Imine compounds, their production methods and applications

Abstract

The present invention relates to imine compounds and their preparation methods and applications, and in particular to compounds of formula I, which can be used to treat diseases such as premature birth. [Formula 1] TIFF2026506654000387.tif53170

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field, and specifically relates to imine compounds and their preparation methods and applications. [Background technology]

[0002] Oxytocin is a cyclic nonapeptide that exerts its physiological effects by binding to specific receptors (oxytocin receptors, OTR). Oxytocin's physiological effects are known to be diverse, including social contact, sexual reproduction, and childbirth. Oxytocin receptors are structurally very similar to vasopressin receptors (including V1a, V1b, and V2 receptors). V1a and V2 receptors are primarily expressed in the periphery and regulate blood pressure and the kidney, respectively. V1b receptors are primarily expressed in the brain and pituitary gland and can regulate the release of adrenocorticotropic hormone and β-endorphin.

[0003] Research has shown that oxytocin plays an important role in mammalian, especially human, childbirth. During the birth process, oxytocin can bind to its receptor and induce strong uterine contractions, which are beneficial for the delivery of the fetus. However, untimely uterine contractions can lead to miscarriage and premature birth. Downregulation of oxytocin or blocking the binding of oxytocin to its receptor can block the uterine contractile action of oxytocin, which is an important approach to preventing premature birth.

[0004] Atosiban is a peptide oxytocin receptor antagonist approved for the treatment of preterm labor, and other oxytocin receptor antagonists, including nolasiban, cligosiban, and retosiban, are under clinical investigation.

[0005] [ka]

[0006] Patent applications WO 2001072705A1, WO 2002074741A1, WO 2002102799A2, WO 2004005249A1, WO 2004076407A2, WO 2015036160A1 disclose a series of compounds that can function as oxytocin receptor antagonists, which can be used to treat sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, dyspareunia disorder, premature ejaculation, preterm birth, obstetric complications, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive and behavioral disorders, neuropsychiatric disorders, and the like. Summary of the Invention

[0007] The object of the present disclosure is to provide a compound of formula I that can function as an oxytocin receptor antagonist. The compound of formula I according to the present invention has improved OTR antagonistic activity. The compound of formula I according to the present invention also has lower V1aR antagonistic activity and improved OTR / V1a target selectivity.

[0008] The present disclosure provides compounds of formula I:

[0009] [ka]

[0010] or an isotopic derivative thereof, or a pharmaceutically acceptable salt of either of the foregoing, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 3-8 Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a , -S(O)2N(R 5a )(R 5b ), -Si(R 5a )3, -Si(R 5a )2(OR 5b ), -OSi(R 5a )3, -Si(R 5a )(OR 5b )2, -OP(O)(OR 5a )(OR 5b ), -P(O)(OR 5a )(OR 5b ), -OP(O)(OR 5a )(R 5b ), -P(O)(OR 5a )(R 5b ), -OP(O)(R 5a )(R 5b ) or -P(O)(R 5a )(R 5b ) and

[0011] R 3a is hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6Haloalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 3-8 a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, or -L 1 -R 3c and R 3b is hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, -L 1 -R 3c , -C(O)OR 3d , -C(O)N(R 3d )(R 3e ), -S(O)R 3d , -S(O)2N(R 3d )(R 3e ), -P(O)(OR 3d )(OR 3e ), -P(O)(OR 3d )(R 3e ), -P(O)(R 3d )(R 3e ), C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group or the 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8a condensed ring is formed with a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups;

[0012] Or R 3a and R 3b C, along with the carbon atoms attached to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, and 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group and the 3- to 8-membered heterocycloalkenyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups;

[0013] Each L 1are independently -[C(R a )(R b )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 Form a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C 1-6 Alkyl group, C 3-8 The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups;

[0014] Each R 3c are independently -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a , -S(O)2N(R7a )(R 7b ), -Si(R 7a )3, -Si(R 7a )2(OR 7b ), -OSi(R 7a )3, -Si(R 7a )(OR 7b )2, -OP(O)(OR 7a )(OR 7b ), -P(O)(OR 7a )(OR 7b ), -OP(O)(OR 7a )(R 7b ), -P(O)(OR 7a )(R 7b ), -OP(O)(R 7a )(R 7b ) or -P(O)(R 7a )(R 7b ) and L 2 is -[C(R 10a )(R 10b )] t -, where one C(R 10a )(R 10b ) moiety is optionally -O- or -N(R 10a )-, s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2,

[0015] R 9a and R 9b are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group or halo C 2-6 an alkynyl group, or R 9a and R 9b C, along with the atoms bonded to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, or R 9a and R 3a are bonded to each other to form -CH2- or -CH2CH2-, R 10a and R 10b are each independently hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group or halo C 2-6 an alkynyl group, or R 10a and R 10b C, along with the carbon atoms attached to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, or R 10a and R 3a C, along with the atoms bonded to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 forming a cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group, Ring A is

[0016] [ka]

[0017] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each ---- bond is independently a single bond or a double bond; Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a ) and Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ) and A 3 are CH, C(O), N, N(R 4c ) or C(R 4c ) and Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ) and A 5 is CH, N, O, S, NH, C(R 4d ) or N(R 4d ) and Each A 6 are independently C or N, Each A 7 are independently C or N,

[0018] Each R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 3-8 Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R8c )S(O)2R 8a , -S(O)2N(R 8a )(R 8b ), -Si(R 8a )3, -Si(R 8a )2(OR 8b ), -OSi(R 8a )3, -Si(R 8a )(OR 8b )2, -OP(O)(OR 8a )(OR 8b ), -P(O)(OR 8a )(OR 8b ), -OP(O)(OR 8a )(R 8b ), -P(O)(OR 8a )(R 8b ), -OP(O)(R 8a )(R 8b ) or -P(O)(R 8a )(R 8b ) and

[0019] Or R 4a and R 4b C, along with the atoms bonded to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups; In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and

[0020] Each R 2a , R 2b and R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 3-8 Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a , -S(O)2N(R 6a )(R 6b ), -Si(R 6a )3, -Si(R 6a )2(OR 6b ), -OSi(R 6a )3, -Si(R 6a )(OR 6b )2, -OP(O)(OR 6a )(OR 6b ), -P(O)(OR 6a)(OR 6b ), -OP(O)(OR 6a )(R 6b ), -P(O)(OR 6a )(R 6b ), -OP(O)(R 6a )(R 6b ) or -P(O)(R 6a )(R 6b ) and

[0021] Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups; Or R 2a and R 4b are bonded together to form -(CH2) p -, where p is 2, 3, or 4, and one or two CH2 moieties are optionally replaced with -O- or -NH-;

[0022] Each R 3d , R 3e , R 5a , R 5b , R 6a, R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group or the 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 a condensed ring is formed with a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 3-8 substituted by one or more substituents independently selected from a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, and a 5- or 6-membered heteroaryl group;

[0023] Each R 5c , R 6c , R 7cand R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group or halo C 2-6 is an alkynyl group, the number of heteroatoms in the heterocycloalkyl group, heterocycloalkenyl group, and heteroaryl group is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, S, Si, P, or Se;

[0024] As a prerequisite, at least one of the following conditions (a), (b), (c), (d), and (e) must be met: Condition (a): R 2a and R 2b are not hydrogen and R 2a C 1-6 is an alkyl group, and R 3a is hydrogen and R 3b Ga-L 1 -R 3c When R is a group other than 2b is C 1-6 Not an alkyl group, Condition (b): R 3a is C 1-6 Alkyl group or -L 1 -R 3c , R 3b -L 1 -R 3c or R 3a and R 3b C, along with the carbon atoms attached to them 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, and 3-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups, C 3-8 The cycloalkenyl group and the 3- to 8-membered heterocycloalkenyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl and Halo C 2-6 substituted with one or more substituents independently selected from alkynyl groups; Condition (c): R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and ring A is

[0025] [ka]

[0026] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and R 2a is not hydrogen, where each A 1 are independently CH, N, or C(R 4a ) and each A 2 are independently CH, N, or C(R 4b ) and each A 3 are independently CH, N, or C(R 4c ) and each A 4 are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and Condition (d): R 3b is -CH(C 1-6 alkyl group)-OH,

[0027] [ka]

[0028] -CHNHC(O)CHOH or -CHOCHCHOH, Condition (e): R 9a and R 3a are bonded to each other to form -CH2- or -CH2CH2-.

[0029] In some embodiments, in the structure of Formula I

[0030] [ka]

[0031] is.

[0032] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0033] [ka]

[0034] where s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2; X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and

[0035] R 3b -L 1 -R 3c , -C(O)OR 3d , -C(O)N(R 3d )(R 3e ), -S(O)R 3d , -S(O)2N(R 3d )(R 3e ), C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6substituted with one or more substituents independently selected from alkoxy groups; Each L 1 are independently -[C(R a )(R b )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 Form a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C 1-6 Alkyl group, C 3-8 The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0036] Each R 3c are independently -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R7b ) and Ring A is

[0037] [ka]

[0038] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each ---- bond is independently a single bond or a double bond; Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a ) and Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ) and A 3 are CH, C(O), N, N(R 4c ) or C(R 4c ) and Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ) and A 5 is CH, N, O, S, NH, C(R 4d ) or N(R 4d ) and Each A 6 are independently C or N, Each A 7 are independently C or N,

[0039] Each R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R 4b C, along with the atoms bonded to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0040] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2c are independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and Each R 2a and R 2b are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b) and

[0041] Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Or R 2a and R 4b are bonded together to form -(CH2) p -, where p is 2, 3, or 4, and one or two CH2 moieties are optionally replaced with -O- or -NH-; As a condition, R 2a C 1-6 is an alkyl group, and R 3a is hydrogen and R 3b Ga-L 1 -R 3c When R is a group other than 2b is C 1-6 Not an alkyl group,

[0042] Each R 3d , R 3e , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-8 substituted with one or more substituents independently selected from a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group;

[0043] Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0044] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0045] [ka]

[0046] where s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2; X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and

[0047] Each L 1 are independently -[C(R a )(R b )]n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 Form a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C 1-6 Alkyl group, C 3-8 The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 3c are independently -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0048] [ka]

[0049] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each ---- bond is independently a single bond or a double bond; Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a ) and Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ) and A 3 are CH, C(O), N, N(R 4c ) or C(R 4c ) and Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ) and A 5 is CH, N, O, S, NH, C(R 4d ) or N(R 4d ) and Each A 6 are independently C or N, Each A 7 are independently C or N,

[0050] Each R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a, -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R 4b C, along with the atoms bonded to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0051] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2c are independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and Each R 2a and R 2b are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and

[0052] Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Or R 2a and R 4b are bonded together to form -(CH2) p -, where p is 2, 3, or 4, and one or two CH2 moieties are optionally replaced with -O- or -NH-;

[0053] Each R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 3-8 substituted with one or more substituents independently selected from a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group; Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0054] In some embodiments, in the definition of formula I, I-1, s is 1 and t is 1.

[0055] In some embodiments, s is 2 and t is 1 in the definition of formula I, I-1.

[0056] In some embodiments, s is 1 and t is 2 in the definition of formula I, I-1.

[0057] In some embodiments, in the definition of formula I, I-1, ring A is

[0058] [ka]

[0059] wherein each ---- bond is independently a single bond or a double bond, forming an aromatic ring, and each A 1 are independently CH, N, NH, O, S, N(R 4a ) or C(R 4a ) and each A 2 are independently CH, N, NH, O, S, N(R 4b) or C(R 4b ) and A 3 is CH, N, N(R 4c ) or C(R 4c ) and each A 4 are independently CH, N, N(R 4d ) or C(R 4d ) and A 5 is CH, N, O, S, NH, C(R 4d ) or N(R 4d ) and each A 6 are independently C or N, and each A 7 are independently C or N, and R 4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0060] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0061] [ka]

[0062] where s is 1, t is 1, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and

[0063] Each L 1 are independently -[C(R a )(R b )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen or C 1-6 is an alkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, Each R 3c are independently -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0064] [ka]

[0065] wherein the * end is bonded to the carbonyl group in formula I and the # end is bonded to ring B in formula I; Each A 1 are independently CH, N, or C(R 4a ) and Each A 2 are independently CH, N, or C(R 4b ) and A 3 is CH, N or C(R 4c ) and Each A 4 are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and

[0066] Or R 4a and R 4b C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2a , R 2b and R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a)(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and

[0067] Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0068] Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, the number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; As a prerequisite, at least one of the following conditions (a), (b), (c), and (d) must be met: Condition (a): R 2a and R 2b are not hydrogen, Condition (b): R 3a is not hydrogen, Condition (c): Ring A is

[0069] [ka]

[0070] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and R 2a is not hydrogen, Condition (d): R 3b is -CH(C 1-6 alkyl group)-OH.

[0071] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0072] [ka]

[0073] where s is 1, t is 1, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c)S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and L 1 is -[C(R a )(R b )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen or C 1-6 is an alkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, R 3c -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0074] [ka]

[0075] wherein the * end is bonded to the carbonyl group in formula I and the # end is bonded to ring B in formula I; Each A 1 are independently CH, N, or C(R 4a ) and Each A 2 are independently CH, N, or C(R 4b ) and A 3 is CH, N or C(R 4c ) and Each A 4 are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R4b C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0076] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and R 2a and R 2b are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and

[0077] Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5a , R5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0078] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0079] [ka]

[0080] where s is 1, t is 1, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and

[0081] Each L 1 are independently -[C(R a )(Rb )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen or C 1-6 is an alkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, Each R 3c are independently -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0082] [ka]

[0083] wherein the * end is bonded to the carbonyl group in formula I and the # end is bonded to ring B in formula I; Each A 1 are independently CH, N, or C(R 4a ) and Each A 2 are independently CH, N, or C(R 4b ) and A 3 is CH, N or C(R 4c ) and Each A 4 are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R 4b C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0084] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2a , R 2b and R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0085] Each R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0086] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0087] [ka]

[0088] where s is 1, t is 1, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b -L 1 -R 3c and L 1 is -[C(R a )(R b )] n where n is 1, 2, or 3, and each R a and R b are each independently hydrogen or C 1-6 is an alkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, R 3c -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0089] [ka]

[0090] wherein the * end is bonded to the carbonyl group in formula I and the # end is bonded to ring B in formula I; Each A 1 are independently CH, N, or C(R 4a ) and Each A 2 are independently CH, N, or C(R 4b ) and Each A 3 are independently CH, N, or C(R 4c ) and Each A 4 are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R 4bC, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0091] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and R 2a is a halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b )

[0092] Each R 2b and R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0093] Each R 5a , R5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0094] In some embodiments, the Formula I compound has the structure shown in Formula I-1:

[0095] [ka]

[0096] where s is 1, t is 1, X is N-OR 1 and R 1 is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be one or more R 1a is replaced by Each R 1a are independently a halogen, a cyano group, a nitro group, an oxo group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 5a , -SR 5a , -N(R 5a )(R 5b ), -C(O)R 5a , -OC(O)R 5a , -C(O)OR 5a , -C(O)N(R 5a )(R 5b ), -N(R 5c )C(O)R 5a , -N(R 5c )C(O)N(R 5a )(R 5b ), -S(O)R 5a , -N(R 5c )S(O)2R 5a or -S(O)N(R 5a )(R 5b ) and R 3a is hydrogen, C 1-6 Alkyl group or -L 1 -R 3c and R 3b is -CH(C 1-6 alkyl group)-OH, L 1 is -[C(R a )(R b )] nwhere n is 1, 2, or 3, and each R a and R b are each independently hydrogen or C 1-6 is an alkyl group, or R a and R b C, along with the carbon atoms attached to them 3-8 forming a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, R 3c -OR 7a , -SR 7a , -N(R 7a )(R 7b ), -C(O)R 7a , -OC(O)R 7a , -C(O)OR 7a , -C(O)N(R 7a )(R 7b ), -N(R 7c )C(O)R 7a , -N(R 7c )C(O)N(R 7a )(R 7b ), -S(O)R 7a , -N(R 7c )S(O)2R 7a or -S(O)N(R 7a )(R 7b ) and Ring A is

[0097] [ka]

[0098] wherein the * end is bonded to the carbonyl group in formula I and the # end is bonded to ring B in formula I; Each A 1 are independently CH, N, or C(R 4a ) and Each A 2 are independently CH, N, or C(R 4b ) and A 3 is CH, N or C(R 4c ) and Each A 4are independently CH, N, or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and R 4a , R 4b , R 4c and R 4d are each independently a halogen, a cyano group, a nitro group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -OC(O)R 8a , -C(O)OR 8a , -C(O)N(R 8a )(R 8b ), -N(R 8c )C(O)R 8a , -N(R 8c )C(O)N(R 8a )(R 8b ), -S(O)R 8a , -N(R 8c )S(O)2R 8a or -S(O)N(R 8a )(R 8b ) and Or R 4a and R 4b C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0099] In ring B, G 1 , G 2 and G 3 are each independently N or C(R 2c ) and Each R 2a , R 2b and R 2c are each independently hydrogen, halogen, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, phenyl groups, 5- to 6-membered heteroaryl groups, -OR 6a , -SR 6a , -N(R 6a )(R 6b ), -C(O)R 6a , -OC(O)R 6a , -C(O)OR 6a , -C(O)N(R 6a )(R 6b ), -N(R 6c )C(O)R 6a , -N(R 6c )C(O)N(R 6a )(R 6b ), -S(O)R 6a , -N(R 6c )S(O)2R 6a or -S(O)N(R 6a )(R 6b ) and Or R 2b and R 2a or R 2c C, along with the carbon atoms attached to them 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups;

[0100] Each R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, 3-8 The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C 3-8 a condensed ring is formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein 1-6 Alkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy and haloC 1-6 substituted with one or more substituents independently selected from alkoxy groups; Each R 5c , R 6c , R 7c and R 8c are each independently hydrogen, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 is a hydroxyalkyl group, The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0101] In some embodiments, in the definition of formula I, I-1, R 1 is C 1-6 It is an alkyl group.

[0102] In some embodiments, in the definition of formula I, I-1, R 1 is a methyl group.

[0103] In some embodiments, in the definition of formula I, I-1, L 1 is -[CH(R a )] n -, where n is 1, 2 or 3, and R a is hydrogen, C 1-6 Alkyl group or C 3-8 is a cycloalkyl group, 1-6 Alkyl group, C 3-8 The cycloalkyl group is optionally substituted with one or more hydroxy groups.

[0104] In some embodiments, in the definition of formula I, I-1, L 1 is -[CH(R a )] n -, where n is 1, 2 or 3, and R a is hydrogen or C 1-6 is an alkyl group, 1-6 The alkyl group is optionally substituted with one or more hydroxy groups.

[0105] In some embodiments, n is 1 in the definition of formula I, I-1.

[0106] In some embodiments, in the definition of formula I, I-1, R 3c is -OH.

[0107] In some embodiments, in the definition of formula I, I-1, R 3a is hydrogen or C 1-6 It is an alkyl group.

[0108] In some embodiments, in the definition of formula I, I-1, R 3a is hydrogen or a methyl group.

[0109] In some embodiments, in the definition of formula I, I-1, R 3a is hydrogen.

[0110] In some embodiments, in the definition of formula I, I-1, R 3a is C 1-6 An alkyl group, for example, a methyl group.

[0111] In some embodiments, in the definition of formula I, I-1, R 3b -L 1 -R 3c and L 1 and R 3c The definitions are as set forth in any one aspect of this disclosure.

[0112] In some embodiments, in the definition of formula I, I-1, R 3b is -CH2OH, -CH(CH3)OH, -C(CH3)2OH, -CH(OH)CH2OH, -CH2CH2OH or

[0113] [ka]

[0114] is.

[0115] In some embodiments, in the definition of formula I, I-1, R 3b teeth,

[0116] [ka]

[0117] -CH2NHC(O)CH3, -CH2NHC(O)OCH3, -CH2NHC(O)CH2OH or -CH2OCH2CH2OH.

[0118] In some embodiments, in the definition of formula I, I-1, R 3b is -CHOH.

[0119] In some embodiments, in the definition of formula I, I-1, R 3b is -CH(CH3)OH.

[0120] In some embodiments, in the definition of formula I, I-1, R 3b is a benzoxazolyl group (e.g.,

[0121] [ka]

[0122] -C(O)NHCH3, -C(O)OCH3 or

[0123] [ka]

[0124] is.

[0125] In some embodiments, in the definition of formula I, I-1, R 3a is hydrogen and R 3b is -CHOH.

[0126] In some embodiments, in the definition of formula I, I-1, R 3a is hydrogen and R 3b is -CH(CH3)OH.

[0127] In some embodiments, in the definition of formula I, I-1, R 3ais a methyl group, and R 3b is -CHOH.

[0128] In some embodiments, in the definition of formula I, I-1, R 3a and R 3b are combined with each other

[0129] [ka]

[0130] Form.

[0131] In some embodiments, in the definition of formula I, I-1, R 4c and R 4d are each independently a halogen, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -C(O)OR 8a or -C(O)N(R 8a )(R 8b )

[0132] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b are each independently a halogen, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -OR 8a , -SR 8a , -N(R 8a )(R 8b ), -C(O)R 8a , -C(O)OR 8a or -C(O)N(R 8a )(R 8b )

[0133] In some embodiments, in the definition of formula I, I-1, R 8a and R 8b are each independently hydrogen, C 1-6 Alkyl group, C 3-8 is a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, 1-6 The alkyl group may optionally be a hydroxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl groups and C 1-6 It is substituted with one or more substituents independently selected from alkoxy groups.

[0134] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b are each independently a halogen, a cyano group, or C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 It is an alkoxy group.

[0135] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b are each independently a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, -OCH2CH2OH, -OCH2CH2OCH3, -NHCH2CH2OCH3,

[0136] [ka]

[0137] is.

[0138] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atom to which they are attached form a 3- to 8-membered heterocycloalkyl group, which optionally contains one or more of the aforementioned substituents, such as C 1-6It is substituted with an alkyl group, a carbonyl group, etc.

[0139] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atom to which they are attached form a 5- to 6-membered heteroaryl group, which may optionally contain one or more of the aforementioned substituents, such as C 1-6 It is substituted with an alkyl group, a carbonyl group, etc.

[0140] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atoms attached to them,

[0141] [ka]

[0142] wherein the ring optionally contains one or more of the aforementioned substituents, such as C 1-6 It is substituted with an alkyl group, a carbonyl group, etc.

[0143] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atoms attached to them,

[0144] [ka]

[0145] Form.

[0146] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atoms attached to them,

[0147] [ka]

[0148] Form.

[0149] In some embodiments, in the definition of formula I, I-1, R 4a and R 4b together with the carbon atoms attached to them,

[0150] [ka]

[0151] Form.

[0152] In some embodiments, in the definition of formula I, I-1, R 4c and R 4d are each independently a halogen, a cyano group, or C 1-6 Alkyl group, C 1-6 haloalkyl group or C 1-6 It is an alkoxy group.

[0153] In some embodiments, in the definition of formula I, I-1, R 4c and R 4d are each independently fluorine, chlorine, a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a methoxy group, for example, fluorine.

