Piperazine derivatives and their use in medicine

Abstract

The present application relates to piperazine-based compounds, compositions thereof, and their use in the manufacture of antitumor drugs.

Description

[Technical Field]

[0001] The present invention relates generally to the field of medicinal chemistry, and specifically to piperazine derivatives, or pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, and their use in medicine. [Background technology]

[0002] Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-transcriptional protein modification process that incorporates one or more adenosine diphosphate ribosyl (ADP-ribosyl) groups into amino acid residues of proteins. ADP-ribosylation is a reversible process involved in physiological regulation, including cell signaling, DNA damage repair, transcription, gene expression control, and apoptosis. ADP-ribose is derived from the redox cofactor nicotinamide adenine dinucleotide (NAD+), and the enzyme that mediates this incorporation is ADP-ribosyltransferase. This physiological reaction involves cleavage of the N-glycosidic bond of NAD+ that connects the ADP-ribose molecule to the nicotinamide group, allowing it to subsequently capture and bind to the corresponding amino acid residue in its target protein. ADP-ribosylation enzymes can carry out two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are subjected to pressure stress, PARPs are activated, resulting in an increase in the amount of poly-ADP-ribose and a decrease in the amount of NAD+. For over a decade, PARP1 has been recognized as the sole poly-ADP-ribose polymerase in mammalian cells, and therefore has received the most research attention. To date, scientists have identified 17 distinct PARPs. Mono-PARPs make up the majority of the PARP family and mediate important biological functions and various stress responses, such as the unfolded protein response, NF-κB signaling, antiviral responses, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzodioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP-7) is a member of the MonoPARP family, and its expression is regulated by the TCDD-activated aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the toxic activities of many environmental xenobiotics.AHR upregulates the expression of PARP-7, which interacts with the kinase TBK1 and ADP-ribosylates it, leading to the suppression of TBK1 activity, a decrease in IFN-I (type I interferon) response, and ultimately to the suppression of the body's antiviral and tumor immune responses. Summary of the Invention [Means for solving the problem]

[0003] One or more embodiments of the present application provide selective PARP7 inhibitors, or pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, and uses in medicine, such as in anti-cancer.

[0004] One or more embodiments of the present application provide a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof: [ka]

[0005] During the ceremony, X1 is NH, O or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, or R 1a , R 1b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 an alkyl group, or R6 and R7 together with the carbon atom to which they are attached form =O; R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O, or R8 and R9 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R 10 are each independently, C 1-6 Alkyl group, C 1-6 Alkoxy group, CONR 10a R 10b , halogen, cyano group, S(O)2R 10c , S.R. 10d or a 3- to 5-membered cycloalkyl group, 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10a , R 10b , R 10c , R 10d are each independently H, D or C 1-6 is an alkyl group, A is, [ka] and R a is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-10 membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, and the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

[0006] In one or more embodiments, X1 is NH, O or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogen atoms; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R10 are each independently, C 1-6 Alkyl group, C 1-6 Alkoxy group, CONR 10a R 10b , halogen, cyano group, S(O)2R 10c , S.R. 10d or a 3- to 5-membered cycloalkyl group, 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10a , R 10b , R 10c , R 10d are each independently H, D or C 1-6 is an alkyl group, A is, [ka] and R a is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- or 6-membered heterocycle, and the 5- or 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

[0007] In one or more embodiments, the compounds of the present application have the structure represented by formula (I-1): [ka]

[0008] During the ceremony, X1 is NH or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O, X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, R3 is H, D, C 1-6 is an alkyl group or a halogen atom, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is an alkyl group, R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group or SR 10d and C 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10d is H, D or C 1-6 is an alkyl group, A is, [ka] and B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- or 6-membered heterocycle, and the 5- or 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0009] In one or more embodiments, the compounds of the present application have the structure represented by formula (I-2): [ka]

[0010] During the ceremony, X1 is NH; X2 is O, R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, R3 is H, D, C 1-6 is an alkyl group or a halogen atom, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is an alkyl group, R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group or SR 10d and C 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10dis H, D or C 1-6 is an alkyl group, A is, [ka] and B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0011] In one or more embodiments, X1 is NH; X2 is O, R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, R3 is H, D, C 1-6 is an alkyl group or a halogen atom, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 is an alkyl group, R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is C 1-6 Alkyl group, cyano group, or SR 10d and C 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 is an alkyl group, A is, [ka] and B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0012] In one or more embodiments, X1 is selected from NH; X2 is selected from O; R 1a , R 1b are each independently H, D or C 1-6 alkyl groups, R 2a , R 2b are each independently H, D or C 1-6 alkyl groups, R3 is H, D, C 1-6 is an alkyl group or a halogen atom, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 is CF3 or SR 10d and R 10d is H, D or C 1-6 is an alkyl group, A is, [ka] and B is [ka] and m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0013] In one or more embodiments, X1 is selected from NH; X2 is selected from O; R 1a , R 1b are each independently H, D or C 1-3 alkyl groups, R 2a , R 2b are each independently H, D or C 1-3 alkyl groups, R3 is selected from H, D or CF3; R4 and R5 are each independently selected from H or D; R6 and R7 are each independently selected from H or D; R8 and R9 are each independently selected from H or D; R 10 is selected from CF3, A is, [ka] and B is [ka] and m is 1, 2 or 3; n is 0, 1 or 2.

[0014] In one or more embodiments, the compounds of the present application have the structure represented by formula (I-3): [ka]

[0015] During the ceremony, X1 is NH or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O, R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, R4 and R5 are each independently H, D, or C 1-6 is an alkyl group, R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group or SR 10d and C 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10d is H, D or C 1-6 alkyl groups, A is, [ka] and B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0016] In one or more embodiments, X1 is NH or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O, R 1a , R1b are each independently H, D or C 1-3 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-3 is an alkyl group, R4 and R5 are each independently H, D, or C 1-3 is an alkyl group, R6 and R7 are each independently H, D, or C 1-3 is an alkyl group, R8 and R9 are each independently H, D, or C 1-3 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is C 1-6 Alkyl group, cyano group or SR 10d and C 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R 10d is H, D or C 1-6 alkyl groups, A is, [ka] and B is [ka] and m is 1, 2 or 3; n is 0, 1 or 2.

[0017] In one or more embodiments, X1 is NH; X2 is O, R 1a , R 1b are each independently H, D or C 1-3 is an alkyl group, R 2a , R 2b are each independently H or D; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 is CF3, A is, [ka] and B is [ka] and m is 1, 2 or 3; n is 0, 1 or 2.

[0018] One or more embodiments of the present application provide a compound of formula (I'), or a stereoisomer thereof: [ka]

[0019] X1 is NH or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, or R 1a , R 1b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H or C 1-6 an alkyl group, or R6 and R7 together with the carbon atom to which they are attached form =O; R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O, or R8 and R9 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R 10 each independently represents a halogen-substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkoxy group, CONR 10a R 10b , cyano group, S(O)R 10c , S.R. 10d or a 3- to 5-membered cycloalkyl group, R 10a , R 10b , R 10c , R 10d are each independently H, D or C 1-6 is an alkyl group, A is, [ka] and R a is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-10 membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; C is a 5- or 6-membered heterocycle, and the 5- or 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

[0020] One or more embodiments of the present application provide a compound of formula (I-1′), or a stereoisomer thereof: [ka]

[0021] X1 is NH or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, or R 1a , R 1b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or C 1-6or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H or C 1-6 an alkyl group, or R6 and R7 together with the carbon atom to which they are attached form =O; R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O, or R8 and R9 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R 10 is a halogen-substituted C 1-6 Alkyl group, CONR 10a R 10b , a cyano group, or a 3- to 5-membered cycloalkyl group; R 10a , R 10b are each independently H, D or C 1-6 is an alkyl group, A is, [ka] and R a is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- or 6-membered heterocycle, and the 5- or 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0022] One or more embodiments of the present application provide a compound of formula (I-2'), or a stereoisomer thereof: [ka]

[0023] X1 is NH; X2 is O or a bond; X3 and X4 are C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, or R 1a , R 1b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R3 is H, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or C 1-6 is an alkyl group, R6 and R7 are each independently H or C 1-6 an alkyl group, or R6 and R7 together with the carbon atom to which they are attached form =O; R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 is CF3, a cyano group, or a 3- to 5-membered cycloalkyl group, A is, [ka] and R a is C 1-6 Alkyl group, C 3-5is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- or 6-membered heterocycle, and the 5- or 6-membered heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0024] One or more embodiments of the present application provide a compound of formula (I-3'), or a stereoisomer thereof: [ka]

[0025] During the ceremony, X1 is NH; X2 is O or a bond; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, or R 1a , R 1b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b optionally form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached; R3 is H or C 1-6 is an alkyl group, R4 and R5 are each independently H or C 1-6 is an alkyl group, R6 and R7 are each independently H or C 1-6 is an alkyl group, R8 and R9 are each independently H or C1-6 is an alkyl group, R 10 is CF3 or a 3- to 5-membered cycloalkyl group, A is, [ka] and B is [ka] and m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0026] In one or more embodiments, X1 is NH; X2 is O, R 1a , R 1b are each independently H or C 1-6 is an alkyl group, R 2a , R 2b are each independently H or C 1-6 is an alkyl group, R3 is H or C 1-6 is an alkyl group, R4 and R5 are each independently H or C 1-6 is an alkyl group, R6 and R7 are each independently H or C 1-6 is an alkyl group, R8 and R9 are each independently H or C 1-6 is an alkyl group, R 10 is CF3 or a 3- to 5-membered cycloalkyl group, A is, [ka] and B is [ka] and m is 1 or 2; n is 0 or 1.

[0027] In one or more embodiments of the present application, the compound has the following structure: [ka] [ka] [ka] [ka] [ka]

[0028] One or more embodiments of the present application provide an intermediate for producing a compound according to Formula (I), (I-1), (I-2), (I-3), (I'), (I-1'), (I-2'), or (I-3'), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the intermediate, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, has a structure represented by Formula (I-4). [ka]

[0029] During the ceremony, Y1 is -NH2, -OH, -NHP1 or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; P1 is an amino protecting group, preferably -Boc; P0 is H or an amino-protecting group, and the amino-protecting group is preferably -PMB; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; C is a 5- to 6-membered heterocycle, and the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0030] In one or more embodiments of the present application, the compound of the present application has the following structure: [ka]

[0031] One or more embodiments of the present application provide an intermediate for producing a compound according to Formula (I), (I-1), (I-2), (I-3), (I'), (I-1'), (I-2'), or (I-3'), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the intermediate, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, has a structure represented by Formula (I-5). [ka]

[0032] During the ceremony, X1 is NH, O or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; P0 is H or an amino-protecting group, and the amino-protecting group is preferably -PMB; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; G is [ka] and R a is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; P2 is H or an amino-protecting group, and the amino-protecting group is preferably -SEM or -PMB; C is a 5- to 6-membered heterocycle, and the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

[0033] In one or more embodiments of the present application, the compound of the present application has the following structure: [ka]

[0034] One or more embodiments of the present application provide an intermediate for producing a compound according to Formula (I), (I-1), (I-2), (I-3), (I'), (I-1'), (I-2'), or (I-3'), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the intermediate, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, has a structure represented by Formula (I-6). [ka]

[0035] During the ceremony, Y2 is NHR Y, OH, or a 4- to 6-membered heterocycle, the 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N and O; R Y is H or an amino protecting group, and the amino protecting group is preferably -Boc; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b are each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 are each independently, C 1-6 Alkyl group, C 1-6 Alkoxy group, CONR 10a R 10b , halogen, cyano group, S(O)2R 10c , S.R. 10d or a 3- to 5-membered cycloalkyl group, 1-6 Alkyl group, C 1-6The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10a , R 10b , R 10c , R 10d are each independently H, D or C 1-6 is an alkyl group, B is a 5-10 membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, and the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

[0036] In one or more embodiments of the present application, the compound of the present application has the following structure: [ka]

[0037] One or more embodiments of the present application provide an intermediate for producing a compound according to Formula (I), (I-1), (I-2), (I-3), (I'), (I-1'), (I-2'), or (I-3'), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein the intermediate, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, has a structure represented by Formula (I-7). [ka]

[0038] During the ceremony, X1 is NH, O or a 4- to 6-membered heterocycle, and the 4- to 6-membered heterocycle contains 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1bare each independently H, D or C 1-6 is an alkyl group, R 2a , R 2b are each independently H, D or C 1-6 is an alkyl group, or R 2a , R 2b form a 3- to 5-membered cycloalkyl group with the carbon atom to which they are attached, R3 is H, D, C 1-6 is an alkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D, or C 1-6 or R4 and R5 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl group; R6 and R7 are each independently H, D, or C 1-6 is an alkyl group, R8 and R9 are each independently H, D, or C 1-6 an alkyl group, or R8 and R9 together with the carbon atom to which they are attached form =O; R 10 are each independently, C 1-6 Alkyl group, C 1-6 Alkoxy group, CONR 10a R 10b , halogen, cyano group, S(O)2R 10c , S.R. 10d or a 3- to 5-membered cycloalkyl group, 1-6 Alkyl group, C 1-6 The alkoxy group may be optionally substituted with 1 to 3 halogen atoms; R 10a , R 10b , R 10c , R 10d are each independently H, D or C 1-6 is an alkyl group, G is [ka] and Ra is C 1-6 Alkyl group, C 3-5 is a cycloalkyl group, a halogen atom, or a cyano group, 1-6 The alkyl group may be optionally substituted with 1 to 3 halogens; P2 is an amino-protecting group, preferably -SEM or -PMB; B is a 5-10 membered carbocyclic or heterocyclic ring, the heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocycle, and the heterocycle contains 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

[0039] In one or more embodiments of the present application, the compound of the present application has the following structure: [ka] [ka] [ka]

[0040] One or more embodiments of the present application provide a pharmaceutical composition comprising: (1) A compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof; (2) one or more other optionally selected active ingredients, and (3) Pharmaceutically acceptable carriers and / or excipients Includes.

[0041] One or more embodiments of the present application provide the use of a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a pharmaceutical composition of the present application in the manufacture of an antitumor medicament.

[0042] One or more embodiments of the present application provide a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition of the present application, for use as a pharmaceutical.

[0043] One or more embodiments of the present application provide a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition of the present application, for use in a method for treating / preventing cancer.

[0044] One or more embodiments of the present application provide a method for treating / preventing cancer, comprising administering to a subject in need thereof a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, or a composition of the present application.

[0045] Terms used in this specification and claims have the following meanings unless stated to the contrary.

[0046] Carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, and I in the groups and compounds described herein include their isotopes, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described herein may optionally be further substituted with one or more of their corresponding isotopes, with the proviso that carbon isotopes are 12 C. 13 C and 14 C, the isotopes of hydrogen are hydrogen (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), the isotopes of oxygen are 16 O. 17 O and 18 O, an isotope of sulfur, 32 S, 33 S, 34 S and 36 S, the nitrogen isotope is 4 N and 15 N, the isotope of fluorine is 17 F and 19 F, the isotope of chlorine is 35 Cl and 37 The isotopes of Cl and bromine are 79 Br and 81Br, respectively.

[0047] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their branched isomers. When the alkyl group is substituted, it may be further substituted with one or more substituents.

[0048] The term "alkoxy group" refers to an alkyl group in which at least one carbon atom has been substituted with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy groups. The definition of such an alkyl group is the same as that of the "alkyl group" above.

[0049] The term "alkenyl group" refers to a linear or branched unsaturated aliphatic hydrocarbon group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon double bonds and consisting of 2 to 20 carbon atoms, preferably an alkenyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkenyl group having 2 to 8 carbon atoms, and even more preferably an alkenyl group having 2 to 6 carbon atoms. Non-limiting examples include vinyl, propylene-2-yl, and butene-2-yl. Lu,Examples of alkenyl groups include penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. Such alkenyl groups may optionally be further substituted with one or more substituents.

[0050] The term "alkynyl group" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms; preferably, it is an alkynyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably, an alkynyl group having 2 to 8 carbon atoms, and even more preferably, an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl, etc. Such alkynyl groups may optionally be further substituted with one or more substituents.

[0051] The term "aryl group" refers to a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (e.g., 5-, 6-, 7-, or 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring, or may be a bridged ring or a spiro ring. Non-limiting examples include phenyl and naphthyl groups. Such aryl groups may be optionally further substituted with one or more substituents.

[0052] The term "heteroaryl group" refers to a substituted or unsubstituted aromatic ring, and may be a 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7-, or 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring system containing 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms selected from N, O, or S. Preferably, the heteroaryl group is a 5- to 8-membered heteroaryl group, and 1 to 4 (e.g., 1, 2, 3, or 4) N or S atoms optionally substituted in the heteroaryl ring may be oxidized to various oxidation states. The heteroaryl group may be bonded to a heteroatom or carbon atom, and may be a bridged or spiro ring. Non-limiting examples include cyclopyridinyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, benzimidazolyl, benzopyridinyl, and pyrrolopyridinyl groups. Heteroaryl groups may optionally be further substituted with one or more substituents.

[0053] The term "carbocyclic group" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as that of "aryl" above. When it is a non-aromatic ring, it may be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring, or it may be a bridged ring or a spiro ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, [ka] Such a "carbocyclic group" or "carbocycle" may optionally be further substituted with one or more substituents.

[0054] The term "heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it may be a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered) monocycle, a 4- to 12-membered (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicycle, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricycle, which may contain 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S, and is preferably a 3- to 8-membered heterocyclic group. One to four (e.g., one, two, three, or four) optionally substituted N and S atoms in the ring of a "heterocyclic group" or "heterocycle" may be oxidized to various oxidation states. A "heterocyclic group" or "heterocycle" may be bonded to a heteroatom or carbon atom, and may be a bridged or spiro ring.Non-limiting examples of "heterocyclic groups" or "heterocycles" include epoxyethyl groups, epoxypropyl groups, aziridinyl groups, oxetanyl groups, azetidinyl groups, thietanyl groups, 1,3-dioxolanyl groups, 1,4-dioxolanyl groups, 1,3-dioxanyl groups, azepanyl groups, oxepanyl groups, thiepanyl groups, oxoazevinyl groups, diazepinyl groups, thiazepinyl groups, pyridinyl groups, homopiperidinyl groups, furanyl groups, thienyl groups, pyranyl groups, N-alkylpyrrolyl groups, pyridinyl groups, and pyridinyl groups. Irimidinyl group, pyrazinyl group, pyridazinyl group, piperazinyl group, homopiperazinyl group, imidazolyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, oxathianyl group, 1,3-dithianyl group, dihydrofuranyl group, dithiolaryl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyridyl group, tetrahydrothiopyranyl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyr nyl group, benzimidazolyl group, benzopyridinyl group, pyrrolopyridinyl group, pyrazolopyrimidinyl group, imidazopyrazinyl group, benzodihydrofuranyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, dihydroindolyl group, 2H-pyranyl group, 4H-pyranyl group, dioxanyl group, 1,3-dioxolanyl group, pyrazolinyl group, dithianyl group, dithiolanyl group, dihydrothienyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, 1,2,3,4-tetrahydrofuranyl group, 2H-pyranyl group, 3H-pyranyl group, dihydroindolyl group, 2H-pyranyl group, 4H-pyranyl group, dioxanyl group, 1,3-dioxolanyl group, pyrazolinyl group, dithianyl group, dithiolanyl group, dihydrothienyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, 1,2,3,4-tetrahydrofuranyl group, Examples of heterocyclic groups include azahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridyl urea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. Such "heterocyclic groups" or "heterocycles" may be optionally further substituted with one or more substituents.

[0055] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, and the ring may be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20-membered) polycyclic ring, and the number of carbon atoms in the ring is preferably 3 to 10, and more preferably 3 to 8. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, cycloheptatrienyl, etc. If a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0056] The term "heterocycloalkyl group" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a 3- to 8-membered (e.g., 3-, 4-, 5-, 6-, 7-, or 8-membered) monocyclic ring, a 4- to 12-membered (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10-, 11-, 12-, 13-, 14-, or 15-membered) tricyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, or S, and is preferably a 3- to 8-membered heterocyclic group. The 1, 2, or 3 N or S atoms optionally substituted in the ring of the "heterocycloalkyl group" may be oxidized to various oxidation states. The "heterocycloalkyl group" may be bonded to a heteroatom or carbon atom, and the "heterocycloalkyl group" may be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl groups" include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl.

