) and 6-(4-chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 16b, peak 2, Rt = 4.943 min, 45.9 mg, 31% yield). Example 16a: H NMR (DMSO-d6, 400 MHz): δ 13.29 (s, 1H), 8.69 (d, J = 5.2 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 2H), 7.56 (dd, J = 1.6, 10.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.71-5.63 (m, 1H), 3.85-3.73 (m, 1H), 3.67-3.57 (m, 1H) , 2.42- 2.23 (m, 2H), 2.09 (s, 3H).LCMS: (ESI, m / z) [M+H]+ = 387.0

[0643] Example 16b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.27 (s, 1H) , 8.69 (d , J = 5.6 Hz, 2H) , 7.69 (t, J = 8.0 Hz, 1H) , 7.60 (d , J = 6.0 Hz, 2H) ,7.57 - 7.52 (m, 1H) , 7.37 (d, J = 8.4 Hz, 1H) , 5.72 - 5.63 (m, 1H) , 3.85 - 3.75 (m, 1H) , 3.67 - 3.57 (m, 1H), 2.43-2.23 (m, 2H), 2.09 (s, 3H). LCMS: (ESI, m / z) [M+H]+ = 387.0

[0644] Examples 17a and 17b

[0645]

[0646] Step 1: Synthesis of 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine Specification 79 / 119 pages 93 CN 121969615 A ​​

[0647]

[0648] K2CO3 (5.6 g, 40.55 mmol) and 4-fluoropyridine (1.6 g, 16.22 mmol) were added to a mixture of 4-bromo-2H-1,2,3-triazole (2.0 g, 13.52 mmol) in DMF (20 mL). The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 50% ethyl acetate in petroleum ether) to give 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine (1.2 g, 39% yield) as a white solid.LCMS: (ESI, m / z) [M+H]+ = 224.9

[0649] Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one

[0650]

[0651] CuI (33 mg, 0.17 mmol), DMEDA (0.02 mL, 0.17 mmol) and K3PO4 were added to a mixture of 4-(4-bromo-2H-1,2,3-triazol-2-yl)pyridine (200 mg, 0.87 mmol) and 6-(4-chloro-3-fluorophenyl)-1,3-oxazin-2-one (216 mg, 0.96 mmol) in 1,4-dioxane (5 mL). (555 mg, 2.61 mmol). The resulting mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 10% methanol in dichloromethane) to give 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazinane-2-one (200 mg, 61% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+ = 374.0.

[0652] Step 3: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one (Examples 17a and 17b)

[0653]

[0654] 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one (200 mg, 0.54 mmol) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 µm), supercritical CO2 / EtOH + 0.1% NH4OH = 45 / 55; 80 mL / min) to obtain 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one (200 mg, 0.54 mmol) as a white solid. (4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one (Example 17a, peak, specification 80 / 119, page 94, CN 121969615 A ​​1, Rt = 2.115 min, 48 mg, 24% yield) and 6-(4-chloro-3-fluorophenyl)-3-(2-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-oxazin-2-one (Example 17b, peak 2, Rt = 2.367 min, 47 mg, 23% yield). Example 17a: H NMR (DMSO-d6, 400 MHz): δ 8.74-8.72 (m, 2H), 8.41 (s, 1H), 7.93-7.91 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.56 (dd , J = 10.4, 2.0, Hz, 1H) , 7.36 (d , J = 8.0 Hz, 1H) , 5.70 ‑ 5.67 (m, 1H) , 4.18 ‑ 4.08 (m, 1H) , 4.04 ‑ 3.95 (m, 1H) , 2.48 - 2.44 (m, 1H) , 2.37 - 2.29 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 374.0

[0656] Example 17b: 1H NMR (DMSO‑d6, 400 MHz): δ 8.74‑8.72 (m, 2H), 8.41 (s, 1H), 7.93‑7.91 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H) , 7.56 (dd , J = 10.4, 2.0 Hz, 1H) , 7.36 (d , J = 8.0 Hz, 1H) , 5.70 ‑ 5.66 (m, 1H) , 4.15 ‑ 4.08 (m, 1H) , 4.05- 3.96 (m, 1H), 2.48-2.44 (m, 1H), 2.38-2.29 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 373.9

[0657] Examples 18a and 18b

[0658]

[0659] Step 1: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0660]

[0661] Selective fluorine reagent (285 mg, 0.80 mmol) was added to a solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (200 mg, 0.54 mmol) in MeCN (3 mL) at 0 °C. The mixture was then stirred at room temperature for 1.5 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 x 3 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 20% ethyl acetate (25% ethanol) in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (110 mg, 53% yield) as a white solid.LCMS: (ESI, m / z) [M+H]+ = 391.0

[0662] Step 2: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Examples 18a and 18b)

[0663] Specification 81 / 119 pages 95 CN 121969615 A ​​

[0664] Separation of 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H- by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 µm), supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) Pyrazol-5-yl)-1,3-oxazin-2-one (110 mg, 0.28 mmol) was used to give 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 18a, peak 1, Rt = 1.303 min, 27 mg, 25% yield) and 6-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 18b, peak 2, Rt = 2.024 min, 28 mg, 25% yield), both of which were white solids.

[0665] Example 18a: 1H NMR (DMSO-d6, 400 MHz): δ 8.71 (d, J = 5.2 Hz, 2H), 7.71-7.67 (m, 3H), 7.57-7.54 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.69-5.66 (m, 1H), 3.89-3.84 (m, 1H), 3.77-3.75 (m, 1H), 2.42-2.22 (m, 2H).LCMS: (ESI, m / z) [M+H]+ = 391.0

[0666] Example 18b: 1H NMR (DMSO-d6, 400 MHz): δ 8.71 (d, J = 5.2 Hz, 2H), 7.71-7.67 (m, 3H), 7.56-7.54 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.69-5.66 (m, 1H), 3.90-3.83 (m, 1H), 3.77-3.72 (m, 1H), 2.42-2.22 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 391.0.

[0667] Examples 19a and 19b

[0668]

[0669] Step 1: Synthesis of 4-(4-bromo-1H-pyrazole-1-yl)pyridine

[0670]

[0671] 4-fluoropyridine (0.99 g, 10.21 mmol) was added to a mixture of 4-bromo-1H-pyrazole (1.0 g, 6.80 mmol) and K2CO3 (2.82 g, 20.41 mmol) in DMF (25 mL). The mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (25 mL) and filtered to give 4-(4-bromo-1H-pyrazol-1-yl)pyridine (600 mg, 39% yield) as a white solid, which was used directly in the next step without further purification.

[0672] Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinane-2-one, specification 82 / 119 pages, 96 CN 121969615 A ​​

[0673]

[0674] DMEDA (0.02 mL, 0.17 mmol), CuI (33 mg, 0.17 mmol), and K3PO4 (555 mg, 2.61 mmol) were added to a mixture of methyl 4-(4-bromo-1H-pyrazol-1-yl)pyridine (195 mg, 0.87 mmol) and 6-(4-chloro-3-fluorophenyl)-1,3-oxazinane-2-one (200 mg, 0.87 mmol) in 1,4-dioxane (4 mL). The resulting mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 70% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinan-2-one (200 mg, 62% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+ = 373.0.

[0675] Step 3: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinan-2-one (Examples 19a and 19b)

[0676]

[0677] 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinan-2-one (200 mg, 0.54 mg) was separated by chiral SFC (Chiralpak IH (250 mm x 30 mm, 10 µm), supercritical CO2 / MeOH + 0.1% NH4OH = 55 / 45; 150 mL / min) (mmol) to give 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazin-2-one as a white solid (Example 19a, peak 1, Rt = 3.790 min, 43.1 mg, 22% yield) and 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazin-2-one (Example 19b, peak 2, Rt = 3.962 min, 40.9 mg, 20% yield). Example 19a: H NMR (DMSO-d6, 400 MHz): δ 8.79 (s, 1H), 8.64 (d, J = 6.4 Hz, 2H), 8.17 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.63-5.59 (m, 1H), 3.92-3.84 (m, 1H), 3.78 - 3.72 (m, 1H), 2.45-2.40 (m, 1H), 2.35-2.25 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 372.9

[0679] Example 19b: 1H NMR (DMSO‑d6, 400 MHz): δ 8.79 (s, 1H), 8.64 (d, J = 6.4 Hz, 2H), 8.17 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 10.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.63-5.59 (m, 1H) , 3.93- 3.83 (m, 1H), 3.79-3.72 (m, 1H), 2.44-2.40 (m, 1H), 2.35-2.24 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 372.9

[0680] Examples 20a and 20b Specification 83 / 119 pages 97 CN 121969615 A ​​

[0681]

[0682] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propane-1-amine

[0683]

[0684] TBSCl (4.9 g, 32.4 mmol) was added to a mixture of 3-amino-1-(4-chloro-3-fluorophenyl)propane-1-ol (4.4 g, 21.6 mmol) and imidazole (4.4 g, 64.8 mmol) in DCM (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 57% to 87% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propane-1-amine (1.0 g, 15% yield) as a yellow oil.H NMR (DMSO-d6, 400 MHz): δ = 7.54 (t, J = 8.0 Hz 1H), 7.35-7.25 (m, 1H), 7.22-7.14 (m, 1H), 5.90-5.85 (m, 1H) , 2.63 ‑ 2.51 (m, 2H) , 1.77 ‑ 1.55 (m, 2H) , 0.85 (s, 9H) , 0.08 ‑ 0.01 (s, 3H) , ‑0.15 (s, 3H).

[0686] Step 2: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3-(pyridin-4-yl)isothiazol-5-amine

[0687]

[0688] Cs2CO3 (1.05 g, 3.24 mmol) and Brettphos Pd G3 (98 mg, 0.11 mmol) were added to a mixture of 5-bromo-3-(4-pyridinyl)isothiazol (260 mg, 1.08 mmol) and 3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propane-1-amine (514 mg, 1.62 mmol) in 2-methyl-2-butanol (16 mL). The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 50% EtOAc in petroleum ether) to give N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3-(pyridin-4-yl)isothiazol-5-amine (350 mg, 89% yield) as a yellow oil.