[0154] In some embodiments, in the definition of formula I, I-1, ring A is

[0155] [ka]

[0156] and A 1 is CH, N or C(R 4a ) and A 2 is CH, N or C(R 4b ) and A 3 is CH, N or C(R 4c) and A 4 is CH, N or C(R 4d ) and A 5 is O, S, NH or N(R 4d ) and Ar is a 3- to 8-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, where R 4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0157] In some embodiments, in the definition of formula I, I-1, ring A is

[0158] [ka]

[0159] where A 1 is CH, N or C(R 4a ) and A 2 is CH, N or C(R 4b ) and A 3 is CH, N or C(R 4c ) and A 4 is CH, N or C(R 4d ) and R 4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0160] In some embodiments, in the definition of formula I, I-1, ring A is

[0161] [ka]

[0162] where A 1 , A 2 , A 3 and A 4 are each independently CH or N, and R4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0163] In some embodiments, in the definition of formula I, I-1, ring A is

[0164] [ka]

[0165] where A 1 is CH or C(R 4a ) and A 2 is CH or C(R 4b ) and A 3 is CH or C(R 4c ) and A 4 is CH or C(R 4d ) and R 4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0166] In some embodiments, in the definition of formula I, I-1, ring A is

[0167] [ka]

[0168] where R 4a , R 4b , R 4c and R 4d The definitions are as set forth in any one aspect of this disclosure.

[0169] In some embodiments, in the definition of formula I, I-1, ring A is

[0170] [ka]

[0171] where A 1 , A 2 , A 3 and A 4 are each independently CH or N.

[0172] In some embodiments, in the definition of formula I, I-1, ring A is

[0173] [ka]

[0174] is.

[0175] In some embodiments, in the definition of formula I, I-1, ring A is

[0176] [ka]

[0177] where R 4a is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0178] [ka]

[0179] may be.

[0180] In some embodiments, in the definition of formula I, I-1, ring A is

[0181] [ka]

[0182] where R 4bis as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0183] [ka]

[0184] may be.

[0185] In some embodiments, in the definition of formula I, I-1, ring A is

[0186] [ka]

[0187] where R 4a and R 4b is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0188] [ka]

[0189] In some embodiments, in the definition of formula I, I-1, ring A may be:

[0190] [ka]

[0191] In some embodiments, in the definition of formula I, I-1, ring A is

[0192] [ka]

[0193] is.

[0194] In some embodiments, in the definition of formula I, I-1, ring A is

[0195] [ka]

[0196] is.

[0197] In some embodiments, in the definition of formula I, I-1, ring A is

[0198] [ka]

[0199] where R 4a The definitions are as set forth in any one aspect of this disclosure.

[0200] In some embodiments, in the definition of formula I, I-1, ring A is

[0201] [ka]

[0202] where R 4b The definitions are as set forth in any one aspect of this disclosure.

[0203] In some embodiments, in the definition of formula I, I-1, ring A is

[0204] [ka]

[0205] where R 4a , R 4b , R 4c is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0206] [ka]

[0207] may be.

[0208] In some embodiments, in the definition of formula I, I-1, ring A is

[0209] [ka]

[0210] where R 4a , R 4b , R 4d is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0211] [ka]

[0212] may be.

[0213] In some embodiments, in the definition of formula I, I-1, ring A is

[0214] [ka]

[0215] where R 4a , R 4b , R 4c , R 4d is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0216] [ka]

[0217] may be.

[0218] In some embodiments, in the definition of formula I, I-1, ring A is

[0219] [ka]

[0220] where R 4a , R 4b is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0221] [ka]

[0222] may be.

[0223] In some embodiments, in the definition of formula I, I-1, ring A is

[0224] [ka]

[0225] where R 4a , R 4b is as defined in any one of the embodiments of the present disclosure, for example, ring A is

[0226] [ka]

[0227] may be.

[0228] In some embodiments, in the definition of formula I, I-1, ring A is

[0229] [ka]

[0230] [ka]

[0231] is.

[0232] In some embodiments, in the definition of formula I, I-1, R 2c is hydrogen, halogen or a cyano group.

[0233] In some embodiments, in the definition of formula I, I-1, R 2c is hydrogen, fluorine or a cyano group, for example hydrogen or fluorine.

[0234] In some embodiments, in the definition of formula I, I-1, G 1 is CH or C(F). In some embodiments, in the definition of formula I, I-1, G 1 is CH.

[0235] In some embodiments, in the definition of formula I, I-1, G 2 is CH or C(F). In some embodiments, in the definition of formula I, I-1, G 2 is CH.

[0236] In some embodiments, in the definition of formula I, I-1, G 3 is CH, C(F), C(CN) or N, for example, CH or C(F). In some embodiments, in the definition of Formula I, I-1, G 3 is CH.

[0237] In some embodiments, in the definition of formula I, I-1, R 2a is a halogen, a cyano group, C 1-6 Alkyl group or C 1-6In some embodiments, in the definition of formula I, I-1, R 2a is C 1-6 In some embodiments, R 2a Substituents, particularly halogens, methyl groups, etc., can improve OTR / V1a selectivity by maintaining or improving OTR targeting activity and reducing V1a activity.

[0238] In some embodiments, in the definition of formula I, I-1, R 2a is a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorine group, or a cyano group. 2a is a methyl group. In some embodiments, in the definition of Formula I, I-1, R 2a is a difluoromethyl group. In some embodiments, in the definition of Formula I, I-1, R 2a is a trifluoromethyl group. In some embodiments, in the definition of Formula I, I-1, R 2a is chlorine. In some embodiments, in the definition of formula I, I-1, R 2a is a cyano group.

[0239] In some embodiments, in the definition of formula I, I-1, R 2b is hydrogen.

[0240] In some embodiments, in the definition of formula I, I-1, R 2b is C 1-6 Alkyl group, cyano group, C 1-6 Haloalkyl group, C 1-6 It is an alkoxy group or a halogen.

[0241] In some embodiments, R 2bSubstituents, particularly halogens, alkyl groups, alkoxy groups, cyano groups, and the like, can improve OTR / V1a selectivity by maintaining or improving OTR targeting activity and reducing V1a activity. In some embodiments, in the definition of Formula I, I-1, R 2b is a methyl group, a cyano group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, or a chlorine group. 2b is a methyl group. In some embodiments, in the definition of Formula I, I-1, R 2b is a cyano group. In some embodiments, in the definition of Formula I, I-1, R 2b is chlorine. In some embodiments, in the definition of formula I, I-1, R 2b is a trifluoromethyl group. In some embodiments, in the definition of Formula I, I-1, R 2b is a methoxy group. In some embodiments, in the definition of Formula I, I-1, R 2b is a difluoromethyl group.

[0242] In some embodiments, in the definition of formula I, I-1, R 2b and R 2a is defined as any one of the following combinations (i) to (x): (i) R 2a is a methyl group, and R 2b is a methyl group, (ii) R 2a is a methyl group, and R 2b is chlorine, (iii) R 2a is a methyl group, and R 2b is a cyano group, (iv) R 2a is a methyl group, and R 2b is a difluoromethyl group, (v) R 2a is a methyl group, and R 2b is a trifluoromethyl group, (vi) R 2a is a methyl group, and R 2b is a methoxy group, (vii) R 2a is chlorine and R 2b is a cyano group, (viii) R 2a is a cyano group, and R 2b is a methyl group, (ix) R 2a is a difluoromethyl group, and R 2b is a cyano group, (x) R 2a is a trifluoromethyl group, and R 2b is a cyano group.

[0243] In some embodiments, in the definition of formula I, I-1, R 2b and R 2a C, along with the carbon atoms attached to them 3-8 It forms a cycloalkyl group, for example a cyclopentyl group.

[0244] In some embodiments, in the definition of Formula I, I-1,

[0245] [ka]

[0246] The structural part is

[0247] [ka]

[0248] is.

[0249] In some embodiments, in the definition of Formula I, I-1,

[0250] [ka]

[0251] In some embodiments, in the definition of formula I, I-1,

[0252] [ka]

[0253] In some embodiments, in the definition of formula I, I-1,

[0254] [ka]

[0255] In some embodiments, in the definition of formula I, I-1,

[0256] [ka]

[0257] In some embodiments, in the definition of formula I, I-1,

[0258] [ka]

[0259] In some embodiments, in the definition of formula I, I-1,

[0260] [ka]

[0261] In some embodiments, in the definition of formula I, I-1,

[0262] [ka]

[0263] is.

[0264] In some embodiments, in the definition of Formula I, I-1,

[0265] [ka]

[0266] is.

[0267] In some embodiments, a compound according to Formula I, an isotopic derivative, or a pharmaceutically acceptable salt is provided:

[0268] [ka]

[0269] X is N-OR 1 and R 1 is -CH3, R 3a is hydrogen or C 1-6 alkyl groups, R 3b -L 1 -R 3c and L 1 are independently -[C(R a )(R b )] n where n is 1 and each R a and R b are each independently hydrogen or -CH3, R 3c are independently -OR 7a and R 7a is hydrogen or C 1-6 alkyl groups, L 2 is -[C(R 10a )(R 10b )] t - and s is 1, t is 1, R9a , R 9b , R 10a and R 10b is hydrogen, Ring A is

[0270] [ka]

[0271] wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each ---- bond is independently a single bond or a double bond; A 1 is CH or C(R 4a ) and A 2 is CH or C(R 4b ) and A 3 is CH, A 4 is CH, Each A 6 are independently C or N, Each A 7 are independently C or N, R 4a and R 4b are each independently selected from H, or R 4a and R 4b together with the atoms bonded to them,

[0272] [ka]

[0273] Forming In ring B, G 1 , G 2 and G 3 is CH, R 2a is halogen or -CH3, R 2b is a cyano group.

[0274] In some embodiments, Formula I, I-1 is the following Formula Ia, its stereoisomer Formula Ib, or a mixture of Formula Ia and Formula Ib:

[0275] [ka]

[0276] where R 1 , R 2a , R 2b , R 3a , R 3b ,s,t,G 1 , G 2 , G 3 and the definition of ring A is as described in formula I, I-1.

[0277] In some embodiments, in Formula I, I-1, Ia, Ib, R 3a and R 3b may be in the R configuration, the S configuration, or a mixture of both when the carbon atom to which they are attached is a chiral carbon atom. 3a and R 3b may be in the S configuration if the carbon atom to which they are attached is a chiral carbon atom.

[0278] In some embodiments, the compound is

[0279] [ka]

[0280] [ka]

[0281] [ka]

[0282]

change

[0283]

change

[0284]

change

[0285]

change

[0286]

change

[0287]

change

[0288]

change

[0289]

change

[0290]

change

[0291]

change

[0292]

change

[0293] [ka]

[0294] or a mixture thereof (for example, a mixture of formula Ia and its stereoisomer formula Ib).

[0295] In some embodiments, Formula I or I-1 is Formula Ia or its stereoisomer Formula Ib, whichever has a higher oxytocin receptor antagonist activity, or a mixture of the one with the higher oxytocin receptor antagonist activity and the other, wherein the content of the one with the higher oxytocin receptor antagonist activity in the mixture is equal to or greater than the content of the other. Methods for measuring oxytocin receptor antagonist activity are well known in the art, for example, the method disclosed in Biological Test 1 of the present specification.

[0296] In some embodiments, Formula I or I-1 is a mixture of the more polar of Formula Ia and its stereoisomer Formula Ib, or a mixture of the more polar and less polar of Formula Ia and its stereoisomer Formula Ib, wherein the content of the more polar of Formula Ia and its stereoisomer Formula Ib is equal to or greater than the content of the less polar of Formula Ib. In some embodiments, Formula I or I-1 is a mixture of the less polar of Formula Ia and its stereoisomer Formula Ib, or a mixture of the less polar and more polar of Formula Ib, wherein the content of the less polar of Formula Ib is equal to or greater than the content of the more polar of Formula Ib. The relative polarity of two molecules can be determined by experimental methods well known in the art, exemplary methods include silica gel thin layer chromatography, reverse phase HPLC, etc.

[0297] In some embodiments, the isotopic derivative is

[0298] [ka]

[0299] The structure has one of the following structures:

[0300] The present disclosure further provides pharmaceutical compositions, which comprise the aforementioned compounds, isotopic derivatives or pharmaceutically acceptable salts, and a pharmaceutical excipient.

[0301] The present disclosure further provides the application of the aforementioned compounds, isotopic derivatives or pharmaceutically acceptable salts as drugs.

[0302] The present disclosure further provides the application of the aforementioned compounds, isotope derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing same, in the manufacture of oxytocin receptor antagonists.

[0303] The present disclosure further provides the application of the aforementioned compounds, isotopic derivatives or pharmaceutically acceptable salts in the manufacture of a medicament for preventing and / or treating a disease or condition in which inhibition of oxytocin is known or may exhibit beneficial effects.

[0304] The present disclosure further provides a method for preventing and / or treating a disease or condition for which inhibition of oxytocin is known or may exhibit beneficial effects, said method comprising administering to a subject an effective amount of a compound, isotopic derivative or pharmaceutically acceptable salt.

[0305] In some embodiments, the disease or condition is sexual dysfunction, decreased sexual desire disorder, sexual arousal disorder, orgasmic disorder, dyspareunia disorder, premature ejaculation, preterm birth, obstetric complications, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder, and behavioral or neuropsychiatric disorders.

[0306] In some embodiments, the disease or condition is preterm birth.

[0307] Each preferred example of the present disclosure can be obtained by arbitrarily combining the above-described embodiments or preferred conditions without going against common knowledge in the art.

[0308] The compounds of formula I of the present disclosure can be prepared by reference to the methods in the Examples and methods disclosed in the art. Exemplary methods are as follows:

[0309] [ka]

[0310] In Formula II, Y is CH(OH) or C(=N-OR 1 ) and when Y is CH(OH), NH2-OR 1 reacts with C(=N-OR 1 ) can be formed, where s, L 2 , R 9a , R 9b , R 1 is defined as described in Formula I, In formula II, R g teeth,

[0311] [ka]

[0312] hydrogen or an amino group protecting group, R g is an amino protecting group, the amino protecting group can be removed to form a hydrogen, and R g If is hydrogen,

[0313] [ka]

[0314] and acylation reaction,

[0315] [ka]

[0316] can be formed, R g but

[0317] [ka]

[0318] where R f may be bromine or iodine, LG may be a leaving group such as chlorine, and rings A, R 2a , R 2b , G 1 , G 2 , G 3 is defined as described in Formula I, In Formula II, R 3a’’ is R 3a or by reactions known in the art 3a can be converted into precursor groups, e.g., R 3a’’ is hydrogen, the compound of formula II can be treated with iodide C 1-6 Alkyl or IL 1 -R 3c C 1-6 Alkyl group or -L 1 -R 3c where R 3a , L 1 and R 3c is defined as described in Formula I, In Formula II, R 3b’’ is R 3b or by reactions known in the art 3b For example, in some embodiments, R 3b’’ may be -COOMe, which may be reduced to -CHOH, which may be further converted to various groups. DETAILED DESCRIPTION OF THE INVENTION

[0319] Definitions and Explanations Unless otherwise indicated, the following terms and phrases used herein have the following meanings: A particular term or phrase should not be considered indefinite or uncertain unless specifically defined, but should be interpreted according to its ordinary meaning.

[0320] If any variable (e.g., R) appears more than once in the structure of a compound, that variable is independent of each other in each occurrence. For example, if a group is substituted with 0 to 2 R, that group may optionally be substituted with at most 2 R, and in each occurrence R has independent options.

[0321] The term "substituted" or "substituent" refers to the replacement of a hydrogen atom in a group with a specified group. If the substitution position is not specified, the substitution may occur at any position, provided that a stable or chemically feasible chemical entity is formed.

[0322] [ka]

[0323] For example, the structure is R a and the hydrogen atoms on the pyridine ring are substituted with q R b Each R represents a substitution a , R b When a group is described as being substituted with "one or more" listed substituents, the number of substituents may be any number provided that it is chemically feasible, for example, the number of substituents may be 1, 2, 3, or 4.

[0324] The term "optionally" or "optionally" means that the subsequently described event or circumstance is possible, but not necessarily, to occur, and the description includes both the occurrence of the event or circumstance and the absence of the event or circumstance. Thus, the term "optionally substituted" refers to either substitution or non-substitution.

[0325] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0326] The term "oxo" refers to =O.

[0327] The term "amino group" refers to -NH2.

[0328] The term "hydroxy group" refers to -OH.

[0329] The term "nitro group" refers to -NO2.

[0330] The term "cyano" refers to -CN.

[0331] The term "alkyl group" refers to a monovalent linear or branched chain hydrocarbon group. 1-6 The alkyl group may be a C1, C2, C3, C4, C5 or C6 alkyl group, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0332] The term "alkenyl group" refers to a monovalent straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond. An alkenyl group can be attached to other structures through any carbon atom (e.g., saturated carbon atom, double-bonded carbon atom) contained therein, provided that a stable or chemically feasible chemical entity is formed. 2-6 The alkenyl group may be a C2, C3, C4, C5 or C6 alkenyl group, examples of which include, but are not limited to, vinyl, 1-propenyl, and 2-propenyl groups.

[0333] The term "alkynyl group" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond. An alkynyl group can be attached to other structures through any of its carbon atoms (e.g., saturated carbon atoms, triple-bonded carbon atoms) as long as a stable or chemically feasible chemical entity is formed. 2-6The alkynyl group may be a C2, C3, C4, C5 or C6 alkynyl group, examples of which include, but are not limited to, an ethynyl group.

[0334] The term "alkoxy group" refers to an -O-alkyl group, where the definition of alkyl group is as set forth above. 1-6 The alkoxy group may be a C1, C2, C3, C4, C5 or C6 alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.

[0335] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where the definitions of alkyl group and halogen are both as defined above. 1-6 The haloalkyl group may be a haloC1, C2, C3, C4, C5, or C6 alkyl group, examples of which include, but are not limited to, a fluoromethyl group (e.g., a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group), a fluoroethyl group (e.g., a 1-fluoroethyl group, a 1,1-difluoroethyl group, a 2,2,2-trifluoroethyl group, or a pentafluoroethyl group), a 1-fluoro-2-chloroethyl group. 1-6 A haloalkyl group is a C1, C2, C3, C4, C5 or C6 fluoroalkyl group.

[0336] The term "haloalkenyl group" refers to an alkenyl group substituted with one or more halogens, where the definitions of alkenyl group and halogen are as defined above. 2-6 The alkenyl group may be a halo C2, C3, C4, C5 or C6 alkenyl group, examples of which include, but are not limited to, 1-fluorovinyl, 2-fluorovinyl, and 1-fluoro-2-chlorovinyl groups. 2-6The alkenyl group is a fluoro C2, C3, C4, C5 or C6 alkenyl group.

[0337] The term "haloalkynyl group" refers to an alkynyl group substituted with one or more halogens, where the definitions of alkynyl group and halogen are as defined above. 2-6 The alkynyl group may be a halo C, C, C, C, or C alkynyl group. 2-6 The alkynyl group is a fluoro C2, C3, C4, C5 or C6 alkynyl group.

[0338] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where all alkyl groups are as defined above. 1-6 A hydroxyalkyl group may be a C1, C2, C3, C4, C5 or C6 alkyl group substituted with one or more hydroxy groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl.

[0339] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the definitions of alkoxy group and halogen are as defined above. 1-6 The alkoxy may be a halo C, C, C, C, C, C, or C alkoxy group, examples of which include, but are not limited to, a trifluoromethoxy group. 1-6 The alkoxy group is a fluoro C1, C2, C3, C4, C5 or C6 alkoxy group.

[0340] The term "cycloalkyl group" refers to a monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) saturated cyclic hydrocarbon group. 3-8The cycloalkyl group may be a C3, C4, C5, C6, C7 or C8 cycloalkyl group, for example, a C3 monocyclic cycloalkyl group, a C4 monocyclic cycloalkyl group, a C5 monocyclic or polycyclic cycloalkyl group, a C6 monocyclic or polycyclic cycloalkyl group, a C7 monocyclic or polycyclic cycloalkyl group or a C8 monocyclic or polycyclic cycloalkyl group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups.

[0341] The term "cycloalkenyl group" refers to a non-aromatic monocyclic or polycyclic (e.g., fused, spiro, or bridged) cyclic hydrocarbon group containing at least one carbon-carbon double bond. A cycloalkenyl group can be attached to other structures through any atom in the ring (e.g., saturated carbon atom, doubly bonded carbon atom) provided that a stable or chemically feasible chemical entity is formed. As used herein, C 3-8 The cycloalkenyl group may be a C3, C4, C5, C6, C7 or C8 cycloalkenyl group, for example, a C3 monocyclic cycloalkenyl group, a C4 monocyclic cycloalkenyl group, a C5 monocyclic or polycyclic cycloalkenyl group, a C6 monocyclic or polycyclic cycloalkenyl group, a C7 monocyclic or polycyclic cycloalkenyl group, or a C8 monocyclic or polycyclic cycloalkenyl group, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl groups.

[0342] The term "heterocycloalkyl group" refers to a monocyclic or polycyclic (e.g., fused, spiro, or bridged) saturated cyclic group consisting of carbon atoms and at least one heteroatom. In some embodiments, the heteroatoms in the heterocycloalkyl group are independently selected from N, O, and S. A heterocycloalkyl group can be attached to other structures through any atom (e.g., carbon atom, heteroatom) in the ring, provided that a stable or chemically feasible chemical entity is formed. The 3- to 8-membered heterocycloalkyl group in this specification may be a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl group, for example, a 3-membered monocyclic heterocycloalkyl group, a 4-membered monocyclic heterocycloalkyl group, a 5-membered monocyclic or polycyclic heterocycloalkyl group, a 6-membered monocyclic or polycyclic heterocycloalkyl group, a 7-membered monocyclic or polycyclic heterocycloalkyl group, or an 8-membered monocyclic or polycyclic heterocycloalkyl group, examples of which include, but are not limited to, an oxetanyl group, an azetidinyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, a tetrahydropyrrolyl group, a piperidinyl group, a piperazinyl group, and a morpholinyl group.

[0343] The term "heterocycloalkenyl group" refers to a non-aromatic monocyclic or polycyclic (e.g., fused, spiro, or bridged) ring group containing at least one double bond, which consists of carbon atoms and at least one heteroatom, and the atoms attached to both ends of the double bond can be carbon atoms or heteroatoms. In some embodiments, the heteroatoms in the heterocycloalkenyl group are independently selected from N, O, and S. A heterocycloalkenyl group can be attached to other structures through any atom in the ring (e.g., a saturated carbon atom, a doubly bonded carbon atom, a heteroatom) as long as a stable or chemically feasible chemical entity is formed. As used herein, the 3- to 8-membered heterocycloalkenyl group may be a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocycloalkenyl group, for example, a 3-membered monocyclic heterocycloalkenyl group, a 4-membered monocyclic heterocycloalkenyl group, a 5-membered monocyclic or polycyclic heterocycloalkenyl group, a 6-membered monocyclic or polycyclic heterocycloalkenyl group, a 7-membered monocyclic or polycyclic heterocycloalkenyl group, or an 8-membered monocyclic or polycyclic heterocycloalkenyl group, examples of which include, but are not limited to, a dioxolyl group, a dioxinyl group, a dihydroimidazolyl group, a dihydrofuranyl group, a dihydropyrazolyl group, and a dihydropyrrolyl group.