[0057] The above-mentioned "alkyl group", "alkoxy group", "alkenyl group", "alkynyl group", "aryl group", "heteroaryl group", "carbocyclic group", "carbocycle", "heterocyclic group", "heterocycle", "cycloalkyl group", or "Heterocycloalkyl group "but If substituted, F, Cl, Br, I, hydroxyl group, mercapto group, nitro group, cyano group, amino group, C 1-6 Alkylamino group, =O, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -NR q4 R q5 , =NRq6 , -C(=O)OC 1-6 Alkyl group, -OC(=O)C 1-6 Alkyl group, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl groups, C 3-8 Heterocycloalkyl groups, C 6-10 Aryl group, C 5-10 Heteroaryl group, -C(=O)OC 6-10 Aryl group, -OC(=O)C 6-10 Aryl group, -OC(=O)C 5-10 Heteroaryl group, -C(=O)OC 5-10 Heteroaryl group, -OC(=O)C 3-8 Heterocycloalkyl groups, -C(=O)OC 3-8 Heterocycloalkyl groups, -OC(=O)C 3-8 Cycloalkyl groups, -C(=O)OC 3-8 Cycloalkyl groups, -NHC(=O)C 3-8 Heterocycloalkyl groups, -NHC(=O)C 6-10 Aryl group, -NHC(=O)C 5-10 Heteroaryl group, -NHC(=O)C 3-8 Cycloalkyl groups, -NHC(=O)C 3-8 Heterocycloalkyl groups, -NHC(=O)C 2-6 Alkenyl group or -NHC(=O)C 2-6 alkynyl groups, and 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, C 3-8 Heterocycloalkyl groups, C 6-10 Aryl group, C 5-10 Heteroaryl group, -NHC(=O)C 6-10 Aryl group, -NHC(=O)C 5-10 Heteroaryl group, -NHC(=O)C 3-8 Heterocycloalkyl group or -NHC(=O)C 3-8The cycloalkyl group substituents are optionally OH, F, Cl, Br, I, C 1-6 Alkyl group, C 1-6 Alkoxy group, -NR q4 R q5 or ═O. q1 is C 1-6 Alkyl group, C 1-6 Alkoxy group or C 6-10 aryl groups, R q2 , R q3 is H or C 1-6 alkyl, where R q4 , R q5 is H, C 1-6 Alkyl group, -NH(C=NR q1 )NR q2 R q3 , -S(=O)2NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 wherein C is selected from 1-6 The alkyl group is optionally selected from the group consisting of OH, F, Cl, Br, I, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-10 Aryl group, C 5-10 Heteroaryl groups, C 3-8 Cycloalkyl group or C 3-8 may be further substituted by one or more substituents selected from heterocycloalkyl groups, or R q4 , R q5 forms a 3- to 8-membered heterocycle together with the N atom, and this heterocycle may contain one or more heteroatoms selected from N, O, and S.

[0058] Halogens include F, Cl, Br, and I.

[0059] "Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" means a salt obtained by reacting a compound of the present application with a non-toxic inorganic or organic base, while the compound retains its biological effectiveness and properties as a free acid or free base, and by reacting the free acid with a non-toxic inorganic or organic acid.

[0060] "Pharmaceutical composition" means a mixture of one or more compounds described herein, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, where "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0061] The term "carrier" refers to a material that is not significantly irritating to the living body and that does not eliminate the biological activity and properties of the administered compound.

[0062] "Excipient" means an inactive substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0063] "Stereoisomer" means an isomer formed by a difference in the way the atoms in a molecule are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0064] "Optionally" or "optionally" or "selectively" or "selectively" means that the event or situation described below may occur but does not necessarily occur, and includes cases where the event or situation occurs and cases where it does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be present but is not necessarily present, and includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group. DETAILED DESCRIPTION OF THE INVENTION

[0065] The technical solutions of the present invention are described in detail in the following examples, which do not limit the scope of the patent of the present invention.

[0066] In the examples, unless otherwise specified, the reaction temperature is room temperature, and the optimum reaction temperature at room temperature is 20°C to 30°C.

[0067] Intermediate 1 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1) 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0068] Step 1: 4,5-Dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1b) 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (1a, 50 g, 196.94 mmol, 1.0 equiv) in N,N-dimethylformamide (500 mL) was added sodium hydride (11.82 g, 295.41 mmol, 1.5 equiv, 60%) at 0-10 °C, followed by the addition of 1-(chloromethyl)-4-methoxybenzene (46.06 g, 294.11 mmol, 1.49 equiv) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the reaction was quenched by slowly pouring the reaction mixture into 1.0 L of ice-water mixture and extracted with dichloromethane (2 × 500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL × 2) to give 1b as a yellow solid (48.4 g, 66% yield). LC-MS m / z (ESI) = 375.00 [M+1].

[0069] Step 2: 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1c) 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one 1b (48.4 g, 129.40 mmol, 1.0 equiv) and potassium hydroxide (21.78 g, 388.30 mmol, 3.00 equiv) were dissolved in methanol (417 mL), and the reaction mixture was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated to 80 mL and filtered to give the crude product. The resulting cake was slurried in water (160 mL) for 1 h and filtered to give 1c (38.72 g, 92% yield) as a white solid. LC-MS m / z (ESI) = 326.30 [M+1].

[0070] Step 3: 5-Methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1d) 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one 1c (14 g, 43.04 mmol, 1.0 equiv) and CuI (4.10 g, 21.52 mmol, 0.50 equiv) were weighed into a 250 mL reaction flask and dissolved in N-methylpyrrolidone (72 mL). Then, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (16.4 mL, 129.11 mmol, 3.0 equiv) was slowly added. After the addition was complete, the reaction was stirred in an oil bath at 100 °C for 3 h. Upon completion of the reaction, the reaction was quenched by adding 90 mL of water. The resulting solution was extracted with dichloromethane (3 × 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1d (12.1 g, 89% yield) as a white solid. LC-MS m / z (ESI) = 315.10 [M+1].

[0071] Step 4: 5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1e) 5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Iodotrimethylsilane (9.97 g, 50.07 mmol, 1.3 equiv) was added dropwise to a solution of 1d (12.1 g, 38.52 mmol, 1.0 equiv) in N,N-dimethylformamide (60 mL) at room temperature. The resulting reaction mixture was stirred at 85 °C for 20 h. After completion of the reaction, the reaction mixture was quenched by adding 60 mL of water, and the resulting solution was then extracted with dichloromethane (3 × 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1e (10.4 g, 90% yield) as a white solid. LC-MS m / z (ESI) = 301.07 [M+1].

[0072] Step 5: 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 1) 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Oxalyl chloride (8.79 g, 69.32 mmol, 2.0 equiv) was slowly added dropwise to a solution of compound 1e (10.4 g, 34.66 mmol, 1.0 equiv) in N,N-dimethylformamide (52 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 8 hours. Upon completion of the reaction, the reaction was quenched by adding 550 mL of water. The mixture was filtered to give intermediate 1 (11.04 g, 99%) as a white solid. LC-MS m / z (ESI) = 319.68 [M+1].

[0073] Intermediate 2 (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 2) (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine [ka]

[0074] Step 1: 5-(4-Methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxyethyl (2b) ethyl-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine -2-carboxylate Ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (2a, 5.0 g, 24 mmol, 1.0 equiv) and p-methoxybenzyl bromide (4.2 mL, 28.8 mmol, 1.2 equiv) were weighed and dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (1.15 g, 28.8 mmol, 1.2 equiv) was slowly added in an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 3 h. Upon completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The crude product was purified by high-performance column chromatography (dichloromethane:methanol = 20:1) to give 2b (7.5 g, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.33 - 7.23 (m, 2H), 7.14 (s, 1H), 6.94 - 6.87 (m, 2H), 4.62 (s, 2H), 4.50 - 4.38 (m, 2H), 4.28 (q, 2H), 3.76 - 3.69 (m, 5H), 1.29 (t, 3H). LC-MS m / z (ESI) = 330.10 [M+1].

[0075] Step 2: (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (2c) (5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol 2b (4.1 g, 12.5 mmol, 1.0 equiv) was weighed and dissolved in tetrahydrofuran (100 mL). Under nitrogen gas protection and in an ice bath, a solution of lithium aluminum hydride in tetrahydrofuran (50 mL, 50 mmol, 4.0 equiv) was slowly added dropwise. After the addition was complete, the mixture was heated to 70 °C and reacted for 10 minutes. Upon completion of the reaction, the mixture was cooled to room temperature, quenched in an ice-water bath, suction filtered, and the filtrate was spin-dried. The crude product was purified by high-performance column chromatography (dichloromethane:methanol = 10:1) to give 2c (2.45 g, 71% yield) as a yellow solid. LC-MS m / z (ESI) = 274.10 [M+1].

[0076] Step 3: (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 2) (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine 2c (864 mg, 3.16 mmol, 1.0 equiv) was dissolved in anhydrous N,N-dimethylformamide (18 mL) in a 25 mL reaction bottle. Under N2 protection, sodium hydride (300 mg, 7.51 mmol, 2.5 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 30 min. Then, a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide in N,N-dimethylformamide (18 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition, and stirring was continued for 2 h. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Purification by column chromatography (dichloromethane:methanol=40:1) gave Intermediate 2 as a white solid (252 mg, 24% yield). LC-MS m / z (ESI) = 331.50 [M+1].

[0077] Intermediate 3 (S)-5-((1-((4,5,6,7-tetrahydropyrazolone[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 3) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0078] Step 1: (S)-2-(4-Methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3a) (S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Intermediate 2 (252 mg, 0.764 mmol, 1.0 equiv) and intermediate 1 (291.4 mg, 0.916 mmol, 1.1 equiv) were weighed into a 10 mL reaction bottle and dissolved in N,N-dimethylformamide (3.0 mL). N,N-diisopropylethylamine (0.5 mL, 3.06 mmol, 4.0 equiv) was then added sequentially. The mixture was stirred at 100 °C for 4 hours. After completion of the reaction, the mixture was concentrated under vacuum, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1.5) to give 3a (359.8 mg, 77% yield) as a white solid. LC-MS m / z (ESI) = 613.62 [M+1].

[0079] Step 2: (S)-5-((1-(((4,5,6,7-tetrahydropyrazolone[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 3) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 10 mL reaction flask containing 3a (359.8 mg, 0.588 mmol, 1.0 equiv), trifluoroacetic acid (3.4 mL) and trifluoromethanesulfonic acid (0.42 mL, 4.7 mmol, 8.0 equiv) were sequentially added. After the addition was complete, the reaction was stirred at 25 °C for 1 h. The reaction solution was then stirred in an oil bath at 70 °C. After the reaction was complete, the reaction solution was quenched by adding 15 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give intermediate 3 (48 mg, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.81 (s, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.11 (s, 1H), 5.01 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.16 (t, 3H), 3.55 - 3.45 (m, 2H), 1.15 (d, 3H). LC-MS m / z (ESI) = 373.1 [M+1].

[0080] Intermediate 4 (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-amine (Intermediate 4) (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-amine [ka]

[0081] Step 1: (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methane-d2-ol (4a) (5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methane-d2-ol 2b (3.3 g, 10.0 mmol, 1.0 equiv) was weighed and dissolved in tetrahydrofuran (60 mL). Under nitrogen gas protection and in an ice bath, lithium aluminum deuteride (1.68 g, 40.0 mmol, 4.0 equiv) was slowly added. After the dropwise addition was completed, the temperature was raised to 70 °C and the reaction was allowed to proceed for 10 minutes. Upon completion of the reaction, the mixture was cooled to room temperature, quenched in an ice-water bath, suction filtered, and the filtrate was spin-dried. The crude product was purified by high-performance column chromatography (dichloromethane:methanol = 10:1) to give 4a (2.60 g, 93.8% yield) as a white solid. 1 H NMR (400 MHz, Chloroform-d): δ 7.28 (d, 1H), 6.89 (d, 1H), 5.95 (s, 1H), 4.16 (t, 1H), 3.81 (s, 2H), 3.68 (s, 1H). LC-MS m / z (ESI) = 278.10 [M+1].

[0082] Step 2: (S)-1-((5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-amine (Intermediate 4) (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-amine 4a (2.6 g, 9.3 mmol, 1.0 equiv) was added to a 25 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (26 mL). Under N2 protection, sodium hydride (720 mg, 18.6 mmol, 2.0 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 10 min. Then, a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide in N,N-dimethylformamide (3.0 g, 18 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition and stirring was continued for 2 h. Upon completion of the reaction, the reaction mixture was adjusted to pH = 3 with 2 M hydrochloric acid and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Purification by gas chromatography (dichloromethane:methanol=40:1) gave Intermediate 4 as a white solid (2.8 g, 94% yield). LC-MS m / z (ESI) = 335.10 [M+1].

[0083] Intermediate 5 (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)-amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 5) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0084] Step 1: (S)-2-(4-Methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-4,4-d2)methoxy-d2)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (5a) (S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Intermediate 4 (6 g, 16.2 mmol, 1.5 equiv) and Intermediate 1 (3.4 g, 10.7 mmol, 1.0 equiv) were weighed into a 10 mL reaction bottle and dissolved in acetonitrile (30 mL). Then, triethylamine (6.2 mL, 45 mmol, 4.5 equiv) was added. The mixture was reacted at 80 °C with stirring for 4 hours. After the reaction was complete, the mixture was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1.5) to give 5a (2.0 g, 30% yield) as a white solid. LC-MS m / z (ESI) = 617.10 [M+1].

[0085] Step 2: (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one-one (Intermediate 5) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 10 mL reaction flask containing 5a (2.0 g, 3.2 mmol, 1.0 equiv), trifluoroacetic acid (8 mL) and trifluoromethanesulfonic acid (1.4 mL, 16 mmol, 5.0 equiv) were sequentially added. After the addition was complete, the reaction was stirred at 25 °C for 1 h. The reaction solution was then stirred in an oil bath at 70 °C. After the reaction was complete, the reaction solution was quenched by adding 15 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give intermediate 5 (500 mg, 42% yield) as a white solid.

[0086] Intermediate 6 (S)-2-((2-aminopropoxy)methyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 6) (S)-2-((2-aminopropoxy)methyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one [ka]

[0087] Step 1: 2-(Hydroxymethyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazol[1,5-a]pyrazin-4(5H)-one (6a) 2-(hydroxymethyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 2b (4.0 g, 12.0 mmol, 1.0 equiv) was weighed and dissolved in anhydrous methanol (40 mL). Under nitrogen gas protection and an ice bath, sodium borohydride (9.8 g, 259.0 mmol, 21.5 equiv) was slowly added. The reaction was allowed to proceed at room temperature for 48 hours, quenched in an ice-water bath, extracted with dichloromethane, and the organic phase was concentrated. The crude product was purified by high-performance column chromatography (dichloromethane:methanol = 10:1) to give 6a (2.80 g, 81% yield) as a white solid. 1 H NMR (400 MHz, Chloroform-d): δ 7.26 - 7.21 (m, 2H), 6.91 - 6.84 (m, 3H), 4.70 (s, 2H), 4.68 (s, 2H), 4.31 - 4.20 (m, 2H), 3.80 (s, 3H), 3.66 - 3.58 (m, 2H). LC-MS m / z (ESI) = 288.10 [M+1].

[0088] Step 2: (S)-2-((2-aminopropoxy)methyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 6) (S)-2-((2-aminopropoxy)methyl)-5-(4-methoxybenzyl)-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one 6a (2.6 g, 9.0 mmol, 1.0 equiv) was added to a 25 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (20 mL). Under N2 protection, sodium hydride (540 mg, 13.5 mmol, 1.5 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at this temperature for 10 min. Then, a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide in N,N-dimethylformamide (4.2 g, 20 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition and stirring was continued for 2 h. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 with 2 M hydrochloric acid and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. Purification by gas chromatography (dichloromethane:methanol=40:1) gave Intermediate 6 as a white solid (3.0 g, 97% yield). LC-MS m / z (ESI) = 345.10 [M+1].

[0089] Intermediate 7 (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 7) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ka]

[0090] Step 1: (S)-5-(4-Methoxybenzyl)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (7a) (S)-5-(4-methoxybenzyl)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Intermediate 6 (3.7 g, 10.7 mmol, 1.5 equiv) and Intermediate 1 (2.3 g, 7.2 mmol, 1.0 equiv) were weighed into a 100 mL reaction bottle and dissolved in acetonitrile (20 mL). Then, triethylamine (4.5 mL, 32.4 mmol, 4.5 equiv) was added. The mixture was reacted at 80 °C with stirring for 4 hours. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1.5) to give 7a (5.0 g, 74% yield) as a white solid. LC-MS m / z (ESI) = 627.10 [M+1].

[0091] Step 2: (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 7) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl) -6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one To a 10 mL reaction flask containing 7a (4.7 g, 7.5 mmol, 1.0 equiv), trifluoroacetic acid (18 mL) and trifluoromethanesulfonic acid (4.0 mL, 45 mmol, 6 equiv) were sequentially added. After the addition was complete, the reaction was stirred at 25 °C for 2 h. After the reaction was complete, the reaction solution was quenched by adding 15 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo, and the residue was purified by MPLC (water / acetonitrile = 1:1) to give intermediate 7 (2.6 g, 89% yield) as a white solid. LC-MS m / z (ESI) = 387.10 [M+1].

[0092] Intermediate 8 (2S)-1-(1-(5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazol[1,5-a]pyrazin-2-yl)ethoxy)propan-2-amine (Intermediate 8) (2S)-1-(1-(5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy) propan-2-amine [ka]

[0093] Step 1: 5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-formaldehyde (8a) 5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (2c, 1.4 g, 5.1 mmol, 1.0 equiv.) and Dess-Martin oxidant (2.6 g, 6.2 mmol, 1.2 equiv.) were weighed and dissolved in dichloromethane (20 mL). After the addition was complete, the mixture was allowed to react at room temperature for 3 h. After the reaction was complete, the mixture was filtered and the organic phase was spun dry to give crude 8a as a pale pink oil, which was used directly in the next reaction (1.0 g, 71.4% yield). LC-MS m / z (ESI) =272.4[M+1].

[0094] Step 2: 1-(5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethan-1-ol (8b) 1-(5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethane-1-ol 8a (1.0 g, 3.7 mmol, 1.0 equiv) was weighed and dissolved in tetrahydrofuran (20 mL). Under nitrogen gas protection, a solution of methylmagnesium bromide in tetrahydrofuran (3.7 mL, 11 mmol, 3.0 equiv) was slowly added dropwise in a dry ice / ethanol bath. The reaction was continued for 2 hours to complete the reaction. The mixture was quenched with saturated ammonium chloride, and the resulting solution was extracted with ethyl acetate (3 × 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give 8b (600 mg, 57% yield) as a pale yellow oil. LC-MS m / z (ESI) = 288.10 [M+1].

[0095] Step 3: (2S)-1-(1-(5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazol[1,5-a]pyrazin-2-yl)ethoxy)propan-2-amine (Intermediate 8) (2S)-1-(1-(5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy) propan-2-amine 8b (600 mg, 2 mmol, 1.0 equiv) was dissolved in anhydrous N,N-dimethylformamide (10 mL) in a 25 mL reaction bottle. Under N2 protection, sodium hydride (120 mg, 5 mmol, 2.5 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 30 min. Then, a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide in N,N-dimethylformamide (10 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition, and stirring was continued for 2 h. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Purification by column chromatography (ethyl acetate:petroleum ether=1:0) gave Intermediate 8 as a pale yellow solid (600 mg, 90% yield). LC-MS m / z (ESI) = 334.50 [M+1].

[0096] Intermediate 9 5-(((2S)-1-(1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 9) 5-(((2S)-1-(1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0097] Step 1: 2-(4-Methoxybenzyl)-5-((2S)-1-(1-(5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (9a) 2-(4-methoxybenzyl)-5-(((2S)-1-(1-(5-(4-methoxybenzyl)-4,5,6,7-tetrahydro pyrazolo [1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one Intermediate 8 (600 mg, 1.75 mmol, 1.0 equiv) and intermediate 1 (660 mg, 1.92 mmol, 1.1 equiv) were weighed into a 10 mL reaction bottle and dissolved in N,N-dimethylformamide (5.0 mL). Triethylamine (1.21 mL, 8.75 mmol, 5.0 equiv) was then added sequentially. The mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 9a (630 mg, 52% yield) as a white solid. LC-MS m / z (ESI) = 627.28 [M+1].