[0689] LCMS: (ESI, m / z) [M+H]+ = 478.2

[0690] Step 3: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)isothiazolyl-5-yl)amino)propane-1-ol, specification 84 / 119 pages 98 CN 121969615 A ​​

[0691]

[0692] TBAF (1.0 M, 1.46 mL, 1.46 mmol in THF) was added to a mixture of N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3-(pyridin-4-yl)isothiazolyl-5-amine (350 mg, 0.73 mmol) in THF (10 mL). The mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere.The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 80% EE in petroleum ether (25% ethanol in ethyl acetate)) to give 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)isothiazolyl-5-yl)amino)propane-1-ol (200 mg, 75% yield) as a colorless oil.

[0693] LCMS: (ESI, m / z) [M+H]+ = 364.1

[0694] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazolyl-5-yl)-1,3-oxazinane-2-one

[0695]

[0696] CDI (112 mg, 0.69 mmol) was added to a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)isothiazolyl-5-yl)amino)propane-1-ol (200 mg, 0.35 mmol) and DIPEA in DMF (5 mL). The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The residue was purified by reversed-phase chromatography (acetonitrile: 50% to 80% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazo-5-yl)-1,3-oxazinan-2-one (100 mg, 47% yield) as a white solid.

[0697] Step 5: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazo-5-yl)-1,3-oxazinan-2-one (Examples 20a and 20b)

[0698]

[0699] 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazo-5-yl)-1,3-oxazinan-2-one (130 mg, 0.33 μm) was separated by chiral SFC (Chiralpak IG (250 mm x 30 mm, 10 μm), supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min) mmol), to obtain 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazo-5-yl)-1,3-oxazin-2-one (20a, peak 1, Rt = 1.659 min, 45.1 mg, 35% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)isothiazo-5-yl)-1,3-oxazin-2-one (20b, peak 2, Rt = 2.771 min, 44.3 mg, 34% yield), both of which were white solids. Example 20a: H NMR (DMSO-d6, 400 MHz): δ = 8.71 (d, J = 5.6 Hz, 2H), 7.99 (d, J = 6.0 Hz, 2H), 7.84 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H) , 7.62 ‑ 7.57 (m, 1H) , 7.38 (d, J = 8.8 Hz, 1H) , 5.82 ‑ 5.72 (m, 1H) , 4.16 ‑ 4.03 (m, 2H) , 2.59 ‑ 2.53 (m, 1H) , 2.48 ‑ 2.38 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 389.9

[0701] Example 20b: 1H NMR (DMSO-d6, 400 MHz): δ = 8.71 (d, J = 5.2 Hz, 2H), 7.99 (d, J = 5.6 Hz, 2H), 7.84 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.42-7.33 (m, 1H), 5.84-5.71 (m, 1H), 4.16-4.03 (m , 2H), 2.59 - 2.53 (m, 1H), 2.48 - 2.38 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 389.9

[0702] Example 21

[0703]

[0704] Step 1: Synthesis of 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionate

[0705]

[0706] A mixture of zinc (10.31 g, 157.67 mmol), 1,2-dibromoethane (1.1 mL, 12.61 mmol) and trichloromethylsilane (1.6 mL, 12.61 mmol) in THF (200 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then, a solution of ethyl 2-bromo-2,2-difluoroacetate (19.20 g, 94.6 mmol) and 4-chloro-3-fluorobenzaldehyde (10.0 g, 63.07 mmol) in THF (100 mL) was added dropwise to the mixture at room temperature. The resulting mixture was heated at 75 °C for 2 hours. After cooling to room temperature, the reaction was quenched with ice / water (200 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with water (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 3% EtOAc in petroleum ether) to give ethyl 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionate (9.00 g, 50% yield) as a yellow oil.1H NMR (400 MHz, CDC13): δ 7.42 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 5.20-5.14 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.64 (s, 1H), 1.33 (t, J = 7.2 Hz, 3H).

[0708] Step 2: Synthesis of 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionamide

[0709]

[0710] A mixture of ethyl 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionate (9.00 g, 31.84 mmol) and NH3 (7 M in methanol, 45.49 mL, 318.43 mmol) was stirred at room temperature for 4 hours. The mixture was concentrated to give crude 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionamide (8.00 g, 99% yield) as a white solid, which was used directly in the next step without further purification. H NMR (DMSO-d6, 400 MHz): δ 8.06 (s, 1H), 7.92 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.39 (d, J=10.0 Hz, 1H), 7.27 (d, J= 8.0 Hz, 1H), 6.65 (d, J = 5.6 Hz, 1H), 5.19‑5.11 (m, 1H).

[0712] Step 3: Synthesis of 3-amino-1-(4-chloro-3-fluorophenyl)-2,2-difluoropropane-1-ol

[0713]

[0714] BH3-Me2S (10 M, 22.08 mL, 220.80 mmol) was added dropwise to a mixture of 3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropionamide (8.0 g, 31.54 mmol) in THF (160 mL) at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction was quenched with MeOH (60 mL) and the resulting mixture was then concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 3% methanol in dichloromethane + 1% NH4OH) to give 3-amino-1-(4-chloro-3-fluorophenyl)-2,2-difluoropropane-1-ol (3.70 g, 49% yield) as a white solid.

[0715] 1H NMR (DMSO-d6, 400 MHz): δ 7.57 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 10.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.03–4.97 (m, 1H), 3.09–2.98 (m, 1H), 2.91–2.80 (m, 1H).

[0716] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-1,3-oxazinan-2-one

[0717]

[0718] Then, under a nitrogen atmosphere at 0°C, CDI (2.17 g, 13.35 mmol) was added to a solution of 3-amino-1-(4-chloro-3-fluorophenyl)-2,2-difluoropropane-1-ol (1.60 g, 6.68 mmol) and DIPEA (5.82 mL, 33.39 mmol) in DMA (30 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by rapid column chromatography (SiO2, 10% to 50% EE in petroleum ether (EtOAc / EtOH = 3:1)) to give 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-1,3-oxazinan-2-one (1.6 g, 90% yield) as a white solid.

[0719] H NMR (DMSO-d6, 400 MHz): δ 8.01 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 10.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 21.6 Hz, 1H), 3.89-3.73 (m, 1H), 3.70-3.59 (m, 1H).

[0720] Step 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (Instructions for Synthesis, 87 / 119 pages, 101 CN 121969615 A)

[0721]

[0722] Add K3PO4 (276 mg, 0.65 mmol) to a solution of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (230 mg, 0.65 mmol) and 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-1,3-oxazinane-2-one (241 mg, 0.91 mmol) in 1,4-dioxane (10 mL). 1.3 mmol) and tBuBrettPhos Pd G3 (56 mg, 0.06 mmol). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), and the organic layer was washed with water (10 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (100 mg, 29% yield) as a yellow solid.

[0723] LCMS: (ESI, m / z) [M+H]+ = 539.2

[0724] Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 21)

[0725]

[0726] A solution of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (100 mg, 0.19 mmol) in 5% TFA / HFIP (2.90 mL, 1.90 mmol) was incubated at room temperature for 16 hours. Concentrate the mixture and dilute the residue with EtOAc (6 mL). Adjust the pH of the organic layer to 8 with saturated NaHCO3 solution (2 mL).The organic layer was washed with brine (3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 34% to 64% / 0.05% NH₄OH in water + 10 mM NH₄HCO₃) to give 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (15.5 mg, 20% yield) as a white solid.

[0727] Example 21: 1H NMR (DMSO-d6, 400 MHz): δ = 13.54 (s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 7.80-7.72 (m, 3H), 7.52 (d, J = 10.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 6.20 (d, J = 21.6 Hz, 1H), 4.52-4.40 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 409.0

[0728] Examples 22a and 22b Specification 88 / 119 pages 102 CN 121969615 A ​​

[0729]

[0730] Step 1: Synthesis of ethyl 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionate

[0731]

[0732] A mixture of zinc (4.2 g, 64.24 mmol), 1,2-dibromoethane (0.14 mL, 1.6 mmol) and TMS-Cl (0.21 mL, 1.66 mmol) in THF (50 mL) was stirred at 50 °C for 0.5 h under a nitrogen atmosphere. After cooling to room temperature, a solution of 4-chloro-3-fluorobenzaldehyde (5.0 g, 31.53 mmol) and ethyl 2-bromo-2-fluoroacetate (4.47 mL, 37.84 mmol) in THF (10 mL) was added dropwise. Following the addition, the reaction was heated at 90 °C for 0.5 h. After cooling to room temperature, the reaction was quenched with 1 M HCl solution and the pH was adjusted to 4-6. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 0% to 15% EtOAc in petroleum ether) to give ethyl 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionate (5 g, 56% yield), which was a pale yellow oil. 1H NMR (400 MHz, CDC13) δ 7.44-7.37 (m, 1H), 7.27-7.21 (m, 1H), 7.15-7.10 (m, 1H), 5.18-5.08 (m, 1H) , 5.06-4.91 (m, 1H), 4.30-4.19 (m, 2H), 3.23-2.95 (m, 1H), 1.30-1.21 (m, 3H).