[0344] The term "heteroaryl group" refers to an aromatic monocyclic or fused ring group consisting of carbon atoms and at least one heteroatom. In some embodiments, the heteroatoms in the heteroaryl group are independently selected from N, O, and S. A heteroaryl group can be attached to other structures through any atom (e.g., carbon atom, heteroatom) in the ring, provided that a stable or chemically feasible chemical entity is formed. The 5- to 6-membered heteroaryl group in this specification may be a 5-membered heteroaryl group or a 6-membered heteroaryl group, examples of which include a pyrrolyl group (e.g., pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), a furanyl group (e.g., furan-2-yl, furan-3-yl), a thiophene group (e.g., thiophen-2-yl, thiophen-3-yl), an oxazolyl group (e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), an isoxazolyl group (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), a thiazolyl group (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), an isothiazolyl group (e.g., isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), a pyrazolyl group (e.g., For example, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), imidazolyl group (for example, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), oxadiazolyl group (for example, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group), thiadiazolyl group (for example, 1, Examples of thiadiazolyl groups include, but are not limited to, 2,3-thiadiazolyl groups, 1,2,4-thiadiazolyl groups, and 1,3,4-thiadiazolyl groups, pyridyl groups (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl groups (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl), and pyrazinyl groups (e.g., pyrazin-2-yl and pyrazin-3-yl).

[0345] The term "pharmaceutically acceptable salt" refers to a salt formed from a compound and a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of a pharmaceutically acceptable base, either in pure solution or in a suitable inert solvent. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of a pharmaceutically acceptable acid, either in pure solution or in a suitable inert solvent.

[0346] The term "isotopic derivative" refers to a derivative formed after an atom in a compound is replaced with its isotopic atom. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 18 F, 35 S, 36 Isotopic derivatives include, but are not limited to, isotopic derivatives of isotopic groups, such as HCl. Isotopic derivatives can be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent, typically according to the methods described herein. In some embodiments, the isotopic derivative is a deuterated derivative, e.g., a deuterated derivative formed when 1, 2, 3, 4, 5, or 6 hydrogen atoms in a compound are replaced with deuterium.

[0347] The term "treatment" refers to therapeutic therapy. When referring to a specific medical condition, treatment refers to (1) alleviating one or more biological manifestations of a disease or condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the medical condition or (b) one or more biological manifestations of the medical condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the medical condition or one or more symptoms, effects, or side effects of the medical condition or its treatment, or (4) slowing the progression of one or more biological manifestations of a disease or condition.

[0348] The term "prevention" refers to the reduction of the risk of developing or occurring a disease or condition.

[0349] The term "effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is sufficient to effectively treat or prevent a disease or condition described herein. The effective amount will vary depending on the compound, the condition and its severity, and the age of the patient being treated, but can be adjusted as needed by one skilled in the art.

[0350] The term "subject" refers to any animal that will receive or has received the administration of a compound or composition, preferably a mammal, and most preferably a human.

[0351] Unless otherwise specified, the present invention encompasses various isomers or mixtures thereof of the compounds or isotopic derivatives of the present disclosure, such as tautomers, stereoisomers (e.g., geometric isomers or optical isomers), or any mixtures thereof (e.g., racemic mixtures). Optical isomers may be enantiomers or diastereomers. These stereoisomers can be separated, purified, and concentrated by asymmetric synthesis or chiral separation techniques (including, but not limited to, thin-layer chromatography, rotary chromatography, column chromatography, gas-phase chromatography, high-pressure liquid-phase chromatography, etc.), or can be obtained by chiral resolution, such as by combining with or forming a salt with another chiral compound. In the stereoisomeric mixtures described above (e.g., E and Z isomer mixtures, R and S isomer mixtures), the proportion of each stereoisomer can range from 5% to 95% (e.g., 10% to 90%, 20% to 80%, 30% to 70%, 40% to 60%, 50%).

[0352] The compounds of the present disclosure, their isotopic derivatives, and pharmaceutically acceptable salts in their various solid and mixture forms, including, for example, crystalline forms, amorphous forms, solvates (e.g., hydrates), or any mixture thereof, are all within the scope of the present invention. DISCLOSURE OF THE INVENTION [Effects of the Invention]

[0353] 1. The compounds of formula I according to the present invention have improved OTR antagonistic activity.

[0354] 2. The compounds of formula I according to the present invention further have lower V1aR antagonistic activity and improved OTR / V1a target selectivity.

[0355] 3. The compounds of formula I according to the present invention have improved exposure AUC, half-life T 1 / 2 and clearance Cl.

[0356] 4. The compound of formula I according to the present invention exhibited a low brain tissue distribution rate after oral administration, reducing the risk of off-target occurrence of OTR antagonism in the brain. [Example]

[0357] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. Although the following examples do not specify specific experimental conditions, they can be selected according to conventional methods and conditions or according to product instructions.

[0358] All raw materials and reagents in the examples are known and commercially available or can be synthesized according to methods known in the art.

[0359] In the following examples, PE represents petroleum ether, EA represents ethyl acetate, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, DCM represents dichloromethane, THF represents tetrahydrofuran, TEA represents triethylamine, Pd(dppf)Cl2 represents [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, DIEA, DI PEA represents N,N-diisopropylethylamine, HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, DAST represents diethylaminosulfur trifluoride, EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMAP represents 4-dimethylaminopyridine, and TsOH represents p-toluenesulfonyl ether. Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium, Pd(dtbpf)Cl2 represents 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride, Tf2O represents trifluoromethanesulfonic anhydride, DPPF represents 1,1'-bis(diphenylphosphino)ferrocene, Boc2O represents di-tert-butyl dicarbonate, and TFA represents trifluoromethanesulfonic acid. ACN represents trifluoroacetic acid, ACN represents acetonitrile, t-BuONO represents tert-butyl nitrite, DPPP represents 1,3-bis(diphenylphosphino)propane, BF3·Et2O represents boron trifluoride ethyl ether complex, t-BuOH represents tert-butanol, DMP represents Dess-Martin oxidant, BTC represents bis(trichloromethyl)carbonate, and CDI represents N,N'-carbonyldiimidazole, TBSCl represents tert-butyldimethylsilyl chloride, LiHMDS represents lithium bis(trimethylsilyl)amide, DEAD represents diethyl azodicarboxylate, PPTS represents 4-methylbenzenesulfonate pyridin-1-ium, DMK represents acetone, NMP represents N-methylpyrrolidone, Prep-TLC represents preparative thin-layer chromatography, HPLC represents high-performance liquid chromatography, and rt represents room temperature (20 to 30°C).

[0360] Examples C0020 & C0021 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0361] [ka]

[0362] [ka]

[0363] Step 1 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate 20b N-Boc-trans-4-hydroxy-L-proline methyl ester 20a (15 g, 61.16 mmol) was dissolved in DMF (200 mL), and imidazole (20.82 g, 305.80 mmol) and tert-butyldimethylchlorosilane (27.65 g, 183.48 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed with 1 N HCl (100 mL) and saturated brine (100 mL), respectively, and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to give 20b (14 g, yield: 60.5%). MS m / z (ESI): 260.1 [M+1-Boc] + .

[0364] Step 2 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate 20c 20b (14 g, 36.99 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium bistrimethylsilylamide (11.14 g, 66.8 mmol) was added dropwise at −15°C. The mixture was allowed to react for 1 hour at −15°C. Iodomethane (9.45 g, 66.8 mmol) was then added at −15°C. The mixture was allowed to react for 16 hours at room temperature. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL × 2) and dried over sodium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1 to 30:1) to give 20c (2.7 g, yield: 18.6%). MS m / z (ESI): 374.1 [M+1] + .

[0365] Step 3 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate 20d 20c (3.2 g, 8.57 mmol) was dissolved in tetrahydrofuran (50 mL), tetrabutylammonium fluoride (3.36 g, 12.86 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove tetrahydrofuran. Ethyl acetate (50 mL) and water (50 mL) were added to the residue, followed by extraction with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL × 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give product 20d (1.6 g, yield: 68.4%). 1 H NMR (300MHz,DMSO-d6) δ 5.13-5.10 (m,1H),4.29-4.27 (m,1H),3.63 (d,J=16.5Hz,3H),3.55-3.50 (m,1H),3.34-3.30 (m,1H),2.27-2.15 (m,1H),1.92-1.82 (m,1H),1.58 (d,J=3.9Hz,3H),1.38 (d,J=17.7Hz,9H).

[0366] Step 4 1-(tert-butyl) 2-methyl (S)-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate 20e 20d (1.6 g, 6.17 mmol) was dissolved in dichloromethane (30 mL), Dess-Martin oxidant (3.92 g, 9.25 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (30 mL × 2). The organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL). After drying over sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1 to 10:1) to give 20e (1.2 g, yield: 71.8%). 1 H NMR (300MHz,DMSO-d6) δ 3.89 (s,2H),3.70 (s,3H),3.02-2.87 (m,1H),2.78 (d,J=18.9Hz,1H),1.62 (s,3H),1.41 (s,9H) .

[0367] Step 5 (S)-2-Methyl-4-oxopyrrolidine-2-carboxylic acid methyl ester 20f 20e (0.3 g, 1.11 mmol) was dissolved in 4N hydrochloric acid / dioxane (10 mL) and reacted at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated to give 20f (0.18 g, yield: 98.22%). 1 H NMR (300MHz,DMSO-d6) δ 10.80 (brs,1H),3.95-3.76 (m,5H),3.03 (d,J=18.6Hz,1H),2.80-2.75 (d,J=18.6Hz,1H),1.73 (s,3H).

[0368] Step 6 (S)-2-Methyl-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-4-oxopyrrolidine-2-carboxylic acid methyl ester 20g 2f (0.18 g, 1.09 mmol) was dissolved in dichloromethane (10 mL), 4-(2-methylphenyl)benzoyl chloride (0.38 g, 1.64 mmol), and triethylamine (0.33 g, 3.27 mmol) were added, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (10 mL) was added to the mixture, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was washed with saturated brine (10 mL × 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by pre-TLC (petroleum ether / ethyl acetate = 3 / 1) to give 2f (0.3 g, yield: 74.5%). MS m / z (ESI): 374.1 [M + Na] + .

[0369] Step 7 (S,EZ)-4-(methoxyimino)-2-methyl-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 20h 20g (0.30g, 0.81mmol) was dissolved in methanol (15mL), and methoxyamine hydrochloride (0.23g, 2.83mmol) and triethylamine (0.20g, 2.03mmol) were added. The mixture was allowed to react at 60°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove the methanol. Ethyl acetate (20mL) was added to the residue, which was then washed with water (10mL x 2) and saturated sodium chloride (10mL) once. After drying over sodium sulfate, the solvent was evaporated, and the residue was purified by pre-TLC (petroleum ether / ethyl acetate = 5 / 1) to give 20h (0.2g, yield: 61.6%). MS m / z (ESI): 381.1 [M+1] + .

[0370] Step 8 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 20h (0.20 g, 0.50 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), cooled to 0°C, and lithium borohydride (0.23 mL, 2.0 mmol) was added under nitrogen gas protection, followed by reaction at room temperature for 16 hours. The reaction was quenched by the addition of water, concentrated, and the residue was dissolved in dichloromethane and water. After layering, the aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed once with brine, then dried, filtered, and rotary evaporated. The crude product was separated by silica gel pre-TLC (EA:PE=2:1) ​​to give the less polar isomer C0021 (Rf=0.5) and the crude more polar isomer C0020 (Rf=0.4). The crude product was then separated and purified by HPLC and lyophilized to give the more polar isomer C0020 (11.27 mg, yield: 6.3%) and the less polar isomer C0021 (7.80 mg, yield: 4.3%).

[0371] C0020: MS m / z (ESI):353.1[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.51 (d,J=8.0Hz,2H),7.40 (d,J=8.0Hz,2H),7.33-7.22 (m,4H),5.06 (t,J=5.6Hz,1H),4.19-4.04 (m,3H),3.70 (s,3H),3.51-3.47 (m,1H),2.90 (dd,J=16.8,1.2Hz,1H),2.57-2.53 (m,1H),2.25 (s,3H),1.50 (s,3H). C0021: MS m / z (ESI):353.1[M+1] + . 1H NMR (300MHz,DMSO-d6) δ 7.53 (d,J=8.1Hz,2H),7.41 (d,J=8.1Hz,2H),7.32-7.24 (m,4H),5.12 (t,J=5.1Hz,1H),4.22-4.05 (m,3H),3.78 (s,3H),3.51-3.47 (m,1H),3.00 (d,J=18.3Hz, 1H),2.56-2.50 (m,1H),2.27 (s,3H),1.50 (s,3H).

[0372] Examples C0035 & C0036 (S,E)-(2',3'-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(2',3'-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0373] [ka]

[0374] [ka]

[0375] Step 1 2',3'-Dimethyl-[1,1'-biphenyl]-4-carbonyl chloride 35b 35a (1.35 g, 5.37 mmol) was dissolved in sulfinyl chloride (10 mL), and the mixture was reacted at 80 °C for 3 h. After the reaction was completed, the crude product 35b (1.31 g, 89.7% yield) was obtained without further workup.

[0376] Step 2 (S)-Methyl 1-(2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-oxopyrrolidine-2-carboxylate 35d 35b (1.31 g, 5.35 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (2.10 g, 20.79 mmol) and 35c (0.85 g, 5.94 mmol) were added at 0 °C. The mixture was reacted at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated to remove dichloromethane, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give product 35d (900 mg, yield: 38.4%). MS m / z (ESI): 351.8 [M+1] + .

[0377] Step 3 (S,EZ)-Methyl 1-(2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylate 35e 35d (0.9 g, 2.56 mmol) was dissolved in methanol (10 mL), and methoxyamine hydrochloride (0.43 g, 5.12 mmol) and triethylamine (0.65 g, 6.40 mmol) were added at room temperature. The mixture was then reacted at 50°C for 18 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 3:1) to obtain product 35e (0.9 g, yield: 83.1%). MS m / z (ESI): 380.8 [M+1] + .

[0378] Step 4 (S,Z)-(2',3'-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2',3'-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 35e (120 mg, 0.30 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), cooled to 0 °C, and lithium borohydride (0.32 mL, 0.64 mmol) was added under nitrogen gas protection. The mixture was then incubated at room temperature for 2 hours. The reaction was quenched with water, concentrated, and the residue was dissolved in dichloromethane and water. After layering, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was separated by silica gel prep-TLC (EA:PE = 2:1) to give the less polar isomer C0035 (Rf = 0.5) and the more polar isomer C0036 (Rf = 0.4). The crude C0035 was purified by HPLC and lyophilized to give C0035 (10 mg, yield: 9.3%). The crude product C0036 was separated and purified by HPLC (FA), and then lyophilized to give C0036 (15 mg, yield: 14.1%).

[0379] C0035: ESI-MS: m / z= 353.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.60 (d,J=7.2Hz,2H),7.40-7.38 (m,2H),7.18-7.10 (m,2H),7.04-7.02 (m,1H),4.76-4.01 (m,4H),3.85-3.80 (m,4H),3.71-3.57 (m,1H),2.88(s,2H),2.34 (s,3H),2.14 (s,3H). C0036: ESI-MS: m / z= 353.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.60 (d,J=7.6Hz,2H),7.40-7.38 (m,2H),7.16-7.12 (m,2H),7.04-7.02 (m,1H),4.79-4.10 (m,3H),3.87-3.79 (m,4H),3.71-3.69 (m,1H),3.48-3.39 (m,1H),2.95-2.73 (m,2H),2.34 (s,3H),2.15 (s,3H).

[0380] Examples C0038 & C0038A (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0381] [ka]

[0382] [ka]

[0383] Step 1 4-Bromo-2-methoxybenzoyl chloride 38b 38a (1.2 g, 5.19 mmol) was dissolved in sulfinyl chloride (10 mL), and the mixture was reacted at 80 °C for 3 h. After the reaction was completed, the crude product 38b (1.5 g) was obtained without further workup. MS m / z (ESI): 246.1 [M+1] + .

[0384] Step 2 (S,EZ)-1-(4-bromo-2-methoxybenzoyl)-4-(methoxyimino)pyrrolidine-2-carboxylate methyl ester 38d To a solution of 38b (1 g, 4.01 mmol) in DCM (20 mL) were added 38c (0.83 g, 4.81 mmol) and triethylamine (2.03 g, 20.05 mmol). After purging with nitrogen gas, the mixture was stirred at room temperature for 20 min. After completion of the reaction, ethyl acetate was added and washed with saturated sodium chloride. The organic phases were combined, dried, and rotary evaporated. The crude product was subjected to column chromatography (PE / EA = 10:1 to 1:1) to give 38d (1.2 g, yield: 77.7%). MS m / z (ESI): 369.1 [M+1] + .

[0385] Step 3 (S,EZ)-1-(3-Methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylate methyl ester 38e To a solution of 38d (200 mg, 0.52 mmol) in dioxane / water (15 mL / 1.5 mL) was added (2,3-dimethylphenyl)boronic acid (94 mg, 0.62 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (38 mg, 52 mmol). After purging with nitrogen gas, the mixture was reacted at 85 °C for 2 h. After cooling, the reaction mixture was poured into a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was applied to a silica gel column and eluted with PE / EA (10:1 to 1:1). The eluate was collected and rotary evaporated to give 38e (150 mg, yield: 66.8%). MS m / z (ESI): 410.8 [M+1] + .

[0386] Step 4 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone Under nitrogen gas protection, LiBH4 (7.4 mg, 0.34 mmol) was slowly added to a solution of 38e (140 mg, 0.34 mmol) in tetrahydrofuran / methanol (5 mL / 5 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. After cooling, the reaction mixture was poured into a mixture of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was separated by silica gel prep-TLC (EA:PE=2:1) ​​to give the less polar isomer C0038A (Rf=0.5) and the crude more polar isomer C0038 (Rf=0.4). Then, after separation and purification by HPLC and lyophilization, a more polar product C0038 (9.39 mg, yield: 7.2%) and a less polar product C0038A (7.42 mg, yield: 5.7%) were obtained.

[0387] C0038:MS m / z (ESI):383.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.35-7.30 (m,1H),7.17-7.02 (m,3H),6.98-6.93 (m,2H),4.69-4.47 (m,1H),4.22-4.15 (m,1H),4.04-3.95 (m,1H),3.88-3.70 (m,7H),3.38-3.35 (m,1H),2.96-2.90 (m,1H),2.80-2.66 (m,1H),2.33 (s,3H),2.1 (d,J=2.0Hz,3H). C0038A:MS m / z (ESI):383.1[M+1] + . 1H NMR (400MHz,CD3OD-d) δ 7.35-7.32 (m,1H),7.17-7.02 (m,3H),6.98-6.94 (m,2H),4.69-4.51 (m,1H),4.20-4.15 (m,1H),4.04-3.95 (m,1H),3.88-3.70 (m,7H),3.38-3.35 (m,1H),2.96-2.75 (m,2H),2.80-2.66 (m,1H),2.33 (s,3H),2.17 (s,3H).

[0388] Examples C0044 & C0044A (S,Z)-(2',3-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2',3-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0389] [ka]

[0390] [ka]

[0391] Following the synthesis method of compound C0038, a more polar product C0044 (10 mg, yield: 14.20%) and a less polar product C0044A (10 mg, yield: 14.20%) were obtained.

[0392] C0044A:MS m / z (ESI):353.1[M+1] + . 1H NMR (400MHz,CD3OD-d) δ 7.35-7.31 (m,1H),7.26-7.18 (m,6H),4.71-4.55 (m,1H),4.19-4.11 (m,1H),3.95-3.70 (m,5H),3.37-3.36 (m,1H), 2.92-2.89 (m,2H), 2.37 (s,1H), 2.24 (s,1H). C0044:MS m / z (ESI):353.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.36-7.32 (m,1H),7.26-7.21 (m,6H),4.70-4.51 (m,1H),4.21-4.08 (m,1H),3.91-3.76 (m,5H),3.38-3.37 (m,1H),3.01-2.94 (m,1H),2.80-2.66 (m,1H),2.36 (s,1H),2.24 (d,J=2.0Hz,1H).

[0393] Examples C0045 & C0045A (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methyl-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methyl-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0394] [ka]

[0395] [ka]

[0396] By referring to the synthesis method of compound C0038, a more polar product C0045 (15 mg, yield: 17.0%) and a less polar product C0045A (17 mg, yield: 19.3%) were obtained.

[0397] C0045:MS m / z (ESI):367.0[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.36-7.31 (m,1H),7.21-7.09 (m,4H),7.03-6.99 (m,1H),4.70-4.51 (m,1H),4.26-4.08 (m,1H),3.91-3.72 (m,5H),3.38 (d, J=4.8Hz,1H),3.01-2.66 (m,2H),2.36 (s,3H),2.33 (s,3H),2.13 (d,J=2.0Hz,3H). C0045A:MS m / z (ESI):367.0[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.37-7.32 (m,1H),7.21-7.09 (m,4H),7.02-6.99 (m,1H),4.74-4.55 (m,1H),4.19-4.07 (m,1H),3.95-3.70 (m,5H),3.38-3.34 (m,1H),2.91-2.85 (m,2H),2.36 (s,3H),2.33 (s,3H),2.13 (s,3H).

[0398] Examples C0046 & C0046A (S,Z)-(2',2-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2',2-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0399] [ka]

[0400] [ka]

[0401] By referring to the synthesis method of compound C0038, a more polar product C0046 (Rf=0.4, 10.06 mg, yield: 5.8%) and a less polar product C0046A (Rf=0.5, 5.2 mg, yield: 2.96%) were obtained.

[0402] C0046:MS m / z (ESI):353.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.66-7.52 (m,1H),7.48-7.30 (m,2H),7.30-7.16 (m,4H),7.07 (d,J=6.4Hz,1H),4.74-4.11 (m,3H),3.89-3.68 (m,5H),3.42-3.35 (m,1H),3.11-2.82 (m,1H),2.77-2.73 (m,1H),2.08 (s,3H),2.04 (s,3H). C0046A:MS m / z (ESI):353.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.47 (s,1H),7.41 (d,J=7.6Hz,1H),7.30-7.16 (m,4H),7.06 (d,J=7.2Hz,1H),4.83-4.06 (m,3H),3.96-3.37 (m,6H),2.91-2.79 (m,2H),2.08 (s,3H),2.03 (s,3H).

[0403] Examples C0047 & C0047A (S,Z)-(2,2',3'-trimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2,2',3'-trimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0404] [ka]

[0405] [ka]

[0406] Following the above synthesis route and referring to the synthesis method of compound C0038, a more polar product C0047 (34.80 mg, yield: 15.0%) and a less polar product C0047A (30.80 mg, yield: 13.2%) were obtained.

[0407] C0047:MS m / z (ESI):367.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.45 (s,1H),7.39 (d,J=7.6Hz,1H),7.18-7.10 (m,3H),6.90 (d,J=6.8Hz,1H),4.83-4.10 (m,3H),3.87-3.40 (m,6H),2.95-2.89 (m,1H),2.77-2.65 (m,1H),2.33 (s,3H),2.07 (s,3H),1.96 (s,3H). C0047A:MS m / z (ESI):367.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.46 (s,1H),7.40 (d,J=7.6Hz,1H),7.18-7.10 (m,3H),6.89 (d,J=7.2Hz,1H),4.80-4.05 (m,3H),3.96-3.37 (m,6H),2.94-2.81 (m,2H),2.33 (s,3H),2.07 (s,3H),1.95 (s,3H).

[0408] Examples A0061 & A0042 (S,Z)-(5-(2,3-dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(5-(2,3-dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0409] [ka]

[0410] [ka]

[0411] Step 1 Methyl 5-(2,3-dimethylphenyl)pyrazine-2-carboxylate 61c The raw materials 61b (2 g, 11.59 mmol) and 61a (1.91 g, 12.75 mmol) were dissolved in 40 mL of 1,4-dioxane, and potassium carbonate (4.81 g, 34.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.42 g, 0.58 mmol) were added. The reaction was then stirred under nitrogen gas protection at 75°C for 16 hours. The mixture was quenched with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give product 61c (1.7 g, white solid, yield: 60.5%). MS m / z (ESI): 243 [M+1] + .