[0098] Step 2: (S)-5-((1-(((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (9b) (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 25 mL reaction flask containing 9a (630 mg, 1 mmol, 1.0 equiv), trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (1 mL, 8 mmol, 8.0 equiv) were sequentially added. After the addition was complete, the reaction was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was quenched by adding 15 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo, and the residue was purified by MPLC (water / acetonitrile = 4:6) to give 9b as a white solid (370 mg, 73.21% yield). LC-MS m / z (ESI) = 507.23 [M+1].

[0099] Step 3: 5-(((2S)-1-(1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 9) 5-(((2S)-1-(1-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 25 mL reaction flask containing 9b (370 mg, 0.73 mmol, 1.0 equiv), 1,2-dichloroethane (5 mL), 1-chloroethyl chloroformate (0.78 mL, 7.3 mmol, 10.0 equiv), and potassium carbonate (203 mg, 1.46 mmol, 2.0 equiv) were added sequentially. After the addition was complete, the reaction was stirred at room temperature for 8 hours. After the reaction was complete, the 1,2-dichloroethane was spin-dried, and methanol (10 mL) was added and the mixture was refluxed for 2 hours. After concentration in vacuo, the residue was purified by MPLC (water / acetonitrile = 4:6) to give intermediate 9 (100 mg, 35.40% yield) as a white solid. LC-MS m / z (ESI) = 387.17 [M+1].

[0100] Intermediate 10 (S)-2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate 10) (S)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ka]

[0101] To a solution of intermediate 7 (386 mg, 1.0 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at 10 °C, sodium hydride (60 mg, 1.5 mmol, 1.5 equiv, 60%) was added, followed by the addition of 1-(chloromethyl)-4-methoxybenzene (187 mg, 1.2 mmol, 1.2 equiv) at 0 °C. After the addition was complete, the reaction was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction was quenched by slowly pouring the reaction mixture into an ice-water mixture. The mixture was extracted with dichloromethane (2 × 5 mL), and the organic phase was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give intermediate 10 (300 mg, 59% yield) as a white oil. LC-MS m / z (ESI) = 507.1 [M+1].

[0102] Intermediate 11 (S)-5-((1-((3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 11) (S)-5-((1-((3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0103] Step 1: Diethyl 4-chloro-1H-pyrazole-3,5-dicarboxylate (11b) diethyl 4-chloro-1H-pyrazole-3,5-dicarboxylate 11a (16.0 g, 75.47 mmol, 1.0 equiv) was placed in a 500 mL bottle at room temperature, dissolved in 200 mL of acetic acid, and 10% sodium hypochlorite (100 mL) was added. The mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the mixture was poured into 600 mL of water, and the solid was filtered, washed, and dried to give 11b (13 g, 70% yield) as a white solid. LC-MS m / z (ESI) = 246.04 [M+1].

[0104] Step 2: Diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate (11c) diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate 11b (13 g, 52.8 mmol, 1.0 equiv) was weighed into a 500 mL three-necked bottle and dissolved in anhydrous N,N-dimethylformamide (150 mL). tert-Butyl (2-bromoethyl)carbamate (13 g, 58.1 mmol, 1.1 equiv) was slowly added. After the addition was complete, cesium carbonate (25.8 g, 79.2 mmol, 1.5 equiv) was added and the mixture was heated to 50 °C and reacted for 3 hours. After the reaction was complete, the mixture was poured into 500 mL of water, and the solid was filtered, washed, and dried to give 11c (12.2 g, 59% yield) as a white solid. LC-MS m / z (ESI) = 389.13 [M+1].

[0105] Step 3: Diethyl 1-(2-aminoethyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate (11d) Diethyl-1-(2-aminoethyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate 11c (12.2 g, 30.77 mmol, 1.0 equiv) was added to a 500 mL reaction bottle and dissolved in 4 N hydrochloric acid in dioxane (100 mL) in an ice bath. The mixture was stirred for 1 h. After the reaction was complete, the mixture was concentrated in vacuo to give 11d (11 g, 99% yield) as a white solid. LC-MS m / z (ESI) = 289.08 [M+1].

[0106] Step 4: Ethyl 3-chloro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (11e) Ethyl-3-chloro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate 11d (12.2 g, 41.4 mmol, 1.0 equiv) was placed in a 500 mL reaction bottle and dissolved in 250 mL of potassium carbonate (17.25 g, 124 mmol, 3.0 equiv). The mixture was stirred for 1 hour. The solid was filtered, washed, and dried to give 11e (8.0 g, 79% yield) as a white solid. LC-MS m / z (ESI) = 243.04 [M+1].

[0107] Step 5: Ethyl 3-chloro-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (11f) Ethyl-3-chloro-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Following the synthesis of 2b above, 11f was obtained as a white solid (7 g, 54% yield). LC-MS m / z (ESI) =363.10 [M+1].

[0108] Step 6: (3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (11g) (3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol Following the synthesis method for 2c above, 11g was obtained as a white solid (4.2g, 65% yield). LC-MS m / z (ESI) =307.11 [M+1].

[0109] Step 7: tert-Butyl-(S)(1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (11h) tert-butyl-(S)-(1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate A 250 mL reaction bottle was charged with 11g (4.2 g, 11.5 mmol, 1.0 equiv) and dissolved in anhydrous N,N-dimethylformamide (100 mL). Under nitrogen protection, sodium hydride (552 mg, 23 mmol, 2.0 equiv) was added batchwise at 0°C. After the addition was complete, stirring was continued at the same temperature for 30 minutes. A solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (4.1 g, 17.3 mmol, 1.5 equiv) in N,N-dimethylformamide (50 mL) was then slowly added dropwise to the reaction mixture. The temperature was maintained at 0°C during the addition, and stirring was continued for 2 hours. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 and stirred at room temperature for 0.5 hours. The reaction mixture was extracted with ethyl acetate (3 x 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude product, which was purified by column chromatography (dichloromethane:methanol=40:1) to give 11h (3.6 g, 67% yield) as a yellow oil. LC-MS m / z (ESI) =464.22 [M+1].

[0110] Step 8: (S)-1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (11i) (S)-1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine 11h (3.6 g, 9.13 mmol, 1.0 equiv) was added to a 100 mL reaction bottle and dissolved in hydrochloric acid (4 N, 30 mL) in an ice bath. The mixture was stirred for 1 h. After the reaction was complete, the mixture was concentrated in vacuo to give 11i (3.2 g, 92% yield) as a yellow oil. LC-MS m / z (ESI) =364.17 [M+1].

[0111] Step 9: (S)-5-((1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (11j) (S)-5-((1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Following the synthesis method of 3a above, 11j was obtained as a white solid (2.2 g, 76% yield). LC-MS m / z (ESI) =646.29 [M+1].

[0112] Step 10: (S)-5-((1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (11k) (S)-5-((1-((3-chloro-5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 100 mL reaction flask containing 11j (2.6 g, 4.0 mmol, 1.0 equiv) were added trifluoroacetic acid (20 mL) and trifluoromethanesulfonic acid (1.37 mL, 16 mmol, 4.0 equiv), sequentially. After the addition was complete, the reaction was stirred at 25 °C for 1 h. Upon completion of the reaction, the resulting solution was quenched with saturated potassium carbonate to adjust the pH to 8-9 and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated in vacuo to afford 11k as a white solid (2.1 g, 99% yield). LC-MS m / z (ESI) =526.17[M+1].

[0113] Step 11: (S)-5-((1-((3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 11) (S)-5-((1-((3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one To a 25 mL reaction flask containing 11k (1.8 g, 3.4 mmol, 1.0 equiv), 1,2-dichloroethane (20 mL), 1-chloroethyl chloroformate (2.45 mL, 17.1 mmol, 5.0 equiv), and N,N-diisopropylethylamine (2.24 mL, 13.6 mmol, 4 equiv) were added sequentially. After the addition was complete, the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the 1,2-dichloroethane was spin-dried, and methanol (20 mL) was added and refluxed for 2 hours. After concentration in vacuo, the residue was purified by MPLC (water / acetonitrile = 4:6) to give intermediate 11 (400 mg, 29% yield) as a white solid. LC-MS m / z (ESI) = 406.11 [M+1].

[0114] Intermediate 12 (5,6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (Intermediate 12) (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol [ka]

[0115] Step 1: tert-Butyl 4-amino-3-oxopiperazine-1-carboxylate (12c) tert-butyl 4-amino-3-oxopiperazine-1-carboxylate 12a (2.0 g, 10 mmol, 1.0 equiv) was weighed and dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (600 mg, 15 mmol, 1.5 equiv) was added in an ice bath and the mixture was allowed to react for 20 min. 12b (3.0 g, 13 mmol, 1.3 equiv) was added in batches, and the mixture was stirred at room temperature for 24 h. The mixture was then suction filtered and the filtrate was spin-dried to give crude 12c (2.0 g, 93% yield), which was used directly in the next reaction. LC-MS m / z (ESI) = 216.10 [M+1].

[0116] Step 2: tert-Butyl 4-(2-ethoxy-2-oxoacetimidamido)-3-oxopiperazine-1-carboxylate (12d) tert-butyl 4-(2-ethoxy-2-oxoacetimidamido)-3-oxopiperazine-1-carboxylate 12c (1.3 g, 6.0 mmol, 1.0 equiv) was weighed and dissolved in absolute ethanol, and 2-ethoxy-2-imineethyl acetate (2.0 mL, 15 mmol, 2.5 equiv) was added and reacted at 90 °C for 3 hours. After cooling to room temperature, the reaction solution was spin-dried to obtain crude 12d (1.8 g, 95% yield), which was used directly in the next reaction. LC-MS m / z (ESI) = 315.10 [M+1].

[0117] Step 3: 5,6-Dihydro-[1,2,4]triazolo[1,5-a]pyrazine-2,7(8H)-dicarboxylic acid 7-(tert-butyl) 2-ethyl ester (12e) 7-(tert-butyl) 2-ethyl 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-2,7(8H)-dicarboxylate 12d (4.4 g, 14 mmol, 1.0 equiv) was weighed and dissolved in toluene (60 mL), p-toluenesulfonic acid (3.1 g, 16.7 mmol, 1.2 equiv) was added, and the mixture was refluxed at 130 °C for 2 hours (water was separated using a water separator). After the reaction was complete, the mixture was cooled to room temperature, the reaction mixture was concentrated, and the crude product was purified by column chromatography (n-hexane:ethyl acetate = 2:1) to obtain 12e (1.5 g, 36% yield) as a brown oil. LC-MS m / z (ESI) = 297.10 [M+1].

[0118] Step 4: tert-Butyl 2-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-7(8H)-carboxylate (12f) tert-butyl 2-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-7(8H)-carboxylate 12e (0.9 g, 3 mmol, 1.0 equiv) was weighed and dissolved in anhydrous methanol (10 mL), sodium borohydride (1.1 g, 30 mmol, 10 equiv) was added, and the mixture was allowed to react at room temperature for 24 hours. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane (10 mL), and the organic phase was concentrated. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to give 12f (0.7 g, 92% yield) as a brown oil. LC-MS m / z (ESI) = 255.10 [M+1].

[0119] Step 5: (5,6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (Intermediate 12) (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol 12f (300 mg, 1.2 mmol, 1.0 equiv) was weighed and dissolved in hydrochloric acid dioxane (3 mL, 4 M), reacted at room temperature for 2 hours, filtered by suction, and the cake was dried to obtain intermediate 12 (120 mg, 65% yield) as a colorless liquid. LC-MS m / z (ESI) = 155.10 [M+1].

[0120] Intermediate 13 (S)-1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 13) (S)-1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine [ka]

[0121] Step 1: Diethyl 4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate (13c) diethyl 4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate 13a (12.0 g, 75 mmol, 2.0 equiv) was added to a 500 mL bottle at room temperature, dissolved in 200 mL of tetrahydrofuran, and 13b (4.275 g, 37.5 mmol, 1.0 equiv) was added and reacted at room temperature for 2 h. After the reaction was complete, the organic layers were combined, concentrated in vacuo, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 13c (12.1 g, 58% yield) as a yellow oil. LC-MS m / z (ESI) = 280.07 [M+1].

[0122] Step 2: Diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate (13d) Diethyl-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate Following the synthesis method for 11c above, 13d was obtained as a pale yellow solid (15 g, 63% yield). LC-MS m / z (ESI) = 423.16 [M+1].

[0123] Step 3: Diethyl 1-(2-aminoethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate (13e) Diethyl-1-(2-aminoethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate Following the synthesis method for 11d above, 13e was obtained as a white solid (15 g, 62% yield). LC-MS m / z (ESI) = 323.11 [M+1].

[0124] Step 4: Ethyl 4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (13f) Ethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Following the synthesis method for 11e above, 13f was obtained as a white solid (12 g, 75% yield). LC-MS m / z (ESI) = 277.07 [M+1].

[0125] Step 5: 5-(4-Methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (13g) 5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-2-carboxylic acid Following the synthesis method for 2b above, 13g was obtained as a yellow oil (12g, 68% yield). LC-MS m / z (ESI) = 369.09 [M+1].

[0126] Step 6: (5-(4-Methoxybenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (13h) (5-(4-methoxybenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol Following the synthesis method for 2c above, 13h was obtained as a white solid (500 mg, 35% yield). LC-MS m / z (ESI) = 341.14 [M+1].

[0127] Step 7: tert-Butyl-(S)-(1-((5-(4-methoxybenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (13i) tert-butyl-(S)-(1-((5-(4-methoxybenzyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate 13h (500 mg, 1.47 mmol, 1.0 equiv) was added to a 100 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (10 mL). Under nitrogen protection, sodium hydride (70 mg, 2.93 mmol, 2.0 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 30 min. Then, a solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (696.78 mg, 2.93 mmol, 2.0 equiv) in N,N-dimethylformamide (10 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition, and stirring was continued for 2 h. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 × 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product, which was purified by column chromatography (dichloromethane:methanol=40:1) to give 13i as a white solid (300 mg, 41% yield). LC-MS m / z (ESI) =498.24 [M+1].

[0128] Step 8: tert-Butyl-(S)-(1-((3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (13j) tert-butyl-(S)-(1-((3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following a similar synthetic method to that described above for Intermediate 11, crude 13j was obtained as a yellow oil (300 mg, 70% yield). LCMS m / z = 378.19 [M+l].

[0129] Step 9: tert-Butyl-(S)-(1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (13j) tert-butyl-(S)-(1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate 13j (300 mg, 0.6 mmol, 1.0 equiv) and 2-chloro-5-trifluoromethylpyrimidine (163 mg, 0.9 mmol, 1.5 equiv) were weighed into a 50 mL reaction bottle and dissolved in N,N-dimethylformamide (10.0 mL). N,N-diisopropylethylamine (0.495 mL, 3 mmol, 5.0 equiv) was added to the mixture and stirred at 90 °C for 1 h. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give 13k (200 mg, 64% yield) as a yellow oil. LCMS m / z = 524.20 [M+l].

[0130] Step 10: (S)-1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 13) (S)-1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine 13k (200 g, 0.38 mmol, 1.0 equiv) was added to a 100 mL reaction bottle and dissolved in hydrochloric acid (4 N, 5 mL) in an ice bath. The mixture was stirred for 1 hour. After the reaction was complete, the mixture was concentrated in vacuo to give Intermediate 13 (161.8 mg, 98.3% yield) as a white solid. LCMS m / z = 424.20 [M+l].

[0131] Intermediate 14 2-Chloro-5-cyclopropylpyrimidine (Intermediate 14) 2-chloro-5-cyclopropylpyrimidine [ka]

[0132] 14a (2.0 g, 10.34 mmol, 1.0 equiv) was added to a toluene / water (50 mL / 2.5 mL) mixed solution, and cyclopropyl borate (1.15 g, 13.44 mmol, 1.3 equiv), Pd(dppf)Cl2 (0.422 g, 0.517 mmol, 0.05 equiv), and cesium carbonate (10.11 g, 31.019 mmol, 3.0 equiv) were added sequentially. After the addition was completed, the reaction was carried out at 80 °C for 5.0 hours. After the reaction was complete, 30 mL of water was added to the reaction solution, and the reaction mixture was vinegarThe organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give Intermediate 14 (1.32 g, 83% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 2H), 2.00 - 1.93 (m, 1H), 1.09 - 1.02 (m, 2H), 0.90 - 0.84 (m, 2H). LC-MS m / z (ESI) = 155.03 [M+1].

[0133] Intermediate 15 tert-Butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Intermediate 15) tert-butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate [ka]

[0134] Step 1: tert-Butyl-(S)-(1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (15a) tert-butyl (S)-(1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate 2c (864 mg, 3.16 mmol, 1.0 equiv) was added to a 50 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (18 mL). Under nitrogen protection, sodium hydride (300 mg, 7.51 mmol, 2.5 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 30 min. A solution of (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide in N,N-dimethylformamide (18 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition, and stirring was continued for 2 h. Upon completion of the reaction, the reaction mixture was adjusted to pH 6 and concentrated in vacuo to partially remove the N,N-dimethylformamide. 40 mL of water was added, and the reaction mixture was extracted with EA (3 × 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (ethyl acetate:petroleum ether=1:1) to give 15a as a yellow oil (544 mg, 40% yield). LC-MS m / z (ESI) = 431.55 [M+1].

[0135] Step 2: tert-Butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Intermediate 15) tert-butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate The synthesis method was similar to that of Intermediate 11, and crude Intermediate 15 was obtained as a dark brown oil (280 mg, yield 72%).

[0136] Intermediate 16 5-Chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile (Intermediate 16) 5-chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile [ka]

[0137] Step 1: 5-Methoxy-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile (16a) 5-methoxy-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile 1c (650 mg, 2.0 mmol, 1.0 equiv) was weighed and dissolved in anhydrous tetrahydrofuran (8 mL). Under nitrogen protection in an ice-water bath, isopropylmagnesium chloride (1 mL, 2.0 mmol, 1.0 equiv) was added dropwise and the mixture was allowed to react for 10 minutes. p-Tolylsulfonyl cyanide (360 mg, 2.0 mmol, 1.0 equiv) was added and the mixture was allowed to react for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was concentrated, and the crude product was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to give 16a (160 mg, 30% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 7.25 (d, 2H), 6.89 (d, 2H), 5.18 (s, 2H), 4.15 (s, 3H), 3.72 (s, 3H). LC-MS m / z (ESI) = 272.10 [M+1].

[0138] Step 2: 5-Hydroxy-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile (16b) 5-hydroxy-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile Following a similar synthetic method to 1e, 16b was obtained as a white solid (90 mg, 81% yield). LC-MS m / z (ESI) = 258.10 [M+1].

[0139] Step 3: 5-Chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile (Intermediate 16) 5-chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile Referring to a similar synthetic method to Intermediate 1, Intermediate 16 was obtained as a white solid (30 mg, 50% yield). LC-MS m / z (ESI) = 276.10 [M+1].

[0140] Intermediate 17 (S)-1-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-amine (Intermediate 17) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-amine [ka]

[0141] Step 1: Diethyl 4-bromo-1H-pyrazole-3,5-dicarboxylate (17b) Diethyl-4-bromo-1H-pyrazole-3,5-dicarboxylate 17a (15.0 g, 70 mmol, 1.0 equiv) was placed in a 500 mL bottle at room temperature and dissolved in 150 mL of acetic acid. N-bromosuccinimide (15.1 g, 84 mmol, 1.2 equiv) was added, and 15 mL of dilute nitric acid was added in an ice bath. The mixture was reacted at 120° C. for 2 hours. After the reaction was complete, the organic layers were combined, concentrated in vacuo, and purified by column chromatography (petroleum ether:ethyl acetate=4:1) to give 17b (17.6 g, 87% yield) as a white solid. LC-MS m / z (ESI) = 289.99 [M+1].

[0142] Step 2: Diethyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate (17c) 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate Following a similar synthetic method to 11c above, 17c was obtained as a white solid (7.2 g, 81% yield). LC-MS m / z (ESI) = 433.08[M+1].

[0143] Step 3: Diethyl 4-bromo-1-(2-aminoethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate (17d) 4-bromo-1-(2-aminoethyl)-4-(trifluoromethyl)-1H-pyrazole-3,5-dicarboxylate Following a similar synthesis method to that described for 11d above, crude 17d was obtained as a white solid (6.4 g, 97% yield). LC-MS m / z (ESI) = 333.08[M+1].