[0734] Step 2: Synthesis of 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionamide

[0735]

[0736] To a solution of ethyl 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionate (5.0 g, 18.89 mmol) in MeOH (5 mL), NH3 solution (7 M, 20 mL, 140 mmol in MeOH) was added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionamide (4.2 g, 94% yield) as a white solid. The crude product was used directly in the next step without further purification. H NMR (400 MHz, DMSO-d6): δ 7.60-7.50 (m, 2H), 7.47-7.12 (m, 3H), 6.14-6.03 (m, 1H), 5.13-4.89 (m, 2H). Instructions for Use, pages 89 / 119, 103, CN 121969615 A ​​

[0738] Step 3: Synthesis of 3-amino-1-(4-chloro-3-fluorophenyl)-2-fluoropropane-1-ol

[0739]

[0740] Under a nitrogen atmosphere at room temperature, a BH3-Me2S solution (10 M, 10 mL, 100 mmol) was added dropwise to a solution of 3-(4-chloro-3-fluorophenyl)-2-fluoro-3-hydroxypropionamide (4.2 g, 17.83 mmol) in THF (45 mL). The reaction mixture was then heated at 80 °C for 2 hours. After cooling to room temperature, the reaction was quenched with methanol (70 mL) and then stirred at room temperature for 4 hours.The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by rapid column chromatography (0% to 6% MeOH (0.1% NH3·H2O) in SiO2, DCM) to give 3-amino-1-(4-chloro-3-fluorophenyl)-2-fluoropropane-1-ol (2 g, 49% yield) as a colorless oil. H NMR (400 MHz, DMSO-d6): δ 7.55 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 10.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.85-4.72 (m, 1H), 4.52-4.31 (m, 1H), 2.80-2.67 (m, 2H). LCMS: (ESI, m / z) [M+H]+ = 222.0

[0742] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one

[0743]

[0744] CDI (5.8 g, 35.77 mmol) was added to a solution of 3-amino-1-(4-chloro-3-fluorophenyl)-2-fluoropropane-1-ol (2.0 g, 9.02 mmol) and DIPEA (2.5 mL, 14.04 mmol) in DMA (25 mL) at 0 °C. The resulting mixture was stirred at room temperature for 12 hours. Then DMAP (70 mg, 0.57 mmol) was added and the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, H2O (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 45% in petroleum ether (EtOAc / EtOH = 3 / 1)) to give trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (1 g crude) and cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (0.4 g crude).

[0745] The crude trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (1.4 g) was purified by reversed-phase chromatography (acetonitrile: 25% to 55% / 0.05% NH4OH in water + 10 mM NH4HCO3) to obtain trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (590 mg, 26% yield) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.71 (t, J = 8.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.43 (d, J = 2.0, 10.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.77-5.69 (m, 1H), 5.38-5.21 (m, 1H), 3.40-3.33 (m, 1H), 3.21-3.05 (m, 1H).

[0747] Crude cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (0.4 g) was purified by reversed-phase chromatography (acetonitrile: 25% to 55% / 0.05% NH4OH in water + 10 mM NH4HCO3) to obtain cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one (200 mg, 9% yield) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.67 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 1.6, 10.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 29.6 Hz, 1H), 5.23 (d, J = 47.2 Hz, 1H), 3.70-3.54 (m, 1H), 3.53-3.43 (m, 1H).Instructions 90 / 119 pages 104 CN 121969615 A ​​

[0749] Step 5: Synthesis of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one

[0750]

[0751] 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (750 mg, 2.12 mmol), trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazinan-2-one (800 mg, 3.23 mmol), tBuBrettPhos Pd G3 (120 mg, 0.14 mmol) were prepared. A mixture of K3PO4 (1.0 g, 4.71 mmol) and K2PO4 (1.0 g, 4.71 mmol) in 1,4-dioxane (15 mL) was heated at 110°C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 20% in petroleum ether (EtOAc / EtOH = 3:1)) to give trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (450 mg, 16% yield) as a pale yellow solid.

[0752] LCMS: (ESI, m / z) [M+H]+ = 521.2

[0753] Step 6a: Synthesis of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 22a)

[0754]

[0755] A solution of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (400 mg, 0.77 mmol) in 5% TFA / HFIP (10 mL) was incubated for 12 hours. The reaction residue was then poured into a saturated NaHCO3 solution (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by reversed-phase chromatography (acetonitrile: 44% to 74% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (21 mg, 8% yield) as a white solid. Example 22a: H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.75-7.70 (m, 3H), 7.56-7.51 (m, 1H), 7.29 ‑ 7.24 (m, 1H) , 7. 18 (s, 1H) , 5.99 ‑ 5.91 (m, 1H) , 5.68 ‑ 5.52 (m, 1H) , 4.29 ‑ 4.14 (m, 1H) , 3.84 ‑ 3.67 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 391.0

[0757] Step 6b: Synthesis specification of cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Example 22b) 91 / 119 pages 105 CN 121969615 A ​​

[0758]

[0759] Using the general procedure described for the preparation of trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (23a) by step 5 In this study, cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one was used to replace trans-6-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-oxazin-2-one to prepare cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (23b). The title compound was purified by reversed-phase chromatography (acetonitrile: 44% to 74% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give cis-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (6.7 mg, 8% yield) as a white solid.Example 22b: H NMR (400 MHz, DMSO-d6): δ 13.35 (br s, 1H), 8.67-8.62 (m, 2H), 7.77-7.74 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.53 ‑ 7.48 (m, 1H) , 7.38 (d, J = 8.4 Hz, 1H) , 7.18 (s, 1H) , 5.94 (d, J = 29.2 Hz, 1H) , 5.52 (d, J = 46.8 Hz, 1H) , 4.38 ‑ 4.29 (m, 1H) , 4.28–4.13 (m, 1H). LCMS: (ESI, m / z) [M+ H]+ = 390.9

[0761] Examples 23a and 23b

[0762]

[0763] Step 1: Synthesis of (2-(4-chloro-3-fluorophenyl)-2-oxoethyl)triphenylphosphine bromide

[0764]

[0765] A solution of 2-bromo-1-(4-chloro-3-fluorophenyl)ethane-1-one (4 g, 15.91 mmol) and PPh3 (4.17 g, 15.91 mmol) in toluene (30 mL) was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filter cake was washed with toluene (10 mL x 3) to give (2-(4-chloro-3-fluorophenyl)-2-oxoethyl)triphenylphosphine bromide (7.6 g, 90% yield) as a white solid.

[0766] LCMS: (ESI, m / z) [M+H]+ = 433.0

[0767] Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(oxetane-3-ylyl)ethane-1-one, specification 92 / 119 pages 106 CN 121969615 A ​​

[0768]

[0769] A solution of (2-(4-chloro-3-fluorophenyl)-2-oxoethyl)triphenylphosphine bromide (7.6 g, 14.79 mmol) in DCM (10 mL) and NaOH (1 M, 30 mL, 29.59 mmol) was added at room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with H2O (5 mL) and extracted with DCM (40 mL x 3). The combined organic layers were diluted with brine (20 mL x 3), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 6.4 g of crude product.6.4 g of the crude product was then dissolved in THF (60 mL), and oxetane-3-one (1.28 g, 17.74 mmol) was added at 25 °C. The mixture was stirred at 70 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 10% ethyl acetate in petroleum ether) to give 1-(4-chloro-3-fluorophenyl)-2-(oxetane-3-ylylene)ethane-1-one (2.2 g, 66% yield) as a white solid. H NMR (400 MHz, CDC13): δ = 7.76-7.63 (m, 2H), 7.56-7.50 (m, 1H), 6.78-6.74 (m, 1H), 5.70-5.65 (m, 2H), 5.49- 5.41 (m, 2H).

[0771] Step 3: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-one

[0772]

[0773] A solution of 1-(4-chloro-3-fluorophenyl)-2-(oxetane-3-yl)ethane-1-one (1 g, 4.41 mmol) in MeCN (10 mL) was slowly added to a stirred solution of 3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-amine (848 mg, 5.29 mmol) and TEA (223 mg, 2.21 mmol) in acetonitrile (3 mL) at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (SiO2, 0% to 50% ethyl acetate in petroleum ether) to give 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-one (800 mg, 46% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=5.6 Hz, 2H), 7.99 (d, J=9.6 Hz, 1H), 7.84-7.89 (m, 1H), 7.75-7.83 (m, 1H) , 7.16 (d , J = 5.6 Hz, 2H) , 4.56 (d , J = 6.0 Hz, 2H) , 4.47 (d , J = 6.0 Hz, 2H) , 3.75 (s, 2H) , 3.14 (s, 1H) , 2.03 (s, 6H). LCMS: (ESI, m / z) [M+H]+ = 387.0

[0775] Step 4: Synthesis of 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-ol

[0776]

[0777] 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-ol was prepared at 0°C under a nitrogen atmosphere. (Instructions 93 / 119, page 107, CN 121969615 A ​​[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-ol (800 mg, 2.07 mmol) was prepared in THF (10 mL) LiAlH4 (2.5 M in THF, 0.9 mL, 2.25 mmol) was slowly added to the stirred solution. After stirring at 0 °C for 1 hour, the reaction was quenched at 0 °C with H2O (0.1 mL), 15% NaOH solution (0.1 mL), and H2O (0.3 mL). After 5 minutes, anhydrous Na2SO4 was added. After 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 50% in petroleum ether (ethyl acetate / ethanol = 3 / 1)) to give 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-ol (468 mg, 54% yield) as a yellow solid.

[0778] LCMS: (ESI, m / z) [M+H]+ = 389.1

[0779] Step 5: Synthesis of 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one

[0780]

[0781] At room temperature, 1-(4-chloro-3-fluorophenyl)-2-(3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)oxetane-3-yl)ethane-1-ol (438 mg, 1.13 mmol) and N-ethyl-N-isopropyl-propane-2-amine (582 mg, 4.51 mmol) were added to DMF CDI (365 mg, 2.25 mmol) was added to a solution of (10 mL). The reaction was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was quenched with NH4Cl (10 mL), diluted with H2O (5 mL), and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 50% ethyl acetate in petroleum ether) to give 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one (321 mg, 67% yield) as a yellow oil.

[0782] LCMS: (ESI, m / z) [M+H+2]+ = 417.1

[0783] Step 6: Chiral separation of 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one (Examples 23a and 23b)

[0784]

[0785] by chiral SFC (Chiralcel OD (250 mm x 30 mm, 10 µm), supercritical CO2 / EtOH + 0.1% NH4OH = 60 / 40; 150 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one (321 mg, 0.77 mmol) was separated at a rate of mL / min to obtain 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one (Example 23a, peak 1, Rt = 1.831 min, 101.4 mg, 31%) as a white solid. (Yield) and 8-(4-chloro-3-fluorophenyl)-5-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-2,7-dioxa-5-azaspiro[3.5]nonane-6-one (Example 23b, peak 2, Rt = 2.013 min, 77.5 mg, 24% yield).