[0412] Step 2 5-(2,3-dimethylphenyl)pyrazine-2-carboxylic acid 61d The raw material 61c (1.7 g, 7.02 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide (0.50 g, 21.06 mmol) was added. The reaction was allowed to proceed at 25°C for 2 hours. 2 M diluted hydrochloric acid was added to adjust the pH to acidic. Extraction was performed with ethyl acetate (40 mL x 3), and the combined organic phases were washed with brine (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give product 61d (1.4 g, white solid, yield: 90.5%). MS m / z (ESI): 251 [M+1] + .

[0413] Step 3 (S,EZ)-1-(5-(2,3-dimethylphenyl)pyrazine-2-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylate methyl ester 61f The raw material 61d (1.45 g, 6.35 mmol) was dissolved in 50 mL of DMF, and 38c (1.20 g, 6.99 mmol) and HATU (3.14 g, 8.25 mmol) were added. Ethyl diisopropyl ether (3.28 g, 25.4 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 2 hours. 50 mL of water was added, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give product 61f (560 mg, white solid, yield: 23.1%). MS m / z (ESI): 383.3 [M+1] + .

[0414] Step 4 (S,Z)-(5-(2,3-dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(5-(2,3-dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone The starting material 61f (300 mg, 0.78 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of methanol, and lithium borohydride (0.051 g, 2.34 mmol) was added. The reaction was allowed to proceed at 25°C for 1 hour. 10 mL of water was added, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel prep-TLC (EA:PE = 2:1) to give the less polar isomer A0042 (Rf = 0.4) and the crude more polar isomer A0061 (Rf = 0.3). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0061 (101.55 mg, yield: 35.8%) and a less polar product A0042 (60 mg, yield: 21.3%).

[0415] A0061:MS m / z (ESI):355.3[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 9.27 (d,J=18.4Hz,1H),8.70-8.60 (m,1H),7.29-7.22 (m,3H),4.95-4.89 (m,1H),4.76 (s,1H),3.94-3.82 (m,5H),2.95-2.66 (m,2H),2.37 (s,3H),2.26 (s,3H). A0042: MS m / z (ESI): 355.3 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 9.30-9.25 (m,1H),8.69-8.60 (m,1H),7.29-7.24 (m,3H),4.95-4.89 (m,1H),4.77 (d,J=18.4Hz,1H),3.94-3.88 (m,3H),3.85-3.60 (m,2H),2.95-2.65 (m,2H),2.38 (s,3H),2.26 (d,J=5.2Hz,3H).

[0416] Examples C0041 & C0041A (S,Z)-(5-(3-chloro-2-methylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(5-(3-chloro-2-methylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0417] [ka]

[0418] Refer to the method of A0061, and add raw material 61a in step 1.

[0419] [ka]

[0420] to give a more polar product C0041 (23.5 mg, yield: 16.9%) and a less polar product C0041A (5.6 mg, yield: 4.0%).

[0421] C0041:MS m / z (ESI):375.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 9.13-9.08 (m,1H),8.81-8.76 (m,1H),7.55-7.53 (m,1H),7.43-7.32 (m,2H),5.08-4.78 (m,1H),4.70-4.68 (m,1H),4.60-4.31 (m,1H),3.89-3.82 (m,3H),3.86-3.69 (m,1H),3.59-3.58 (m,1H),3.04-2.89 (m,1H),2.78-2.65 (m,1H),2.39 (s,3H). C0041A:MS m / z (ESI):375.0[M+1] + . 1H NMR (400MHz,CD3OD) δ 9.11 (dd,J=20,1.2Hz,1H),8.78 (dd,J=16,1.2Hz,1H),7.54 (d,J=7.6Hz,1H),7.42 (d,J=7.6Hz,1H),7.36-7.32 (m,1H),5.10-4.79 (m,1H),4.66-4.63 (m,1H),4.63-4.20 (m,1H),3.88-3.67 (m,4H),3.58-3.56 (m,1H),2.96-2.83 (m,2H),2.39 (s,3H).

[0422] Synthesis of intermediate 4 (S,EZ)-5-(hydroxymethyl)pyrrolidin-3-one O-methyloxime hydrochloride

[0423] [ka]

[0424] [ka]

[0425] Step 1 (S,EZ)-1-(tert-butyl)-2-methyl 4-(methoxyimino)pyrrolidine-1,2-dicarboxylate 2 Compound 1 (13.5 g, 55.50 mmol) was dissolved in methanol (150 mL), and methoxyamine hydrochloride (20.86 g, 249.75 mmol) and triethylamine (19.66 g, 194.25 mmol) were added. The mixture was reacted at 60° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove the methanol. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to give 2 (14 g, yield: 88.0%), which was used directly in the next step. MS m / z (ESI): 216.9 [M+1-56] + .

[0426] Step 2 (S,EZ)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carboxylic acid tert-butyl ester 3 Compound 2 (14 g, 48.84 mmol) was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (150 mL). Lithium borohydride (2.13 g, 97.68 mmol) was added dropwise at room temperature, and the mixture was allowed to react for 2 hours. After the reaction was complete, water (100 mL) and ethyl acetate (500 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the solvent was removed by distillation. Silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) gave 3 (10.0 g, yield: 79.6%). MS m / z (ESI): 188.9 [M+1] + .

[0427] Step 3 (S,EZ)-5-(hydroxymethyl)pyrrolidin-3-one O-methyloxime hydrochloride 4 Compound 3 (400 mg, 1.56 mmol) was dissolved in 4 mL of 4N hydrochloric acid in dioxane and reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to remove the solvent, yielding crude compound 4 (400 mg), which was used directly in the next step. MS m / z (ESI): 145.0 [M+1] + .

[0428] Examples C0055 & C0056 (S,E)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0429] [ka]

[0430] [ka]

[0431] Step 1 3'-Chloro-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 56c To a solution of 56a (1.0 g, 4.97 mmol) in 1,4-dioxane / water (18 mL / 3 mL) was added 56b (1.10 g, 6.46 mmol), potassium carbonate (1.72 g, 12.42 mmol), and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (365 mg, 0.5 mmol). After purging with nitrogen gas, the mixture was reacted at 80 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated, and the crude product was subjected to column chromatography (PE / EA = 3:1 to 1:1) to give 56c (450 mg, yield: 36.8%). MS m / z (ESI): 247.0 [M+1] + .

[0432] Step 2 (S,Z)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 56c (150 mg, 0.61 mmol) and intermediate 4 (120 mg) were dissolved in DMF (4 mL). HATU (254 mg, 0.67 mmol) and triethylamine (184 mg, 1.83 mmol) were added at room temperature. After purging with nitrogen gas, the reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was added to a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was separated by silica gel prep-TLC (EA:PE=2:1) ​​to give crude more polar isomer C0056 (Rf=0.4) and crude less polar isomer C0055 (Rf=0.5). The crude product was then separated and purified by HPLC, and lyophilized to give more polar product C0056 (20.01 mg, yield: 8.8%) and less polar product C0055 (13.2 mg, yield: 6.0%).

[0433] C0056:MS m / z (ESI): 373.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.64-7.62 (m,2H),7.42-7.39 (m,3H),7.23-7.18 (m,2H),4.78-4.10 (m,3H),3.85-3.36 (m,5H),3.07-2.65 (m,2H),2.28 (s,3H). C0055:MS m / z (ESI): 373.1[M+1] + . 1 H NMR (400MHz,CD3OD-d) δ 7.64-7.62 (m,1H),7.42-7.40 (m,3H),7.23-7.17 (m,2H),4.79-4.09 (m,3H),3.86-3.36 (m,5H),2.88-2.72 (m,2H),2.27 (s,3H).

[0434] Examples C0057 & C0058 (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0435] [ka]

[0436] [ka]

[0437] Step 1 3'-Cyano-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 58b To a solution of 58a (409.72 mg, 2.09 mmol) in methanol (20 mL) and water (10 mL) was added 4-(dihydroxyboranyl)benzoic acid (0.38 g, 2.30 mmol), tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol), and potassium carbonate (0.87 g, 6.27 mmol). After purging with nitrogen gas, the mixture was reacted at 85 °C overnight. After completion of the reaction, the methanol was removed by rotary evaporation. The aqueous phase was extracted with ethyl acetate, and the pH of the aqueous phase was adjusted to 3-4. The organic phases were combined, dried over sodium sulfate, filtered, and rotary evaporated to give 58b (400 mg, 72.6% yield). MS m / z (ESI): 238.1 [M+1] + .

[0438] Step 2 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile To a solution of 58b (400 mg, 1.69 mmol) in DMF (5 mL), intermediate 4 (0.29 g, 2.03 mmol), triethylamine (0.51 g, 5.07 mmol), and HATU (0.96 g, 2.54 mmol) were added. After purging with nitrogen gas, the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was separated by silica gel pre-TLC (EA:PE=5:1) to obtain the less polar isomer C0057 (Rf=0.5) and the crude more polar isomer C0058 (Rf=0.4). Then, after separation and purification by HPLC and lyophilization, less polar product C0057 (34 mg, yield: 5.6%) and more polar product C0058 (22 mg, yield: 3.6%) were obtained.

[0439] C0057:MS m / z (ESI):364.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.72-7.65 (m,3H),7.54-7.42 (m,4H),4.81-4.74 (m,1H),4.41-4.06 (m,2H),3.91-3.67 (m,4H),3.39-3.36 (m,1H),2.88-2.86 (m,2H),2.45 (s,3H). C0058:MS m / z (ESI):364.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.72-7.65 (m,3H),7.55-7.42 (m,4H),4.76-4.74 (m,1H),4.48-4.08 (m,2H),3.88-3.67 (m,4H),3.39-3.36 (m,1H),3.13-2.73 (m,2H),2.45 (s,3H).

[0440] Examples C0059 & C0060 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanone

[0441] [ka]

[0442] [ka]

[0443] Following the above synthesis route, and referring to the synthesis method of compound C0057, the less polar isomer C0059 (Rf=0.5) and the crude more polar isomer C0060 (Rf=0.4) were obtained. After separation and purification by HPLC and lyophilization, the less polar product C0059 (36 mg, yield: 9.9%) and the more polar product C0060 (27 mg, yield: 7.5%) were obtained.

[0444] C0059:MS m / z (ESI):407.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.71-7.64 (m,3H),7.47-7.40 (m,4H),4.81-4.75 (m,1H),4.43-4.01 (m,2H),3.88-3.69 (m,4H),3.39-3.33 (m,1H),2.97-2.73 (m,2H),2.33 (s,3H). C0060:MS m / z (ESI):407.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.71-7.64 (m,3H),7.48-7.40 (m,4H),4.76-4.74 (m,1H),4.48-4.08 (m,2H),3.88-3.67 (m,4H),3.39-3.36 (m,1H),3.13-2.73 (m,2H),2.45 (s,3H)

[0445] Examples C0061 & C0062 (S,E)-(7-(2,3-dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(7-(2,3-dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0446] [ka]

[0447] [ka]

[0448] Step 1 Methyl 4-bromo-2,3-dihydroxybenzoate 62b Liquid bromine (5.70 g, 35.69 mmol) was added dropwise to a solution of tert-butylamine (4.35 g, 59.48 mmol) in dichloromethane (10 mL) at -60 °C. The reaction mixture was cooled to -78 °C, and within 20 min, a solution of 62a (5 g, 29.74 mmol) in dichloromethane (25 mL) was added dropwise. The mixture was stirred at -78 °C for 30 min and then slowly heated to room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate / water. The combined organic phases were dried over sodium sulfate, filtered, and rotary evaporated to give the crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile:water = 5:95 to 45:55) to give product 62b (1.3 g, yield: 17.7%). 1 H NMR (400MHz,CDCl3) δ 11.02 (s,1H),7.19 (d,J=8.8Hz,1H),6.98 (d,J=8.8Hz,1H),5.99 (s,1H),3.87 (s,3H).

[0449] Step 2 7-Bromo-benzo[d][1,3]dioxole-4-carboxylate methyl ester 62c Cesium carbonate (3.69 g, 11.34 mmol) was added to a solution of 62b (1.4 g, 5.67 mmol) in DMF (20 mL). The mixture was stirred for 30 min, then dihydrodiiodomethane (2.43 g, 9.07 mmol) was added. After purging with nitrogen gas, the mixture was stirred at 70 °C for 12 h. The reaction mixture was extracted with ethyl acetate / water, and the combined organic phases were washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporated to give the product. The crude product was purified by silica gel pre-TLC (PE:EA = 5:1) to give product 62c (500 mg, yield: 34.1%).

[0450] Step 3 Methyl 7-(2,3-dimethylphenyl)benzo[d][1,3]dioxole-4-carboxylate 62d To a solution of 62c (0.50 g, 1.93 mmol) in dioxane / water (10 mL / 1 mL) was added potassium carbonate (0.80 g, 5.79 mmol), tetrakis(triphenylphosphine)palladium (0.21 g, 0.19 mmol), and (2,3-dimethylphenyl)boronic acid (0.33 g, 2.19 mmol). The mixture was purged with nitrogen and stirred at 80 °C for 3 h. The reaction mixture was extracted with ethyl acetate / water, and the combined organic phases were washed with saturated brine. The combined organic phases were dried over sodium sulfate, filtered, and rotary evaporated to give the crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile:water = 5:95 to 70:30) to give product 62d (0.30 g, yield: 54.7%). MS m / z (ESI): 285.0 [M+1] + .

[0451] Step 4 7-(2,3-dimethylphenyl)benzo[d][1,3]dioxole-4-carboxylic acid 62e Lithium hydroxide monohydrate (70.2 mg, 1.68 mmol) was added to a solution of 62d (200 mg, 0.67 mmol) in tetrahydrofuran / water (6 mL / 3 mL), and the reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to ~2 with 1N aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate / water. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and rotary evaporated to give the crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile:water = 5:95 to 50:50) to give product 62e (150 mg, yield: 78.9%). MS m / z (ESI): 270.9 [M+1] + .

[0452] Step 5 (S,E)-(7-(2,3-dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(7-(2,3-dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone To a solution of 62e (120 mg, 0.42 mmol) in DMF (4 mL), intermediate 4 (91 mg, 0.63 mmol), triethylamine (108 mg, 0.84 mmol), and HATU (239 mg, 0.63 mmol) were added, and the reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was poured into a mixed solvent of ethyl acetate and water, and the aqueous phase was extracted once more after layering. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated to give the crude product. The crude product was separated by silica gel pre-TLC (EA:PE = 2:1) to give the less polar isomer C0061 (Rf = 0.6) and the more polar isomer C0062 (Rf = 0.55). Then, after separation and purification by HPLC and lyophilization, less polar product C0061 (6.02 mg, yield: 3.4%) and more polar product C0062 (6.1 mg, yield: 3.4%) were obtained.

[0453] C0061: MS m / z (ESI):397.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.18-7.01 (m,4H),6.83 (d,J=8.0Hz,1H),6.07-6.02 (m,2H),4.84-4.40 (m,2H),4.20-4.14 (m,1H),3.87-3.39 (m,5H),2.95-2.81 (m,2H),2.32 (s,3H),2.13 (s,3H). C0062: MS m / z (ESI):397.1[M+1] + . 1H NMR (400MHz,CD3OD) δ 7.18-7.00 (m,4H),6.83 (d,J=8.4Hz,1H),6.08-6.01 (m,2H),4.84-4.33 (m,2H),4.25-4.16 (m,1H),3.87-3.41 (m,5H),3.02-2.89 (m,1H),2.79-2.66 (m,1H),2.32 (s,3H),2.14 (s,3H).

[0454] Examples C0063 & C0064 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0455] [ka]

[0456] [ka]

[0457] Following the above synthesis route, and referring to the synthesis method of compound C0056, the less polar isomer C0063 (Rf=0.5) and the crude more polar isomer C0064 (Rf=0.4) were obtained. After separation and purification by HPLC and lyophilization, the less polar product C0063 (26 mg, yield: 5.0%) and the more polar product C0064 (28 mg, yield: 5.4%) were obtained.

[0458] C0063:MS m / z (ESI):383.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.22-7.06 (m,5H),6.93 (d,J=7.2Hz,1H),4.78-4.77 (m,1H),4.41-4.13 (m,2H),3.90-3.81 (m,4H),3.69-3.40 (m,1H),2.89-2.87 (m,2H),2.31 (s,3H),1.98 (s,3H).

[0459] C0064:MS m / z (ESI):383.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.21-7.06 (m,5H),6.93 (d,J=6.4Hz, 1H),4.78-4.49 (m,1H),4.43-4.11 (m,2H),3.90-3.80 (m,4H),3.72-3.43 (m,1H),2.99-2.67 (m,2H),2.31 (s,3H),1.99 (s,3H).

[0460] Examples C0065 & C0066 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0461] [ka]

[0462] [ka]

[0463] Step 1 3'-Methoxy-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 66b 1-Bromo-3-methoxy-2-methylbenzene (500 mg, 2.49 mmol), 66a (496 mg, 2.99 mmol), potassium carbonate (1.03 g, 7.47 mmol), and tetrakis(triphenylphosphine)palladium (288 mg, 0.25 mmol) were dissolved in a mixture of methanol (20 mL) and water (10 mL). The mixture was purged with nitrogen gas three times and heated to 80 °C under nitrogen gas protection and stirred for 17 h. After completion of the reaction, the mixture was rotary evaporated to remove methanol, filtered, and the filtrate was extracted with a small amount of ethyl acetate. The aqueous phase was retained and adjusted to pH 3–4. The aqueous phase was extracted twice with a toluene / tetrahydrofuran (1 / 1) mixture. The combined organic phases were dried over sodium sulfate and concentrated to give 66b (470 mg, yield: 78.0%). MS m / z (ESI): 241.0 [M+1] + .

[0464] Step 2 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone Under nitrogen gas protection, HATU (570 mg, 1.5 mmol), diisopropylethylamine (517 mg, 4 mmol), and 66b (242 mg, 1 mmol) were added to a solution of intermediate 4 (180 mg, 1 mmol) in DMF (5 mL). The reaction mixture was incubated overnight at room temperature. Water (50 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel pre-TLC (PE:EA = 1:1) to give the less polar product C0065 (15 mg, yield: 4.1%, Rf = 0.3) and the more polar product C0066 (20 mg, yield: 14.6%, Rf = 0.2).

[0465] C0065:MS m / z (ESI):369.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.60 (d,J=7.6Hz,2H),7.39 (d,J=8.0Hz,2H),7.21 (t,J=8.0,7.6Hz,1H),6.94 (d,J=8.0Hz,1H),6.81 (d,J=7.6Hz,1H),4.77-4.41 (m,1H),4.38-4.07 (m,2H),3.86-3.68 (m,8H),3.41-3.31 (m,1H),2.88-2.86 (m,2H),2.08 (s,3H). C0066:MS m / z (ESI):369.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.59 (d,J=7.2Hz,2H),7.39 (d,J=8.4Hz,2H),7.21 (t,J=8.0Hz,1H),6.94 (d,J=8.0Hz,1H),6.82 (d,J=7.2Hz,1H),4.76-4.53 (m,1H),4.53-4.09 (m,2H),3.86-3.68 (m,7H),3.38-3.31 (m,1H),2.98-2.73 (m,2H),2.08 (s,3H).

[0466] Examples A0134 & A0145 (S,Z)-(2-(difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0467] [ka]

[0468] [ka]

[0469] Step 1 Methyl 4-bromo-3-difluoromethylbenzoate 134b 134a (500 mg, 2.06 mmol) was dissolved in DCM (5 mL), cooled to 0 °C, and diethylaminosulfur trifluoride (0.50 g, 3.09 mmol) was added. The mixture was then allowed to react at room temperature for 16 h. The reaction mixture was poured into saturated sodium carbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 30:1) to give 134b (400 mg, yield: 73.4%). MS m / z (ESI): 265 [M+1] + .

[0470] Step 2 Methyl 2-(difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-carboxylate 134d Following the synthesis method for compound A0061, 134d (200 mg, yield: 45.6%) was obtained. MS m / z (ESI): 291 [M+1] + .

[0471] Step 3 2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-carboxylic acid 134e The synthesis of compound A0061 was followed to obtain crude product 134e (0.2 g, yield: 94.4%). MS m / z (ESI): 277 [M+1] + .

[0472] Step 4 (S,Z)-(2-(difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 134e (100 mg, 0.42 mmol) and Intermediate 4 (0.061 g, 0.36 mmol) were dissolved in DCM (1.7 mL) and DMF (4 mL), and DMAP (0.10 g, 0.84 mmol) and EDCI (0.081 g, 0.42 mmol) were slowly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with brine and 1N hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel prep-TLC (EA:PE=5:1) to give the more polar crude product A0134 (Rf=0.4) and the less polar crude product A0145 (Rf=0.5). The product was then separated and purified by HPLC, and lyophilized to give A0134 (5.37 mg, yield: 3.7%), which had high polarity, and A0145 (6.82 mg, yield: 4.6%), which had low polarity.

[0473] A0134: MS m / z (ESI): 403.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.91-7.89 (m,1H),7.68-7.61 (m,1H),7.29-7.22 (m,2H),7.20-7.13 (m,1H),6.99-6.95 (m,1H),6.47-6.12 (m,1H),4.89-4.88 (m,1H),4.42-4.16 (m,2H),3.97-3.76 (m,5H),3.00-2.90 (m,1H),2.71-2.66 (m,1H),2.34 (s,3H),1.96 (s,3H). A0145: MS m / z (ESI): 403.0 [M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.88 (s,1H),7.64 (d,J=8.0Hz,1H),7.28-7.21 (m,2H),7.20-7.14 (m,1H),6.98-6.85 (m,1H),6.44-6.16 (m,1H),4.89 (brs,1H),4.40-4.18 (m,2H),3.94-3.78 (m,5H),2.95-2.69 (m,2H),2.33 (s,3H),1.93 (s,3H).

[0474] Examples C0067 & C0068 (S,Z,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,E,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0475] [ka]

[0476] [ka]

[0477] Step 1 (S)-7-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylate methyl ester 67b 67a (800 mg, 2.37 mmol, prepared according to the method of 20 g) was dissolved in toluene (7 mL) and added to ethylene glycol (221 mg, 3.56 mmol) and p-toluenesulfonic acid hydrate (90 mg, 0.47 mmol) and reacted at 120 °C for 16 h. After completion of the reaction, the solvent was removed by rotary evaporation, and prep-TLC (PE / EA = 6 / 1) gave product 67b (500 mg, yield: 55.3%). MS m / z (ESI): 382.0 [M+1] + .

[0478] Step 2 (S)-(8-(hydroxymethyl)-1,4-dioxo-7-azaspiro[4.4]nonan-7-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 67c 67b (160 mg, 0.42 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). Lithium borohydride in tetrahydrofuran (2 mol / L, 0.42 mL) was added dropwise at −10°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 hours. After the reaction was complete, water was added to quench the reaction. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane and water. After layering, the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed once with brine, dried, filtered, and rotary evaporated. The crude product was applied to a silica gel column and eluted with (3:1 to 1:1 PE / EA). The eluate was collected and concentrated to give product 67c (100 mg, yield: 67.4%). MS m / z (ESI): 354.0 [M+1] + .