[0144] Step 4: Ethyl 3-bromo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (17e) Ethyl-3-bromo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Following a similar synthetic method to 11e above, 17e was obtained as a white solid (2.6 g, 64% yield). LC-MS m / z (ESI) = 286.99 [M+1].

[0145] Step 5: Ethyl 3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (17f) Ethyl-3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-2-carboxylate Following a similar synthetic method to 2b above, 17f was obtained as a white solid (3.2 g, 78% yield). LC-MS m / z (ESI) = 407.04 [M+1].

[0146] Step 6: Ethyl 5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate-3-d (17g) Ethyl-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate-3-d 17f (3 g, 7.4 mmol, 1.0 equiv), deuterated sodium formate (2.4 g, 37 mmol, 5.0 equiv), tris(dibenzylideneacetone)dipalladium (703 mg, 0.74 mmol, 0.1 equiv), and tri-tert-butylphosphine (594.96 mg, 1.48 mmol, 0.2 equiv) were sequentially added to a 250 mL three-necked bottle under nitrogen protection, dissolved in dimethyl sulfoxide (30 mL), and stirred at 85 °C for 5 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (50 mL x 3). The combined organic layer was concentrated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give 17f as a white solid (1.3 g, 53% yield). LC-MS m / z (ESI) = 330.14 [M+1].

[0147] Step 7: (5-(4-Methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methanol (17h) (5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methanol Following a similar synthetic method to 2c above, crude 17h was obtained as a pale yellow oil (1.02 g, 74% yield). LC-MS m / z (ESI) = 274.15 [M+1].

[0148] Step 8: tert-Butyl-(S)-(1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)carbamate (17i) tert-butyl-(S)-(1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)carbamate Following a similar synthetic method to 13i above, 17i was obtained as a pale yellow oil (1.07 g, 56% yield). LC-MS m / z (ESI) = 431.26 [M+1].

[0149] Step 9: tert-Butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)carbamate (17j) tert-butyl-(S)-(1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propane-2-yl)carbamate Following a similar synthetic method to Intermediate 11 above, crude 17j was obtained as a pale yellow oil (300 mg, 65% yield). LCMS m / z = 311.14 [M+l].

[0150] Step 10: tert-Butyl-(S)-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)carbamate (17k) tert-butyl-(S)-(1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)carbamate Following a similar synthetic method to 13k above, crude 17k was obtained as a pale yellow oil (100 mg, 24% yield). LCMS m / z = 457.22 [M+l].

[0151] Step 11: (S)-1-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-amine (Intermediate 17) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-amine Following a similar synthetic method to Intermediate 13 above, Intermediate 17 was obtained as a pale yellow oil (80 mg, 90% yield).

[0152] Intermediate 18 (S)-2-(4-Methoxybenzyl)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 18) (S)-2-(4-methoxybenzyl)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0153] 3a (8.0 g, 13 mmol, 1.0 equiv) was placed in a 250 mL bottle and dissolved in 60 mL of dichloroethane. 1-Chloroethyl chloroformate (8 mL, 65 mmol, 5.0 equiv) and N,N-diisopropylethylamine (6 mL, 39 mmol, 3.0 equiv) were then added sequentially. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. The solvent was removed by vacuum concentration, and 60 mL of methanol was added to the residue, followed by reflux for 2 hours. The mixture was concentrated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 18 (5.0 g, 78% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.22 (d, 2H), 6.89 (d, 2H), 6.38 - 6.35 (m, 1H), 6.05 (s, 1H), 5.12 - 4.95 (m, 2H), 4.40 (d, 2H), 4.20 (s, 2H), 4.17 - 4.14 (m, 3H), 3.72 (d, 4H), 3.54 - 3.41 (m, 4H), 1.14 (d, 3H). LCMS m / z = 493.10 [M+l].

[0154] Intermediate 19 (S)-4-(((tert-butoxycarbonyl)amino)pentyl 4-toluenesulfonate (Intermediate 19) (S)-4-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate [ka]

[0155] Step 1: tert-Butyl (S)-(5-hydroxypentan-2-yl)carbamate (19b) tert-butyl (S)-(5-hydroxypentan-2-yl)carbamate 19a (1.05 g, 5 mmol, 1.0 equiv) was placed in a 50 mL three-necked reaction bottle and dissolved in anhydrous tetrahydrofuran (20 mL). Under nitrogen gas protection and an ice bath, lithium aluminum hydride (1 N, 10 mL) was added batchwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was concentrated in vacuo to give 19b (800 mg, 90% yield) as a pale yellow oil. LC-MS m / z (ESI) = 204.15 [M+1].

[0156] Step 2: (S)-4-(((tert-butoxycarbonyl)amino)pentyl 4-toluenesulfonate (Intermediate 19) (S)-4-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate 19b (609 mg, 3 mmol, 1.0 equiv) was weighed into a 50 mL three-necked reaction bottle and dissolved in anhydrous tetrahydrofuran (20 mL). Under nitrogen gas protection and an ice bath, sodium hydride (216 mg, 9 mmol, 3.0 equiv) was added in batches. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. Then, p-toluenesulfonyl chloride (801 mg, 4.5 mmol, 1.5 equiv) was added to the mixture. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under vacuum and passed through a column (petroleum ether:ethyl acetate = 10:1) to give intermediate 19 (600 mg, 56% yield) as a white oil. LC-MS m / z (ESI) = 358.16 [M+1].

[0157] Intermediate 20 (S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)penta-2-amine (Intermediate 20) (S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl)pentan-2-amine [ka]

[0158] Step 1: 4,5,6,7-Tetrahydro-2H-pyrazolo[4,3-c]pyridine (20b) 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine 20a (1.1 g, 5 mmol, 1.0 equiv) was weighed into a 50 mL reaction bottle, and HCl-dioxane (4 N, 10 mL) was added to the system in an ice bath. After the addition was complete, the mixture was allowed to react for 1 hour with stirring. After the reaction was complete, the mixture was concentrated under vacuum to give crude 20b (1 g, 99% yield) as a white solid. LC-MS m / z (ESI) = 124.08 [M+1].

[0159] Step 2: 5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (20c) 5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine Purification by medium pressure preparative separation, following a similar synthetic method to that described above for 13k, gave 20c as a white solid (800 mg, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.73 (s, 2H), 7.58 (s, 1H), 4.87 (s, 2H), 4.15 (t, 2H), 2.74 (s, 2H). LC-MS m / z (ESI) = 269.09 [M+1].

[0160] Step 3: tert-Butyl-(S)-(5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-)yl)pent-2-yl)carbamate (20d) tert-butyl-(S)-(5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)carbamate 20c (124 mg, 0.46 mmol, 1.5 equiv) was weighed into a 50 mL reaction bottle and dissolved in anhydrous N,N-dimethylacetamide (3 mL). Intermediate 19 (110 mg, 0.31 mmol, 1.0 equiv) and cesium carbonate (293 mg, 0.93 mmol, 3.0 equiv) were then added sequentially to the reaction mixture. After the addition was complete, the mixture was stirred at 80 °C for 1 h. After the reaction was complete, the reaction mixture was purified by medium-pressure fractionation (water:acetonitrile = 75:25) to give 20d as a white solid (58 mg, 75% yield). LC-MS m / z (ESI) = 455.23 [M+1].

[0161] Step 4: (S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)penta-2-amine (Intermediate 20) (S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-amine Referring to a similar synthetic method to Intermediate 13, Intermediate 20 was obtained as a white solid (48 mg, 99% yield). LC-MS m / z (ESI) =355.23 [M+1].

[0162] Intermediate 21 (2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 21) (2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine [ka]

[0163] Step 1: Diethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrazole-3,5-dicarboxylate (21b) diethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrazole-3,5-dicarboxylate 21a (1.06 g, 5 mmol, 1.0 equiv) was weighed into a 100 mL three-necked bottle, dissolved in anhydrous tetrahydrofuran (20 mL), and tert-butyl (2-hydroxypropyl)carbamate (1.75 g, 10 mmol, 2.0 equiv) was added. After the addition was complete, di-tert-butyl azodicarboxylate (2.07 g, 9 mmol, 1.8 equiv) was added, and triphenylphosphine (2.36 g, 9 mmol, 1.8 equiv) was slowly added. The mixture was heated to 70 °C and reacted for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL), concentrated, and passed through a column (PE:EA = 5:1) to obtain 21b as a white solid (2.2 g, 99% yield). LC-MS m / z (ESI) = 369.19 [M+1].

[0164] Step 2: Diethyl 1-(1-aminopropan-2-yl)-1H-pyrazole-3,5-dicarboxylate (21c) diethyl 1-(1-aminopropan-2-yl)-1H-pyrazole-3,5-dicarboxylate Following a similar synthetic method to intermediate 11d, 21c was obtained as a white solid (1.8 g, 99% yield). LC-MS m / z (ESI) = 269.19 [M+1].

[0165] Step 3: Ethyl 7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (21d) ethyl 7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Referring to a similar synthetic method to intermediate 11e, intermediate 21d was obtained as a white solid (820 mg, 79% yield). LC-MS m / z (ESI) = 224.10 [M+1].

[0166] Step 4: Ethyl 5-(4-methoxybenzyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (21e) ethyl 5-(4-methoxybenzyl)-7-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Following a similar synthetic method to 2b above, 21e was obtained as a white solid (780 mg, 54% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, 2H), 6.89 (d, 2H), 6.15 (s, 1H), 4.82 (d, 2H), 4.50 - 4.37 (m, 4H), 3.66 - 3.53 (m, 1H), 3.57 (d, 3H), 1.45 (d, 3H), 1.32 (d, 3H). LC-MS m / z (ESI) = 344.15 [M+1].

[0167] Step 5: (5-(4-Methoxybenzyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (21f) (5-(4-methoxybenzyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol Following the synthesis method for 2c above, 21f was obtained as a white solid (510 mg, 65% yield). 1 H NMR (400 MHz, DMSO- d6) δ 7.52 (d, 2H), 6.89 (d, 2H), 6.15 (s, 1H), 4.82 (d, 2H), 4.50 - 4.37 (m, 4H), 3.66 - 3.53 (m, 1H), 3.57 (d, 3H) 1.45 (d, 3H). LC-MS m / z (ESI) = 307.11 [M+1].

[0168] Step 6: tert-Butyl ((2S)-1-((5-(4-methoxybenzyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (21g) tert-butyl((2S)-1-((5-(4-methoxybenzyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following a similar synthetic method to intermediate 11h, 21g was obtained as a white solid (380 mg, 67% yield). 1 H NMR (400 MHz, DMSO- d6) δ 8.78 (s, 2H), 7.52 (d, 2H), 6.89 (d, 2H), 6.15 (s, 1H), 5.163- 4.99 (m, 2H), 4.50 - 4.37 (m, 4H), 4.10-4.01 (m, 2H), 3.66 - 3.53 (m, 1H),3.57 (d, 3H) 3.23 (q, 1H), 1.45 (d, 3H), 1.36 (s, 9H), 1.01 (d, 3H). LC-MS m / z (ESI) = 444.27 [M+1].

[0169] Step 7: tert-Butyl ((2S)-1-((7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (21h) tert-butyl((2S)-1-((7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following a similar synthetic method to that described above for 13j, crude 21h was obtained as a pale yellow oil (400 mg, 90% yield). 1 H NMR (400 MHz, DMSO-d6) δ.74 (s, 2H), 6.15 (s, 1H), 5.16 - 4.90 (m, 2H), 4.50 - 4.30 (m, 4H), 4.05-4.01 (m, 2H), 3.66 - 3.53 (m, 1H), 3.20 (q, 1H), 1.41 (d, 3H), 1.36 (s, 9H), 0.99 (d, 3H). LCMS m / z = 457.16 [M+l].

[0170] Step 8: tert-Butyl ((2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (21i) tert-butyl((2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following the synthesis method for 13k above, 21i was obtained as a pale yellow solid (250 mg, 63% yield). LCMS m / z = 471.50 [M+l].

[0171] Step 9: (2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Intermediate 21) (2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Referring to a similar synthetic method as for 11d, intermediate 21 was obtained as a white solid (190 mg, 99% yield). LC-MS m / z (ESI) = 357.16 [M+1].

[0172] Intermediate 22 (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (Intermediate 22) (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol [ka]

[0173] 22a (1.5 g, 10 mmol, 1 equiv) was weighed and dissolved in N,N-dimethylformamide (10 mL). 22b (1.8 g, 10 mmol, 1 equiv) and N,N-diisopropylethylamine (2.4 g, 20 mmol, 2 equiv) were added and reacted at 100°C for 4 hours. The reaction solution was cooled and poured into ice water to precipitate a solid. The cake was suction filtered and dried to obtain intermediate 22 as a white solid (2.9 g, 99% yield). LC-MS m / z (ESI) =300.10[M+1].

[0174] Intermediate 23 (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-1,1-d2-2-amine (Intermediate 23) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propane-1,1-d2-2-amine [ka]

[0175] Step 1: tert-Butyl (S)-(1-hydroxypropan-2-yl-1,1-d2)carbamate (23b) tert-butyl (S)-(1-hydroxypropane-2-yl-1,1-d2)carbamate 23a (2.5 g, 17 mmol, 1.0 equiv) was weighed and dissolved in anhydrous tetrahydrofuran (30 mL). Lithium aluminum deuteride (880 mg, 21 mmol, 1.2 equiv) was added slowly in batches under nitrogen gas protection and an ice bath. After the addition was complete, the reaction was allowed to proceed for 1 h. Upon completion of the reaction, the reaction mixture was quenched with sodium sulfate decahydrate, filtered under suction, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give crude 23b (2.0 g, 66% yield) as a yellow oil.

[0176] Step 2: tert-Butyl (4S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2-oxide (23c) tert-butyl (4S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide Imidazole (2.0 g, 30 mmol, 6 equiv) was weighed and dissolved in dichloromethane (15 mL). Sulfoxide chloride (650 μL, 9 mmol, 1.8 equiv) was added dropwise in an ice bath, and the reaction was allowed to proceed at room temperature for 2 hours. A dichloromethane solution (10 mL) of compound 23b (890 mg, 5 mmol, 1.0 equiv) was added dropwise in an ice bath, and the mixture was left at room temperature overnight. The mixture was quenched with 10% citric acid, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 23c (900 mg, 80% yield) as a yellow oil.

[0177] Step 3: tert-Butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-5,5-d2 2,2-dioxide (23d) tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-5,5- d22,2-dioxide Compound 22c (1.1 g, 5 mmol, 1 equiv) was weighed and dissolved in acetonitrile (10 mL) and water (5 mL). Sodium periodate (1.0 g, 5 mmol, 1 equiv) and ruthenium trichloride (55 mg, 0.25 mmol, 0.05 equiv) were added sequentially and the mixture was allowed to react at room temperature for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction. The organic phase was concentrated to give crude product 23d (900 mg, 75% yield) as a brown oil.

[0178] Step 4: tert-Butyl-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)carbamate (23e) tert-butyl (S)-(1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl-1,1-d2)carbamate Following a similar synthetic method to that of intermediate 11h, 23e was obtained as a white solid (480 mg, 47% yield). LC-MS m / z (ESI) = 459.10 [M+1].

[0179] Step 5: (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-1,1-d2-2-amine (Intermediate 23) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-2-yl)methoxy)propan-1,1-d2-2-amine Following a similar synthetic method to that of intermediate 11d, intermediate 23 was obtained as a white solid (190 mg, 99% yield). LC-MS m / z (ESI) = 359.10 [M+1].

[0180] Intermediate 24 (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-1,1-d2-2-amine (Intermediate 24) (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propane-1,1-d2-2-amine [ka]

[0181] Step 1: (7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (24a) (7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol Following a similar synthetic method to that of intermediate 22, 24a was obtained as a white solid (443 mg, 86% yield). LC-MS m / z (ESI) =301.22 [M+1].

[0182] Step 2: tert-Butyl (S)-(1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)carbamate (24b) tert-butyl(S)-(1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro -[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl-1,1-d2)carbamate Following a similar synthetic method to that of intermediate 11h, 24b was obtained as a white solid (360 mg, 52% yield). LC-MS m / z (ESI) =460.11 [M+1].

[0183] Step 3: (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-1,1-d2-2-amine (Intermediate 24) (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propane-1,1-d2-2-amine Following a similar synthetic method to that of intermediate 11d, intermediate 24 was obtained as a white solid (260 mg, 78% yield). LC-MS m / z (ESI) =360.12 [M+1].

[0184] Example 1 (S)-4-(trifluoromethyl)-5-((1-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 1) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0185] Intermediate 3 (48 mg, 0.13 mmol, 1.0 equiv) and 2-chloro-5-trifluoromethylpyrimidine (24 mg, 0.13 mmol, 1.0 equiv) were weighed into a 10 mL reaction bottle and dissolved in N,N-dimethylformamide (4.0 mL). N,N-Diisopropylethylamine (0.086 mL, 0.52 mmol, 4 equiv) was added to the mixture and stirred at 90 °C for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give compound 1 (40 mg, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.81 (s, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.11 (s, 1H), 5.01 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.16 (t, 3H), 3.55 - 3.45 (m, 2H), 1.15 (d, 3H). LCMS m / z = 519.40 [M+l].

[0186] Example 2 (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin)-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 2) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0187] Following a similar synthesis method to compound 1, compound 2 was obtained as a white solid (500 mg, 72% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.81 (s, 2H), 7.90 (s, 1H), 6.27 (dd, 1H), 6.11 (s, 1H), 4.32 (t, 2H), 4.17 - 4.14 (m, 3H), 3.56 - 3.41 (m, 2H), 1.15 (d, 3H). LCMS m / z = 523.10 [M+l].

[0188] Example 3 4-(trifluoromethyl)-5-(((S)-1-((S)-1-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 3-I) 4-(trifluoromethyl)-5-(((S)-1-((S)-1-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one 4-(trifluoromethyl)-5-(((S)-1-((R)-1-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 3-II) 4-(trifluoromethyl)-5-(((S)-1-((R)-1-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethoxy)propan-2-yl)amino) pyridazin-3(2H)-one [ka]

[0189] Intermediate 9 (100 mg, 0.26 mmol, 1.0 equiv) and 2-chloro-5-trifluoromethylpyrimidine (24 mg, 0.26 mmol, 1.0 equiv) were weighed into a 10 mL reaction bottle and dissolved in N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (0.18 mL, 1.04 mmol, 4 equiv) was added to the mixture and stirred at 90 °C for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography (water / acetonitrile = 1:1) to give compound 3 (80 mg, 59% yield) as a white solid. LCMS m / z = 532.45 [M+l].

[0190] Compound 3 (80 mg) was separated by SFC to give compound 3-I (38 mg, 47.2% yield, RT = 7.684 min, 100% ee) and compound 3-II (35 mg, 46.5% yield, RT = 12.365 min, 100% ee). The separation was performed using chiral HPLC (AS) with a mobile phase of n-hexane / ethanol = 90 / 10, column temperature: 35 °C, column pressure: 80 bar, flow rate: 1 mL / min, detector signal channel: 215 nm @ 4.8 nm, and diode array detector on / off wavelength: 200–400 nm.

[0191] Compound 3-I: 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 7.87 (s, 1H), 6.23 (dd, 1H), 6.05 (s, 1H), 5.00 (s, 2H), 4.45 (dd, 1H), 4.36-4.26 (m, 2H), 4.15-4.09 (m, 2H), 3.33-3.18 (m, 2H), 1.33 (d, 3H), 1.12 (d, 3H).

[0192] Compound 3-II: 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 7.86 (s, 1H), 6.25 (dd, 1H), 6.10 (s, 1H), 5.08 (s, 2H), 4.43 (dd, 1H), 4.31-4.24 (m, 2H), 4.14-4.06 (m, 2H), 3.39 -3.24(m, 2H), 1.31 (d, 3H), 1.13 (d , 3H).

[0193] Example 4 (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolol[1,5-a]pyrazin-5(4H)-yl)nicotinonitrile (Compound 4) (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)nicotinitrile [ka]

[0194] Following a similar synthetic method to compound 1, compound 4 was obtained as a white solid (20 mg, 33% yield). 1 H NMR (400 MHz, DMSO- d6): δ 12.46 (s, 1H), 8.57 (d, 1H), 7.97 (m, 1H), 7.90 (s, 1H), 7.10 (d, 1H), 6.28 (dd, 1H), 6.08 (s, 1H), 4.87 (s, 2H), 4.41 (d, 2H), 4.15 (s, 4H), 3.49 (d, 2H), 1.23 (s, 1H), 1.15 (d, 3H). LCMS m / z = 475.45 [M+l].