[0786] Example 23a: 1H NMR (400 MHz, DMSO-d6): δ 8.57–8.48 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.55–7.50 (m, 1H), 7.36–7.29 (m, 3H), 5.28 (d, J = 10.8 Hz, 1H), 5.15 (d, J = 7.6 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H). (See specification 94 / 119 pages 108 CN 121969615 A) 4.44 (d, J = 7.6 Hz, 1H), 2.84-2.76 (m, 4H), 2.74-2.68 (m, 3H), 2.43-2.35 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 415.1

[0787] Example 23b: 1H NMR (400 MHz, DMSO‑d6): δ 8.55‑8.49 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.55‑7.50 (m , 1H), 7.36-7.29 (m, 3H), 5.28 (d, J = 10.8 Hz, 1H), 5.15 (d, J = 7.6 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H) , 4.44 (d, J = 7.6 Hz, 1H), 2.83–2.75 (m, 4H), 2.73–2.68 (m, 3H), 2.43–2.35 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 415.1

[0788] Examples 24a and 24b

[0789]

[0790] Step 1: Synthesis of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propionitrile

[0791]

[0792] n-BuLi (39.48 mL, 98.71 mmol) was added dropwise to a solution of MeCN (5.13 mL, 98.71 mmol) in THF (200 mL) at -78 °C under a nitrogen atmosphere. After stirring at -78°C for 30 minutes, a solution of ethyl 4-chloro-3-fluorobenzoate (10.0 g, 49.36 mmol) in THF (10 mL) was added dropwise at -78°C. After stirring at -78°C for 1 hour, the reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propionitrile (9.7 g) as a brown oil, which was used directly in the next step without further purification.H NMR (400 MHz, CDC13) δ 7.42 (t, J=8.0 Hz, 1H), 7.33 (dd, J=2.0, 10.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 2.80 (d, J=2.4 Hz, 2H), 1.77-1.75 (m, 3H).

[0794] Step 2: Synthesis of crude 4-amino-2-(4-chloro-3-fluoro-phenyl)butane-2-ol

[0795]

[0796] Under a nitrogen atmosphere at 0°C, BH3-Me2S (4.68 mL, 46.81 mmol) was added dropwise to a solution of 3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-butyronitrile (1 g, 4.68 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 0.5 h and then at 60°C for 16 h. After cooling to 0°C, the reaction was quenched with MeOH (5 mL) and heated at 60°C for 1 h. The mixture was concentrated to obtain a brown oily substance, described in the instructions on page 95 / 119, 109 CN 121969615 A, crude 4-amino-2-(4-chloro-3-fluoro-phenyl)butane-2-ol (1 g), which was used directly in the next step without further purification.

[0797] LCMS: (ESI, m / z) [M+H]+ = 218.1

[0798] Step 3: Synthesis of (3-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)carbamate benzyl ester

[0799]

[0800] Cbz-Cl (0.79 mL, 5.51 mmol) was added dropwise to a solution of 4-amino-2-(4-chloro-3-fluorophenyl)butane-2-ol (1.0 g, 4.59 mmol) and TEA (1.28 mL, 9.19 mmol) in DCM (20 mL) at 0 °C under a nitrogen atmosphere. After stirring at room temperature for 16 hours, the reaction was quenched with water (20 mL). The aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO₂, 25% ethyl acetate in petroleum ether) to give benzyl (3-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)carbamate (800 mg, 62% yield) as a white oil.

[0801] LCMS: (ESI, m / z) [M-OH]+ = 334.2

[0802] Step 4: Synthesis of 4-(4-chloro-3-fluorophenyl)-4-methylpiperidin-2-one

[0803]

[0804] NaH (60% of mineral oil, 91 mg, 2.27 mmol) was added to a solution of (800 mg, 2.27 mmol) of benzyl carbamate in anhydrous DMF (10 mL) at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 min, the reaction mixture was warmed to room temperature and then stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0% to 15% ethyl acetate in petroleum ether) to give 4-(4-chloro-3-fluorophenyl)-4-methylpiperidin-2-one (450 mg, 82% yield) as a white solid. 1H NMR (400 MHz, CDC13): δ 7.45-7.36 (m, 1H), 7.19 (dd, J=2.4, 10.4 Hz, 1H), 7.11 (dd, J=2.4, 8.8 Hz, 1H), 5.74-5.59 (m, 1H), 3.37-3.27 (m, 1H), 3.09-3.00 (m, 1H), 2.32-2.22 (m, 1H), 2.21-2.10 (m, 1H), 1.68 (s, 3H).

[0806] Step 5: Synthesis of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)ethyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one

[0807] Specification 96 / 119 pages 110 CN 121969615 A ​​

[0808] DMEDA (25 mg, 0.28 mmol) was added to a mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (500 mg, 1.41 mmol) and 4-(4-chloro-3-fluorophenyl)-4-methylpiperidin-2-one (378 mg, 1.55 mmol) in 1,4-dioxane (20 mL). mmol), CuI (54 mg, 0.28 mmol), and K2CO3 (900 mg, 4.23 mmol). The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)ethyl)-1H-pyrazol-5-yl)-1,3-oxazinane-2-one (45 mg, 69% yield) as a yellow oil.

[0809] LCMS: (ESI, m / z) [M+H]+ = 517.1

[0810] Step 6: Synthesis of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0811]

[0812] The mixture of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (500 mg, 0.97 mmol) in 5% TFA / HFIP solution (6 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and the pH was adjusted to 8 with saturated NaHCO3 solution. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by reversed-phase chromatography (acetonitrile: 39% to 69% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 53% yield) as a white solid.

[0813] LCMS: (ESI, m / z) [M+H]+ = 387.0

[0814] Step 7: Chiral separation of 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 24a and 24b)

[0815]

[0816] 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg, 1 μm) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 μm); supercritical CO2 / EtOH + 0.1% NH4OH = 40 / 60; 45 mL / min) 0.52 mmol) to give 6-6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 24a, 63.2 mg, peak 1, Rt = 1.308 min, 32% yield) and 6-(4-chloro-3-fluorophenyl)-6-methyl-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 24b, 46 mg, peak 2, Rt = 1.769 min, 23% yield), both of which were white solids.

[0817] Example 24a: 1H NMR (400 MHz, DMSO-d6): δ 13.30 (s, 1H), 8.62 (d, J = 6.4 Hz, 2H), 7.71–7.68 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.51 (dd, J = 1.6, 10.8 Hz, 1H), 7.30 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 (s, 1H), 3.97–3.86 (m, 1H), 3.43– 3.37 (m, 1H) , 2.72 - 2.61 (m, 1H) , 2.44 - 2.34 (m, 1H) , 1.65 (s, 3H). LCMS: (ESI, m / z) [M+H]+ = 387.0

[0818] Example 24b: 1H NMR (400 MHz, DMSO‑d6): δ 13.30 (s, 1H), 8.62 (d, J = 6.8 Hz, 2H), 7.70 (d, J = 6.4 Hz, 2H) , 7.66 (t, J = 8.0 Hz, 1H) , 7.54 ‑ 7.49 (m, 1H) , 7.30 (dd, J = 2.4, 8.8 Hz, 1H) , 7.12 ( s, 1H) , 3.98 ‑ 3.87 (m, 1H) , 3.41 - 3.37 (m, 1H), 2.72-2.61 (m, 1H), 2.45-2.31 (m, 1H), 1.65 (s, 3H).LCMS: (ESI, m / z) [M+H]+ = 387.0

[0819] Examples 25a and 25b

[0820]

[0821] Step 1: Synthesis of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)-3-methylpyridine

[0822]

[0823] K2CO3 (1.16 g, 8.42 mmol) and Pd(dppf)Cl2 were added to a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.0 g, 2.81 mmol), 3-methylpyridine-4-organoboronic acid (384 mg, 2.81 mmol) in 1,4-dioxane (10 mL) and water (2 mL). (205 mg, 0.28 mmol). The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (1% methanol in dichloromethane) to give 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-methylpyridine (460 mg, 44% yield) as a brown solid.

[0824] LCMS: (ESI, m / z) [M+H]+ = 368.0

[0825] Step 2: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Instructions for the Synthesis of 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one, pages 98 / 119, 112, CN 121969615 A)

[0826]

[0827] At room temperature, 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-methylpyridine (500 mg, 1.36 mmol), 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (467 mg, 2.04 mmol) were synthesized. K₂CO₃ (563 mg, 4.07 mmol), DMEDA (0.03 mL, 0.27 mmol), and CuI (52 mg, 0.27 mmol) were added to a solution of 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by rapid column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (400 mg, 57% yield) as a yellow oil.

[0828] Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one

[0829]

[0830] A solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (560 mg, 1.12 mmol) in 15% TFA / HFIP (10 mL) was incubated at room temperature for 3 hours. The mixture was concentrated and adjusted to pH = 8 with NaHCO3 (10 mL), and then ethyl acetate (10 mL) was added. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 40% to 70% / 0.1% NH4HCO3 in water) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (210 mg, 51% yield) as a white solid.