[0479] Step 3 (S)-7-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carbaldehyde 67d 67c (450 mg, 1.27 mmol) was dissolved in dichloromethane (3 mL), and Dess-Martin oxidant (539 mg, 0.14 mmol) was added to the reaction mixture. The mixture was then allowed to react at room temperature for 16 hours. After completion of the reaction, dichloromethane and water were added, followed by extraction with dichloromethane twice. The organic phases were combined and rotary evaporated to remove the solvent. After washing with brine once, the mixture was dried, filtered, and rotary evaporated. The crude product was loaded onto a silica gel column and eluted with 2:1 to 1:1 PE / EA. The eluate was collected and concentrated to give product 67d (350 mg, 78.2% yield). MS m / z (ESI): 352.0 [M+1] + .

[0480] Step 4 (S,RS)-(8-(1-hydroxyethyl)-1,4-dioxo-7-azaspiro[4.4]nonan-7-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 67e 67d (320 mg, 0.91 mmol) was dissolved in tetrahydrofuran (5 mL), and 4.5 mL of a 3 M solution of methylmagnesium chloride in tetrahydrofuran was added at −78° C. The mixture was warmed to room temperature and stirred for 20 minutes. After the reaction was completed, the reaction mixture was quenched by adding water and extracted three times with water and ethyl acetate. The organic phase was collected, washed once with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give product 67e (180 mg, yield: 53.8%). MS m / z (ESI): 368.0 [M+1] + .

[0481] Step 5 (S,RS)-5-(1-hydroxyethyl)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-one 67f 67e (130 mg, 0.35 mmol) was dissolved in hydrochloric acid (2 mL) and water (20 mL) and reacted at 100 °C for 1 h. After completion of the reaction, the reaction solution was adjusted to neutral and extracted three times with water and ethyl acetate. The organic phase was collected, washed once with brine, dried over anhydrous sodium sulfate, filtered, and the crude product was loaded onto a silica gel column and eluted with (1:1 to 1:2 PE / EA). The eluate was collected and concentrated to give product 67f (75 mg, yield: 65.5%). MS m / z (ESI): 324.0 [M+1] + .

[0482] Step 6 (S,E,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone (S,Z,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 67f (100 mg, 0.31 mmol) was dissolved in methanol (5 mL), and methoxyamine hydrochloride (26 mg, 0.31 mmol) and triethylamine (78 mg, 0.78 mmol) were added at room temperature. The mixture was then reacted at 50 °C for 18 h. The reaction mixture was rotary evaporated to remove methanol, extracted three times with dichloromethane and water, and the combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was purified by silica gel prep-TLC (PE:EA = 1:3) to give the less polar crude product C0067 (Rf = 0.7) and the more polar crude product C0068 (Rf = 0.5). The crude product was then purified by HPLC and lyophilized to give the less polar product C0067 (3.94 mg, yield: 3.6%) and the more polar product C0068 (8.96 mg, yield: 8.2%).

[0483] C0067: MS m / z (ESI):353.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.64-7.62 (m,2H),7.43 (d,J=8.0Hz,2H),7.28-7.19 (m,4H),4.64-4.41 (m,2H),4.25-4.05 (m,2H),3.85-3.80 (m,3H),2.98-2.94 (m,1H),2.76-2.69 (m,1H),2.25 (s,3H),1.29-1.21 (m,3H). C0068: MS m / z (ESI):353.1[M+1] + .

[0484] Examples A0167 & A0213 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile

[0485] [ka]

[0486] [ka]

[0487] Step 1 4-Bromo-7-chloro-1-methyl-1H-indazole 167b 167a (4 g, 17.28 mmol) was dissolved in DMF (30 mL), sodium hydride (1.38 g, 34.56 mmol) was added at 0 °C, and the mixture was allowed to react for 40 minutes. Iodomethane (2.94 g, 20.74 mmol) was added, and the mixture was heated to 20 °C and allowed to react for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (150 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL × 2), dried, stirred, and purified on a silica gel column (PE:EA = 76:24) to give product 167b (1.67 g, yield: 39.4%). MS m / z (ESI): 244.9 [M+1] + .

[0488] Step 2 Methyl 7-chloro-1-methyl-1H-indazole-4-carboxylate 167c 167b (1.40 g, 5.70 mmol), Pd(dppf)Cl2 (0.42 g, 0.57 mmol), and triethylamine (1.73 g, 17.1 mmol) were dissolved in methanol (15 mL) and reacted at 60°C for 5 hours under a CO atmosphere. The reaction mixture was directly concentrated, stirred, and loaded onto a silica gel column (PE:EA = 3:1) to give 167c (0.73 g, yield: 56.9%). MS m / z (ESI): 224.9 [M+1] + .

[0489] Step 3 Methyl 7-(3-cyano-2-methylphenyl)-1-methyl-1H-indazole-4-carboxylate 167e 167c (0.230 g, 1.02 mmol), 167d (0.25 g, 1.02 mmol), potassium carbonate (0.28 g, 2.04 mmol), and Pd(dtbpf)Cl2 (0.066 g, 0.10 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) and reacted at 100 °C under an argon atmosphere for 16 h. The reaction mixture was directly concentrated, stirred, and purified on a silica gel column (PE:EA = 3:1) to give 167e (0.30 g, yield: 95.9%). MS m / z (ESI): 306.0 [M+1] + .

[0490] Step 4 7-(3-cyano-2-methylphenyl)-1-methyl-1H-indazole-4-carboxylic acid 167f 167e (0.10 g, 0.33 mmol) and lithium hydroxide (0.042 g, 0.99 mmol) were dissolved in methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) and reacted at 40°C for 2 hours. 3 mL of water was added, the pH was adjusted to 2-3, and the mixture was extracted with ethyl acetate (50 mL x 3), dried, and concentrated to give 167f (0.07 g, yield: 73.4%). MS m / z (ESI): 292.1 [M+1] + .

[0491] Step 5 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile 167f (0.07 g, 0.24 mmol), 4 (0.035 g, 0.24 mmol), and DMAP (0.059 g, 0.48 mmol) were dissolved in DMF (3 mL) / DCM (2 mL). EDCI (0.055 g, 0.29 mmol) was added at 15 °C, followed by a 16-hour reaction. The reaction mixture was diluted with ethyl acetate and washed sequentially with brine and 1N hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer A0213 (Rf = 0.4) and the crude more polar isomer A0167 (Rf = 0.35). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0167 (2.14 mg, yield: 2.05%) and a less polar product A0213 (2.03 mg, yield: 1.97%).

[0492] A0167: MS m / z (ESI):418.3[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.11 (s,1H),7.76 (d,J=7.6Hz,1H),7.55-7.52 (m,1H),7.43 (m,1H),7.30 (m,1H),7.15 (dd,J=7.2,4.0Hz,1H),4.97 (brs,1H),4.34-4.30 (m,1H),4.20-3.93 (m,2H),3.90-3.75 (m,4H),3.51 (d,J=4.0Hz,3H),3.03-2.76 (m,2H),2.72-2.63 (m,1H),2.30 (s,3H). A0213: MS m / z (ESI):418.3[M+1] + . 1H NMR (400MHz,Chloroform-d) δ 8.12 (s,1H),7.76 (d,J=7.6Hz,1H),7.52-7.50 (m,1H),7.43 (m,1H),7.30 (m,1H),7.15 (d,J=7.2Hz,1H),4.97 (brs,1H),4.35-4.27 (m,1H),4.20-4.00 (m,1H),3.87-3.82 (m,4H),3.53 (d,J=4.4Hz,3H),3.22-3.10 (m,1H),3.05-2.88 (m,1H),2.80-2.70 (m,1H),2.29 (t,J=4.0Hz,3H).

[0493] Examples A0173 & A0181 2-(3-cyano-2-methylphenyl)-5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile 2-(3-cyano-2-methylphenyl)-5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[0494] [ka]

[0495] [ka]

[0496] Step 1 3-Cyano-4-(3-cyano-2-methylphenyl)benzoic acid 173c 173a (0.25 g, 1.11 mmol), 173b (0.27 g, 1.11 mmol), Pd(dppf)Cl (0.081 g, 0.11 mmol), and potassium carbonate (0.31 g, 2.22 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL) and reacted at 100 °C for 4 hours under argon gas protection. The reaction mixture was filtered, concentrated, dissolved in ethyl acetate (20 mL), washed with 1N hydrochloric acid, dried, and concentrated to give product 173c (350 mg, crude). MS m / z (ESI): 263.0 [M+1] + .

[0497] Step 2 2-(3-cyano-2-methylphenyl)-5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile 2-(3-cyano-2-methylphenyl)-5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile 173c (0.20 g, 0.76 mmol), 4 (0.19 g, 0.99 mmol), and DMAP (0.19 g, 1.52 mmol) were dissolved in DMF (1 mL) and DCM (2 mL). EDCI (0.19 g, 0.99 mmol) was added at 15 °C, followed by a 16-hour reaction. The reaction mixture was diluted with ethyl acetate and washed sequentially with brine and 1N hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer A0181 (Rf = 0.4) and the crude more polar isomer A0173 (Rf = 0.35). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0173 (36.03 mg, yield: 11.6%) and a less polar product A0181 (25.85 mg, yield: 7.25%).

[0498] A0173: MS m / z (ESI): 389.1 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.98 (d,J=17.2Hz,1H),7.85 (d,J=6.0Hz,1H),7.75 (d,J=7.6Hz,1H),7.45-7.41 (m,3H),4.89 (brs,1H),4.41-4.37 (m,1H),4.19-4.10 (m,1H),4.00-3.92 (m,1H),3.87 (d,J=4.0Hz,3H),3.83-3.72 (m,1H),3.02-2.89 (m,1H),2.85-2.69 (m,1H),2.41 (d,J=6.8Hz,3H). A0181: MS m / z (ESI): 389.1 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.96 (d,J=17.2Hz,1H),7.84 (d,J=7.6Hz,1H),7.76-7.74 (m,1H),7.45-7.41 (m,3H),4.89 (brs,1H),4.41-4.37 (m,1H),4.19-4.10 (m,1H),4.00-3.89 (m,1H),3.88 (d,J=4.0Hz,3H),3.82-3.72 (m,1H),2.99-2.89 (m,1H),2.80-2.69 (m,1H),2.41 (d,J=6.4Hz,3H).

[0499] Examples A0183 & A0184 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-(3-hydroxyoxetan-3-yl)phenyl)-2-methylbenzonitrile 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-(3-hydroxyoxetan-3-yl)phenyl)-2-methylbenzonitrile

[0500] [ka]

[0501] [ka]

[0502] Step 1 Methyl 4-chloro-3-(3-hydroxyoxetan-3-yl)benzoate 183b 183a (2 g, 6.75 mmol) and oxetan-3-one (1.46 g, 20.25 mmol) were dissolved in THF (10 mL), and n-butyllithium (0.56 g, 8.78 mmol) was added dropwise at -60 to -70 °C. After the addition was completed, the reaction was allowed to proceed for 30 to 60 minutes. The reaction was quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL × 3), dried, concentrated, stirred, and purified using a silica gel column to give 183b (0.55 g, yield: 33.6%).

[0503] MS m / z (ESI): 225.0 [M-17+1] + Following steps 2 to 4 of the above synthetic route, and referring to the synthesis method for compound A0167, crude less polar isomer A0184 (Rf = 0.4) and crude more polar isomer A0183 (Rf = 0.35) were obtained. These were then separated by HPLC, purified, and lyophilized to give the more polar product A0183 (15.58 mg, yield: 15.6%) and the less polar product A0184 (18.67 mg, yield: 18.0%).

[0504] A0183: MS m / z (ESI):436.0[M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.67 (d,J=7.6Hz,1H),7.52-7.45 (m,2H),7.41 (s,1H),7.34-7.26 (m,1H),7.19-7.16 (m,1H),5.04-4.87 (m,2H),4.55-4.50 (m,1H),4.48-4.10 (m,3H),3.98-3.86 (m,5H),3.80-3.52 (m,2H),2.96-2.59 (m,2H),2.34 (d,J=8.8Hz,3H). A0184: MS m / z (ESI):436.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.66 (d,J=6.8Hz,1H),7.52-7.47 (m,2H),7.41 (s,1H),7.34-7.26 (m,1H),7.18 (d,J=8.0Hz,1H),5.04-4.86 (m,2H),4.54-4.22 (m,5H),4.00-3.83 (m,5H),3.80-3.72 (m,1H),2.98-2.87 (m,1H),2.69-2.60 (m,1H),2.34 (d,J=8.8Hz,3H).

[0505] Examples C0050 & C0051 (S,E)-(4-(2,3-dihydro-1H-inden-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(4-(2,3-dihydro-1H-inden-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0506] [ka]

[0507] [ka]

[0508] Following the above synthetic route, and referring to the synthetic method for compound C0055, the less polar isomer C0050 (Rf=0.6) and the crude more polar isomer C0051 (Rf=0.4) were obtained. Then, after separation and purification by HPLC, the less polar product C0050 (29.1 mg, yield: 11.2%) and the more polar product C0051 (26.2 mg, yield: 10.0%) were obtained.

[0509] C0050:MS m / z (ESI):365.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.62-7.53 (m,4H),7.25-7.16 (m,3H),4.83-3.68 (m,7H),3.31-3.30 (m,1H),2.99-2.86 (m,4H),2.88-2.86 (m,2H),2.08-2.01 (m,2H). C0051:MS m / z (ESI):365.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.62-7.55 (m,4H),7.25-7.16 (m,3H),4.76-4.09 (m,3H),3.84-3.38 (m,5H),2.99-2.75 (m,6H),2.08-2.01 (m,2H).

[0510] Examples C0074 & C0075 (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dimethyl-[1,1'-biphenyl]-4-carbonitrile (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dimethyl-[1,1'-biphenyl]-4-carbonitrile

[0511] [ka]

[0512] [ka]

[0513] Step 1 4-Bromo-2,3-dimethylbenzonitrile 74b 74a (2 g, 6.43 mmol) was dissolved in ethylene glycol (30 mL), followed by the addition of potassium ferricyanide (2.12 g, 6.43 mmol), sodium hydroxide (0.51 g, 12.86 mmol), and cuprous iodide (0.12 g, 0.64 mmol). The reaction mixture was stirred at 140 °C for 18 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and spun to dryness. The crude product was subjected to column chromatography (PE / EA = 10:1) to give 74b (0.9 g, yield: 66.6%). MS m / z (ESI): 210.0 [M+1] + .

[0514] Following Steps 2 and 3 of the above synthetic pathway, and referring to the synthesis method for compound C0065, crude less polar product C0074 (Rf=0.4) and crude more polar product C0075 (Rf=0.3) were obtained. These were then separated and purified by HPLC, and lyophilized to give less polar product C0074 (11 mg, yield: 7.3%) and more polar product C0075 (40 mg, yield: 26.7%), respectively.

[0515] C0074:MS m / z (ESI):378.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.65 (d,J=7.2Hz,2H),7.57 (d,J=8.0Hz,1H),7.41 (d,J=8.4Hz,2H),7.22 (d,J=8.0Hz,1H),4.82-4.36 (m,2H),4.11-3.66 (m,6H),2.88-2.86 (m,2H),2.58 (s,3H),2.21 (s,3H). C0075: ESI-MS: m / z= 378.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.64 (d,J=7.6Hz,2H),7.57 (d,J=8.0Hz,1H),7.42 (d,J=8.0Hz,2H),7.23 (d,J=8.4Hz,1H),4.83-4.75 (m,1H),4.42-4.06 (m,2H),3.88-3.62 (m,4H),3.35-3.11 (m,1H),3.30-2.63 (m,2H),2.56 (s,3H),2.22 (s,3H).

[0516] Examples C0082 & C0083 (S,E)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0517] [ka]

[0518] [ka]

[0519] Step 1 7-Bromo-2,3-dihydro-1H-inden-4-ol 83b 83a (1.0 g, 7.45 mmol) was dissolved in dichloromethane (20 mL). Liquid bromine Br2 (1.43 g, 8.94 mmol) was added dropwise under nitrogen gas protection and an ice bath. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into a 10% sodium thiosulfate solution, and the organic phase was collected and washed twice with saturated sodium bicarbonate solution. The combined organic phases were washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was separated by column chromatography (PE:EA = 10:1 to 5:1) to give 83b (1.1 g, yield: 63.7%). MS m / z (ESI): 212.8 [M+1] + .

[0520] Step 2 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-inden-4-ol 83d To a solution of 83b (1.0 g, 4.41 mmol) in dioxane / water (20 mL / 4 mL), 83c (860 mg, 5.73 mmol) and potassium carbonate (1.52 g, 11.03 mmol) were added. Under nitrogen gas protection, 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (323 mg, 0.44 mmol) was added at room temperature. After purging with nitrogen gas, the mixture was reacted at 80 °C for 3 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product was separated by column chromatography (PE:EA = 6:1 to 4:1) to obtain 83d (1.2 g, crude). MS m / z (ESI): 239.0 [M+1] + .

[0521] Step 3 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate 83e 83d (1.2 g, 4.73 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (1.44 g, 14.19 mmol) and trifluoromethanesulfonic anhydride (2.0 g, 7.10 mmol) were added sequentially at room temperature. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product was separated by column chromatography (PE:EA = 1:0 to 5:1) to give 83e (1.1 g, yield: 60.8%). MS m / z (ESI): 271.0 [M+1] + .

[0522] Step 4 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-indene-4-carboxylic acid 83f 83e (700 mg, 1.85 mmol) was dissolved in acetonitrile / water (14 / 2 mL) and 1,3-bis(diphenylphosphino)propane (76 mg, 0.18 mmol), triethylamine (370 mg, 3.66 mmol), and palladium acetate (43 mg, 0.19 mmol) were added at room temperature. The atmosphere was purged with carbon monoxide three times, the pressure was increased to 3 MPa, and the mixture was reacted at 80 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product was separated using a C18 reverse-phase silica gel column to obtain 83f (230 mg, yield: 45.7%). MS m / z (ESI): 267.0 [M+1] + .

[0523] Step 5 (S,Z)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone To a DMF solution of 83f (110 mg, 0.41 mmol), 4 (80.0 mg, 0.55 mmol), HATU (170 mg, 0.45 mmol), and N,N-diisopropylethylamine (160 mg, 1.42 mmol) were added and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was placed in a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated to obtain the crude product. Silica gel prep-TLC (PE:EA = 1:2) yielded the crude product C0082 (Rf = 0.4), a less polar product, and C0083 (Rf = 0.3). Then, each was separated by HPLC, purified, and freeze-dried to give the less polar product C0082 (10.55 mg, yield: 6.5%) and the more polar product C0083 (14.05 mg, yield: 8.6%).

[0524] C0082:MS m / z (ESI):393.2[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.25 (d,J=7.6Hz,1H),7.16-7.08 (m,2H),7.03 (d,J=7.6Hz,1H),6.93 (d,J=6.4Hz,1H),4.73-4.49 (m,1H),4.21-3.31 (m,7H),3.09-2.83 (m,4H),2.69-2.55 (m,2H),2.32 (s,3H),2.16-2.00 (m,5H). C0083:MS m / z (ESI):393.2[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.25 (d,J=7.2Hz,1H),7.16-7.09 (m,2H),7.04 (d,J=7.6Hz,1H),6.95 (m,1H),4.71-4.58 (m,1H),4.25-3.73 (m,6H),3.36-3.31 (m,1H),3.09-2.83 (m,3H),2.80-2.55 (m,3H),2.32 (s,3H),2.15-2.01 (m,5H).

[0525] Examples C0084 & C0085 (S,E)-(5-(2,3-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0526] [ka]

[0527] [ka]

[0528] Step 1 6-chloro-3-(2,3-dimethylphenyl)-2-(trifluoromethyl)pyridine 85b To a solution of 85a (500 mg, 1.92 mmol) in 1,4-dioxane (20 mL) and water (2 mL), 1A (720 mg, 4.80 mmol), potassium carbonate (663 mg, 4.80 mmol), and Pd(dppf)Cl2 (78.40 mg, 0.096 mmol) were added. The mixture was purged with nitrogen gas and reacted at 80 °C for 3 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified using a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 5:95 to 70:30) to give product 85b (300 mg, yield: 51.9%). MS m / z (ESI): 285.9 [M+1] + .

[0529] Step 2 5-(2,3-Dimethylphenyl)-6-(trifluoromethyl)pyridinecarboxylic acid methyl ester 85c To a solution of 85b (200 mg, 1.92 mmol) in methanol (15 mL), triethylamine (203.4 mg, 2.01 mmol), palladium acetate (30.1 mg, 0.13 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (74.3 mg, 0.13 mmol) were added. The reaction mixture was purged with a carbon monoxide balloon and then reacted at 70 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated to remove methanol. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel pre-TLC (PE / EA = 4:1, Rf = 0.5) to give product 85c (150 mg, yield: 69.3%). MS m / z (ESI): 309.9 [M+1] + .

[0530] Following Steps 3 and 4 of the above synthetic route, and referring to the synthesis method of compound C0061, crude less polar isomer C0084 (Rf=0.6) and crude more polar isomer C0084 (Rf=0.55) were obtained. Then, after separation and purification by HPLC and lyophilization, less polar product C0084 (38.0 mg, yield: 12.7%) and more polar product C0085 (26.0 mg, yield: 18.6%) were obtained.

[0531] C0084:MS m / z (ESI):422.1[M+1] + . 1H NMR (DMSO-d6,400MHz) δ 8.18-8.09 (m,1H),7.98 (d,J=8.0Hz,1H),7.27 (d,J=7.6Hz,1H),7.15 (t,J=7.6Hz,1H),7.00 (m,J=8.0Hz,1H),5.03-4.93 (m,1H),4.78-4.65 (m,1H),4.60-4.58 (m,1H),4.52-4.11(m,1H),3.81-3.80 (m,3H),3.64-3.39 (m,2H),3.30-2.66 (m,2H),2.30 (s,3H),1.91 (d,J=6.0Hz,3H). C0085:MS m / z (ESI):422.1[M+1] + . 1 H NMR (DMSO-d6,400MHz) δ 8.16-8.11 (m,1H),8.00-7.97 (m,1H),7.28-7.26 (m,1H),7.19-7.16 (m,1H),7.03-6.90 (m,1H),5.03-4.93 (m,1H),4.80-4.77 (m,1H),4.63-4.12 (m,3H),3.83-3.75 (m,3H),3.62-3.45 (m,2H),2.99-2.59 (m,2H),2.30 (s,3H),2.31-1.89 (m,3H).

[0532] Examples A0203 & A0217 2-chloro-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 2-chloro-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0533] [ka]

[0534] [ka]

[0535] Step 1 4-(2-chloro-3-cyanophenyl)benzoic acid 203c 203a (0.3 g, 1.39 mmol), 203b (0.28 g, 1.67 mmol), Pd(dppf)Cl2 (0.051 g, 0.069 mmol), and potassium carbonate (0.38 g, 2.78 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 100 °C for 16 hours. The reaction mixture was diluted with 10 mL of ethyl acetate, filtered, concentrated, and dissolved in 10 mL of ethyl acetate. The mixture was washed with 1N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to give 203c (150 mg, yield: 42.0%). MS m / z (ESI): 257.9 [M+1] + .

[0536] Step 2 2-chloro-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 2-chloro-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 203c (0.10 g, 0.39 mmol), 4 (0.056 g, 0.39 mmol), and DIPEA (0.15 g, 1.17 mmol) were dissolved in DMF (2 mL). HATU (0.18 g, 0.47 mmol) was added at 20 °C, followed by a 16-hour reaction. The reaction mixture was diluted with ethyl acetate and washed sequentially with brine and 1N hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer A0217 (Rf = 0.4) and the crude more polar isomer A0203 (Rf = 0.35). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0203 (5.44 mg, yield: 3.32%) and a less polar product A0217 (3.64 mg, yield: 1.99%).