[0195] Example 5 (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin)-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 5) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0196] Following a similar synthetic method to compound 1, compound 5 was obtained as a white solid (25 mg, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.57 (s, 2H), 7.90 (s, 1H), 6.28 (s, 1H), 6.10 (s, 1H), 4.94 (s, 2H), 4.48 - 4.32 (d, 2H), 4.27 - 4.18 (m, 4H), 4.16 (m, 1H), 3.53 - 3.46 (m, 2H), 1.15 (d, 3H). LCMS m / z = 519.42 [M+l].

[0197] Example 6 (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 6) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ka]

[0198] Step 1: (S)-2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 6a) (S)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Intermediate 10 (200 mg, 0.4 mmol, 1.0 equiv) was weighed and dissolved in dioxane (5.0 mL). Under nitrogen protection, potassium phosphate (255 mg, 1.2 mmol, 3.0 equiv), 2-bromo-5-trifluoromethylpyrimidine (136 mg, 0.6 mmol, 1.5 equiv), cuprous iodide (12 mg, 0.06 mmol, 0.15 equiv), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (20 μL, 0.12 mmol, 0.3 equiv) were added sequentially and the reaction mixture was heated at 110 °C for 24 h. The reaction mixture was concentrated in vacuo, and the residue was purified by MPLC (water / acetonitrile = 1:1) to give compound 6a (20 mg, 7% yield) as a white solid. LCMS m / z = 653.10 [M+l].

[0199] Step 2: (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 6) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one To a 25 mL reaction flask containing compound 6a (20 mg, 0.03 mmol, 1.0 equiv), trifluoroacetic acid (2 mL) and trifluoromethanesulfonic acid (0.2 mL, 0.24 mmol, 8.0 equiv) were sequentially added. After the addition was complete, the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was quenched by adding 5 mL of water. The resulting solution was extracted with ethyl acetate (3 × 15 mL). The pH of the organic layer was adjusted to 8–9 with aqueous potassium carbonate. The organic layers were combined and concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 4:6) to give compound 6 as a white solid (8 mg, 50% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 9.28 (d, 2H), 7.93 (s, 1H), 6.91 (s, 1H), 6.33-6.31 (m, 1H), 4.52-4.50 (m, 6H), 4.25-4.15 (m, 1H), 3.55 (d, 2H), 1.17 (d, 3H). LC-MS m / z (ESI) = 533.10 [M+1].

[0200] Example 7 (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrimidine-5-carbonitrile (Compound 7) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrimidine-5-carbonitrile [ka]

[0201] Referring to the similar synthetic method as compound 1, compound 7 was obtained as a white solid (30 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.87 (s, 2H), 7.90 (s, 1H), 6.27 (d, 1H), 6.11 (s, 1H), 5.01 (s, 2H), 4.41 (d, 1H), 4.32 (d, 2H), 4.16 (t, 2H), 4.03 (q, 2H), 3.49 (d, 2H), 1.16 (d, 3H). LCMS m / z = 476.44 [M+l].

[0202] Example 8 (S)-5-((1-((5-(5-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 8) (S)-5-((1-((5-(5-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0203] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 8b) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl) methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 8b was obtained as a yellow solid (68 mg, 29% yield). LCMS m / z (ESI) = 585.6 [M+l].

[0204] Step 2: (S)-5-((1-((5-(5-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 8) (S)-5-((1-((5-(5-methylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Compound 8 was obtained as a white solid (21 mg, 39% yield) by following a synthetic method similar to Step 2 in the synthesis scheme for Compound 6. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.31 (s, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.06 (s, 1H), 4.87 (s, 2H), 4.55 - 4.32 (m, 2H), 4.20 (dd, 3H), 4.09 (t, 2H), 3.48 (d, 2H), 2.11 (s, 3H), 1.15 (d, 4H). 19 F NMR (377 MHz, DMSO-d6) δ -55.43 (s, 3H). LCMS m / z (ESI) = 465.4 [M+l].

[0205] Example 9 (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 9) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0206] Step 1: (7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (compound 9a) (7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol Intermediate 1 (186 mg, 1.2 mmol, 1.0 equiv) was weighed and dissolved in N,N-dimethylformamide (4 mL). 2-Chloro-5-(trifluoromethyl)pyrimidine (214 mg, 1.2 mmol, 1.0 equiv) and N,N-diisopropylethylamine (1.0 mL, 6.0 mmol, 5.0 equiv) were added sequentially and the reaction mixture was heated at 100 °C for 2 h. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography (water / acetonitrile = 1:1) to give compound 9a (340 mg, 94% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.92 - 8.70 (m, 2H), 5.07 (s, 2H), 4.45 - 4.32 (m, 4H), 4.23 (t, 2H). LC-MS m / z (ESI) = 301.10 [M+1].

[0207] Step 2: tert-Butyl-(S)-(1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 9b) tert-butyl -(S)-(1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Referring to a similar synthetic method as in 11h, compound 9b was obtained as a yellow oil (200 mg, 60% yield). LC-MS m / z (ESI) = 458.10 [M+1].

[0208] Step 3: (S)-1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Compound 9c) (S)-1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthesis method to 11i, compound 9c was obtained as a white solid (50 mg, 90% yield), which was used directly in the next reaction. LC-MS m / z (ESI) =358.10 [M+1].

[0209] Step 4: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 9d) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl) methyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl)amino)pyridazin-3(2H)-one Following a similar synthesis as for 3a, compound 9d was obtained as a yellow oil (250 mg, 78% yield). LC-MS m / z (ESI) = 640.10 [M+1].

[0210] Step 5: (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 9) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Following a similar synthetic method to compound 6, compound 9 was obtained as a white solid (50 mg, 60% yield). 1 H NMR (400 MHz, Chloroform-d): δ 11.45 (s, 1H), 8.76 - 8.38 (m, 2H), 7.69 (s, 1H), 5.87 (d, 1H), 5.19 (s, 2H), 4.64 (d, 2H), 4.47 (t, 2H), 4.30 (t, 2H), 4.04 - 3.97 (m, 1H), 3.75 - 3.61 (m, 2H), 1.33 (d, 3H). LC-MS m / z (ESI) =520.10 [M+1].

[0211] Example 10 (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 10) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0212] Step 1: (7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (compound 10b) (7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol Following a similar synthetic method to compound 9a, compound 10b was obtained as a white solid (200 mg, 90% yield). LC-MS m / z (ESI) = 301.10 [M+1].

[0213] Step 2: tert-Butyl-(1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 10c) tert-butyl (S)-(1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Referring to a synthetic method similar to that of intermediate 11h, compound 10c was obtained as a yellow oil (170 mg, 80% yield). LC-MS m / z (ESI) =458.10 [M+1].

[0214] Step 3: (S)-1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Compound 10d) (S)-1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthesis method to that of intermediate 11i, compound 10d was obtained as a white solid (120 mg, 97% yield), which was used crude in the next reaction. LC-MS m / z (ESI) =358.10 [M+1].

[0215] Step 4: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 10e) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoro methyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one Compound 10e was synthesized as a yellow oil (180 mg, 76% yield) by following the method of 3a. 1 H NMR (400 MHz, Chloroform-d): δ 8.48 (d, 1H), 8.25 (d, 1H), 7.62 (s, 1H), 7.38 (d, 2H), 6.84 (d, 2H), δ 5.77-5.70 (m, 1H), 5.13 (d, 2H), 4.93 (s, 2H), 4.62 (d, 2H), 4.27 (s, 3H), 3.92 - 3.87 (m, 1H), 3.80-3.77 (m, 4H), 3.73 - 3.70 (m, 1H), 3.64 - 3.60 (m, 1H), 1.30 (d, 3H). LC-MS m / z (ESI) = 640.10 [M+1].

[0216] Step 5: (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 10) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 10 was obtained as a white solid (38 mg, 62% yield). 1 H NMR (400 MHz, Chloroform-d): δ 11.07 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.69 (s, 1H), 5.82 (s, 1H), 4.99 (d, 2H), 4.76 - 4.56 (m, 2H), 4.52 - 4.25 (m, 4H), 3.98 (s, 1H), 3.78- 3.62 (m, 2H), 1.33 (d, 3H). LC-MS m / z (ESI) = 520.10 [M+1].

[0217] Example 11 (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 11) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy) methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one [ka]

[0218] Step 1: (S)-2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 11a) (S)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Following a similar synthetic method to compound 6a, compound 11a was obtained as a white solid (100 mg, yield 50%). LC-MS m / z (ESI) = 652.10 [M+1].

[0219] Step 2: (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 11) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one Following a similar synthesis method to compound 6, compound 11 was obtained as a white solid (40 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.89 - 8.87 (m, 1H), 8.32 - 8.23 ​​(m, 1H), 8.18 - 8.16 (m, 1H), 7.93 (s, 1H), 6.89 (s, 1H), 6.31 (dd, 1H), 4.65 - 4.43 (m, 6H), 4.30 - 4.09 (m, 1H), 3.55 (d 2H), 1.17 (d, 3H). LC-MS m / z (ESI) = 532.10 [M+1].

[0220] Example 12 (S)-5-((1-((5-(5-cyclopropylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one- (Compound 12) (S)-5-((1-((5-(5-cyclopropylpyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0221] Intermediate 3 (50 mg, 0.13 mmol, 1.0 equiv) and Intermediate 14 (23 mg, 0.15 mmol, 1.1 equiv) were weighed into a 10 mL reaction bottle and dissolved in N,N-dimethylformamide (2.0 mL). N,N-Diisopropylethylamine (0.111 mL, 0.67 mmol, 5.0 equiv) was added to the mixture and stirred at 120 °C for 5 hours. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 2:3) to give compound 12 (29 mg, 44% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.80 (s, 2H), 7.91 (s, 1H), 6.25 (dd, 1H), 6.10 (s, 1H), 4.99 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.16 (t, 3H), 3.55 - 3.45 (m, 2H), 2.88 - 2.73(m, 1H), 1.15 (d, 3H), 0.91 - 0.80 (m, 2H), 0.62 - 0.55 (m, 2H). LCMS m / z = 491.49 [M+l].

[0222] Example 13 (S)-5-((1-((3-chloro-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13) (S)-5-((1-((3-chloro-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0223] Referring to the similar synthetic method as for compound 1, compound 13 was obtained as a white solid (40 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.93 (s, 2H), 7.88 (s, 1H), 6.24 (dd, 1H), 4.94 (s, 2H), 4.47 - 4.39 (m, 2H), 4.34 (t, 2H), 4.17 (t, 2H), 3.52 (d, 2H), 1.15 (d, 3H). LCMS m / z = 552.12 [M+l].

[0224] Example 14 (S)-5-((1-((3-chloro-5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14) (S)-5-((1-((3-chloro-5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0225] Referring to the similar synthetic method as compound 1, compound 14 was obtained as a white solid (30 mg, yield 21.73%). 1H NMR (400 MHz, DMSO- d6): δ 12.45 (s, 1H), 8.74 (s, 2H), 7.88 (s, 1H), 6.25 (dd, 1H), 4.87 (s, 2H), 4.43 - 4.39 (m, 2H), 4.23 (t, 2H), 4.15 (t, 2H), 3.55 (d, 2H), 1.15 (d, 3H). LCMS m / z = 552.12 [M+l].

[0226] Example 15 (S)-6-(3-chloro-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)nicotinonitrile (Compound 15) (S)-6-(3-chloro-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)nicotonitrile [ka]

[0227] Referring to the similar synthetic method as for compound 1, compound 15 was obtained as a white solid (18 mg, 35% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.72 (s, 1H), 8.22 (d, 1H), 7.88 (s, 1H), 6.28 (dd, 1H), 4.86 (s, 2H), 4.44 - 4.39 (m, 2H), 4.23 (t, 2H), 4.17 (t, 2H), 3.60 (d, 2H), 1.15 (d, 3H). LCMS m / z = 508.13 [M+l].

[0228] Example 16 (S)-5-((1-((3-chloro-5-(pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 16) (S)-5-((1-((3-chloro-5-(pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0229] Referring to the similar synthetic method as for compound 1, compound 16 was obtained as a white solid (12 mg, 25% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.76 (d, 2H), 7.87 (s, 1H), 6.24 (dd, 1H), 4.82 (s, 2H), 4.44 - 4.40 (m, 2H), 4.25 (d, 2H), 4.17 (d, 2H), 3.62 (d, 2H), 1.15 (d, 3H). LCMS m / z = 484.13 [M+l].

[0230] Example 17 (S)-5-((1-((3-chloro-5-(6-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazin-3(2H)-one (Compound 17) (S)-5-((1-((3-chloro-5-(6-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0231] Referring to the similar synthetic method as for compound 1, compound 17 was obtained as a white solid (16 mg, 29% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.72 (s, 1H), 7.88 (s, 1H), 7.18 (d, 1H), 6.86 (d, 1H), 4.86 (s, 2H), 4.46 - 4.39 (m, 2H), 4.23 (t, 2H), 4.17 (t, 2H), 3.60 (d, 2H), 1.15 (d, 3H). LCMS m / z = 552.12 [M+l].

[0232] Example 18 ((S)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile (Compound 18) (S)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile [ka]

[0233] Step 1: tert-butyl (S) -(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 18a) tert-butyl (S)-(1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following a similar synthetic method to compound 9a, compound 18a was obtained as a white solid (200 mg, 90% yield). LC-MS m / z (ESI) = 458.10 [M+1].

[0234] Step 2: (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (compound 18b) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthesis method to 11i, compound 18b was obtained as a white solid (100 mg, 90% yield), which was used crude in the next reaction. LC-MS m / z (ESI) = 358.10 [M+1].

[0235] Step 3: (S)-2-(4-Methoxybenzyl)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile (Compound 18c) (S)-2-(4-methoxybenzyl)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile Referring to a similar synthetic method to 3a, compound 18c was obtained as a yellow oil (20 mg, 55% yield). LC-MS m / z (ESI) = 596.10 [M+1].

[0236] Step 4: ((S)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile (Compound 18) (S)-3-oxo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2,3-dihydropyridazine-4-carbonitrile Referring to the similar synthetic method as for compound 6, compound 18 was obtained as a white solid (8.0 mg, 50% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.91 - 8.74 (m, 2H), 7.53 (s, 1H), 6.14 (s, 1H), 5.01 (d, 2H), 4.41 (s, 2H), 4.33 (t, 2H), 4.16 (t, 2H), 4.03 (q, 2H), 3.49 (d, 2H), 1.17 (d, 3H). 19F NMR (376 MHz, DMSO-d6) δ -57.26 (3F), -59.38 (3F). LC-MS m / z (ESI) =476.10 [M+1].

[0237] Example 19 (S)-4-(trifluoromethyl-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 19) (S)-4-(trifluoromethyl)-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl) methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0238] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (19a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimi din-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl)amino)pyridazin-3(2H)-one Intermediate 13 (161.8 mg, 0.38 mmol, 1.0 equiv) and Intermediate 1 (145 mg, 0.46 mmol, 1.2 equiv) were weighed into a 25 mL reaction bottle and dissolved in acetonitrile (10 mL). Triethylamine (0.26 mL, 1.9 mmol, 5 equiv) was added to the mixture and stirred at 90 °C for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 19a (130 mg, 48% yield) as a pale yellow solid. LCMS m / z = 706.21 [M+l].

[0239] Step 2: (S)-4-(trifluoromethyl-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 19) (S)-4-(trifluoromethyl)-5-((1-((3-(trifluoromethyl)-5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl) methoxy)propan-2-yl)amino)pyridazin-3(2H)-one To a 10 mL reaction flask containing compound 19a (130 mg, 0.18 mmol, 1.0 equiv), trifluoroacetic acid (3 mL) and trifluoromethanesulfonic acid (0.1 mL, 0.72 mmol, 4.0 equiv) were sequentially added. After the addition was complete, the reaction was stirred at 25 °C for 1 h. Upon completion of the reaction, the resulting solution was quenched with saturated potassium carbonate, the pH was adjusted to 8-9, and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and concentrated in vacuo, and the resulting residue was purified by MPLC (water / acetonitrile = 1:1) to give compound 19 as a white solid (70 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 2H), 7.88 (s, 1H), 6.22 (dd, 1H), 5.14 (s, 2H), 4.49 (s, 2H), 4.37 (t, 2H), 4.24 (t, 2H), 4.16 (d, 1H), 3.52 (d, 2H), 1.14 (d, 3H). LC-MS m / z (ESI) = 586.15[M+1].

[0240] Example 20 (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20) (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0241] Step 1: (7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (compound 20b) (7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol Following a similar synthetic method to compound 9a, compound 20b was obtained as a white solid (125 mg, 62% yield). LC-MS m / z (ESI) =250.10 [M+1].

[0242] Step 2: tert-Butyl-(S)(1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 20c) tert-butyl(S)-(1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Referring to a synthetic method similar to that of intermediate 11h, compound 20c was obtained as a yellow oil (100 mg, 52% yield). LC-MS m / z (ESI) =407.21[M+1].

[0243] Step 3: (S)-1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (Compound 20d) (S)-1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthetic method to that of intermediate 11i, crude compound 20d was obtained as a white solid (87 mg), which was used directly in the next reaction without further purification. LC-MS m / z (ESI) =307.21 [M+1].

[0244] Step 4: (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20e) (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to a similar method as 3a, compound 20e was obtained as a yellow oil (75 mg, 48% yield). LC-MS m / z (ESI) = 589.22 [M+1].

[0245] Step 5: (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20) (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 20 was obtained as a white solid (42 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.17 (d, 1H), 7.91 (s, 1H), 7.64 - 7.59 (m, 1H), 7.12 (dd, 1H), 6.32 (s, 1H), 4.75 (s, 2H), 4.54 - 4.42 (m, 2H), 4.20 - 4.15(m, 3H), 4.08 (t, 2H), 3.57 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.45 (3F), -141.97 (F). LC-MS m / z (ESI) = 469.22 [M+1].

[0246] Example 21 (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 21) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrazin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-4,4-d2)methoxy-d2)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0247] Referring to the similar synthetic method as for compound 1, compound 21 was obtained as a white solid (37 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.57 (s, 2H), 7.90 (s, 1H), 6.42 - 6.21 (m, 1H), 6.10 (s, 1H), 4.38 - 3.94 (m, 5H), 3.56 - 3.44 (m, 2H), 1.15 (d, 3H). LC-MS m / z (ESI) = 523.10 [M+1].

[0248] Example 22 (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl-d2)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl-4,4-d2)pyrimidine-5-carbonitrile (Compound 22) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl-d2)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl-4,4-d2) pyrimidine-5-carbonitrile [ka]

[0249] Referring to the similar synthetic method as for compound 1, compound 22 was obtained as a white solid (50 mg, 65% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.86 (s, 2H), 7.89 (s, 1H), 6.28 - 6.25 (m, 1H), 6.11 (s, 1H), 4.34 - 4.31 (m, 2H), 4.17 - 4.14 (m, 3H), 3.63 - 3.41 (m, 2H), 1.15 (d, 3H). LC-MS m / z (ESI) = 480.10 [M+1].

[0250] Example 23 (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl-d2)-6,7-dihydropyrazol[1,5-a]pyrazin-5(4H)-yl-4,4-d2)nicotinonitrile (Compound 23) (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl-d2)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl-4,4-d2) nicotinonitrile [ka]

[0251] Referring to the similar synthetic method as for compound 1, compound 23 was obtained as a white solid (24 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.56 (d, 1H), 7.97 - 7.94 (m, 1H), 7.90 (s, 1H), 7.09 (d, 1H), 6.25 - 6.29 (m, 1H), 6.08 (s, 1H), 4.20 - 4.13 (m, 5H), 3.49 (d, 2H), 1.15 (d, 3H). LC-MS m / z (ESI) = 478.10 [M+1].

[0252] Example 24 (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)nicotinonitrile (Compound 24) (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) amino)propoxy)methyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl) nicotinonitrile [ka]

[0253] Step 1: 6-(2-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)nicotinonitrile (compound 24b) 6-(2-(hydroxymethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)nicotonitrile Following a similar synthetic method to compound 9a, compound 24b was obtained as a white solid (130 mg, 42% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 7.99 (dd, 1H), 7.18 (d, 1H), 5.17 (s, 1H), 4.94 (s, 2H), 4.40 (s, 2H), 4.26 (dd, 2H), 4.21 (dd, 2H). LC-MS m / z (ESI) = 257.11 [M+1].