[0831] LCMS: (ESI, m / z) [M+H]+ = 386.9

[0832] Step 4: Chiral separation of 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Examples 25a and 25b)

[0833]

[0834] 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (210 mg, 0.56 mmol) to obtain crude product 160 mg peak 1 and 50 mg peak 2.Peak 1 was purified by reversed-phase chromatography (acetonitrile: 28% to 58% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 25a, Rt = 1.965 min, 66.3 mg, 31% yield) and 6-(4-chloro-3-fluorophenyl)-3-(3-(3-methylpyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazin-2-one (Example 25b, Rt = 2.809 min, 59 mg, 28% yield) as white solids. Example 25a: H NMR (DMSO-d6, 400 MHz): δ 13.06 (br s, 1H), 8.61-8.40 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.57-7.42 (m, 2H), 7.35-7.33 (m, 1H), 6.92 (s, 1H), 5.62-5.58 (m, 1H), 4.08-3.98 (m, 1H), 3.94-3.82 (m, 1H), 2.45-2.30 (m, 4H), 2.28- 2.17 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 386.9

[0836] Example 25b: 1H NMR (DMSO‑d6, 400 MHz): δ 13.05 (s, 1H), 8.55 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H) , 7.58 ‑ 7.54 (m, 1H) , 7.49 (d , J = 5.2 Hz, 1H) , 7 .35 ‑ 7 .33 (m , 1H) , 6.92 (d , J = 2.0 Hz, 1H) , 5.65 - 5.55 (m, 1H), 4.08-3.98 (m, 1H), 3.95-3.80 (m, 1H), 2.45-2.32 (m, 4H), 2.31-2.19 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 386.9

[0837] Example 26

[0838]

[0839] Step 1: Synthesis of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine

[0840]

[0841] 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (2.96 g, 4.04 mmol) and K2CO3 (16.75 g) were added to a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (11.2 g, 40.4 mmol) and pyridine-4-ylorganoboronic acid (4.97 g, 40.4 mol) in 1,4-dioxane (150 mL) and water (30 mL). , 121.2 mmol). The resulting mixture was heated at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2, 30% ethyl acetate in petroleum ether) to 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (8.74 g, 61% yield) as a brown solid.

[0842] LCMS: (ESI, m / z) [M+H]+ = 276.2

[0843] Step 2: Synthesis of 4-(2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine, page 100 / 119, 114 CN 121969615 A ​​

[0844]

[0845] n-BuLi (2.5 M, 15.56 mL, 38.89 mmol) was added dropwise to a solution of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (8.24 g, 29.92 mmol) in THF (140 ml) at -78 °C under a nitrogen atmosphere. After stirring at -78°C for 30 minutes, a solution of NBS (6.92 g, 38.89 mmol) in THF (20 mL) was added dropwise at -78°C. After stirring at -78°C for 4 hours, the reaction was quenched by adding water (30 mL) at 0°C and then extracted with EtOAc (100 mL x 3).The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO₂, 30% ethyl acetate in petroleum ether) to give 4-(2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (3.4 g, 30% yield) as a review solid. H NMR (CDCl3, 400 MHz): δ 8.67 (d, J=6.0 Hz, 2H), 7.53 (d, J=5.6 Hz, 2H), 7.29 (s, 1H), 5.33 (s, 2H), 3.72 (t, J=8.0 Hz, 2H), 0.98 (t, J = 8.0 Hz, 2H), 0.02 (s, 9H). LCMS: (ESI, m / z) [M+H]+ = 354.0

[0847] Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,3-oxazinane-2-one

[0848]

[0849] K2CO3 (390 mg, 2.8 mmol) was added to a solution of 4-(2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine (400 mg, 1.13 mmol) and 6-(4-chloro-3-fluorophenyl)-1,3-oxazinane-2-one (389 mg, 1.69 mmol) in 1,4-dioxane (7 mL). The mixture was heated at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 50% ethyl acetate in petroleum ether) to give 6-(4-chloro-3-fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,3-oxazinane-2-one (55 mg, 10% yield) as a brown solid.

[0850] LCMS: (ESI, m / z) [M+H]+ = 503.1

[0851] Step 4: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(4-(pyridin-4-yl)-1H-imidazol-2-yl)-1,3-oxazin-2-one (Example 26)

[0852] Specification 101 / 119 pages 115 CN 121969615 A ​​

[0853] The solution of 6-(4-chloro-3-fluorophenyl)-3-(5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,3-oxazin-2-one (55 mg, 0.11 mmol) in HFIP (2 mL) in 5% TFA was stirred at room temperature for 2 hours. The mixture was diluted with DCM (5 mL) and the pH was adjusted to 8 with a saturated aqueous NaHCO3 solution. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative-TLC (10% methanol in DCM) to give a crude product, which was further purified by reversed-phase chromatography (acetonitrile: 38% to 68% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(4-(pyridin-4-yl)-1H-imidazol-2-yl)-1,3-oxazinan-2-one (Example 26, 13.1 mg, 32% yield). Example 26: H NMR (DMSO-d6, 400 MHz): δ 12.06 (br s, 1H), 8.48 (d, J = 6.0 Hz, 2H), 7.73-7.65 (m, 4H), 7.57-7.54 (m, 1H), 7.38 - 7.33 (m, 1H), 5.68 - 5.62 (m, 1H), 4.24 - 4.17 (m, 1H), 3.99 - 3.91 (m, 1H), 2.43 - 2.38 (m, 1H), 2.34 - 2.24 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 373.0

[0855] Examples 27a and 27b

[0856]

[0857] Step 1: Synthesis of 1-phenyl-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-one

[0858]

[0859] 3-chloro-1-phenyl-propane-1-one (600 mg, 3.56 mmol), K2CO3 (1.97 g, 14.23 mmol), 3-(4-pyridinyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.4 g, 7.12 mmol) and KI (1.7 g, 10.67 mmol) were stirred in a MeCN (25 mL) solution at room temperature. The mixture was stirred at 70 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 3% methanol in dichloromethane) to give 1-phenyl-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-one (1.0 g, 30% yield) as a yellow solid. 1H NMR (DMSO‑d6, 400 MHz): δ 8.49‑8.46 (m, 2H), 7.98‑7.96 (m, 2H), 7.67‑7.63 (m, 1H), 7.56‑7.52 (m, 2H), 7.25 - 7.20 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.02 (s, 6H).

[0860] Step 2: Synthesis of 1-phenyl-3-[[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]amino]propane-1-ol, specification 102 / 119, page 116, CN 121969615 A ​​

[0861]

[0862] NaBH4 (420 mg, 11.0 mmol) was added to a solution of 1-phenyl-3-((3-(pyridyl-4-yl)bicyclo[1.1.1]pentane-1-yl)amino)propane-1-one (1.0 g, 3.42 mmol) in MeOH (100 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated NH4Cl (3 mL), filtered, and concentrated.The residue was purified by rapid column chromatography (SiO2, 3% methanol in dichloromethane) to give 1-phenyl-3-[[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]amino]propane-1-ol (600 mg, 60% yield), which was a yellow oil. 1H NMR (DMSO‑d6, 400 MHz): δ 8.50‑8.45 (m, 2H), 7.34‑7.30 (m, 4H), 7.23‑7.21 (m, 3H), 4.67‑4.64 (m, 1H), 3.34 (s, 1H) , 2.60 (t, J = 6.8 Hz, 2H) , 1.98 (s, 6H) , 1.75 - 1.67 (m, 2H).

[0863] Step 3: Synthesis of 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one

[0864]

[0865] DIPEA (0.34 mL, 2.04 mmol) and CDI (165 mg, 1.02 mmol) were added to a solution of 1-phenyl-3-[[3-(4-pyridinyl)-1-bicyclo[1.1.1]pentyl]amino]propane-1-ol (200 mg, 0.68 mmol) in DMF (6 mL). The reaction was stirred at room temperature for 16 hours. The mixture was purified by reversed-phase chromatography (acetonitrile: 28% to 58% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazin-2-one (105 mg, 48% yield) as a white solid.LCMS: (ESI, m / z) [M+H]+ = 321.0

[0866] Step 4: Chiral separation of 6-phenyl-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]-1,3-oxazinan-2-one (Examples 27a and 27b)

[0867]

[0868] 6-phenyl-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]-1,3-oxazinan-2-one (100 mg, 0.31 μm) was separated by chiral SFC (Chiralpak AD (250 mm x 30 mm, 10 μm), CO2 / EtOH + 0.1% NH4OH = 60 / 40; 80 mL / min). mmol) to obtain 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazin-2-one (Example 27a, peak 1, Rt = 1.966 min, 42 mg, 42% yield) and 6-phenyl-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazin-2-one (Example 27b, peak 2, Rt = 2.458 min, 37 mg, 37% yield), both of which are white solids.

[0869] Example 27a: 1H NMR (DMSO-d6, 400 MHz): δ 8.51 (d, J = 5.6 Hz, 2H), 7.44-7.36 (m, 5H), 7.28 (d, J = 5.6 Hz, 2H), 5.37-5.34 (m, 1H), 3.48-3.42 (m, 1H), 3.38-3.32 (m, 1H), 2.42-2.32 (m, 6H), 2.28-2.20 (m, 1H), 2.15-2.00 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 321.0

[0870] Example 27b: 1H NMR (DMSO-d6, 400 MHz): δ 8.51 (d, J = 5.6 Hz, 2H), 7.44-7.36 (m, 5H), 7.28 (d, J = 5.6 Hz, 2H), 5.37-5.34 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.32 (m, 1H), 2.42-2.32 (m, 6H), 2.29-2.20 (m, 1H), 2.10-1.98 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 321.0 Specification 103 / 119 Page 117 CN 121969615 A ​​

[0871] Example 28

[0872] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.1.1]hexane-1-carboxylic acid

[0873]

[0874] 4-(tert-butoxycarbonyl)amino)-2-oxabicyclo[2.1.1]hexane-1-carboxylic acid (1000 mg, 4.1 mmol, 1 equivalent) and MeOH (50 mL) were added to RBF equipped with a stir bar, followed by a few drops of sulfuric acid. The mixture was stirred until the starting material was confirmed to be completely consumed by LCMS analysis. After completion, Amberlyst A21 resin (free base) was added to remove residual acid, and the mixture was filtered and concentrated. This yielded methyl 4-(tert-butoxycarbonylamino)-2-oxabicyclo[2.1.1]hexane-1-carboxylate as a white solid (812 mg, 3.2 mmol, 77% yield). LCMS (ESI) [M-tBu+H]+ = 202.150. 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 1H), 3.89 (s, 2H), 3.79 (s, 3H), 2.45 (s, 2H), 2.22–2.12 (m, 2H), 1.45 (s, 9H).