[0537] A0203: MS m / z (ESI): 384.1 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.72 (d,J=6.0Hz,1H),7.63-7.57 (m,3H),7.52-7.48 (m,3H),4.89 (brs,1H),4.42-4.18 (m,2H),3.98-3.77 (m,5H),2.99-2.92 (m,2H),2.65 (d,J=17.2Hz,1H). A0217: MS m / z (ESI): 384.1 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.72 (d,J=6.0Hz,1H),7.65-7.55 (m,3H),7.52-7.43 (m,3H),4.91 (brs,1H),4.55-4.17 (m,2H),3.98-3.75 (m,5H),3.24-2.89 (m,3H).

[0538] Examples A0204 & A0218 2-(Difluoromethyl)-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 2-(Difluoromethyl)-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0539] [ka]

[0540] [ka]

[0541] Step 1 4-Chlorocarbonylphenylboronic acid (2.21 g, 12.00 mmol) and triethylamine (3.51 g, 34.7 mmol) were added to a solution of 4 (2.00 g, 13.88 mmol) in dichloromethane (20 mL) at 0 °C, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was washed with water (20 mL), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified using a normal-phase silica gel column (PE:EA = 1:3) to obtain product 204c (2.81 g, yield: 80%).

[0542] Step 2 3-Bromo-2-(difluoromethyl)benzonitrile 204b 204a (0.13 g, 0.62 mmol) was dissolved in DCM (1 mL), and DAST (0.15 g, 0.93 mmol) was added at 15°C. The mixture was allowed to react for 16 hours. The reaction was quenched with 3 mL of saturated sodium bicarbonate and extracted with dichloromethane. The combined organic phases were dried and concentrated to give 204b (130 mg, crude). MS m / z (ESI): 231.8 [M+1] + .

[0543] Step 3 2-(Difluoromethyl)-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 2-(Difluoromethyl)-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile 204b (0.065 g, 0.28 mmol), 204c (0.082 g, 0.28 mmol), Pd(dppf)Cl2 (0.02 g, 0.028 mmol), and potassium carbonate (0.077 g, 0.56 mmol) were dissolved in 1,4-dioxane (2 mL) and water (1 mL) and reacted at 100 °C for 16 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with brine and 1N hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer A0218 (Rf = 0.4) and the crude more polar isomer A0204 (Rf = 0.35). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0204 (28.55 mg, yield: 24.8%) and a less polar product A0218 (23.95 mg, yield: 21.0%).

[0544] A0204: MS m / z (ESI): 400.3 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.92-7.84 (m,1H),7.72-7.58 (m,4H),7.60-7.33 (m,2H),6.66 (td,J=53.2,6.4Hz,1H),4.88 (brs,1H),4.42-4.12 (m,2H),4.03-3.74 (m,5H),2.99-2.93 (m,2H),2.69-2.65 (m,1H). A0218: MS m / z (ESI): 400.3 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.87 (d,J=7.2Hz,1H),7.66-7.63 (m,3H),7.57 (d,J=8.0Hz,1H),7.40 (d,J=7.6Hz,2H),6.65 (t,J=53.2Hz,1H),4.90 (brs,1H),4.38-4.13 (m,2H),3.93-3.72 (m,5H),2.97-2.90 (m,2H),2.80-2.65 (m,1H).

[0545] Examples A0212 & A0221 3-(5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]thiophen-2-yl)-2-methylbenzonitrile 3-(5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]thiophen-2-yl)-2-methylbenzonitrile

[0546] [ka]

[0547] [ka]

[0548] Following the above synthetic route, and referring to the synthetic method of compound A0167, crude less polar isomer A0221 (Rf=0.6) and crude more polar isomer A0212 (Rf=0.55) were obtained. Then, after separation and purification by HPLC, more polar product A0212 (9.55 mg, yield: 6.16%) and less polar product A0221 (9.00 mg, yield: 5.61%) were obtained.

[0549] A0212: MS m / z (ESI): 370.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.66 (d,J=7.6Hz,1H),7.63-7.58 (m,2H),7.35 (t,J=7.6Hz,1H),7.07 (d,J=3.6Hz,1H),4.90 (brs,1H),4.68-4.53 (m,2H),3.92-3.84 (m,4H),3.80-3.75 (m,1H),2.98-2.89 (m,1H),2.82-65 (m,2H),2.62 (s,3H). A0221: MS m / z (ESI): 370.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.66 (d,J=8.0Hz,1H),7.59 (d,J=7.6Hz,1H),7.53 (d,J=3.6Hz,1H),7.35-7.32 (m,1H),7.05 (d,J=3.6Hz,1H),4.98-4.88 (m,1H),4.69 (d,J=15.2Hz,1H),4.60-4.48 (m,1H),3.95-3.87 (m,4H),3.80-3.72 (m,1H),2.91-2.84 (m,1H),2.80-2.73 (m,1H),2.61 (s,3H).

[0550] Examples C0070 & C0071 (S,E)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0551] [ka]

[0552] [ka]

[0553] Following the above synthetic route and referring to the synthetic method for compound C0084, crude less polar isomer C0070 (Rf=0.6) and crude more polar isomer C0071 (Rf=0.55) were obtained. Then, they were separated by HPLC, purified, and lyophilized to give less polar product C0070 (30.0 mg, yield: 21.4%) and more polar product C0071 (19.0 mg, yield: 13.6%), respectively.

[0554] C0070:MS m / z (ESI):422.0[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.63-8.59 (m,1H),8.15-8.09 (m,1H),7.29 (d,J=7.6Hz,1H),7.20-7.17 (m,1H),7.04-7.01 (m,1H),5.03-4.93 (m,1H),4.94-4.67 (m,1H),4.52-4.12 (m,2H),3.82-3.78 (m,3H),3.65-3.36 (m,2H),2.83-2.66 (m,2H),2.31 (s,3H),1.91-1.89 (m,3H). C0071:MS m / z (ESI):422.1[M+1] + . 1 H NMR (DMSO-d6,400MHz) δ 8.65-8.59 (m,1H),8.14-8.09 (m,1H),7.28 (d,J=7.6Hz,1H),7.20-7.17 (m,1H),7.05-7.01 (m,1H),4.99-4.87 (m,1H),4.80-4.64 (m,1H),4.54-4.13 (m,2H),3.82-3.75 (m,3H),3.01-2.67 (m,2H),2.63-2.59 (m,1H),2.31 (s,3H),1.91-1.89 (m,3H).

[0555] Examples C0076 & C0077 (S,E)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyrimidin-4(3H)-one (S,Z)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyrimidin-4(3H)-one

[0556] [ka]

[0557] [ka]

[0558] Step 1 1-(2,3-Dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester 76b 76a (500 mg, 2.97 mmol) was dissolved in dichloromethane (30 mL) and subsequently 1A (535 mg, 3.56 mmol), cupric acetate monohydrate (1.19 g, 5.94 mmol), pyridine (1.17 g, 14.85 mmol), triethylamine (0.60 g, 5.94 mmol), zeolite (1 g), and 1,10-phenanthroline (0.54 g, 2.97 mmol) were added. The atmosphere was purged with nitrogen and the mixture was reacted at room temperature for 17 hours. After completion of the reaction, the reaction mixture was filtered to remove insoluble solids. The filtrate was rotary evaporated to remove the solvent, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL) and dried over sodium sulfate. The solvent was then evaporated, and the residue was purified using a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 5:95 to 70:30) to give product 76b (60 mg, yield: 7.4%). MS m / z (ESI): 273.0 [M+1] + .

[0559] Following Steps 2 and 3 of the above synthetic route, and referring to the synthesis method of compound C0061, crude less polar isomer C0076 (Rf=0.6) and crude more polar isomer C0077 (Rf=0.55) were obtained. Then, after separation and purification by HPLC and lyophilization, the less polar product C0076 (1.9 mg, yield: 2.5%) and the more polar product C0077 (4.9 mg, yield: 6.5%) were obtained.

[0560] C0076:MS m / z (ESI):371.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.38 (d,J=12.0Hz,1H),7.36 (d,J=7.6Hz,1H),7.31-7.29 (m,1H),7.17-7.15 (m,1H),6.91 (s,1H),4.70-4.50 (m,3H),3.87-3.85 (m,3H),3.66-3.48 (m,2H),2.86-2.77 (m,2H),2.38 (s,3H),2.04 (s,3H). C0077:MS m / z (ESI):371.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.38 (d,J=12.8Hz,1H),7.35 (m,1H),7.31-7.29 (m,1H),7.17-7.15 (m,1H),6.91 (s,1H),4.68-4.54 (m,3H),3.88-3.82 (m,3H),3.69-3.60 (m,2H),3.03-2.63 (m,2H),2.38 (s,3H),2.04 (s,3H).

[0561] Examples C0078 & C0079 (S,E)-(3'-(difluoromethyl)-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(3'-(difluoromethyl)-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0562] [ka]

[0563] [ka]

[0564] Step 1 1-Bromo-3-(difluoromethyl)-2-methylbenzene 78b 78a (1 g, 5.02 mmol) was dissolved in dichloromethane (20 mL). Diethylaminotrifluoride (0.95 g, 5.89 mmol) was added dropwise to the reaction mixture under nitrogen gas protection at 0°C and the mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The solvent was then rotary evaporated to give product 78b (500 mg, yield: 44.1%).

[0565] Following Steps 2 and 3 of the above synthetic route, and referring to the synthesis method of compound C0065, crude less polar isomer C0078 (Rf=0.6) and crude more polar isomer C0079 (Rf=0.5) were obtained. Then, after separation and purification by HPLC and lyophilization, the less polar product C0078 (29.0 mg, yield: 14.5%) and the more polar product C0079 (57.6 mg, yield: 28.8%) were obtained.

[0566] C0078:MS m / z (ESI):389.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.65-7.55 (m,3H),7.42-7.36 (m,4H),7.12-6.84 (t,J=54.8Hz,1H),4.76-4.08 (m,3H),3.84 (s,3H),3.69-3.35 (m,2H),2.88-2.87 (m,2H),2.29 (s,3H). C0079:MS m / z (ESI):389.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.65-7.55 (m,3H),7.43-7.37 (m,4H),7.12-6.85 (t,J=54.8Hz,1H),4.77-4.09 (m,3H),3.88-3.80 (m,3H),3.73-3.37 (m,2H),2.98-2.76 (m,2H),2.30 (s,3H).

[0567] Examples C0086 & C0087 (S,E)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0568] [ka]

[0569] [ka]

[0570] Step 1 2-Chloro-5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidine 87c To a solution of 87a (500 mg, 1.91 mmol) in 1,4-dioxane (10 mL), (2,3-dimethylphenyl)boronic acid (290 mg, 1.93 mmol), potassium carbonate (580 mg, 4.19 mmol), and Pd(dppf)Cl2 (140 mg, 0.19 mmol) were added. The mixture was then purged with nitrogen gas and reacted at 80 °C for 2 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified using a silica gel normal phase column (eluted with a gradient of petroleum ether:ethyl acetate = 5:1 to 3:1) to give product 87c (320 mg, yield: 57.2%). MS m / z (ESI): 286.9 [M+1] + .

[0571] Step 2 5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidine-2-carboxylic acid 87d To a solution of 87c (260 mg, 0.89 mmol) in acetonitrile (7 mL) and water (1 mL) was added 1,3-bis(diphenylphosphino)propane (37 mg, 0.09 mmol), triethylamine (185 mg, 1.83 mmol), and palladium acetate (20 mg, 0.089 mmol) at room temperature. The mixture was purged with carbon monoxide three times, pressurized to 4 MPa, and reacted at 80 °C for 4 h. After completion of the reaction, the reaction mixture was concentrated, and the crude product was separated on a C18 reverse-phase silica gel column (eluted with a gradient of acetonitrile:water = 30:70 to 75:25) to obtain 87d (170 mg, yield: 63.3%). MS m / z (ESI): 296.9 [M+1] + .

[0572] Step 3 (S,Z)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone To a solution of 87d (170 mg, 0.52 mmol) in DMF (5 mL) was added 4 (120 mg, 0.75 mmol), HATU (220 mg, 0.58 mmol), and N,N-diisopropylethylamine (200 mg, 1.55 mmol) at room temperature. The mixture was then reacted for 2 hours at room temperature. After the reaction was complete, the mixture was poured into a mixture of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The residue was purified by silica gel pre-TLC (PE:EA = 2:5) to give the crude less polar isomer C0086 (Rf = 0.6) and the crude more polar isomer C0087 (Rf = 0.55). Next, each was separated by HPLC, purified, and freeze-dried to give the less polar product C0086 (16.89 mg, yield: 7.73%) and the more polar product C0087 (20.29 mg, yield: 9.29%).

[0573] C0086:MS m / z (ESI):423.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.98-8.95 (m,1H),7.31 (d,J=8.0Hz,1H),7.20 (t,J=7.6Hz,1H),7.04 (d,J=7.2Hz,1H),4.81-4.26 (m,3H),3.92-3.73 (m,4H),3.69-3.51 (m,1H),2.98-2.89 (m,2H),2.36 (s,3H),2.00 (s,3H). C0087:MS m / z (ESI):423.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 8.97 (d,J=9.2Hz,1H),7.31 (d,J=7.6Hz,1H),7.20 (t,J=7.6Hz,1H),7.06-7.03 (m,1H),4.83-4.30 (m,3H),3.89-3.73 (m,4H),3.64-3.53 (m,1H),3.03-2.94 (m,1H),2.82-2.64 (m,1H),2.36 (s,3H),2.01 (s,3H).

[0574] Examples C0090 & C0091 (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile

[0575] [ka]

[0576] [ka]

[0577] Step 1 (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile 204c (150 mg, 0.50 mmol), 91b (88.5 mg, 0.58 mmol), and potassium carbonate (175 mg, 1.27 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen gas protection, Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added at room temperature and the mixture was reacted at 80 °C for 3 h. After the reaction was completed, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel pre-TLC (DCM:MeOH=10:1) to give the less polar isomer C0090 (Rf=0.65, 17.5 mg, yield: 8.55%) and the crude more polar isomer C0091 (Rf=0.60). The crude more polar isomer was then separated and purified by HPLC, and lyophilized to give C0091 (23.68 mg, yield: 12.8%).

[0578] C0090:MS m / z (ESI):365.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.58 (d,J=4.8Hz,1H),7.70 (d,J=7.6Hz,2H),7.55-7.51 (m,3H),4.76-4.06 (m,3H),3.95-3.76 (m,4H),3.73-3.36 (m,1H),2.90-2.81 (m,2H),2.50 (s,3H). C0091:MS m / z (ESI):365.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.58 (d,J=4.8Hz,1H),7.70 (d,J=7.6Hz,2H),7.56-7.52 (m,3H),4.76-4.06 (m,3H),3.90-3.37 (m,5H),3.05-2.90 (m,1H),2.77-2.55 (m,1H),2.50 (s,3H).

[0579] Examples C0092 & C0093 (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile

[0580] [ka]

[0581] [ka]

[0582] Step 1 (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpyridinecarbonitrile 204c (150 mg, 0.51 mmol), 93b (100 mg, 0.51 mmol), and potassium carbonate (175 mg, 1.27 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen gas protection, Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added at room temperature and the mixture was reacted at 80 °C for 3 h. After the reaction was completed, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel pre-TLC (EA:PE=3:1) to give the less polar isomer C0092 (Rf=0.60, 26.23 mg, yield: 13.6%) and the crude more polar isomer C0093 (Rf=0.55). The crude more polar isomer was then separated and purified by HPLC, and lyophilized to give C0093 (36.68 mg, yield: 19.6%).

[0583] C0092:MS m / z (ESI):364.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.68-7.61 (m,4H),7.47-7.41 (m,3H),4.76-4.04 (m,3H),3.93-3.36 (m,5H),2.92-2.81 (m,2H),2.31 (s,3H). C0093:MS m / z (ESI):364.1[M+1]+. 1 H NMR (400MHz,CD3OD-d4) δ 7.6-7.61 (m,4H),7.46 (d,J=8.0Hz,2H),7.41 (d,J=7.6Hz,1H),4.75-4.08 (m,3H),3.88-3.38 (m,5H),2.96-2.90 (m,1H),2.77-2.63 (m,1H),2.31 (s,3H).

[0584] Examples C0094 & C0095 (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile

[0585] [ka]

[0586] [ka]

[0587] Step 1 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile 204c (150 mg, 0.51 mmol), 95b (100 mg, 0.51 mmol), and potassium carbonate (175 mg, 1.27 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen gas protection, Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added at room temperature and the mixture was reacted at 80 °C for 3 h. After the reaction was completed, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel pre-TLC (EA:PE=3:1) to give the less polar isomer C0094 (Rf=0.60, 30.22 mg, yield: 16.07%) and the crude more polar isomer C0095 (Rf=0.55). The crude more polar isomer was then separated and purified by HPLC, and lyophilized to give C0095 (46.49 mg, yield: 26.82%).

[0588] C0094:MS m / z (ESI):364.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.67-7.59 (m,4H),7.51-7.44 (m,3H),4.77-4.07 (m,3H),3.94-3.38 (m,5H),2.91-2.82 (m,2H),2.33 (s,3H). C0095:MS m / z (ESI):364.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.63-7.60 (m,4H),7.51-7.44 (m,3H),4.76-4.08 (m,3H),3.88-3.38 (m,5H),3.03-2.90 (m,1H),2.77-2.63 (m,1H),2.34 (s,3H).

[0589] Examples C0096 & C0097 (S,E)-(5-(2,3-dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0590] [ka]

[0591] [ka]

[0592] Step 1 (S,EZ)-(5-Bromothiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 97b To a solution of 97a (450 mg, 2.16 mmol) in DMF (9 mL), 4 (373.69 mg, 2.59 mmol), HATU (0.99 g, 2.59 mmol), and TEA (0.66 g, 6.48 mmol) were added. After purging with nitrogen gas, the mixture was allowed to react at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate / water, and the combined organic phases were washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give the crude product. The crude product was purified by reverse-phase column chromatography (HO:ACN = 95:5 to 50:50) to give product 97b (450 mg, yield: 56.0%). MS m / z (ESI): 333.8, 335.8 [M+1] + .

[0593] Step 2 (S,E)-(5-(2,3-dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone To a solution of 97b (200 mg, 0.60 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added (2,3-dimethylphenyl)boronic acid (0.11 g, 0.72 mmol), potassium carbonate (0.25 g, 1.80 mmol), and Pd(dppf)Cl (0.049 g, 0.060 mmol). The atmosphere was purged with nitrogen gas, and the reaction mixture was reacted at 95 °C for 1 hour. The reaction mixture was extracted with ethyl acetate / water, and the combined organic phases were washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give the crude product. The crude product was purified by silica gel pre-TLC (PE:EA=1:5) to give the less polar isomer C0096 (Rf=0.6, 21.0 mg, yield: 9.6%) and the more polar isomer C0097 (Rf=0.5, 55.0 mg, yield: 25.1%).

[0594] C0096:MS m / z (ESI):360.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.85 (d,J=10.4Hz,1H),7.26-7.13 (m,3H),5.66-5.15 (m,1H),4.73-4.69 (m,1H),4.59-4.19 (m,1H),3.90-3.64 (m,5H),3.05-2.82 (m,2H),2.35 (s,3H),2.28 (s,3H). C0097:MS m / z (ESI):360.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.85 (d,J=10.4Hz,1H),7.26-7.13 (m,3H),5.66-5.09 (m,1H),4.180-4.69 (m,1H),4.59-4.26 (m,1H),3.90-3.64 (m,5H),3.05-2.73 (m,2H),2.35 (s,3H),2.28 (s,3H).

[0595] Examples C0098 & C0099 3-(7-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile 3-(7-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile

[0596] [ka]

[0597] [ka]

[0598] Step 1 Methyl 7-(3-cyano-2-methylphenyl)benzo[d][1,3]dioxolane-4-carboxylate 99b To a solution of 99a (200 mg, 0.77 mmol) in dioxane (5 mL) and water (0.5 mL) was added (3-cyano-2-methylphenyl)boronic acid (140 mg, 0.87 mmol), potassium carbonate (210 mg, 1.52 mmol), and Pd(dppf)Cl (63 mg, 0.077 mmol). The mixture was purged with nitrogen gas and reacted at 90 °C for 3 h. The reaction mixture was filtered, rotary evaporated, and purified by silica gel prep-TLC (PE:EA = 5:1) to give product 99b (150 mg, yield: 65.8%). MS m / z (ESI): 296.1 [M+1] + .

[0599] Step 2 7-(3-cyano-2-methylphenyl)benzo[d][1,3]dioxolane-4-carboxylic acid 99c To a solution of 99b (160 mg, 0.54 mmol) in THF (8 mL) and water (4 mL) was added LiOH (90.63 mg, 2.16 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a Buchner funnel, and the filtrate was extracted with EA after removing the methanol. The aqueous phase was collected and the pH of the aqueous phase was adjusted to 1-3 with hydrochloric acid, followed by extraction with EA. The combined organic phases were washed with saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give product 99c (100 mg, yield: 65.6%).

[0600] Step 3 3-(7-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile 3-(7-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile To a solution of 4 (74 mg, 0.52 mmol) in DMF (3 mL), 99c (120 mg, 0.69 mmol), triethylamine (270 mg, 2.07 mmol), and HATU (390 mg, 0.43 mmol) were added. The atmosphere was purged with nitrogen gas, and the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was separated by silica gel pre-TLC (EA:PE=5:1) to obtain the less polar isomer C0098 (Rf=0.6) and the crude more polar isomer C0099 (Rf=0.5). The crude more polar isomer was separated by HPLC, purified, and lyophilized to give the more polar product C0099 (14.0 mg, yield: 7.97%).

[0601] C0098:MS m / z (ESI):408.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.72 (d,J=7.2Hz,1H),7.58 (d,J=7.6Hz,1H),7.43 (t,J=8.0Hz,1H),7.06 (d,J=8.4Hz,1H),6.88 (d,J=8.0Hz,1H),6.16-6.06 (m,2H),4.72-4.13 (m,3H),3.87-3.68 (m,4H),3.39-3.38 (m,1H),2.90-2.81 (m,2H),2.45 (s,3H). C0099: MS m / z (ESI): 408.1 [M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.72 (d,J=8.0Hz,1H),7.58 (dd,J=7.6,2.8Hz,1H),7.43 (t,J=7.6Hz,1H),7.07 (d,J=8.4Hz,1H),6.88 (d,J=8.0Hz,1H),6.10 (dd,J=19.6,5.2Hz,2H),4.72-4.15 (m,3H),3.88-3.69 (m,4H),3.39-3.38 (m,1H),3.03-2.90 (m,1H),2.79-2.65 (m,1H),2.46 (s,3H).

[0602] Examples C0102 & C0103 (S,E)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one (S,Z)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one

[0603] [ka]

[0604] [ka]

[0605] Step 1 5-Bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid 102b 102a (50 mg, 0.23 mmol) was dissolved in a mixture of water (7 mL) and methanol (1 mL), and iodomethane (326 mg, 2.30 mmol) and potassium hydroxide (43 mg, 0.76 mmol) were added. The mixture was then microwaved at 110 °C for 4 hours. After completion of the reaction, the reaction mixture was concentrated to remove the methanol and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The solvent was then rotary evaporated to give product 102b (33 mg, yield: 62.0%).