[0254] Step 2: tert-Butyl-(S)(1-((7-(5-cyanopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 24c) tert-butyl-(S)-(1-((7-(5-cyanopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Referring to a similar synthetic method to intermediate 11h, compound 24c was obtained as a yellow oil (210 mg, 75% yield). LC-MS m / z (ESI) = 414.21[M+1].

[0255] Step 3: (S)-1-((7-(5-cyanopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (compound 24d) (S)-1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthesis method to that of intermediate 11i, compound 24d was obtained as a white solid (150 mg, 90% yield), which was used crude in the next reaction. LC-MS m / z (ESI) =314.21 [M+1].

[0256] Step 4: (S)-5-((1-((7-(5-cyanopyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24e) (S)-5-((1-((7-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Compound 24e was synthesized as a yellow oil (130 mg, 42% yield) by referring to the method for 3a. LC-MS m / z (ESI) = 596.23 [M+1].

[0257] Step 5: (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5,6-dihydro-1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)nicotinonitrile (Compound 24) (S)-6-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl) nicotinonitrile Referring to the similar synthetic method as compound 6, compound 24 was obtained as a white solid (42 mg, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.59 (d, 1H), 8.00 (dd, 1H), 7.91 (s, 1H), 7.17 (d, 1H), 6.39 - 6.27 (m, 1H), 4.94 (s, 2H), 4.54 - 4.42 (m, 2H), 4.28 - 4.10 (m, 5H), 3.57 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.48 (3F). LC-MS m / z (ESI) = 476.17 [M+1].

[0258] Example 25 (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-d)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 25) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0259] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 25a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d) methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Referring to a similar synthetic method to 19a, compound 25a was obtained as a pale yellow solid (32 mg, 24% yield). LCMS m / z = 639.22 [M+l].

[0260] Step 2: (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-d)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 25) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-3-d)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Following a similar synthetic method to compound 19, compound 25 was obtained as a white solid (15 mg, 72% yield). 1 H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 8.81 (s, 2H), 7.93 (s, 1H), 6.26 (dd, 1H), 5.06 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.16 (t, 3H), 3.53 - 3.47 (m, 2H), 1.15 (d, 3H). LCMS m / z = 519.42 [M+l].

[0261] Example 26 (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)one (Compound 26) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)one [ka]

[0262] Step 1: (7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (compound 26b) (7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [1,5-a]pyrazin-2-yl)methanol Following a similar synthetic method to compound 9a, compound 26b was obtained as a white solid (80 mg, 75% yield). LC-MS m / z (ESI) = 300.10 [M+1].

[0263] Step 2: tert-Butyl-(1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 26c) tert-butyl (S)-(1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Referring to a similar synthetic method to intermediate 11h, compound 26c was obtained as a yellow oil (40 mg, 32% yield). LC-MS m / z (ESI) =457.10 [M+1].

[0264] Step 3: (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (compound 26d) (S)-1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Following a similar synthesis method to that of intermediate 11i, compound 26d was obtained as a white solid (30 mg, 96% yield), which was used directly in the next reaction. LC-MS m / z (ESI) =357.10 [M+1].

[0265] Step 4: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 26e) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound 26e was synthesized as a yellow oil (40 mg, 76% yield) by referring to the method for 3a. LC-MS m / z (ESI) = 639.10 [M+1].

[0266] Step 5: (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)one (Compound 26) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)one Referring to the similar synthetic method as compound 6, compound 26 was obtained as a white solid (10 mg, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.51 (d, 1H), 7.95 - 7.90 (m, 2H), 7.20 (d, 1H), 6.38 - 6.23 (m, 1H), 4.92 (s, 2H), 4.57 - 4.34 (m, 2H), 4.25 - 4.20 (m, 4H), 4.17 - 4.13 (m, 1H), 3.57 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.46 (3F), -59.48 (3F). LC-MS m / z (ESI) = 519.10 [M+1].

[0267] Example 27 (R)-4-(trifluoromethyl)-5-(2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 27) (R)-4-(trifluoromethyl)-5-(2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl) pyrrolidin-1-yl)pyridazin-3(2H)-one [ka]

[0268] Step 1: (2R)-2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfite (Compound 27a) (2R)-2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfinic acid Compound 9a (300 mg, 1.0 mmol, 1.0 equiv) was placed in a 50 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (3 mL). Under nitrogen protection, sodium hydride (60 mg, 1.5 mmol, 1.5 equiv) was added batchwise at 0 °C. After the addition was complete, stirring was continued at the same temperature for 20 min. A solution of (R)-1,1-dioxide-tetrahydro-3H-pyrrol[1,2-c][1,2,3]oxathiazole (326 mg, 2 mmol, 2.0 equiv) in N,N-dimethylformamide (3 mL) was slowly added dropwise to the reaction mixture. The temperature was maintained at 0 °C during the addition and stirring was continued for 2 h. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3 and stirred at room temperature for 0.5 h. The reaction mixture was extracted with ethyl acetate (3 × 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product, which was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 27a as a yellow oil (200 mg, 52% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 5.09 (s, 2H), 4.46 - 4.36 (m, 4H), 4.25 (t, 2H), 3.64 - 3.61 (m, 1H), 3.48 - 3.39 (m, 1H), 3.13 (t, 1H), 3.03 - 2.85 (m, 2H), 1.77 - 1.51 (m, 4H). LC-MS m / z (ESI) =464.22 [M+1].

[0269] Step 2: (R)-2-((pyrrolidin-2-ylmethoxy)methyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (compound 27b) (R)-2-((pyrrolidin-2-ylmethoxy)methyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine Compound 27a (200 mg, 0.4 mmol, 1.0 equiv) was placed in a 50 mL reaction bottle and dissolved in anhydrous N,N-dimethylformamide (3 mL). Iodotrimethylsilane (140 μL, 1.0 mmol, 2.5 equiv) was added to the reaction mixture. After the addition was complete, the mixture was stirred at 110 °C for 40 min. Upon completion of the reaction, the mixture was cooled to room temperature, washed with anhydrous sodium sulfite solution, extracted with ethyl acetate (3 × 60 mL), and the organic phase was concentrated to give crude compound 27b (150 mg, 99% yield) as a yellow oil. LC-MS m / z (ESI) =384.10[M+1].

[0270] Step 3: (R)-2-(4-Methoxybenzyl)-5-(2-methyl-2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 27c) (R)-2-(4-methoxybenzyl)-5-(2-methyl-2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl) pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one Compound 27c was synthesized as a yellow oil (40 mg, 76% yield) by following the method of intermediate 3a. LC-MS m / z (ESI) =666.20 [M+1].

[0271] Step 4: (R)-4-(trifluoromethyl)-5-(2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 27) (R)-4-(trifluoromethyl)-5-(2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 27 was obtained as a white solid (68 mg, 52% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.85 (s, 2H), 8.02 (s, 1H), 5.05 (d, 2H), 4.51 (s, 1H), 4.44 (s, 2H), 4.38 (t, 2H), 4.21 (t, 2H), 3.63 - 3.59 (m, 1H), 3.52 - 3.48 (m, 2H), 3.18 (d, 1H), 2.08 (s, 1H), 1.86 (d, 1H), 1.66 (d, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -53.83 (3F), -59.42 (3F). LC-MS m / z (ESI) =546.20 [M+1].

[0272] Example 28 (S)-4-(trifluoromethyl)-5-(2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 28) (S)-4-(trifluoromethyl)-5-(2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one [ka]

[0273] Step 1: (2S)-2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfite (compound 28a) (2S)-2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfinic acid Following a similar synthetic method to compound 27a, compound 28a was obtained as a yellow oil (400 mg, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 5.08 (s, 2H), 4.41- 4.38 (m, 4H), 4.25 (t, 2H), 3.64 - 3.61(m, 1H), 3.46 - 3.42(m, 1H), 3.12 (t, 1H), 3.02 - 2.81 (m, 2H), 1.78 - 1.51 (m, 4H). LC-MS m / z (ESI) =464.22 [M+1].

[0274] Step 2: (S)-2-((pyrrolidin-2-ylmethoxy)methyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (compound 28b) (S)-2-((pyrrolidin-2-ylmethoxy)methyl)-7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine Following a similar synthesis method to compound 27b, compound 28b was obtained as a yellow oil (300 mg, 98% yield), which was used crude in the next step. LC-MS m / z (ESI) =384.10 [M+1].

[0275] Step 3: (S)-2-(4-Methoxybenzyl)-5-(2-methyl-2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy-yl)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 28c) (S)-2-(4-methoxybenzyl)-5-(2-methyl-2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1, 2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to a synthetic method similar to that of 3a, compound 28c was obtained as a yellow oil (500 mg, 76% yield). LC-MS m / z (ESI) =666.20 [M+1].

[0276] Step 4: (S)-4-(trifluoromethyl)-5-(2-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 28) (S)-4-(trifluoromethyl)-5-(2-(((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)methyl) pyrrolidin-1-yl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 28 was obtained as a white solid (80 mg, 56% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.85 (s, 2H), 8.02 (s, 1H), 5.05 (d, 2H), 4.51 (s, 1H), 4.44 (s, 2H), 4.38 (t, 2H), 4.21 (t, 2H), 3.63 - 3.59 (m, 1H), 3.52 - 3.48 (m, 2H),, 3.19 (s, 1H), 2.08 (s, 1H), 1.88 (s, 1H), 1.66 (d, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -53.83 (3F), -59.42 (3F). LC-MS m / z (ESI) =546.20 [M+1].

[0277] Example 29 (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile (Compound 29) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)-methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile [ka]

[0278] Step 1: (S)-2-(2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile (Compound 29a) (S)-2-(2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile Referring to the similar synthetic method as for compound 1, compound 29a was obtained as a yellow solid (480 mg, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.96 (s, 1H), 7.22 (d, 2H), 6.92 - 6.84 (m, 2H), 6.42 - 6.30 (m, 1H), 6.11 (s, 1H), 5.06 - 4.99 (m, 2H), 4.76 (s, 2H), 4.41 (d, 2H), 4.27 - 4.01 (m, 5H), 3.72 (s, 3H), 3.48 (d, 2H), 1.14 (d, 3H). LC-MS m / z (ESI) =601.20 [M+1].

[0279] Step 2: (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-methyl)6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile (Compound 29) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)thiazole-5-carbonitrile Referring to the similar synthetic method as compound 6, compound 29 was obtained as a white solid (98 mg, 56% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 6.30 - 6.27 (m, 1H), 6.13 (s, 1H), 4.79 (s, 2H), 4.42 (d, 2H), 4.30 - 4.01 (m, 5H), 3.50 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.43 (3F). LC-MS m / z (ESI) =481.20 [M+1].

[0280] Example 30 (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 30) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0281] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 30a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoro methyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy) propan-2-yl)amino)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 30a was obtained as a yellow solid (90 mg, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.83 (d, 1H), 7.21 (d, 2H), 6.88 (d, 2H), 6.38 - 6.34 (m, 1H), 6.11 (s, 1H), 5.02 (d, 2H), 4.73 (s, 2H), 4.41 (d, 2H), 4.22 - 4.15 (m, 3H), 4.03 (t, 2H), 3.71 (s, 3H), 3.48 (d, 2H), 1.14 (d, 3H). LC-MS m / z (ESI) =644.20 [M+1].

[0282] Step 2: (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 30) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 30 was obtained as a white solid (38 mg, 52% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 6.31 - 6.28 (m, 1H), 6.12 (s, 1H), 4.76 (s, 2H), 4.42 (d, 2H), 4.23 - 4.15 (m, 3H), 4.06 - 4.04 (m, 2H), 3.50 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -52.92 (3F), -55.43 (3F). LC-MS m / z (ESI) =524.20 [M+1].

[0283] Example 31 (S)-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 31) (S)-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0284] Step 1: (S)-2-(4-Methoxybenzyl-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 31a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoro methyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy) propan-2-yl)amino)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 31a was obtained as a yellow solid (120 mg, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.68 (d, 1H), 7.21 (d, 2H), 6.88 (d, 2H), 6.47 - 6.27 (m, 1H), 6.11 (s, 1H), 5.02 (d, 2H), 4.69 (s, 2H), 4.41 (d, 2H), 4.20 - 4.15 (m, 3H), 3.98 (t, 2H), 3.71 (s, 3H), 3.48 (d, 2H), 1.14 (d, 3H). LC-MS m / z (ESI) =644.20 [M+1].

[0285] Step 2: (S)-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 31) (S)-4-(trifluoromethyl)-5-((1-((5-(4-(trifluoromethyl)thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 31 was obtained as a white solid (58 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.91 (s, 1H), 7.68 (d, 1H), 6.42 - 6.18 (m, 1H), 6.12 (s, 1H), 4.71 (s, 2H), 4.42 (d, 2H), 4.32 - 4.10 (m, 3H), 4.01 - 3.97 (m, 2H), 3.50 (d, 2H), 1.16 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -55.44 (3F), -63.65 (3F). LC-MS m / z (ESI) =524.20 [M+1].

[0286] Example 32 (S)-4-(trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32-I) (S)-4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (R)-4-(trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32-II) (R)-4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one [ka]

[0287] Step 1: Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide (compound 32b) tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide Compound 32a (2.0 g, 17.1 mmol, 1.0 equiv) was placed in a 50 mL reaction bottle and dissolved in anhydrous dichloromethane (25 mL). Imidazole (3.4 g, 50 mmol, 3.0 equiv) and triethylamine (5.8 mL, 42 mmol, 2.5 equiv) were added sequentially to the reaction system at 0 °C. Then, sulfoxide chloride (1.5 mL, 20 mmol, 1.2 equiv) was slowly added dropwise to the system. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride and ethyl acetate (3 × 60 mL), and the organic phase was concentrated to give crude Compound 32b as a yellow oil (2.0 g, 72% yield). LC-MS m / z (ESI) =164.20 [M+1].

[0288] Step 2: Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (compound 32c) tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide Sodium periodate (215 mg, 1 mmol, 1.0 equiv) and ruthenium trichloride (11 mg, 0.05 mmol, 0.05 equiv) were added to a 50 mL reaction bottle, dissolved in water (1.5 mL) and acetonitrile (1.5 mL), and compound 32b (163 mg, 1 mmol, 1.0 equiv) was slowly added and the mixture was allowed to react at room temperature for 1 h. The mixture was quenched with water, extracted with ethyl acetate, and then extracted with ethyl acetate (3 × 60 mL). The organic phase was concentrated to give crude compound 32c (130 mg, 72% yield) as a yellow oil. LC-MS m / z (ESI) =180.10 [M+1].

[0289] Step 3: 3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholine (compound 32d) 3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholine Referring to a similar synthetic method to intermediate 11h, compound 32d was obtained as a yellow oil (170 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 6.19 (s, 1H), 5.03 (s, 2H), 4.47 - 4.31 (m, 4H), 4.17 (t, 2H), 3.76 - 3.58 (m, 3H), 3.35 - 3.24 (m, 3H), 3.16 - 3.06 (m, 1H), 2.93 - 2.82 (m, 1H), 2.76 - 2.63 (m, 2H). LC-MS m / z (ESI) =399.20[M+1].

[0290] Step 4: 2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32e) 2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one Compound 32e was synthesized as a yellow oil (110 mg, 70% yield) by following the method of intermediate 3a. LC-MS m / z (ESI) = 681.61 [M+1].

[0291] Step 5: 4-(Trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32) 4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 32 was obtained as a white solid (53 mg, 57% yield). LC-MS m / z (ESI) = 561.17 [M+1].

[0292] Step 6: (S)-4-(trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32-I) (S)-4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (R)-4-(trifluoromethyl)-5-(3-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one (Compound 32-II) (R)-4-(trifluoromethyl)-5-(3-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)morpholino)pyridazin-3(2H)-one Compound 32 was separated by SFC to give compound 32-I (45 mg, 38% yield, RT = 19.471 min, 100% ee) and compound 32-II (47 mg, 39% yield, RT = 15.946 min, 99.8% ee). The following chiral HPLC (AS) conditions were used: mobile phase: n-hexane / ethanol = 95 / 5, column temperature: 35 °C, column pressure: 80 bar, flow rate: 1 mL / min, detector signal channel: 215 nm @ 4.8 nm, diode array detector on / off wavelength: 200-400 nm. Compound 32-I: 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.82 (s, 2H), 7.95 (s, 1H), 6.01 (s, 1H), 5.00 (s, 2H), 4.40 - 4.28 (m, 4H), 4.16 (t, 2H), 3.91 - 3.76 (m, 3H), 3.68 - 3.55 (m, 3H), 3.49 - 3.45 (m, 2H), 3.12 (d, 1H). Compound 32-II: 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.82 (s, 2H), 7.95 (s, 1H), 6.01 (s, 1H), 5.00 (s, 2H), 4.32 (d, 4H), 4.16 (t, 2H), 3.94 - 3.74 (m, 3H), 3.71 - 3.55 (m, 3H), 3.49 - 3.45 (m, 2H), 3.12 (d, 1H).

[0293] Example 33 (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 33) (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0294] Step 1: 2-Chloro-5-(difluoromethyl)pyrimidine (compound 33b) 2-chloro-5-(difluoromethyl)pyrimidine Compound 33a (1.0 g, 7.0 mmol, 1.0 equiv) was dissolved in dichloromethane (20 mL) and diethylaminosulfur trifluoride (2.33 mL, 17.6 mmol, 2.5 equiv) was slowly added at 0 °C. After 10 min, the ice bath was removed and the mixture was allowed to warm to room temperature and react for 2 h. Upon completion, the reaction was quenched by the dropwise addition of saturated sodium bicarbonate solution at 0 °C (adjusting the reaction solution to pH = 8), followed by extraction with dichloromethane (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 33b (550 mg, 52% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.23 (t, 1H). 19 F NMR (377 MHz, DMSO-d6) δ -113.83 (2F). LCMS m / z (ESI) = 165.2 [M+l].

[0295] Step 2: (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 33c) (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method for compound 1, compound 33c was obtained as a pale yellow solid (85 mg, yield 67.5%). 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 2H), 7.96 (s, 1H), 7.21 (d, 2H), 7.03 (t, 1H) 6.90 - 6.84 (m, 2H), 6.42 - 6.30 (m, 1H), 6.08 (s, 1H), 5.02 (s, 2H), 4.95 (d, 2H), 4.40 (d, 2H), 4.28 (dd, 2H), 4.13 (t, 2H), 3.70 (s, 3H), 3.48 (d, 2H), 2.95 (m, 1H)1.15 - 1.12 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.65 (3F), -109.35 (2 F). LCMS m / z (ESI) = 621.2 [M+l].

[0296] Step 3: (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 33) (S)-5-((1-((5-(5-(difluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 33 was obtained as a white solid (25 mg, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.65 (s, 2H), 7.90 (s,1H), 7.01 (t, 1H), 6.28 (dd, 1H), 6.10 (s, 1H), 4.98 (s, 2H), 4.41 (d, 2H), 4.30 (t, 2H), 4.14 (t, 3H), 3.49 (d, 2H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.43 (3F), -109.35 (2F). LCMS m / z (ESI) = 501.2 [M+1].

[0297] Example 34 (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 34) (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one [ka]

[0298] Step 1: 2-Chloro-5-(1,1-difluoroethyl)pyrimidine (compound 34b) 2-chloro-5-(1,1-difluoroethyl)pyrimidine Following a similar synthetic method to compound 33b, compound 34b was obtained as an off-white solid (450 mg, 42.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 2.07 (t, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -85.52 (2F). LCMS m / z (ESI) = 179.2 [M+1].

[0299] Step 2: (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 34c) (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl) pyridazin-3(2H)-one Referring to the similar synthetic method as compound 1, compound 34c was obtained as a deep yellow solid (230 mg, yield 70.0%). LCMS m / z (ESI) = 635.2 [M+l].

[0300] Step 3: (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 34) (S)-5-((1-((5-(5-(1,1-difluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 34 was obtained as a white solid (90 mg, 80.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.80 (d, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.10 (s, 1H), 4.97 (s, 1H), 4.41 (d, 2H), 4.29 (d, 1H), 4.18 - 4.11 (m, 3H), 3.54 (s, 2H), 3.49 (d, 2H), 2.01 (dd, 16.1 Hz, 3H), 1.15 (d, 3H). 19F NMR (377 MHz, DMSO-d6) δ -55.43 (3F), -82.61 (2F). LCMS m / z (ESI) = 515.2 [M+l].