[0875] Step 2: Synthesis of tert-butyl (1-(4-hydroxyhept-1,6-dien-4-yl)-2-oxabicyclo[2.1.1]hexane-4-yl)carbamate

[0876]

[0877] Methyl 4-(tert-butyloxycarbonylamino)-2-oxabicyclo[2.1.1]hexane-1-carbamate (1000 mg, 3.9 mmol, 1 equivalent) and THF (20 mL) were added to RBF equipped with a stir bar. Allyl magnesium bromide (1 mol / L) in diethyl ether (20 mL, 20 mmol, 5 equivalent) was added to a separate flask cooled to 0 °C. A solution of the ester in THF was slowly added dropwise to this solution. The reaction was stirred at 0 °C for 10 min, then allowed to warm to room temperature and stirred for another 20 min. The reaction was quenched with a saturated aqueous solution of NH4Cl and then extracted with DCM. The organic fraction was dried over MgSO4, filtered, and concentrated. Purification via column chromatography (0% to 100% iPrOAc in heptane) yielded N-[1-(1-allyl-1-hydroxy-but-3-enyl)-2-oxabicyclo[2.1.1]hexane-4-yl]carbamate tert-butyl ester (625 mg, 2.0 mmol, 52% yield). 1H NMR (400 MHz, CDCl3) δ 6.00 – 5.81 (m , 2H) , 5.15 (s , 2H) , 5.12 (d , J = 3.8 Hz, 2H) , 5.03 (s , 1H) , 3.79 (s , 2H) , 2.47 – 2.29 (m, 4H), 2.08 (s, 2H), 2.02 – 1.85 (m, 2H), 1.47 (s, 9H).

[0878] Steps 3 to 4: Synthesis of (1-(pyridin-4-yl)-2-oxabicyclo[2.1.1]hexane-4-yl)carbamate tert-butyl ester

[0879]

[0880] N-[1-(1-allyl-1-hydroxy-but-3-enyl)-2-oxabicyclo[2.1.1]hexane-4-yl]carbamate tert-butyl ester (1700 mg, 5.5 mmol, 1 equivalent) and 9:1 DCM:MeOH (55 mL) were added to a vial equipped with a stir bar. The mixture was cooled to -78°C and ozone was bubbled through the solution until the mixture turned blue (about 10 minutes).At this point, stop the ozone flow, bubble N2 through the mixture until it becomes colorless, then add triphenylphosphine (polymer-supported) (21000 mg, 331 mmol, 6 equivalents) and stir the mixture at -78°C for 30 minutes. Warm the reaction mixture to room temperature and stir for 1 hour. Filter the mixture through diatomaceous earth and concentrate it. Use the crude material unpurified for the next step and absorb it in MeOH (25 mL). Add a solution of ammonium acetate (6353 mg, 82 mmol, 15 equivalents) in MeOH (25 mL) and stir the reaction at 50°C until the starting material is confirmed to be completely consumed by LCMS analysis. After completion, concentrate the mixture directly, then grind it with diethyl ether and filter twice to remove residual ammonium acetate. Concentrate the filtrate. This produces a residue, which is ground with water to obtain a white suspension, which is then filtered. A white solid was collected and identified as pure N-[1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexane-4-yl]carbamate tert-butyl ester (750 mg, 2.7 mmol, 50% yield). The aqueous filtrate was extracted four times with DCM, and the organic layers were combined and concentrated. This provided an additional 360 mg of the desired compound (yellow solid) in slightly lower purity. This material was purified by column chromatography (5% to 10% MeOH in DCM) to give an additional 250 mg of the desired compound as a white solid (67% overall yield via two steps). LCMS (ESI) [M+H]+ = 277.192. 1H NMR (400 MHz, CDCl3) δ 8.59 (d , J = 6.3 Hz, 2H) , 7.33 (d , J = 4.5 Hz, 2H) , 5.18 (s, 1H) , 3.93 (s, 2H) , 2.47 (s, 2H), 2.23 – 2.14 (m, 2H), 1.47 (s, 9H).

[0881] Step 5: Synthesis of 1-(pyridin-4-yl)-2-oxabicyclo[2.1.1]hexane-4-amine dihydrochloride

[0882]

[0883] N-[1-(4-pyridinyl)-2-oxabicyclo[2.1.1]hexane-4-yl]carbamate tert-butyl ester (250 mg, 0.9 mmol, 1 equivalent) and MeOH (5 mL) were added to a vial equipped with a stir bar. An HCl / MeOH solution was prepared in a separate vial by slowly adding acetyl chloride (355 mg, 0.322 mL, 4.5 mmol, 5 equivalent) dropwise to MeOH (5 mL) while stirring.Add this solution to the boc-protected amine. Stir the mixture until the starting material is confirmed to be completely consumed by LCMS analysis. Once complete, concentrate the mixture to give 1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexane-4-amine dihydrochloride (212 mg, 0.85 mmol, 94% yield) as a grayish-white solid. LCMS (ESI) [M+H]+ = 177.200

[0884] Steps 6 to 8: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((1-(pyridin-4-yl)-2-oxabicyclo[2.1.1]hexane-4-yl)amino)propane-1-ol (Example 28)

[0885]

[0886] 1-(4-pyridinyl)-2-oxabicyclo[2.1.1]hexane-4-amine; hydrochloride (25 mg, 0.1 mmol, 1 equivalent), paraformaldehyde (6.4 mg, 0.2 mmol, 2 equivalents), 1-(4-chloro-3-fluorophenyl) ethyl ketone (26 mg, 0.15 mmol, 1.5 equivalents) and EtOH (0.1 mL) were added to a vial equipped with a stir bar. The reaction was heated to 75°C and stirred overnight. After stirring overnight, 100 μL each of water and MeOH were added to the reaction mixture, which was then cooled to 0°C and excess sodium borohydride was added. Once all ketones were reduced, as confirmed by LCM analysis, the reaction was quenched with 2M HCl (aqueous solution) and extracted with DCM (1 mL). The organic layer was re-extracted with dilute HCl (aqueous solution), and the combined aqueous layer was purified by preparative HPLC (5% to 50% MeCN in water, 0.01% TFA modifier). This yielded 1-(4-chloro-3-fluoro-phenyl)-3-[[1-(4-pyridyl)-2-oxabicyclo[2.1.1]hexan-4-yl]amino]propane-1-ol as a bis-TFA salt. The material was then absorbed into DMF (1 mL) and TEA (excess) was added, followed by excess CDI (see page 119 of the manual, CN 121969615 A). The reaction was heated to 50°C and stirred until the starting material was confirmed to be completely consumed by LCMS analysis. At this point, the reaction was quenched with a saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated.The white solid 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-2-oxabicyclo[2.1.1]hexan-4-yl)-1,3-oxazinan-2-one (Example 28, 5 mg, 0.013 mmol, 12% yield after 3 steps) was purified by preparative HPLC (5% to 50% MeCN in water).

[0887] Example 28: LCMS (ESI) [M+H]+ = 389.045 / 391.020 (3:1). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.4 Hz, 2H), 7.43 (td, J = 7.2, 1.9 Hz, 1H), 7.33 (d, J = 4.5 Hz, 2H), 7.21 (d, J = 10.2 Hz, 1H) , 7.12 (d , J = 8.3 Hz, 1H) , 5.30 (d , J = 10.4 Hz, 1H) , 4.11 – 3.96 (m, 2H) , 3.62 – 3.50 (m, 1H) , 3.48 – 3.37 (m, 1H) , 2.50 (t, J = 8.0 Hz, 1H), 2.41 (t, J = 9.4 Hz, 1H), 2.37 – 2.25 (m, 3H), 2.20 – 2.07 (m, 1H).

[0888] Examples 29a and 29b

[0889]

[0890] Step 1: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-one

[0891]

[0892] A mixture of 3-(4-pyridinyl)bicyclo[1.1.1]pentan-1-amine (1.0 g HCl salt, 6.24 mmol) and paraformaldehyde (262 mg, 8.74 mmol) in EtOH (6 mL) was stirred at room temperature for 15 minutes under a nitrogen atmosphere. Then 1-(4-chloro-3-fluorophenyl)ethane-1-one (1.1 g, 6.24 mmol) was added and the mixture was stirred at 75 °C for 10 hours. The reaction mixture was used directly for the next step without further purification.

[0893] Step 2: Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-ol

[0894]

[0895] NaBH4 (1.0 g, 27.07 mmol) was added fractionally to a solution of crude 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-one in MeOH (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. The reaction was quenched with 2 M HCl (10 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (acetonitrile: 35% to 65% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridine-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-ol (400 mg, 18% yield) as a white solid. 1H NMR (DMSO‑d6, 400 MHz): δ 8.47 (d , J = 5.6 Hz, 2H) , 7.53 (t, J = 8.0 Hz, 1H) , 7.35‑7.32 (m, 1H) , 7.23‑7.21 (m, 3H) , 5.57 (s, 1H) , 4.70 (t, J = 6.0 Hz, 1H) , 2.63 - 2.55 (m, 3H) , 1.99 (s, 6H) , 1.74 - 1.69 (m, 2H).

[0896] Step 3: Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one

[0897]

[0898] DIPEA (0.76 mL, 4.61 mmol) and CDI (374 mg, 2.31 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)amino)propane-1-ol (400 mg, 1.15 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by reversed-phase chromatography (acetonitrile: 35% to 65% / 0.05% NH4OH in water + 10 mM NH4HCO3) to give 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one (400 mg, 93% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+ = 373.1

[0899] Step 4: Chiral separation of 6-(4-chloro-3-fluoro-phenyl)-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]-1,3-oxazinan-2-one (Examples 29a and 29b)

[0900]

[0901] 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridyl-4-yl)bicyclo[1.1.1]pentan-1-yl)-1,3-oxazinan-2-one (400 mg, 1.07 mmol) to give 6-(4-chloro-3-fluoro-phenyl)-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]-1,3-oxazinan-2-one (Example 29a, peak 1, Rt = 2.864 min, 164 mg, 41% yield) and 6-(4-chloro-3-fluoro-phenyl)-3-[3-(4-pyridyl)-1-bicyclo[1.1.1]pentyl]-1,3-oxazinan-2-one (Example 29b, peak 2, Rt = 3.455 min, 192 mg, 48% yield), both of which were white solids.