[0606] Step 2 5-(2,3-Dimethylphenyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid 102c To a solution of 102b (700 mg, 3.02 mmol) in 1,4-dioxane (30 mL) and water (3 mL), (2,3-dimethylphenyl)boronic acid (453 mg, 3.02 mmol), potassium carbonate (1252 mg, 9.06 mmol), and Pd(dppf)Cl2 (221 mg, 0.30 mmol) were added. The mixture was then purged with nitrogen gas and reacted at 105 °C for 16 h. After completion of the reaction, water (20 mL) was added to the reaction solution, the pH was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The solvent was then removed by rotary evaporation to give product 102c (720 mg, yield: 92.8%). MS m / z (ESI): 258.0 [M+1] + .

[0607] Step 3 (S,E)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one (S,Z)-3-(2,3-dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one To a DMF solution of 102c (700 mg, 2.72 mmol), 4 (392 mg, 2.72 mmol), HATU (1551 mg, 4.08 mmol), and N,N-diisopropylethylamine (879 mg, 6.80 mmol) were added, and the reaction mixture was incubated at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer C0102 (Rf = 0.5) and the crude more polar isomer C0103 (Rf = 0.4). Next, each was separated by HPLC, purified, and freeze-dried to give the less polar product C0102 (30.0 mg, yield: 2.8%) and the more polar product C0103 (50.0 mg, yield: 4.7%).

[0608] C0102: MS m / z (ESI): 384.1 [M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.44-7.40 (m,1H),7.17-7.09 (m,2H),6.99-6.96 (m,1H),6.59-6.56 (m,1H),4.70-4.15 (m,4H),3.88-3.85 (m,3H),3.68-3.65 (m,1H),3.56 (s,3H),3.48-3.38 (m,1H),2.93-2.91 (m,2H),2.32 (s,3H),2.07 (s,3H). C0103: MS m / z (ESI): 384.1 [M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.44-7.40 (m,1H),7.17-7.10 (m,2H),7.00-7.98 (m,1H),6.59-6.56 (m,1H),4.68-3.91 (m,4H),3.89 (s,3H),3.71-3.70 (m,1H),3.55 (s,3H),3.47-3.31 (m,1H),3.13-2.80 (m,2H),2.32 (s,3H),2.08 (s,3H).

[0609] Examples C0108 & C0109 (S,E)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0610] [ka]

[0611] [ka]

[0612] Step 1 6-(2,3-dimethylphenyl)-1,2,4-triazin-3-amine 109b 109a (3.7 g, 21.14 mmol), (2,3-dimethylphenyl)boronic acid (4.12 g, 27.48 mmol), Pd(dtbpf)Cl (219 mg, 0.34 mmol), and potassium carbonate (7.3 g, 52.85 mmol) were added to a mixture of 1,4-dioxane (100 mL) and water (10 mL). The mixture was purged with nitrogen gas three times and stirred under nitrogen gas protection at 25 °C for 17 h. The mixture was diluted with ethyl acetate (200 mL), washed with saturated brine (200 mL), dried, and concentrated. The concentrate was purified by flash silica gel column chromatography (PE:EA = 3:1) to give 109b (4.0 g, 94.5% yield) as a yellow solid. MS m / z (ESI): 201.0 [M+1] + .

[0613] Step 2 3-Bromo-6-(2,3-dimethylphenyl)-1,2,4-triazine 109c 109b (4.0 g, 19.98 mmol) and copper bromide (8.9 g, 40 mmol) were added to acetonitrile (500 mL), and tert-butyl nitrite (3.09 g, 29.97 mmol) was slowly added dropwise thereto. The mixture was heated to 30° C. and stirred for 1 hour. The mixture was filtered and concentrated. The concentrate was subjected to flash column chromatography (PE:EA=1:1) to give yellow oil 109c (2.05 g, yield: 38.8%). MS m / z (ESI): 263.8, 265.8 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.92 (s,1H),7.39-7.34 (m,2H),7.30 (d,J=7.2Hz,1H),2.34 (s,3H),2.21 (s,3H).

[0614] Step 3 6-(2,3-Dimethylphenyl)-1,2,4-triazine-3-carboxylic acid 109d 109c (2.0 g, 7.57 mmol), palladium acetate (170 mg, 0.76 mmol), 1,3-bis(diphenylphosphino)propane (624 mg, 1.51 mmol), and triethylamine (1.68 g, 16.65 mmol) were dissolved in a mixed solvent of acetonitrile (100 mL) and water (10 mL). The system was purged with CO three times, pressurized to 5 MPa in an autoclave, and stirred at 70 °C for 5 h. The mixture was concentrated and subjected to C18 reverse-phase column chromatography (acetonitrile:water = 10:90) to give yellow solid 109d (980 mg, yield: 56.4%). MS m / z (ESI): 228.1 [M-1] + .

[0615] Step 4 (S,Z)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 109d (500 mg, 2.18 mmol), 4 (393.75 mg, 2.18 mmol), HATU (1.24 g, 3.27 mmol), and N,N-diisopropylethylamine (845 mg, 6.54 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL × 4), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer C0108 (Rf = 0.6) and the crude more polar isomer C0109 (Rf = 0.5). Next, each was separated by HPLC, purified, and freeze-dried to give the less polar product C0108 (46 mg, yield: 5.9%) and the more polar product C0109 (43 mg, yield: 5.5%).

[0616] C0108:MS m / z (ESI):356.1[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 9.13-9.11 (m,1H),7.41-7.39 (m,2H),7.33-7.29 (m,1H),5.09-4.92 (m,1H),4.66-4.43 (m,1H),4.53-4.18 (m,1H),4.34 (s,1H),3.83-3.78 (m,3H),3.71-3.57 (m,1H),3.39-3.27 (m,1H),2.88-2.71 (m,2H),2.36 (s,3H),2.25-2.24 (m,3H). C0109: MS m / z (ESI): 356.1 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 9.13-9.12 (d,J=1.6Hz,1H),7.41-7.39 (m,2H),7.33-7.29 (m,1H),5.09-4.92 (m,1H),4.65-4.17 (m,3H),3.83-3.74 (m,3H),3.66-3.61 (m,1H),3.39-3.31 (m,1H),3.03-2.90 (m,1H),2.71-2.54 (m,1H),2.36 (s,3H),2.25-2.24 (m,3H).

[0617] Examples C0014 & C0015 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone

[0618] [ka]

[0619] [ka]

[0620] Step 1 5-(o-Tolyl)pyridine-2-carboxylic acid 14c 14a (0.74 g, 5.44 mmol) and 14b (1 g, 4.95 mmol) were dissolved in methanol (7 mL) and water (14 mL). Potassium carbonate (2.26 g, 16.32 mmol) and tetrakistriphenylphosphine palladium (63 mg, 0.054 mmol) were added at room temperature under nitrogen gas protection, and the mixture was reacted at 80°C for 16 hours under nitrogen gas protection. After completion of the reaction, the mixture was concentrated to remove methanol, water (10 mL) was added to the reaction mixture, and the pH was adjusted to 3 with 6 M hydrochloric acid. The mixture was then extracted with toluene / tetrahydrofuran. The organic phase was dried over sodium sulfate, and the solvent was evaporated to give 14c (0.7 g, yield: 58.5%). MS m / z (ESI): 214.1 [M+1] + .

[0621] Step 2 5-(o-Tolyl)pyridine-2-carbonyl chloride 14d 14c (0.7 g, 3.28 mmol) was dissolved in sulfinyl chloride (10 mL) and reacted at 80° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain crude 14d (0.43 g, yield: 50.8%).

[0622] Step 3 (S)-4-Oxo-1-(5-(o-tolyl)pyridine-2-formyl)pyrrolidine-2-carboxylate methyl ester 14e (S)-Methyl 4-oxopyrrolidine-2-carboxylate (0.3 g, 1.47 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.52 g, 5.14 mmol) and 14d (0.43 g, 1.76 mmol) were added at 0°C. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove dichloromethane, and the residue was purified by silica gel column chromatography (eluted with a gradient of petroleum ether:ethyl acetate = 5:1 to 3:1) to give product 14e (230 mg, yield: 46.3%). MS m / z (ESI): 339.0 [M+1] + .

[0623] Step 4 (S,EZ)-4-(methoxyimino)-1-(5-(o-tolyl)pyridine-2-formyl)pyrrolidine-2-carboxylic acid methyl ester 14f 14e (0.5 g, 1.40 mmol) was dissolved in methanol (5 mL), and methoxyamine hydrochloride (230 mg, 2.80 mmol) and triethylamine (350 mg, 3.5 mmol) were added at room temperature, followed by a reaction at 50°C for 18 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluted with a gradient of petroleum ether:ethyl acetate = 4:1 to 3:1) to give 14f (230 mg, yield: 40.1%). MS m / z (ESI): 368.1 [M+1] + .

[0624] Step 5 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone 14f (230 mg, 0.59 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), cooled to 0 °C, and lithium borohydride (0.62 mL, 1.23 mmol) was added under nitrogen gas protection. The mixture was then reacted at room temperature for 2 h. Water was added to quench the reaction, and the reaction mixture was concentrated. The residue was dissolved in dichloromethane and water. After layering, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was separated by silica gel prep-TLC (EA:PE=2:1) ​​to give the more polar isomer C0015 (Rf=0.4, 66.09 mg, yield: 32.2%) and the less polar isomer C0014 (Rf=0.5, 48.22 mg, yield: 23.0%).

[0625] C0014:MS m / z (ESI):340.1[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.61-8.58 (m,1H),7.98-7.81 (m,2H),7.37-7.30 (m,4H),4.90-4.62 (m,1H),4.58-4.52 (m,1H),4.47-4.10 (m,2H),3.82-3.75 (m,3H),3.62-3.52 (m,1H),3.40-3.34 (m,1H),2.83-2.62 (m,2H),2.27 (s,3H). C0015:MS m / z (ESI):340.1[M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 8.64-8.58 (m,1H),7.98-7.84 (m,2H),7.37-7.30 (m,4H),4.98-4.95 (m,1H),4.89-4.59 (m,1H),4.54-4.52 (m,1H),4.48-4.10 (m,1H),3.82-3.75 (m,3H),3.57-3.55 (m,1H),3.42-3.33 (m,1H),2.99-2.81 (m,1H),2.66-2.57 (m,1H),2.27 (s,3H).

[0626] Examples C0012 & C0013 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyrazin-2-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyrazin-2-yl)methanone

[0627] [ka]

[0628] See Examples C0014 & C0015, 14b

[0629] [ka]

[0630] The crude product was separated by silica gel prep-TLC (EA:PE=2:1) ​​to give the more polar isomer C0013 (Rf=0.4, 98.17 mg, yield: 24.3%) and the less polar isomer C0012 (Rf=0.5, 75.55 mg, yield: 19.0%).

[0631] C0012: MS m / z (ESI): 341.0 [M+1] + . 1 HNMR (400MHz,DMSO-d6) δ 9.07-9.01 (m,1H),8.87-8.84 (m,1H),7.55-7.53 (m,1H),7.43-7.37 (m,3H),5.00-4.95 (m,1H),4.82-4.64 (m,1H),4.55-4.53 (m,1H),4.50-4.12 (m,1H),3.82 -3.78 (m,3H),3.63-3.56 (m,1H),3.37 (m,1H),2.85-2.67 (m,2H),2.39 (s,3H). C0013: MS m / z (ESI): 341.0 [M+1] +. 1 H NMR (400MHz,DMSO-d6) δ 9.09-9.02 (m,1H),8.90-8.84 (m,1H),7.56-7.54 (m,1H),7.43-7.37 (m,3H),4.83-4.62 (m,1H),4.56-4.55 (m,1H),4.50-4.12 (m,1H),4.50-4.12 (m,1H),3.82 -3.76 (m,3H),3.61-3.53 (m,1H),3.40-3.38 (m,1H),3.01-2.55 (m,2H),2.39 (s,3H).

[0632] Examples C0029 & C0030 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone

[0633] [ka]

[0634] [ka]

[0635] Step 1 1-(tert-butyl) 2-methyl (S,EZ)-4-(methoxyimino)pyrrolidine-1,2-dicarboxylate 29b To a solution of 29a (5.0 g, 20.55 mmol) in methanol (50 mL), methoxyamine hydrochloride (1.16 g, 24.66 mmol) and triethylamine (4.57 g, 45.21 mmol) were added, and the mixture was purged with nitrogen gas and reacted overnight at 60 °C. The crude product was directly rotary dried and subjected to silica gel column chromatography (PE:EA = 5:1) to give 29b (3.2 g, yield: 56.0%). MS m / z (ESI): 173.0 [M+1-56] + .

[0636] Step 2 (S,EZ)-4-(methoxyimino)pyrrolidine-2-carboxylate methyl ester 29c To a solution of 29b (3.2 g, 11.75 mmol) in DCM (8 mL) was added TFA (1.34 g, 11.75 mmol), and the reaction mixture was stirred at room temperature for 20 min. After completion of the reaction, the mixture was directly evaporated to dryness to give crude product 29c (2.0 g, 89.0% yield). MS m / z (ESI): 217 [M+1-56] + .

[0637] Following Steps 3 and 4 of the above synthesis route, crude 2-(o-tolyl)thiazole-5-carbonyl chloride was obtained with reference to the synthesis method of compound C0014.

[0638] Step 5 (2S,4EZ)-4-(methoxyimino)-1-(2-(2-methylphenyl)-1,3-thiazole-5-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 29g To a solution of 29f (400 mg, 1.68 mmol) and 29c (433.89 mg, 2.52 mmol) in DCM (10 mL), TEA (0.68 g, 6.72 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was dried by rotary evaporation to obtain the crude product. The crude product was purified by preparative chromatography (ACN:HO = 5:95 to 45:55) to obtain 29g (400 mg, yield: 62.4%). MS m / z (ESI): 374.1 [M+1] + .

[0639] Step 6 (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone LiBH4 (0.023 g, 1.04 mmol) was slowly added to a solution of 29g (390 mg, 1.04 mmol) in THF (5 mL) and methanol (5 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, water (10 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give the crude product. The residue was purified by silica gel pre-TLC (PE:EA = 1:3) to give the crude less polar isomer C0029 (Rf = 0.5) and the crude more polar isomer C0030 (Rf = 0.4). Then, each was purified by chiral resolution to give a less polar product C0029 (15.9 mg, yield: 4.41%) and a more polar product C0030 (21.4 mg, yield: 5.87%).

[0640] C0029:MS m / z (ESI):346.1[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.26 (s,1H),7.76 (d,J=7.2Hz,1H),7.39-7.27 (m,3H),4.87-4.56 (m,3H),3.91-3.71 (m,5H),2.85-2.83 (m,2H),2.60 (s,3H). C0030:MS m / z (ESI):346.1[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.29 (s,1H),7.77 (d,J=6.8Hz,1H),7.39-7.27 (m,3H),4.87-4.60 (m,3H),3.91-3.75 (m,5H),2.98-2.91 (m,1H),2.75-2.71 (m,1H),2.61 (s,3H).

[0641] Example C0033 (EZ)-(3-(Methoxyimino)hexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0642] [ka]

[0643] [ka]

[0644] Step 1 (S)-4-(((benzyloxy)carbonyl)glycyl)morpholine-3-carboxylic acid 33b 33a (4.67 g, 15.25 mmol), CbzOSU (7 g, 22.8 mmol), and triethylamine (2.31 g, 22.88 mmol) were dissolved in DMF (20 mL), heated to 80 °C, and stirred for 17 h. The reaction mixture was cooled, concentrated, and purified by C18 reverse-phase column chromatography (acetonitrile / water = 50 / 50), followed by concentration to give 33b (3.06 g, yield: 62.2%) as a white solid. MS m / z (ESI): 323.1 [M + H] + .

[0645] Step 2 3-Oxohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylic acid benzyl ester 33c 33b (2 g, 6.21 mmol) and iodobenzene diacetate (4.00 g, 12.42 mmol) were dissolved in dichloromethane (100 mL), cooled to 0 °C, and boron trifluoride ethyl etherate (1.76 g, 12.42 mmol) was added dropwise. The mixture was allowed to react at room temperature for 24 hours. The reaction was quenched with aqueous sodium bicarbonate (100 mL). The layers were separated, and the aqueous phase was extracted twice with 100 mL of water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by C18 reverse-phase column chromatography (water:acetonitrile = 60:40) to give 33c (1.2 g, yield: 70.0%) as a colorless oil. MS m / z (ESI): 277.1 [M + H] + .

[0646] Step 3 3-Oxohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylic acid tert-butyl ester 33d 33c (0.2 g, 0.72 mmol) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (0.2 g, 0.94 mmol) and palladium on carbon (10%, 39 mg) were added under nitrogen atmosphere. The mixture was purged with hydrogen gas three times and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered to remove the palladium on carbon and concentrated to remove the methanol, yielding crude product 33d (0.1 g, yield: 57.0%). MS m / z (ESI): 243.1 [M + H] + .

[0647] Step 4 3-Thiohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylic acid tert-butyl ester 33e 33d (0.8 g, 3.30 mmol) was dissolved in toluene (15 mL), Lawesson's reagent (1.33 g, 3.30 mmol) was added, and the mixture was heated to 50 °C for 30 min. After completion of the reaction, the mixture was filtered to remove solid impurities, and the solvent was evaporated. The mixture was then purified by reverse phase chromatography to give 33e (0.6 g, yield: 62.6%). MS m / z (ESI): 259.0 [M + H] + .

[0648] Step 5 Tetrahydro-1H-imidazo[2,1-c][1,4]oxazine-3(2H)-thione 33f 33e (0.68 g, 2.63 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off to give 33f (0.4 g, yield: 96.0%). MS m / z (ESI): 159.0 [M + H] + .

[0649] Step 6 (2'-methyl-[1,1'-biphenyl]-4-yl)(3-thiohexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)methanone 33g 33f (0.7 g, 4.42 mmol) was dissolved in dichloromethane (10 mL), 2'-methyl-[1,1'-biphenyl]-4-carbonyl chloride (1.02 g, 4.42 mmol), and triethylamine (1.34 g, 13.26 mmol) were added, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was washed with saturated brine (10 mL x 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by pre-TLC (petroleum ether:ethyl acetate = 5:1) to give 33f (1 g, yield: 56.4%). MS m / z (ESI): 353.1 [M + H] + .

[0650] Step 7 (EZ)-(3-(Methoxyimino)hexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 33g (0.2g, 0.57mmol) was dissolved in toluene (5mL), and methoxyamine hydrochloride (0.19g, 2.28mmol) and mercuric acetate (0.36g, 1.14mmol) were added. The mixture was reacted at 100°C for 2 hours. After the reaction was completed, ethyl acetate (20mL) was added to the reaction mixture, which was washed with water (10mL x 2) and saturated sodium chloride (10mL) once. After drying over sodium sulfate, the solvent was evaporated, and the crude product was separated, purified by HPLC (HCOOH), and lyophilized to give C0033 (80mg, yield: 38.6%). MS m / z (ESI): 366.1 [M + H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.72-7.62 (m,2H),7.46-7.44 (m,2H),7.29-7.22 (m,4H),5.46-5.34 (m,1H),4.67-4.60 (m,1H),4.39-4.25 (m,1H),3.79-3.72 (m,2H),3.64 (s,3H),3.52-3.43 (m,1H),3.25-3.15 (m,1H),2.25 (s,3H).

[0651] Examples C0048 & C0049 (S,E)-(4-(benzo[d][1,3]dioxolan-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(4-(benzo[d][1,3]dioxolan-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0652] [ka]

[0653] [ka]

[0654] Following the above synthetic route, and referring to the synthetic method for compound A0203, the less polar isomer C0048 (Rf=0.4) and the crude more polar isomer C0049 (Rf=0.3) were obtained. The crude product was then separated and purified by HPLC, and lyophilized to obtain the less polar product C0048 (39 mg, yield: 15.3%) and the more polar product C0049 (30 mg, yield: 11.8%).

[0655] C0048:MS m / z (ESI):369.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.87-7.85 (m,2H),7.61 (d,J=7.6Hz,2H),7.13 (d,J=7.6Hz,1H),6.97-6.93 (m,1H),6.85 (dd,J=8.0,1.2Hz,1H),6.02 (s,2H),4.80-4.08 (m,3H),4.18-3.65 (m,5H),2.87-2.85 (m,2H). C0049:MS m / z (ESI):369.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.85 (d,J=8.4Hz,2H),7.61 (d,J=7.6Hz,2H),7.13 (d,J=8.4Hz,1H),6.97-6.93 (m,1H),6.85 (dd,J=8.0,0.8Hz,1H),6.02 (s,2H),4.79-4.36 (m,2H),4.35-3.69 (m,6H),2.98-2.67 (m,2H).

[0656] Examples C0080 & C0081 (S,E)-(5-(2,3-dimethylphenyl)-3-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)-3-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0657] [ka]

[0658] [ka]

[0659] Following the above synthesis route and referring to the synthesis method of compound C0102, the less polar isomer C0080 (Rf=0.4) and the crude more polar isomer C0081 (Rf=0.3) were obtained. Then, after separation and purification by HPLC, the less polar product C0080 (19.2 mg, yield: 4.29%) and the more polar product C0081 (22.69 mg, yield: 5.07%) were obtained.

[0660] C0080:MS m / z (ESI):384.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.11-8.09 (m,1H),7.54-7.52 (m,1H),7.24-7.10 (m,3H),4.80-4.55 (m,1H),4.19-4.15 (m,1H),3.91-3.90 (m,4H),3.88-3.83 (m,3H),3.71-3.40 (m,2H),2.98-2.82 (m,2H),2.36 (s,3H),2.18 (s,3H). C0081:MS m / z (ESI):384.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 8.11-8.09 (m,1H),7.54-7.52 (m,1H),7.24-7.08 (m,3H),4.69-4.50 (m,1H),4.26-3.99 (m,2H),3.93-3.92 (m,3H),3.89-3.70 (m,4H),3.43-3.41 (m,1H),2.98-2.66 (m,2H),2.36 (s,3H),2.18 (s,3H).

[0661] Examples C0072 & C0073 (S,E)-(5-(2,3-dimethylphenyl)-6-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(5-(2,3-dimethylphenyl)-6-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0662] [ka]

[0663] Refer to the method of C0080 & C0081, and add raw material 81a in step 1.

[0664] [ka]

[0665] to give the above compound.

[0666] The crude product was separated by silica gel prep-TLC (PE:EA=1:5) to give the crude less polar product C0072 (Rf=0.4) and the purified more polar product C0073 (Rf=0.3, 20 mg, 18.7% yield). The crude less polar isomer was separated by HPLC, purified, and lyophilized to give the less polar product C0072 (34.9 mg, 9.72% yield).

[0667] C0072:MS m / z (ESI):384.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.64-7.18 (m,2H),7.16-7.10 (m,2H),6.95 (d,J=7.2Hz,2H),4.81-4.73 (m,2H),4.60-4.19 (m,1H),3.93-3.58 (m,8H),3.02-2.77 (m,2H),2.32 (s,3H),2.00 (s,3H). C0073:MS m / z (ESI):384.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.64-7.54 (m,2H),7.18-7.10 (m,2H),6.97-6.95 (m,1H),4.83-4.76 (m,2H),4.56-4.24 (m,1H),3.90-3.60 (m,8H),2.99-2.32 (m,2H),2.32 (s,3H),2.00 (s,3H).