[0301] Example 35 (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 35) (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one [ka]

[0302] Step 1: (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 35b) (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 35b was obtained as a yellow solid (160 mg, yield 62.0%). LCMS m / z (ESI) = 637.4 [M+1].

[0303] Step 2: (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 35) (S)-5-((1-((5-(5-(difluoromethoxy)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 35 was obtained as a white solid (70 mg, yield 55.2%). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.46 (d, 2H), 7.90 (s, 1H), 7.11 (t, 1H), 6.28 (dd, 1H), 6.08 (s, 1H), 4.90 (s, 2H), 4.47 - 4.34 (m, 2H), 4.27 - 4.20 (m, 2H), 4.16 - 4.14 (m, 3H), 3.49 (d, 2H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.44 (3F), -82.06 (2F). LCMS m / z (ESI) = 517.4 [M+1].

[0304] Example 36 (S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one (compound 36) (S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino) pyridazin-3(2H)-one [ka]

[0305] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one (compound 36a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl) pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one Following a similar synthetic method to compound 19a, compound 36a was obtained as a pale yellow solid (41 mg, 59% yield). LCMS m / z = 637.24 [M+l].

[0306] Step 2: (S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one (compound 36) (S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino) pyridazin-3(2H)-one Following a similar synthetic method to compound 19, compound 36 was obtained as a white solid (17 mg, 39% yield). 1 H NMR (400 MHz, DMSO-d6) δ12.45 (s, 1H), 8.76 (s, 2H), 7.76(s, 1H),6.70 (d, 1H), 4.74 (d, 1H), 4.61 (d, 4H), 4.12-4.06 (m, 2H), 3.45-3.38 (m, 3H), 1.79 (d, 2H), 1.13 (dd, 3H). LCMS m / z = 517.18 [M+l].

[0307] Example 37 (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino)pyridazin-3(2H)-one (Compound 37) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0308] Step 1: tert-Butyl-(S)-(1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)carbamate (Compound 37b) tert-butyl (S)-(1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)carbamate Referring to a similar synthetic method to intermediate 11h, compound 37b was obtained as a yellow solid (230 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.81 (s, 3H), 6.10 (s, 1H), 5.02 (s, 2H), 4.33 (t, 2H), 4.15 (t, 2H), 3.65 (t, 4H), 3.43 (d, 2H), 3.37 (d, 2H), 2.08 (t, 2H), 1.83 - 1.69 (m, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -59.43 (3F). LCMS m / z (ESI) = 472.2[M+l].

[0309] Step 2: (S)-1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-amine (Compound 37c) (S)-1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-amine Referring to a similar synthetic method to intermediate 11d, compound 37c was obtained as a white solid (190 mg, 98% yield). LCMS m / z (ESI) = 372.2[M+l].

[0310] Step 3: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-((trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino)pyridazin-3(2H)-one (Compound 37d) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoro methyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino) pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 37d was obtained as a yellow solid (350 mg, 85% yield). LCMS m / z (ESI) = 654.4[M+l].

[0311] Step 4: (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino)pyridazin-3(2H)-one (Compound 37) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)butan-2-yl)amino)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 37 was obtained as a white solid (120 mg, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.85 (s, 2H), 7.93 (s, 1H), 6.27 (dd, 1H), 5.07 (s, 2H), 4.48 (q, 2H), 4.39 (t, 2H), 4.23 (t, 2H), 3.99 (d, 1H), 3.60 (t, 2H), 1.67 - 1.41 (m, 2H), 0.85 (t, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.53 (3F), -59.43 (3F). LCMS m / z (ESI) = 534.4[M+l].

[0312] Example 38 (S)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 38) (S)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one [ka]

[0313] Step 1: 2-Chloro-5-(methylsulfonyl)pyrimidine (compound 38b) 2-chloro-5-(methylsulfonyl)pyrimidine Compound 38a (400 mg, 2.5 mmol, 1.0 equiv) was weighed into a 100 mL reaction bottle and dissolved in dichloromethane (15 mL). Metachloroperbenzoic acid (2.58 g, 14.9 mmol, 6.0 equiv) was added under ice bath conditions. The ice bath was removed and the mixture was allowed to react at room temperature for 4 hours. The reaction was quenched with saturated sodium thiosulfate (10 mL), adjusted to pH 8 with saturated sodium bicarbonate, and extracted with dichloromethane (3 x 140 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give compound 38b (410 mg, 86% yield) as a white solid. LCMS m / z (ESI) = 193.3[M+l].

[0314] Step 2: (S)-2-(4-Methoxybenzyl)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 38c) (S)-2-(4-methoxybenzyl)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 38c was obtained as a yellow solid (340 mg, 85% yield). LCMS m / z (ESI) = 649.4[M+l].

[0315] Step 3: (S)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 38) (S)-5-((1-((5-(5-(methylsulfonyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 38 was obtained as a white solid (80 mg, 40% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.82 (s, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.12 (s, 1H), 5.05 (s, 2H), 4.41 (d, 2H), 4.36 (t, 2H), 4.17 (t, 3H), 3.49 (d, 2H), 3.25 (s, 3H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.44 (3F). LCMS m / z (ESI) = 529.4[M+l].

[0316] Example 39 (S)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 39) (S)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin -3(2H)-one [ka]

[0317] Step 1: (S)-2-(4-Methoxybenzyl)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 39a) (S)-2-(4-methoxybenzyl)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as for compound 1, compound 39a was obtained as a yellow solid (340 mg, 45% yield). LCMS m / z (ESI) = 617.2[M+l].

[0318] Step 2: (S)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 39) (S)-5-((1-((5-(5-(methylthio)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin -3(2H)-one Referring to the similar synthetic method as compound 6, compound 39 was obtained as a white solid (75 mg, 83% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.51 (s, 2H), 7.90 (s, 1H), 6.29 (dd, 1H), 6.08 (s, 1H), 4.91 (s, 2H), 4.44 - 4.35 (m, 2H), 4.23 (dd, 2H), 4.17 (d, 1H), 4.12 (t, 2H), 3.49 (d, 2H), 2.40 (s, 3H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.43 (3F). LCMS m / z (ESI) = 497.2[M+l].

[0319] Example 40 (S)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 40) (S)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin -3(2H)-one [ka]

[0320] Step 1: (S)-2-(4-Methoxybenzyl)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 40b) (S)-2-(4-methoxybenzyl)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7 -tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to a synthetic method similar to that of compound 1, compound 40b was obtained as a yellow solid (290 mg, 35% yield). LCMS m / z (ESI) = 610.3[M+l].

[0321] Step 2: (S)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 40) (S)-5-((1-((5-(pyrazolo[1,5-a]pyrimidin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin -3(2H)-one Referring to the similar synthetic method as compound 6, compound 40 was obtained as a white solid (24 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.76 (d, 1H), 7.90 (d, 2H), 6.87 (d, 1H), 6.29 (dd, 1H), 6.18 - 6.00 (m, 2H), 4.88 (s, 2H), 4.41 (d, 2H), 4.16 (s, 5H), 3.49 (d, 2H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.42 (3F). LCMS m / z (ESI) = 490.3[M+l].

[0322] Example 41 (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoromethyl)nicotinonitrile (Compound 41) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoro methyl)nicotinitrile [ka]

[0323] Step 1: (S)-2-(2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoromethyl)nicotinonitrile (Compound 41b) (S)-2-(2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoro methyl)nicotinotrile Referring to the similar synthetic method as for compound 1, compound 41b was obtained as a yellow solid (380 mg, 74% yield). LCMS m / z (ESI) = 663.3 [M+1].

[0324] Step 2: (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-6,7-dihydropyrazol[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoromethyl)nicotinonitrile (Compound 41) (S)-2-(2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-5-(trifluoro methyl)nicotinitrile Referring to the similar synthetic method as compound 6, compound 41 was obtained as a white solid (83 mg, 42% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.77 (s, 1H), 8.64 (d, 1H), 7.91 (s, 1H), 6.41 - 6.23 (m, 1H), 6.12 (s, 1H), 4.99 (s, 2H), 4.46 - 4.37 (m, 2H), 4.27 (s, 4H), 4.16 (s, 1H), 3.50 (d, 2H), 1.15 (d, 3H). 19F NMR (377 MHz, DMSO-d6) δ -55.44 (3F), -59.80 (3F). LCMS m / z (ESI) = 543.2 [M+1].

[0325] Example 42 5-(((S)-1-(((S)-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 42-I) 5-(((S)-1-(((S)-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 5-((S)-1-((R)-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 42-II) 5-(((S)-1-((R)-7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one [ka]

[0326] Step 1: 2-(4-Methoxybenzyl)-5-(((2S)-1-(((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 42a) 2-(4-methoxybenzyl)-5-(((2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin -2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoro methyl)pyridazin-3(2H)-one Referring to a synthetic method similar to that of compound 19a, compound 42a was obtained as a pale yellow solid (264 mg, 52% yield). LCMS m / z = 653.23 [M+l].

[0327] Step 2: 5-(((2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 42) 5-(((2S)-1-((7-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Following a similar synthetic method to compound 19, compound 42 was obtained as a white solid (114 mg, 65% yield). LCMS m / z = 533.18 [M+l].

[0328] Step 3: Compound 42 was resolved by SFC to give compound 42-I (45 mg, 38% yield, RT = 19.471 min, 100% ee) and compound 42-II (47 mg, 39% yield, RT = 15.946 min, 99.8% ee). The chiral HPLC (AS) mobile phase was n-hexane / ethanol = 95 / 5, column temperature: 35 °C, column pressure: 80 bar, flow rate: 1 mL / min, detector signal channel: 215 nm @ 4.8 nm, diode array detector on / off wavelength: 200-400 nm. Compound 42-I: 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.80 (s, 2H), 7.89 (s, 1H), 6.28 (dd, 1H), 6.08 (s, 1H), 5.11 - 4.90 (m, 2H), 4.45 - 4.33 (m, 4H), 4.20 - 4.10 (m, 1H), 4.05 (dd, 1H), 3.52 - 3.47 (m, 2H), 1.40 (d, 3H), 1.15 (d, 3H). Compound 42-II: 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.82 (s, 2H), 7.91 (s, 1H), 6.29 (dd, 1H), 6.09 (s, 1H), 5.01-4.89 (m, 2H), 4.48 - 4.33 (m, 4H), 4.21 - 4.13 (m, 1H), 4.12 - 4.02 (m, 1H), 3.50 (d, 2H), 1.40 (d, 3H), 1.15 (d, 3H).

[0329] Example 43 ((S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 43) (S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin -3(2H)-one [ka]

[0330] Step 1: (S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 43b) (S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one Following a similar synthesis method to that of Compound 1, crude Compound 43b was obtained as a yellow solid (70 mg, 29% yield). LCMS m / z (ESI) = 610.6 [M+l].

[0331] Step 2: ((S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 43) (S)-5-((1-((5-(imidazo[1,2-a]pyrazin-8-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Referring to the similar synthetic method as compound 6, compound 43 was obtained as a white solid (25 mg, 44% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.02 (d, 1H), 8.00 (d, 1H), 7.91 (s, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 6.30 (dd, 1H), 6.09 (s, 1H), 5.39 - 5.28 (m, 2H), 4.81 - 4.64 (m, 2H), 4.44 - 4.33 (m, 2H), 4.20 (t, 2H), 4.15 (m, 1H), 3.49 (d, 2H), 1.15 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -55.43 (3F). LCMS m / z (ESI) = 490.4 [M+1].

[0332] Example 44 (S)-4-Bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 44) (S)-4-bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0333] Step 1: (S)-4-Bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin)-3(2H)-one (Compound 44b) (S)-4-bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one Following a synthesis similar to that of compound 3a, compound 44b was obtained as a yellow oil (450 mg, 27% yield). LCMS m / z (ESI) = 659.5 [M+1].

[0334] Step 2: (S)-4-Bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 44) (S)-4-bromo-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound 44b (55 mg, 0.083 mmol) was added to 3 mL of hydrochloric acid / dioxane (4 mol / L) and reacted at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated and purified by column chromatography (DCM / MeOH = 20 / 1) to give compound 44 (20 mg, 45% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.81 (s, 2H), 7.77 (s, 1H), 6.11 (s, 1H), 5.73 (d, 1H), 5.01 (s, 2H), 4.40 (s, 2H), 4.32 (t, 2H), 4.16 (t, 2H), 4.08( m, 1H), 3.48 (d, 2H), 3.48 (d, 2H), 1.16 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -59.37 (3F). LCMS m / z (ESI) = 530.3 [M+1].

[0335] Example 45 (S)-4-Cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 45) (S)-4-cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0336] Step 1: (S)-4-Cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (Compound 45b) (S)-4-cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one Compound 44b (150 mg, 0.23 mmol), compound 45a (39 mg, 0.46 mmol), Pd(OAC) (4.8 mg, 0.023 mmol), tricyclohexylphosphine (13 mg, 0.046 mmol), and potassium phosphate (138 mg, 0.69 mmol) were weighed into a 20 mL reaction vial. The mixture was dissolved in dioxane (3 mL) and water (0.3 mL). After the addition was complete, the mixture was stirred at 100 °C for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 1:5) to give compound 45b (90 mg, 64% yield) as a yellow solid. LCMS m / z (ESI) = 621.7 [M+1].

[0337] Step 2: (S)-4-Cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 45) (S)-4-cyclopropyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Following the synthesis method of compound 44, compound 45 was obtained as a white solid (22 mg, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.81 (s, 2H), 7.68 (s, 1H), 6.14 (s, 1H), 5.42 (d, 1H), 5.01 (s, 2H), 4.41 (d, 2H), 4.33 (t, 2H), 4.16 (t, 2H), 3.99 - 3.90 (m, 1H), 3.46 (d, 2H), 1.23 (d, 1H), 1.15 (d, 3H), 0.79 (d, 2H), 0.70 - 0.60 (m, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -59.38 (3F). LCMS m / z (ESI) = 491.5 [M+1].

[0338] Example 46 (S)-4-Methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 46) (S)-4-methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one [ka]

[0339] Step 1: (S)-4-Methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (Compound 46b) (S)-4-methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one Referring to the method for preparing compound 45b, compound 46b was obtained as a yellow solid (50 mg, 37% yield). LCMS m / z (ESI) = 595.6 [M+1].

[0340] Step 2: (S)-4-Methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (Compound 45) (S)-4-methyl-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound 46 was obtained as a white solid (15 mg, 38% yield) following the procedure for preparing compound 44. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.81 (d, 2H), 7.69 (s, 1H), 6.12 (s, 1H), 5.36 (d, 1H), 5.01 (s, 2H), 4.39 (d, 2H), 4.33 (t, 2H), 4.16 (t, 2H), 3.92 (m, 1H), 3.53 - 3.37 (m, 2H), 1.78 (s, 3H), 1.14 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -59.37 (3F). LCMS m / z (ESI) = 465.4 [M+1].

[0341] Example 47 (S)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 47) (S)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one [ka]

[0342] Step 1: (7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol (compound 47b) (7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methanol Following the synthesis method of compound 9a, compound 47b was obtained as a white solid (80 mg, 20% yield). LC-MS m / z (ESI) =310.09 [M+1].

[0343] Step 2: tert-Butyl-(1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate (Compound 47c) tert-butyl(S)-(1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate Following the synthesis method of intermediate 11h, compound 47c was obtained as a yellow oil (60 mg, 35% yield). LC-MS m / z (ESI) =467.20[M+1].

[0344] Step 3: (S)-1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine (compound 47d) (S)-1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine Compound 47d was obtained as a white solid (40 mg, 90% yield) by following the synthesis method of intermediate 11i. The crude product was used directly in the next reaction. LC-MS m / z (ESI) =367.20 [M+1].

[0345] Step 4: (S)-2-(4-Methoxybenzyl)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 47e) (S)-2-(4-methoxybenzyl)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Following the synthesis method of intermediate 3a, compound 47e was obtained as a yellow oil (22 mg, 35% yield). LC-MS m / z (ESI) = 649.21 [M+1].

[0346] Step 5: (S)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 47) (S)-5-((1-((7-(5-(methylsulfonyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one Following the synthesis method of compound 6, compound 47 was obtained as a white solid (10 mg, yield 55%). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.59 (d, 1H), 8.02 (dd, 1H), 7.91 (s, 1H), 7.21 (d, 1H), 6.37 - 6.29 (m, 1H), 4.96 (s, 2H), 4.54 - 4.44 (m, 2H), 4.32 - 4.12 (m, 5H), 3.57 (d, 2H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.48 (3F). LC-MS m / z (ESI) = 529.21 [M+1].

[0347] Example 48 (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one (Compound 48) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one [ka]

[0348] Step 1: (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-ol (compound 48b) (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-ol Intermediate 22 (1.0 g, 3.33 mmol) was weighed into a 100 mL reaction bottle and dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, sodium hydride (60%, 334 mg, 8.3 mmol) was added at 0 °C and the mixture was stirred for 30 minutes. Compound 48a (552 mg, 4.0 mmol) was then added. After the addition was complete, the mixture was allowed to react at room temperature overnight. Hydrochloric acid solution (10 mL, 2 N) was added to the reaction mixture in an ice bath and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3 x 40 mL). The organic phases were combined, dried over anhydrous Na2SO4, concentrated, mixed, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 48b (750 mg, 63% yield) as a pale yellow solid. LCMS m / z (ESI) = 358.3 [M+1].

[0349] Step 2: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one (Compound 48c) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one Compound 48b (150 mg, 0.42 mmol) and intermediate 1 (160 mg, 0.51 mmol) were weighed into a 25 mL reaction bottle and dissolved in dichloromethane (5 mL). Sodium tert-butoxide (60 mg, 0.63 mmol) was added to the reaction bottle at 0 °C. After the addition was complete, the reaction was stirred at the same temperature for 1 hour. Upon completion of the reaction, the reaction was quenched by adding water, extracted with ethyl acetate (40 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 48c (160 mg, 60% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.33 (s, 1H), 7.33 - 7.18 (m, 2H), 6.96 - 6.82 (m, 2H), 6.04 (s, 1H), 5.13 (d, 2H), 4.97 (s, 2H), 4.38 (d, 2H), 4.45 - 4.35(t, 3H), 4.13 (t, 2H), 3.71 (s, 3H), 3.66 - 3.47 (m, 2H), 1.25 (d, 3H). LCMS m / z (ESI) = 641.10 [M+1].

[0350] Step 3: (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one (Compound 48) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)oxy)pyridazin-3(2H)-one Following the synthesis method of compound 6, compound 48 was obtained as a white solid (83 mg, yield 57%). 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.81 (d, 2H), 8.27 (s, 1H), 6.06 (s, 1H), 5.16 (s, 1H), 5.00 (s, 2H), 4.39 (d, 2H), 4.32 (t, 2H), 4.15 (t, 2H), 3.62 (dd, 1H), 3.52 (dd, 1H), 1.26 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -59.38 (3F). LCMS m / z (ESI) = 521.10 [M+1].

[0351] Example 49 (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (Compound 49) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1- d2)amino)pyridazin-3(2H)-one [ka]

[0352] Step 1: (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (compound 49a) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1- d2)amino)pyridazin-3(2H)-one Following the synthesis method of compound 19a, compound 49a was obtained as a pale yellow solid (300 mg, yield 92%). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, 2H), 7.95 (s, 1H), 7.26 - 7.17 (m, 2H), 6.93 - 6.83 (m, 2H), 6.34 (d, 1H), 6.09 (s, 1H), 5.02 (s, 2H), 4.98 (d, , 2H), 4.40 (d, 2H), 4.34 - 4.26 (m, 2H), 4.14 (t, 2H), 4.03 (q, 1H), 3.70 (s, 3H), 1.14 (d, 3H). LCMS m / z = 641.30 [M+l].

[0353] Step 2: (S)-4-(trifluoromethyl)-5-((1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (Compound 49) (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1- d2)amino)pyridazin-3(2H)-one Following the synthesis method of compound 19, compound 49 was obtained as a white solid (124 mg, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.81 (s, 2H), 7.90 (s, 1H), 6.27 (s, 1H), 6.11 (s, 1H), 5.01 (s, 2H), 4.41 (d, 2H), 4.34 - 4.31 (m, 2H), 4.17 - 4.13 (m, 3H), 1.15 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.48 (3F), -59.41 (3F). LCMS m / z = 521.20 [M+l].