[0902] Example 29a: 1H NMR (DMSO-d6, 400 MHz): δ 8.51 (d, J = 5.2 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 10.4 Hz, 1H), 7.30-7.27 (m, 3H), 5.41-5.38 (m, 1H), 3.48-3.37 (m, 2H), 2.47-2.34 (m, 6H), 2.30-2.19 (m, 1H), 2.12-1.95 (m, 1H).LCMS: (ESI, m / z) [M+H]+ = 373.0

[0903] Example 29b: 1H NMR (DMSO‑d6, 400 MHz): δ 8.51 (d , J = 5.2 Hz, 2H) , 7.64 (t , J = 8.0 Hz, 1H) , 7.47 (d , J = 10.4 Hz, 1H) , 7.30 ‑ 7.27 (m, 3H) , 5.41 ‑ 5.38 (m, 1H) , 3.48 ‑ 3.35 (m, 2H) , 2.44 ‑ 2.33 (m, 6H) , 2.30 ‑ 2.20 (m, 1H) , 2.12-1.95 (m, 1H). LCMS: (ESI, m / z) [M+H]+ = 373.0

[0904] Characteristic Table Specification 107 / 119 Page 121 CN 121969615 A ​​

[0905] Specification 108 / 119 Page 122 CN 121969615 A ​​Specification 109 / 119 Page 123 CN 121969615 A ​​Specification 110 / 119 Page 124 CN 121969615 A ​​Specification 111 / 119 Page 125 CN 121969615 A ​​

[0906] Preparation of recombinant human SARM1 protein.

[0907] The pRK5 plasmid containing human SARM1 (E26-T274, EC 3.2.2.6) with N-terminal His and C-terminal Avi and Flag tags was transfected into Expi293FTM cells (ThermoFisher Scientific manual 112 / 119 pages 126 CN 121969615 A ​​#A14527) and cultured in Expi293 expression medium at 37°C and 8% CO2. Cells were seeded at 2.5 to 3 × 10⁶ viable cells / ml and transfected with 0.8 mg / ml DNA construct using 1:3 PEI Max transfection reagent (PolySciences #24765). After transfection, cells were fed and 4 mM valproic acid was added. Cells were harvested after 48 h by centrifugation at 500 × g, 4°C for 15 min.For purification, the cell paste was resuspended in ice-cold lysis buffer (50 mM Tris-HCl pH 8.0, 200 mM NaCl, 5% Glycerol, 1.0 mM TCEP (Tris-HCl (2-hydroxyethyl)phosphine), 10 Roche completely EDTA-free protease inhibitor mixture tablets (Millipore Sigma #4693132001)) at 100 mL / L cell paste, and the cells were homogenized and then disrupted via a two-channel process using a Microfluidizer® processor (Microfluidics Model M-110Y). Insoluble material was separated by ultracentrifugation at 40,000 RPM for 1 hour. The soluble supernatant was decanted and passed through a monoclonal ANTI-FLAG® M2 antibody (Millipore Sigma #F1804). The resin column was equipped with lysis buffer and the bound proteins were eluted with 100 μg / mL 3X FLAG® peptide (Sigma-Aldrich #F4799). The eluted proteins were injected onto a Superdex 200 16 / 60 (Amersham Biosciences #GE28-9893-35) column equilibrated in 25 mM Tris pH 8.0, 1 mM TCEP, 150 mM NaCl, and 5% glycerol.

[0908] LCMS Assay Protocol

[0909] The enzyme assay was performed in 384-well polypropylene plates with a final assay volume of 15 µL in assay buffer (50 mM Tris pH 7.5, 0.5 mM dithiothreitol, 0.05% w / v bovine gamma globulin). Recombinant full-length SARM1 (E26-T274) with a final concentration of 7.5 nM was pre-incubated with the corresponding compound at a final determination concentration of 1% DMSO for 15 min at room temperature. The reaction was initiated by adding 20 µM NAD and 20 µM NMN (final concentration). After incubation at room temperature for 45 min, the reaction was terminated by adding 60 µL methanol. The sample was diluted in water (4 µL sample + 80 µL water) and the nicotinamide concentration was analyzed by liquid chromatography-mass spectrometry using a Waters Acquity UPLC coupled to an AB Sciex 4500 triple quadrupole mass spectrometer. The percentage of inhibition was calculated as (sample – low control) / (high control – low control) x 100. The IC50 value was calculated from the 11-point dose-response curve using a four-parameter logic model.

[0910] Cell Viability Assay

[0911] The ability of the compound to rescue cells from SARM1-induced death was tested in HEK cells stably transfected with a doxycycline-inducible construct encoding a constitutively active form of SARM1 lacking the ARM domain (SAM-TIR). Cell viability was determined 24 hours after doxycycline addition by measuring ATP levels using a commercially available kit (CellTiter-Glo, Promega). The results of the dose-response experiment were normalized relative to the natural control (doxycycline plus DMSO) and the blank control (no doxycycline plus DMSO) and fitted to a four-parameter logistic model to calculate EC50 values. References: CellTiter-Glo Assay. CellTiter-Glo® 2.0 Assay Technical Manual TM403 (promega.com).

[0912] Efficacy Data Sheet Instruction Manual 113 / 119 Page 127 CN 121969615 A ​​

[0913] Instruction Manual 114 / 119 Page 128 CN 121969615 A ​​Instruction Manual 115 / 119 Page 129 CN 121969615 A ​​Instruction Manual 116 / 119 Page 130 CN 121969615 A ​​Instruction Manual 117 / 119 Page 131 CN 121969615 A ​​

[0914] Automated Hepatocyte Stability Assay

[0915] The depletion of the parent compound was measured by comparing the amount of drug at time points 60, 120, 180 and 240 minutes with the reference amount at the initial start time of 0 minutes. Metabolic stability studies in hepatocytes were conducted using cryopreserved primary human, rat, and mouse hepatocytes. Incubation was performed at 37°C and 5% CO2 at a drug concentration of 1 µM and 500,000 cells / mL. Hepatocytes were manually prepared by thawing in INVITROGRO HT medium and diluting to 1 million cells / mL with DMEM buffer. Compound dilution, incubation, and various liquid handling procedures were performed using a Tecan Fluent liquid handling system.

[0916] Automated assays consisted of two separately coded protocols. The first protocol was a compound dilution protocol in which the test compound was diluted from the stock vial and aliquoted onto incubation plates. The second protocol was an incubation protocol in which hepatocytes were added, the plates were incubated, and the plates were quenched at their respective time points.

[0917] In the dilution protocol, 1 mM of the compound in DMSO was diluted 500-fold to 2 µM using DMEM in a two-step sequential dilution.First, the compound was diluted to 10 µM by adding 5 µL of the test compound to 495 µL of DMEM and mixing via aspiration. Subsequently, 200 µL of the 10 µM compound was added to 800 µL of DMEM and mixed to achieve a target concentration of 2 µM. 50 µL of the 2 µM drug was added in triplicate to five separate round-bottom 96-well plates using Fluent FCA. One plate was dispensed at each time point during the time process (i.e., 0 min, 60 min, 120 min, 180 min, 240 min).

[0918] In the incubation protocol, 50 µL of 1 million cells mL⁻¹ was added to each well of each plate using a wide-well pipette tip (Tecan Pure, Männedorf, Switzerland). Hepatocytes were placed in an INHECO Thermoshake RM plate shaking incubator set at 37°C and 650 rpm to keep the cells in suspension until they were added to each plate. After adding cells, the plates were immediately capped and placed in a connected Thermo Cytomat 2 incubator set at 37°C and 5% CO2, and quenched with 200 µL of ACN containing internal standard (IS) at the appropriate time points. Plates were quenched immediately after adding hepatocytes at T0 minutes. The ACN quenching solution was stored in the same on-deck incubator set at 4°C to mitigate evaporation during the experiment. After quenching, samples were centrifuged at 3700 rpm for 10 minutes using an Agilent vSpin under-deck centrifuge, and the supernatant was added to separate plates for LC-MS analysis. Standard 200 µL Tecan MCA pipette tips were used to aliquot the ACN quenching solution and supernatant, and the plates were rinsed with methanol (MeOH) between uses to prevent cross-time point contamination. Instructions for Use, Pages 118 / 119, 132, CN 121969615 A ​​

[0919] Permeability Assay Protocol

[0920] Madin-Darby kidney cells (MDCKI) were obtained from ATCC (Manassas, Virginia). The endogenous canine Mdr1 gene was knocked out using CRISPR Cas9 to generate the gMDCK cell line. Human MDR1 and ABCG2 (BCRP) genes were stably overexpressed in gMDCKI cells.Cells were maintained in Durbeco-modified Igor medium supplemented with 10% fetal bovine serum, Streptococcus, puromycin, and plasmacytogen, and then seeded at 2.5 x 10⁵ cells / mL in Millipore Millicell-24 wells and allowed to grow for 5 days. Prior to permeability assays, cell monolayers were equilibrated for 60 min at 37°C, 5% CO₂, and 95% RH in transport buffer (Hankes balanced salt solution containing 10 mM HEPES, pH 7.4). A dose solution of the test compound was prepared at 1 µM in transport buffer containing fluorescein (100 µM), a monolayer integrity marker. The dose solution was added to the donor chamber, and the transport buffer was added to all receiver chambers. Permeability was examined in the top-to-base-outer (A:B) and base-outer-to-top (B:A) directions. Receiver chambers were sampled at 60, 120, and 180 min and replenished with fresh transport buffer. Fluorescein was measured using a fluorescence plate reader (ex: 425 nm; em: 530 nm), and the concentration concentration of the compound in the donor and acceptor compartments was determined by LC-MS / MS analysis. The apparent permeability (Papp) in the A:B and B:A directions was calculated as follows:

[0921] Papp = (dQ / dt)•(1 / CO),

[0922] where: dQ / dt = rate of appearance of the compound in the acceptor compartment; A = surface area of ​​the insert; and CO = initial substrate concentration at time 0 minutes.