[0354] Example 50 (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazol[1,5-a]pyrazin-4(5H)-one (Compound 50) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ka]

[0355] Step 1: (S)-2-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 50b) (S)-2-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Following the synthesis method of compound 6a, compound 50b was obtained as a white solid (220 mg, 53% yield). LC-MS m / z (ESI) = 658.60 [M+1].

[0356] Step 2: (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazol[1,5-a]pyrazin-4(5H)-one (Compound 50) (S)-2-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)methyl)-5-(5-(trifluoromethyl)thiazol-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Following the synthesis method of compound 6, compound 50 was obtained as a white solid (43 mg, yield 49%). 1 H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.87 - 8.88 (m, 1H), 6.89 (s, 1H), 6.31 (dd, 1H), 4.65 - 4.43 (m, 5H), 4.30 - 4.09 (m, 1H), 3.55 (d 2H), 1.17 (d, 3H). LC-MS m / z (ESI) = 537.44 [M+1].

[0357] Example 51 (S)-4-(trifluoromethyl)-5-(2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin)-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 51) (S)-4-(trifluoromethyl)-5-(2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one [ka]

[0358] Step 1: (2S)-2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfinic acid (compound 51a) (2S)-2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidine-1-sulfinic acid Following the synthesis method of compound 27a, compound 51a was obtained as a yellow oil (360 mg, 82% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 6.17 (s, 1H), 5.03 (s, 2H), 4.33 (d, 4H), 4.24 - 4.15 (m, 2H), 3.58 (dd, 1H), 3.53 - 3.38 (m, 1H), 3.07 (t, 1H), 2.99 - 2.85 (m, 2H), 1.77 - 1.51 (m, 4H). LC-MS m / z (ESI) = 447.43 [M+1].

[0359] Step 2: (S)-2-(pyrrolidin-2-ylmethoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (compound 51b) (S)-2-((pyrrolidin-2-ylmethoxy)methyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Following the synthesis of compound 27b, compound 51b was obtained as a yellow oil (268 mg, 91% yield), which was used directly in the next step. LC-MS m / z (ESI) =384.36 [M+1].

[0360] Step 3: (S)-2-(4-Methoxybenzyl-4-(trifluoromethyl)-5-(2-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 51c) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-(2-(((5-(5-(trifluoro methyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl) methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one Following the synthesis method of 3a, compound 51c was obtained as a yellow oil (480 mg, 72% yield). LC-MS m / z (ESI) =666.64 [M+1].

[0361] Step 4: (S)-4-(trifluoromethyl)-5-(2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin)-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one (Compound 51) (S)-4-(trifluoromethyl)-5-(2-(((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)methyl)pyrrolidin-1-yl)pyridazin-3(2H)-one Following the synthesis method of compound 6, compound 51 was obtained as a white solid (80 mg, yield 56%). 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.81 (s, 2H), 8.01 (s, 1H), 6.04 (s, 1H), 4.99 (s, 2H), 4.59 - 4.48 (m, 1H), 4.38 (s, 2H), 4.32 (t, 2H), 4.15 (t, 2H), 3.56 - 3.46 (m, 3H), 3.20 (dd, 1H), 2.12 - 2.02 (m, 1H), 1.91 - 1.86 (m, 1H), 1.70 - 1.55 (m, 2H). LC-MS m / z (ESI) =546.49 [M+1].

[0362] Example 52 (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4])triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (Compound 52) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one [ka]

[0363] Step 1: (S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (Compound 52a) (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl) methyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl-1,1-d2)amino)pyridazin-3(2H)-one Following the synthesis method of compound 19a, compound 52a was obtained as a pale yellow solid (340 mg, yield 87%). LCMS m / z = 642.60 [M+l].

[0364] Step 2: (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4])triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one (Compound 52) (S)-4-(trifluoromethyl)-5-((1-((7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl-1,1-d2)amino)pyridazin-3(2H)-one Following the synthesis method of compound 19, compound 52 was obtained as a white solid (144 mg, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ 16.94 (s, 1H),12.44 (s, 1H), 8.80 (s, 2H), 7.79 (s, 1H), 6.25 (s, 1H), 5.00 (s, 2H), 4.39 (d, 2H), 4.36 - 4.30 (m, 2H), 4.18 - 4.12 (m, 3H), 1.14 (d, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -55.47 (3F), -59.40 (3F). LCMS m / z = 522.40 [M+l].

[0365] Biological Testing 1. PARP Enzymatic Biochemical Test This experiment involved a PARP enzymatic biochemical test using a PARP1, TNKS1, TNKS2, PARP7, and PARP14 chemiluminescence detection kit (BPS, Cat. No. 80551 / 80552 / 80573 / 80578 / 79729 / 80568). The specific protocol was as follows: 50 μL of 1× histone mixture was added to a 96-well plate at each well and incubated overnight at 4°C. The next day, after washing with PBST, 200 μL of blocking buffer was added per well and incubated for 90 minutes. After washing again with PBST, 5 μL of inhibitor, 20 μL of 1× PARP buffer, and 25 μL of streptavidin-HRP were added per well and incubated at room temperature for 30 minutes. After washing with PBST, 100 μL of a mixture of ELISA ECL substrates A and B was added per well. The chemiluminescence values ​​were immediately read using a microplate reader, and the IC was calculated. 50 The values ​​were calculated, and the results are shown in Tables 1 and 2.

[0366] [Table 1]

[0367] As a result, the compounds of the present invention exhibit significant biological inhibitory activity against PARP7.

[0368] [Table 2]

[0369] As a result, the compounds of the present invention are shown to have higher kinase selectivity than the comparative compounds.

[0370] 2. NCI-H 1373 cell proliferation inhibition test Human lung adenocarcinoma cells NCI-H1373 (ATCC, CRL-5866 TM) were cultured in a cell culture chamber at 37°C, 5% CO2 in RPMI-1640 medium containing 10% FBS and 1% bispecific antibody. Cells in the logarithmic growth phase were digested and counted, seeded into a 96-well plate at 1500 NCI-H1373 cells per well, and cultured overnight in the culture chamber. The next day, test compounds were prepared in a 10 mM stock solution using DMSO, and a 3-fold gradient dilution was performed in RPMI-1640 medium starting from the highest dose of 10 μM, resulting in a total of 10 gradient concentrations. concentration gradient Two parallel wells were placed in each well. After 6 days of culture, 100 μL of Cell Titer Blue working solution was added to each well, and chemiluminescence values ​​were read using a microplate reader. IC was calculated using GraphPad Prism 7.0 software. 50 was calculated and the results are shown in Table 3.

[0371] [Table 3]

[0372] As a result, the compounds of the present invention show a significant inhibitory effect on the proliferation of NCI-H1373 cells.

[0373] 3. Liver Microsome Metabolic Stability Test Protocol A 0.5 mg / mL CD1 mouse liver microsome solution, 0.5 μM test compound, 1.0 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), and 1.0 mM uridine diphosphate-A-glucuronic acid (UDPGA) were added to an incubation plate, mixed, and incubated at 37°C for 0, 30, 60, and 120 min, respectively. The positive control group consisted of 0.5 μM testosterone (a probe substrate for CYP3A4) and 0.5 μM 7-hydroxycoumarin (a probe substrate for UGT) incubated with microsomes in the presence of NADPH and UDPGA for 0 and 120 min. The negative control group (NC) consisted of the test compound incubated with microsomes in the absence of any coenzyme for 0 and 120 min. At each time point, the reaction was terminated by adding pre-chilled methanol, and the mixture was centrifuged at 4000 rpm for 10 minutes. The supernatant was then removed and the amount of the test substance remaining in the sample was measured by LC-MS / MS. The results are shown in Table 4.

[0374] [Table 4]

[0375] As a result, the compounds of the present invention are clearly superior in hepatic microsomal metabolic stability to the comparative compounds.

[0376] 4. MDCKII-MDR1 cell permeability assay Density is 1.56×10 6 50 μL of the MDCKII-MDR1 cell suspension (cells / mL) was seeded into a Transwell well of a 96-well plate and cultured in a cell culture chamber at 37°C and 5% CO2. After culturing the cells to a certain degree of confluence, the electrical resistance (TEER) was measured, and the TEER value was 42 ohm cm. 2The results exceeded the 100 μM threshold, indicating that the cells had grown into a monolayer and met the experimental requirements. The medium in the Transwell was discarded, and HBSS equilibration solution was added and allowed to equilibrate at 37°C for 30 minutes. The apical-to-basolateral drug transport rate was then measured. A 1 μM test compound solution was added to the AB side of the Transwell, and blank equilibration solution was added to the BL side. The reverse procedure was used to measure the basolateral-to-apical drug transport rate. The cells were then placed in a culture chamber and incubated for 2 hours. After incubation, samples were taken from the basolateral and apical sides, centrifuged, and the supernatant was analyzed by LC-MS / MS to calculate the apparent permeability coefficient (Papp). The results are shown in Table 5.

[0377] [Table 5]

[0378] As a result, the compounds of the present invention have higher cell membrane permeability and lower excretion rate compared to the comparative examples.

[0379] 5. In vivo Pharmacokinetic Studies The appropriate amount of compound was weighed and prepared into a clear, transparent solution of 1 mg / mL in 5% DMSO and 30% HP-β-CD. Male ICR mice were fasted overnight and then orally administered 30 mpg of benzodiazepine. Blood was collected from the jugular plexus at 0 min, 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h. After anticoagulation with EDTA-K2, plasma was separated by centrifugation, and the parent drug concentration in plasma was measured using LC / MS / MS.

[0380] As a result, it is shown that the compounds of the present invention exhibited clearly superior pharmacokinetic properties in mice compared to the comparative compounds.

[0381] Although the specification of the present invention has described specific embodiments in detail, it will be understood by those skilled in the art that the above embodiments are illustrative and should not be construed as limiting the present invention. Those skilled in the art can make various changes and modifications without departing from the principles of the present invention, and the results of these changes and modifications are also included in the scope of the claims of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof. 【Chemical 1】 (In the formula, X １ is NH, O, or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ are each independently C １－６ Alkyl group, C １－６ Alkoxy group, halogen, cyano group, S(O) ２ R １０ｃ or SR10d, wherein said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｃ , R １０ｄ are each independently H, D or C １－６ is an alkyl group, A is, 【Chemistry 2】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

2. The compound has the structure represented by formula (I-1): 【Chemistry 3】 (In the formula, X １ is NH or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group or a halogen atom, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is C １－６ Alkyl group, C １－６ Alkoxy group, cyano group or SR １０ｄ and said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 4】 and B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, having the formula:

3. The compound has the structure represented by formula (I-2): 【Chemistry 5】 (In the formula, X １ is NH, X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group or a halogen atom, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is C １－６ Alkyl group, C １－６ Alkoxy group, cyano group or SR １０ｄ and said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 6】 and B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, having the formula:

4. X １ is NH, X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group or a halogen atom, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is C １－６ Alkyl group, cyano group, or SR １０ｄ and said C １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 7】 and B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; m is 1, 2 or 3; n is 0, 1, 2 or 3; The compound according to claim 3, its isomer, or its deuterated derivative.

5. X １ is selected from NH; X ２ is selected from O, R １ａ , R １ｂ are each independently H, D or C １－６ alkyl groups, R ２ａ , R ２ｂ are each independently H, D or C １－６ alkyl groups, R ３ H, D, C １－６ is an alkyl group or a halogen atom, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H or D; R ６ , R ７ are each independently H or D; R ８ , R ９ are each independently H or D; R １０ is CF ３ or SR １０ｄ and R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 8】 and B is, 【Chemistry 9】 and m is 1, 2 or 3; n is 0, 1, 2 or 3; The compound according to claim 4, its isomer, or its deuterated derivative.

6. X １ is selected from NH; X ２ is selected from O, R １ａ , R １ｂ are each independently H, D or C １－３ alkyl groups, R ２ａ , R ２ｂ are each independently H, D or C １－３ alkyl groups, R ３ is H, D or CF ３ is selected from R ４ , R ５ are each independently selected from H or D; R ６ , R ７ are each independently selected from H or D; R ８ , R ９ are each independently selected from H or D; R １０ is CF ３ and A is, 【Chemistry 10】 and B is, 【Chemistry 11】 and m is 1, 2 or 3; n is 0, 1 or 2; The compound according to claim 5, its isomer, or its deuterated derivative.

7. The compound has the structure represented by formula (I-3): 【Chemistry 12】 (In the formula, X １ is NH or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is C １－６ Alkyl group, C １－６ Alkoxy group, cyano group or SR １０ｄ and said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 13】 and B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, having the formula:

8. X １ is NH or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－３ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－３ is an alkyl group, R ４ , R ５ are each independently H, D or C １－３ is an alkyl group, R ６ , R ７ are each independently H, D or C １－３ is an alkyl group, R ８ , R ９ are each independently H, D or C １－３ is an alkyl group, R １０ is C １－６ Alkyl group, cyano group or SR １０ｄ and said C １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R １０ｄ is H, D or C １－６ is an alkyl group, A is, 【Chemistry 14】 and B is, 【Chemistry 15】 and m is 1, 2 or 3; n is 0, 1 or 2; 8. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

9. X １ is NH, X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－３ is an alkyl group, R ２ａ , R ２ｂ are each independently H or D; R ４ , R ５ are each independently H or D; R ６ , R ７ are each independently H or D; R ８ , R ９ are each independently H or D; R １０ is CF ３ and A is, 【Chemistry 16】 and B is, 【Chemistry 17】 and m is 1, 2 or 3; n is 0, 1 or 2; 9. The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

10. A compound of formula (I') or a stereoisomer thereof. 【Chemistry 18】 (In the formula, X １ is NH or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, X ３ , X ４ is C or N, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H or C １－６ is an alkyl group, R ６ , R ７ are each independently H or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ each independently represents a C substituted with halogen; １－６ alkyl group, halogen-substituted C １－６ Alkoxy group, cyano group, S(O) ２ R １０ｃ or SR10d, R １０ｃ , R １０ｄ are each independently H, D or C １－６ is an alkyl group, A is, 【Chemistry 19】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

11. The compound has the structure represented by formula (I-1′): 【Chemistry 20】 (In the formula, X １ is NH or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H or C １－６ is an alkyl group, R ６ , R ７ are each independently H or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is a halogen-substituted C １－６ an alkyl group or a cyano group, R １０ａ , R １０ｂ are each independently H, D or C １－６ is an alkyl group, A is, 【Chemical Formula 21】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

11. The compound of claim 10, or a stereoisomer thereof, having the formula:

12. A compound of formula (I-2') or a stereoisomer thereof: 【Chemical 22】 (In the formula, X １ is NH, X ２ is O, X ３ , X ４ is C or N, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ is H, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H or C １－６ is an alkyl group, R ６ , R ７ are each independently H or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ is CF ３ or a cyano group, A is, 【Chemical 23】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; B is a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

13. The compound has the structure represented by formula (I-3'): 【Chemistry 24】 (In the formula, X １ is NH, X ２ is O, R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ is H or C １－６ is an alkyl group, R ４ , R ５ are each independently H or C １－６ is an alkyl group, R ６ , R ７ are each independently H or C １－６ is an alkyl group, R ８ , R ９ are each independently H or C １－６ is an alkyl group, R １０ is CF3, A is, 【Chemistry 25】 and B is, 【Chemical Formula 26】 and m is 1, 2 or 3; n is 0, 1, 2 or 3.

11. The compound of claim 10, or a stereoisomer thereof, having the formula:

14. X １ is NH, X ２ is O, R １ａ , R １ｂ are each independently H or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H or C １－６ is an alkyl group, R ３ is H or C １－６ is an alkyl group, R ４ , R ５ are each independently H or C １－６ is an alkyl group, R ６ , R ７ are each independently H or C １－６ is an alkyl group, R ８ , R ９ are each independently H or C １－６ is an alkyl group, R １０ is CF3, A is, [Chemical 27] and B is, 【Chemical 28】 and m is 1 or 2; n is 0 or 1; 13. The compound of claim 12, or a stereoisomer thereof.

15. 2. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. 【Chemical Formula 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】

16. (1) The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof; (2) optionally one or more other active ingredients; and (3) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or excipient.

17. 10. Use of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, in the manufacture of an antitumor drug.

18. An intermediate for producing a compound according to formula (I) of claim 1, formula (I-1) of claim 2, formula (I-2) of claim 3, formula (I-3) of claim 7, formula (I') of claim 10, formula (I-1') of claim 11, formula (I-2') of claim 12, or formula (I-3') of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein the intermediate, or the pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof has a structure represented by formula (I-4). 【Chemical 34】 (In the formula, Y １ is -NH ２ , -OH, -NHP １ or a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N and O; P １ is -Boc, P ０ is H or -PMB, X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

19. 20. The intermediate of claim 18, wherein the intermediate has the structure: 【Chemical 35】

20. An intermediate for producing a compound according to formula (I) of claim 1, formula (I-1) of claim 2, formula (I-2) of claim 3, formula (I-3) of claim 7, formula (I') of claim 10, formula (I-1') of claim 11, formula (I-2') of claim 12, or formula (I-3') of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein the intermediate, or the pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof has a structure represented by formula (I-5). 【Chemical 36】 (In the formula, X １ is NH, O, or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; P ０ is H or -PMB, X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, G is, 【Chemical 37】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; P ２ is H or an amino protecting group, and the amino protecting group is preferably -SEM or -PMB; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

21. 21. The intermediate of claim 20, wherein the intermediate has the structure: or a pharmaceutically acceptable salt, stereoisomer, or deuterated salt thereof: 【Chemical 38】

22. An intermediate for producing a compound according to formula (I) of claim 1, formula (I-1) of claim 2, formula (I-2) of claim 3, formula (I-3) of claim 7, formula (I') of claim 10, formula (I-1') of claim 11, formula (I-2') of claim 12, or formula (I-3') of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, said intermediate having a structure represented by formula (I-6). 【Chemical Formula 39】 (In the formula, Y ２ is NHR Ｙ , OH, or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; R Ｙ is H or -Boc, X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ are each independently C １－６ Alkyl group, C １－６ Alkoxy group, halogen, cyano group, S(O) ２ R １０ｃ or SR10d, wherein said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｃ , R １０ｄ are each independently H, D or C １－６ is an alkyl group, B is a 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

23. 23. The intermediate of claim 22, wherein the intermediate has the structure: or a pharmaceutically acceptable salt, stereoisomer, or deuterated salt thereof: 【Chemistry 40】

24. An intermediate for producing a compound according to formula (I) of claim 1, formula (I-1) of claim 2, formula (I-2) of claim 3, formula (I-3) of claim 7, formula (I') of claim 10, formula (I-1') of claim 11, formula (I-2') of claim 12, or formula (I-3') of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, said intermediate having a structure represented by formula (I-7). 【Chemistry 41】 (In the formula, X １ is NH, O, or a 4- to 6-membered heterocycloalkyl group, said 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N and O; X ２ is O, X ３ , X ４ are each independently C or N; R １ａ , R １ｂ are each independently H, D or C １－６ is an alkyl group, R ２ａ , R ２ｂ are each independently H, D or C １－６ is an alkyl group, R ３ H, D, C １－６ is an alkyl group, a halogen atom, or a cyano group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; R ４ , R ５ are each independently H, D or C １－６ is an alkyl group, R ６ , R ７ are each independently H, D or C １－６ is an alkyl group, R ８ , R ９ are each independently H, D or C １－６ is an alkyl group, R １０ are each independently C １－６ Alkyl group, C １－６ Alkoxy group, halogen, cyano group, S(O) ２ R １０ｃ or SR10d, wherein said C １－６ Alkyl group, C １－６ The alkoxy group may be optionally substituted with 1 to 3 halogens; R １０ｃ , R １０ｄ are each independently H, D or C １－６ is an alkyl group, G is, 【Chemistry 42】 and R ａ is C １－６ is an alkyl group, １－６ the alkyl group may be optionally substituted with 1 to 3 halogens; P ２ is an amino protecting group, preferably -SEM or -PMB, B is a 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from N and S; C is a 5-membered heteroaryl ring containing 2-3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

25. 25. The intermediate of claim 24, wherein the intermediate has the structure: or a pharmaceutically acceptable salt, stereoisomer, or deuterated salt thereof: 【Chemistry 43】 【Chemical Formula 44】 【Chemistry 45】

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