[0923] This written description uses examples to disclose the invention, including the best mode, and also enables those skilled in the art to practice the invention, including making and using any device or system and performing any incorporated method. The scope of the invention is defined by the claims and may include other examples that may be thought of by those skilled in the art. These other examples are intended to fall within the scope of the claims if they have structural elements that are not indistinguishable from the literal language of the claims, or if they include equivalent structural elements that are not substantially indistinguishable from the literal language of the claims. Instruction manual, pages 119 / 119, 133 CN 121969615 A.

Claims

1. A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is ;or X 1 For CR 7 Or N; X 2 For CR 4 CHR 4 Or N; X 3 For non-existent, CH, CH2, NH or S; X 4 For N, CH2, CH, NH, O, or S; X 5 For CR 8 ; Y represents non-existent, CR 5 R 6 Or CH2CH2, where R 5 and R 6 Independently H, OH, CN, halogenated, C 1-6 Alkyl or C 1-6 cycloalkyl, or R 5 and R 6 Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl; Z is CH or N; Q 1 and Q 2 One of them is N and the other is CR 4 Q 3 and Q 4 One of them is N and the other is CR 4 ; or Q 3 and Q 4 For CR 4 ;R 1a For H or C 1-6 Alkyl; R 1b Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, bicyclo[1.1.1]pentan-1-yl and C 6-10 Aryl or C 1-6 Halogenated alkoxy-substituted C 1-6 Alkyl; wherein each aryl, heteroaryl, cycloalkyl, and bicyclo[1.1.1]pentan-1-yl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C10. 1-6 Alkyl, Halogenated, C 1-6 Halogenated alkyl groups and C 3-6 cycloalkyl; or R 1a and R 1b Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl; R 2 For H, OH, CN or C 1-6 Alkyl; R 3 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; R 4 H, halogenated, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Hydroxyalkyl; R 7 and R 8 They either do not exist, or -CH2- bridges are formed between the carbon atoms they are connected to; Indicates the connection point with the rest of the compound; and Indicates a single bond or a double bond.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 For CR 7 ;X 2 For CHR 4 ;X 3 For non-existent or CH2; X 4 It is CH2 or O; X 5 For CR 8 And R 7 and R 8 -CH2- bridges are formed between the carbon atoms they are connected to.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 For CR 7 ;X 2 For CHR 4 ;X 3 It does not exist; X 4 CH2; X 5 For CR 8 And R 7 and R 8 -CH2- bridges are formed between the carbon atoms they are connected to.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 For CR 7 ;X 2 For CHR 4 ;X 3 CH2; X 4 For O; X 5 For CR 8 And R 7 and R 8 -CH2- bridges are formed between the carbon atoms they are connected to.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... 、 、 and 。 7. The compound according to claim 6, having formula (III): (III), or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, having formula (IV): (IV), or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 6, having formula (V): Or its pharmaceutically acceptable salt.

10. The compound according to claim 6, having the formula (Va): (Va) or its pharmaceutically acceptable salt.

11. The compound according to claim 1, wherein ring A is And the compound has formula (II): (II), or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For C; X 2 For N; X 3 For NH; and X 4 Let N be the number of elements in the array.

13. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For C; X 2 For CR 4 ;X 3 For NH; and X 4 Let N be the number of elements in the array.

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For N; X 2 For CR 4 ;X 3 For CH; and X 4 Let N be the number of elements in the array.

15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For C; X 2 For CR 4 ;X 3 Let S be the number of S; and X be the number of X. 4 Let N be the number of elements in the array.

16. The compound according to any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

17. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For N; X 2 For N; X 3 For CH; and X 4 Let N be the number of elements in the array.

18. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For C; X 2 For N; X 3 Let S be the number of S; and X be the number of X. 4 Let N be the number of elements in the array.

19. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein X 1 For C; X 2 For N; X 3 For NH; and X 4 CH, 16. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... 、 、 、 、 、 and 。 20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 4 H, halogenated, methylated, or C 1-6 Hydroxyalkyl.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

22. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... 、 、 、 、 、 、 、 、 and 。 23. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... 、 、 and 。 24. The compound according to claim 11, having formula (IIa): (IIa), or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

26. The compound according to claim 11, having formula (IIb): (IIb), or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 11, having formula (IIc): (IIc), or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 11, having formula (IId): (IId), or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 11, having formula (IIe): (IIe), or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 11, having the formula (IIf): (IIf), or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 11, having the formula (IIg): (IIg), or a pharmaceutically acceptable salt thereof.

32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is N.

33. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

34. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3 For H.

35. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3 It can be methyl, phenyl, or pyridyl.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein Y is absent.

37. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein Y is CH2CH2.

38. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Y is CR 5 R 6 .

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 It can be H, OH, CN, or halogenated independently.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 For H.

41. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R 5 For H and R 6 For OH or CN, 37.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 2 It can be H, OH, CN or methyl.

43. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1a It can be H or methyl.

45. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1a For H.

46. ​​The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Together with the carbon atoms they are bonded to, they form C 3-6 Cycloalkyl.

47. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 1b Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl and C 6-10 Aryl or C 1-6 Halogenated alkoxy-substituted C 1-6 Alkyl; wherein each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently selected from C10. 1-6 Alkyl, Halogenated, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl.

48. The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein R 1b Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl and C 1-6 Haloalkyl, wherein each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently selected from C10. 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

49. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 1b Selected from 、 、 、 、 、 、 , where each R 9 Selected independently from C 1-6 Alkyl, Halogenated, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl; and p is 0, 1, 2, 3 or 4.

50. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 1b Selected from 、 、 、 、 、 、 、 and , where p is 1 or 2.

51. The compound according to claim 49 or 50, or a pharmaceutically acceptable salt thereof, wherein each R 9 Selected independently from C 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

52. The compound according to claim 49 or 50, or a pharmaceutically acceptable salt thereof, wherein each R 9 It is independently selected from methyl, halogenated and C1 halogenated alkyl groups.

53. The compound according to claim 1, having formula (IIIa) or (IIIb): (IIIa) (IIIb), or a pharmaceutically acceptable salt thereof, wherein R 6 It can be H, OH, or CN.

54. The compound according to claim 1, having formula (IVa) or (IVb): (IVa) (IVb), or a pharmaceutically acceptable salt thereof, wherein R 6 It can be H, OH, or CN.

55. The compound according to claim 1, having the formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf). (And) (Vb) (Vc) (CEO) (Ve) (Vf) or its pharmaceutically acceptable salt.

56. The compound according to claims 53 to 54 or a pharmaceutically acceptable salt thereof, wherein R 1a For H and R 1b Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl and C 1-6 Haloalkyl, wherein each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently selected from C10. 1-6 Alkyl, halogenated and C 1-6 Halogenated alkyl groups.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein each aryl or heteroaryl group is optionally substituted with one to four substituents, wherein each substituent is independently halogenated.

58. The compound according to claim 1, having a formula selected from the following: (IIa-1)、 (IIa-2)、 (IIa-3)、 (IIa-4)、 (IIa-5)、 (IIa-6), or a pharmaceutically acceptable salt thereof.

59. The compound of claim 58 or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

60. The compound according to claim 1, having a formula selected from the following: (IIb-1)、 (IIb-2)、 (IIb-3)、 (IIb-4)、 (IIb-5)、 (IIb-6), or a pharmaceutically acceptable salt thereof.

61. The compound according to claim 1, having a formula selected from the following: (IIc-1)、 (IIc-2)、 (IIc-3)、 (IIc-4)、 (IIc-5)、 (IIc-6), or a pharmaceutically acceptable salt thereof.

62. The compound according to claim 1, having a formula selected from the following: (IId-1)、 (IId-2)、 (IId-3)、 (IId-4)、 (IId-5)、 (IId-6), or a pharmaceutically acceptable salt thereof.

63. The compound according to claim 1, having a formula selected from the following: (IIe-1)、 (IIe-2)、 (IIe-3)、 (IIe-4)、 (IIe-5)、 (IIe-6), or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 1, having a formula selected from the following: (IIf-1)、 (IIf-2)、 (IIf-3)、 (IIf-4)、 (IIf-5)、 (IIf-6), or a pharmaceutically acceptable salt thereof.

65. The compound according to claim 1, having a formula selected from the following: (IIg-1)、 (IIg-2)、 (IIg-3)、 (IIg-4)、 (IIg-5)、 (IIg-6), or a pharmaceutically acceptable salt thereof.

66. A compound or a pharmaceutically acceptable salt thereof, as provided in Table 1.

67. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

68. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is formulated for oral administration.

69. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition is formulated for injection.

70. A method of treating or preventing axonal degeneration, the method comprising administering to an individual in need a therapeutically effective amount of a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 66 to 68.

71. The method of claim 70, wherein the individual is a person.

72. The method according to claim 70 or 71, wherein the individual (i) has a condition characterized by axonomutability or (ii) is at risk of developing a condition characterized by axonomutability.

73. A method of treating a neurodegenerative disease, the method comprising administering to an individual in need a therapeutically effective amount of a compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 66 to 68.

74. The method of claim 73, wherein the neurodegenerative disease is selected from ALS, CIPN, peripheral neuropathy and MS.

75. The method according to any one of claims 70 to 74, wherein the administration is via an oral route.

76. The method according to any one of claims 70 to 74, wherein the application is via injection.

77. A method for inhibiting SARM1, the method comprising contacting a biological sample with a therapeutically effective amount of a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 66 to 68.