[0668] Examples C0110&C0111&C0112&C0113 (S,S,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,S,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,R,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,R,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0669] [ka]

[0670] [ka]

[0671] Step 1 Methyl (S)-7-(3'-cyano-2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylate 110b 110a (1.8 g, 4.97 mmol, prepared according to the method of 35d in Examples C0035 & C0036) was dissolved in toluene (15 mL), and ethylene glycol (463 mg, 7.46 mmol) and p-toluenesulfonic acid hydrate (331 mg, 1.74 mmol) were added to the reaction mixture, which was then reacted at 120°C for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and column chromatography (PE / EA=6 / 1) was performed to obtain product 110b (500 mg, yield: 24.8%). MS m / z (ESI): 406.8 [M+1] + .

[0672] Step 2 (S)-4'-(8-(hydroxymethyl)-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110c 110b (6 g, 14.76 mmol) was dissolved in methanol (100 mL) and tetrahydrofuran (100 mL). Lithium borohydride tetrahydrofuran solution (2 M, 14.8 mL) was added dropwise at -10°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 hours. After the reaction was completed, water was added to quench the reaction. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane and water. After layering, the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried, filtered, and rotary evaporated. The crude product was applied to a silica gel column and eluted with PE / EA (3:1 to 1:1). The eluate was collected and concentrated to give product 110c (4 g, yield: 71.6%). MS m / z (ESI): 378.9 [M+1] + .

[0673] Step 3 (S)-4'-(8-formyl-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110d 110c (4.2 g, 11.10 mmol) was dissolved in dichloromethane (200 mL), Dess-Martin oxidant (4.71 g, 11.1 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, dichloromethane and water were added, followed by extraction with dichloromethane twice. The organic layers were combined and rotary evaporated to remove the solvent. After washing with brine once, the mixture was dried, filtered, and rotary evaporated. The crude product was loaded onto a silica gel column and eluted with PE / EA (2:1 to 1:1). The eluate was collected and concentrated to give product 110d (3.5 g, yield: 83.8%). MS m / z (ESI): 376.9 [M+1] + .

[0674] Step 4 (S)-4'-(8-(1-hydroxyethyl)-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110e 110d (3.5 g, 9.30 mmol) was dissolved in tetrahydrofuran (125 mL), and 24.7 mL of a 3 M solution of methylmagnesium chloride in tetrahydrofuran was added at -78 °C. The mixture was warmed to room temperature and stirred for 20 minutes. After the reaction was completed, the reaction mixture was quenched by adding water, extracted three times with water and ethyl acetate, and the organic phase was collected. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give product 110e (1.5 g, yield: 41.1%). MS m / z (ESI): 392.9 [M+1] + .

[0675] Step 5 (S)-4'-(2-(1-hydroxyethyl)-4-oxopyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110f 110e (50 mg, 0.13 mmol) was dissolved in hydrochloric acid (2 mL) and water (20 mL) and reacted at 105°C for 20 minutes. After the reaction was completed, the reaction solution was adjusted to neutral and extracted three times with water and ethyl acetate. The organic phase was collected, washed once with brine, dried over anhydrous sodium sulfate, filtered, and the crude product was loaded onto a silica gel column and eluted with PE / EA (1:1 to 1:2). The eluate was collected and concentrated to give product 110f (28 mg, yield: 63.0%). MS m / z (ESI): 348.9 [M+1] + .

[0676] Step 6 (S,S,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,R,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,S,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,R,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110f (400 mg, 1.15 mmol) was dissolved in methanol (20 mL), and methoxyamine hydrochloride (144 mg, 1.72 mmol) and triethylamine (349 mg, 3.45 mmol) were added at room temperature. The mixture was reacted at 50°C for 18 hours. The reaction mixture was rotary evaporated to remove methanol, extracted three times with dichloromethane and water, and the combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The residue was purified by silica gel pre-TLC (PE:EA=1:2) to give a crude less polar isomer (Rf=0.6) and a crude more polar isomer (Rf=0.5). Next, by chiral separation, the first peak C0110 (30 mg, yield: 6.9%, peak time: 5.85 min) of a less polar product and the second peak C0111 (52 mg, yield: 12.0%, peak time: 7.98 min) of a less polar product were obtained. The chiral analysis method was as follows: instrument: high-throughput semi-preparative chromatography GX-281, chromatographic column: Daicel CHIRALPAK (registered trademark) IA-3.0 cm column, mobile phase: n-hexane:ethanol = 40:60, column temperature: 30 °C, flow rate: 25 ml / min, detection wavelength: 254 nm. The first peak of a more polar product, C0112 (72 mg, yield: 12.6%, peak time: 6.59 min), and the second peak of a more polar product, C0113 (47 mg, yield: 10.9%, peak time: 8.42 min), were obtained. The chiral analysis method was as follows: instrument: high-throughput semi-preparative chromatography GX-281; ​​chromatographic column: Daicel CHIRALPAK® IC-3.0 cm column; mobile phase: n-hexane:ethanol=40:60; column temperature: 30°C; flow rate: 25 ml / min; detection wavelength: 254 nm.

[0677] C0110: MS m / z (ESI):378.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.72-7.67 (m,3H),7.55-7.53 (m,1H),7.46-7.42 (m,3H),4.45-4.02 (m,4H),3.83 (s,3H),2.93-2.88 (m,2H),2.45 (s,3H),1.24-1.22 (m,3H). C0111: MS m / z (ESI):378.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.72-7.66 (m,3H),7.55-7.53 (m,1H),7.46-7.42 (m,3H),4.61-4.07 (m,4H),3.86-3.83 (m,3H),2.99-2.94 (m,1H),2.73-2.68 (m,1H),2.45 (s,3H),1.22-1.21 (m,3H). C0112: MS m / z (ESI):378.1[M+1] + . 1H NMR (400MHz,CD3OD) δ 7.72-7.66 (m,3H),7.55-7.54 (m,1H),7.46-7.42 (m,3H),4.62-4.40 (m,2H),4.11-4.06 (m,2H),3.87-3.78 (m,3H),2.84-2.78 (m,2H),2.45 (s,3H),1.29-1.23 (m,3H). C0113: MS m / z (ESI):378.1[M+1] + . 1 H NMR (400MHz,CD3OD) δ 7.72-7.67 (m,3H),7.56-7.54 (m,1H),7.46-7.42 (m,3H),4.47-4.03 (m,4H),3.87-3.78 (m,3H),2.87-2.69 (m,2H),2.45 (s,3H),1.17-1.16 (m,3H).

[0678] Example A0086 (S,EZ)-(2-(benzo[d]oxazol-2-yl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0679] [ka]

[0680] [ka]

[0681] Step 1 (2S,4R)-Benzyl 4-hydroxy-2-((2-hydroxyphenyl)aminoformyl)pyrrolidine-1-carboxylate 86c 86a (9 g, 33.93 mmol) and ethyl diisopropyl ether (17.54 g, 135.72 mmol) were dissolved in 100 mL of DMF, and HATU (16.77 g, 44.11 mmol) was added. After 5 minutes of reaction, 86b (4.44 g, 40.72 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give crude product 86c (5 g, yield: 41.3%). MS m / z (ESI): 357.2 [M+1] + .

[0682] Step 2 Benzyl (2S,4R)-2-(benzo[d]oxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate 86d 86c (5.3 g, 14.87 mmol) was dissolved in 50 mL of toluene, and toluene-4-sulfonic acid (0.51 g, 2.97 mmol) was added. The reaction mixture was refluxed at 110°C for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 86d (184 mg, yield: 3.66%). MS m / z (ESI): 339.2 [M+1] + .

[0683] Step 3 (3R,5S)-5-(benzo[d]oxazol-2-yl)pyrrolidin-3-ol 86e The raw material 86d (270 mg, 0.8 mmol) was dissolved in 5 mL of methanol, and wet palladium carbon (0.085 g, 0.8 mmol) was added. After purging with H2, the reaction was allowed to proceed at 25°C for 16 hours. The reaction solution was filtered, and the filter cake was washed twice with methanol. The filtrate was concentrated to give crude product 86e (140 mg). MS m / z (ESI): 205.2 [M+1] + .

[0684] Step 4 ((2S,4R)-2-(benzo[d]oxazol-2-yl)-4-hydroxypyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 86f 86e (140 mg, 0.69 mmol) and 4-(2-methylphenyl)benzoic acid (0.18 g, 0.83 mmol) were dissolved in 5 mL of DMF, and HATU (0.34 g, 0.90 mmol) and ethyl diisopropyl ether (0.36 g, 2.76 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. 10 mL of water was added, followed by extraction with ethyl acetate (10 mL × 3). The organic phases were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 86f (140 mg, yield: 51.3%). MS m / z (ESI): 399.2 [M+1] + .

[0685] Step 5 ((S)-5-(benzo[d]oxazol-2-yl)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-one 86g Raw material 86f (260 mg, 0.65 mmol) was dissolved in 5 mL of dichloromethane, and Dess-Martin reagent (0.55 g, 1.3 mmol) was added. The reaction was allowed to proceed at 25°C for 16 hours. 20 mL of saturated sodium bicarbonate solution was added to quench the reaction. Extraction was performed with dichloromethane (10 mL x 3), and the combined organic phases were washed with brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give product 86g (250 mg, yield: 96.6%). MS m / z (ESI): 397.2 [M+1] + .

[0686] Step 6 (S,EZ)-(2-(benzo[d]oxazol-2-yl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 86g (270mg, 0.68mmol) and methoxyamine hydrochloride (0.17g, 2.04mmol) were dissolved in 2mL of tetrahydrofuran and 2mL of water, and sodium bicarbonate (0.17g, 2.04mmol) was added. The reaction was allowed to proceed at 25°C for 5 hours. 10mL of water was added, and the mixture was extracted with ethyl acetate (10mL x 3). The organic phases were combined, washed with brine (10mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified to obtain product A0086 (55.67mg, yield: 96.6%). MS m / z (ESI): 426.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.78-7.62 (m,2H),7.56-7.38 (m,1H),7.37-7.26 (m,6H),7.23-7.12 (m,3H),6.16 (s,1H),4.68-4.33 (m,2H),3.86 (s,3H),3.34-3.11 (m,2H),2.30-2.25 (m,2H).

[0687] Example A0087&A0101 [(3Z)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone [(3E)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone

[0688] [ka]

[0689] [ka]

[0690] Step 1 Methyl 3-oxo-7-azabicyclo[2.2.1]heptane-1-carboxylate 87d 87a (20 mg, 0.074 mmol) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (4.59 g, 40.26 mmol) was added. The reaction was allowed to proceed at 25° C. for 30 minutes, and the reaction mixture was concentrated under reduced pressure to give crude product 87b (125 mg). MS m / z (ESI): 170.0 [M+1] + .

[0691] Step 3 Methyl 7-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-3-oxo-7-azabicyclo[2.2.1]heptane-1-carboxylate 87e 87d (125 mg, 0.74 mmol) and 87b (0.20 g, 0.89 mmol) were dissolved in 5 mL of tetrahydrofuran solution, potassium carbonate (0.31 g, 2.22 mmol) was added, and the reaction was allowed to proceed at 25° C. for 6 hours. 10 mL of water was added, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 87e (268 mg). MS m / z (ESI): 364.3 [M+1] + .

[0692] Step 4 (EZ)-3-(methoxyimino)-7-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate methyl ester 87e (200 mg, 0.55 mmol) was dissolved in 2 mL of tetrahydrofuran and 2 mL of water, and methoxyamine hydrochloride (0.18 g, 2.2 mmol) and sodium bicarbonate (0.14 g, 1.65 mmol) were added, and the reaction was allowed to proceed at 25° C. for 16 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give product 87f (299 mg). MS m / z (ESI): 364.2 [M+1] + .

[0693] Step 5 [(3Z)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone [(3E)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone 87f (100 mg, 0.25 mmol) was dissolved in 2 mL of tetrahydrofuran and purged with nitrogen. Lithium borohydride (8.2 mg, 0.38 mmol) was added, and the reaction was allowed to proceed at 25°C for 16 hours. 5 mL of water was added, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Separation by silica gel prep-TLC (EA:PE = 2:1) gave the less polar isomer A0101 (Rf = 0.4) and the crude more polar isomer A0087 (Rf = 0.3). Next, each product was separated and purified by HPLC, and after freeze-drying, a more polar product was obtained. The resulting residue was separated and purified to obtain a more polar product A0087 (3.3 mg, yield: 3.5%) and a less polar product A0101 (2.94 mg, yield: 3.15%).

[0694] A0087:MS m / z (ESI):365.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.54 (d,J=8.4Hz,2H),7.39-7.37 (m,2H),7.30-7.26 (m,2H),7.25-7.22 (m,2H),5.39-5.30 (m,1H),4.70 (d,J=4.4Hz, 1H),4.11-4.05 (m,2H),3.84 (s,3H),3.01-2.93 (m,1H),2.36-2.25 (m,1H),2.27 (s,3H),2.18-2.13 (m,2H),1.84-1.76 (m,1H),1.69-1.63 (m,1H). A0101: MS m / z (ESI): 365.0 [M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.55-7.53 (m,2H),7.41-7.25 (m,6H),5.38-5.30 (m,2H),4.72 (s,1H),4.17-4.01 (m,1H),3.86 (s,3H),3.02-2.97 (m,1H),2.40-2.22 (m,7H),2.20-2.12 (m,1H).

[0695] Examples A0130 & A0144 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile

[0696] [ka]

[0697] [ka]

[0698] Step 1 2'-cyano-3'-methyl-[1,1'-biphenyl]-4-carboxylic acid 130c Under argon gas protection, 130a (200 mg, 1.02 mmol), 130b (0.17 g, 1.02 mmol), bis(triphenylphosphine)palladium dichloride (0.072 g, 0.10 mmol), and potassium carbonate (0.70 g, 5.1 mmol) were mixed in 1,4-dioxane (3 mL) and water (0.5 mL). The reaction mixture was stirred at 100°C for 2 hours. Ethyl acetate was added to the reaction mixture, and the aqueous phase was adjusted to pH 4-5 with 1N hydrochloric acid. A solid precipitated, which was filtered and dried to give 130c (120 mg, yield: 44.6%). MS m / z (ESI): 238 [M+1] + .

[0699] Step 2 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile 130c (100 mg, 0.42 mmol) and 4 (0.061 g, 0.36 mmol) were dissolved in DCM (1.7 mL) and DMF (4 mL), and 4-dimethylaminopyridine (0.10 g, 0.84 mmol) and EDCI (0.081 g, 0.42 mmol) were slowly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove dichloromethane, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel prep-TLC (EA:PE = 1:3) to give the less polar isomer A0144 (Rf = 0.4) and the more polar isomer A0130 (Rf = 0.3). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0130 (11.53 mg, yield: 7.15%) and a less polar product A0144 (9.14 mg, yield: 5.76%).

[0700] A0130: MS m / z (ESI): 364.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.64-7.58 (m,4H),7.53 (t,J=7.6Hz,1H),7.36-7.29 (m,2H),4.92-4.82 (m,1H),4.43-4.17 (m,2H),3.95-3.75 (m,5H),2.98-2.91 (m,1H),2.70-2.63 (m,4H). A0144: MS m / z (ESI): 364.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.64-7.61 (m,4H),7.53 (t,J=7.6Hz,1H),7.34 (d,J=7.6Hz,1H),7.29 (d,J=7.6Hz,1H),4.92-4.81 (m,1H),4.47-4.16 (m,2H),4.00-3.72 (m,5H),2.99-2.68 (m,2H),2.62 (s,3H).

[0701] Examples A0131 & A0153 5-(2,3-dimethylphenyl)-2-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimine)pyrrolidine-1-carbonyl]benzonitrile 5-(2,3-Dimethylphenyl)-2-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimine)pyrrolidine-1-carbonyl]benzonitrile

[0702] [ka]

[0703] [ka]

[0704] Step 1 Methyl 2-cyano-4-(2,3-dimethylphenyl)benzoate 131b 131a (0.200 g, 1.33 mmol), methyl 4-bromo-2-cyanobenzoate (0.30 g, 1.26 mmol), Pd(dppf)Cl2 (0.11 g, 0.13 mmol), and potassium carbonate (0.37 g, 2.66 mmol) were dissolved in 1,4-dioxane (4 mL) and reacted at 100 °C for 12 h under argon gas protection. The reaction mixture was directly concentrated and purified by column chromatography to give 131b (0.300 g, yield: 67.8%). MS m / z (ESI): 266.0 [M+1] + .

[0705] Step 2 2-Cyano-4-(2,3-dimethylphenyl)benzoic acid 131c 131b (0.200 g, 0.75 mmol) and lithium hydroxide (0.094 g, 2.25 mmol) were dissolved in methanol (1 mL), water (1 mL), and tetrahydrofuran (1 mL) and reacted at 40°C for 1 to 2 hours. The reaction mixture was adjusted to pH 3 to 4 with 1 M hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried, and concentrated to give crude product 131c (0.210 g). MS m / z (ESI): 252.1 [M+1] + .

[0706] Step 3 5-(2,3-dimethylphenyl)-2-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimine)pyrrolidine-1-carbonyl]benzonitrile 5-(2,3-Dimethylphenyl)-2-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimine)pyrrolidine-1-carbonyl]benzonitrile 131c (0.080 g, 0.32 mmol), 4 (0.082 g, 0.32 mmol), EDCI (0.074 g, 0.38 mmol), and 4-dimethylaminopyridine (0.078 g, 0.64 mmol) were dissolved in N,N-dimethylformamide (0.7 mL) and dichloromethane (0.3 mL) and reacted at 15 °C for 2 to 12 hours. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel prep-TLC (PE:EA = 1:2) to give the less polar isomer A0153 (Rf = 0.25) and the more polar isomer A0131 (Rf = 0.2), which were then separated by HPLC, purified, and lyophilized to give the more polar products A0131 (9.52 mg, yield: 7.32%) and A0153 (4.51 mg, yield: 3.68%).

[0707] A0131: MS m / z (ESI): 378.3 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.67-7.56 (m,3H),7.25-7.17 (m,2H),7.04 (d,J=7.2Hz,1H),4.87-4.83 (m,1H),4.37-4.33 (m,1H),4.28-3.75 (m,6H),3.28-3.12 (m,1H),3.15-2.95 (m,1H),2.84-2.80 (m,1H),2.36 (s,3H),2.15 (s,3H). A0153: MS m / z (ESI): 378.3 [M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.66-7.56 (m,3H),7.25-7.17 (m,2H),7.04-6.95 (m,1H),4.89-4.83 (m,1H),4.39-4.33 (m,1H),4.20-3.70 (m,6H),3.30-3.12 (m,1H),3.02-2.83 (m,2H),2.36 (s,3H),2.12 (s,3H).

[0708] Examples A0137 & A0154 [(2S,4Z)-1-(5-(2,3-dimethylphenyl)-6-(trifluoromethyl)pyrazine-2-carbonyl)-4-(methoxyimine)pyrrolidine-butan-2-yl]methanone [(2S,4E)-1-(5-(2,3-dimethylphenyl)-6-(trifluoromethyl)pyrazine-2-carbonyl)-4-(methoxyimine)pyrrolidine-butan-2-yl]methanone

[0709] [ka]

[0710] [ka]

[0711] Following the above synthesis route and referring to the synthesis method of compound A0131, highly polar products A0154 (15.93 mg, yield: 11.8%) and A0137 (4.71 mg, yield: 3.48%) were obtained.

[0712] A0137: MS m / z (ESI): 423.3 [M+1] + . 1H NMR (400MHz,Chloroform-d) δ 9.48 (d,J=16.4Hz,1H),7.33-7.26 (m,1H),7.22-7.20 (m,1H),7.03-7.01 (m,1H),5.14-4.32 (m,3H),3.93-3.80 (m,5H),3.03-2.73 (m,2H),2.45 (s,1H),2.35 (s,3H),1.98 (s,3H). A0154: MS m / z (ESI): 423.3 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 9.49 (d,J=7.2Hz,1H),7.32-7.26 (m,1H),7.22-7.15 (m,1H),7.02-7.00 (m,1H),5.20-4.25 (m,3H),3.99-3.78 (m,5H),3.03-2.83 (m,2H),2.35 (s,3H),1.97 (s,3H).

[0713] Examples A0147 & A0170 (S,Z)-(2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0714] [ka]

[0715] [ka]

[0716] By referring to the synthesis method of 131b in Step 1 of Examples A0131 & A0153, and replacing the raw material methyl 4-bromo-2-cyanobenzoate with methyl 4-bromo-3-hydroxybenzoate, 147a was obtained.

[0717] Step 1 2',3'-dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-carboxylic acid methyl ester 147c Under argon gas protection, 147a (300 mg, 1.17 mmol), 147b (0.22 g, 1.17 mmol), and potassium carbonate (0.49 g, 3.51 mmol) were mixed in DMF (3 mL). The reaction mixture was heated at 100°C for 16 hours. Ethyl acetate was added to the reaction mixture, which was then washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to give 147c (290 mg, yield: 47.6%). MS m / z (ESI): 313.0 [M+1] + .

[0718] Step 2 2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-carboxylic acid 147d 147c (290 mg, 0.56 mmol) was dissolved in methanol (3 mL), THF (3 mL), and water (3 mL). Lithium hydroxide (0.067 g, 2.80 mmol) was added, and the reaction mixture was stirred at 40 °C for 2 h. The pH of the reaction mixture was adjusted to 4-5 with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude product 147d (260 mg). MS m / z (ESI): 299.0 [M+1] + .

[0719] Step 3 (S,Z)-(2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 147d (260 mg, 0.52 mmol) and 4 (0.061 g, 0.36 mmol) were dissolved in DCM (3 mL) and DMF (7 mL), and 4-dimethylaminopyridine (0.13 g, 1.04 mmol) and EDCI (0.10 g, 0.52 mmol) were slowly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove dichloromethane, diluted with 30 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel prep-TLC (EA:PE = 2:1) to give the less polar isomer A0170 (Rf = 0.3) and the more polar isomer A0147 (Rf = 0.2). Next, each product was separated by HPLC, purified, and freeze-dried to give a more polar product A0147 (60.71 mg, yield: 27.1%) and a less polar product A0170 (58.91 mg, yield: 26.0%).

[0720] A0147: MS m / z (ESI): 425.0 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.21-7.12 (m,4H),7.02-6.97 (m,1H),6.80-6.76 (m,1H),5.32-5.25 (m,1H),5.10-4.93 (m,1H),4.90-4.80 (m,2H),4.62-4.52 (m,1H),4.53-4.27 (m,3H),4.15-3.92 (m,1H),3.87-3.72 (m,3H),3.62-3.48 (m,1H),3.28-3.15 (m,1H),2.98-2.72 (m,1H),2.68-2.58 (m,1H),2.30 (s,3H),2.02 (s,3H). A0170: MS m / z (ESI): 425.0 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.20-7.15 (m,4H),7.01-6.99 (m,1H),6.85-6.72 (m,1H),5.45-5.23 (m,1H),5.08-4.94 (s,1H),4.91-4.82 (m,2H),4.65-3.92 (m,5H),3.88-3.72 (m,3H),3.68-3.45 (m,1H),3.30-3.15 (m,1H),2.82-2.65 (m,2H),2.30 (s,3H),2.02 (s,3H).

[0721] Examples A0149 & A0171 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(2-methoxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(2-methoxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0722] [ka]

[0723] [ka]

[0724] Following the above synthetic route and referring to the synthesis method of compound A0147, the less polar isomer A0171 (Rf = 0.35) and the more polar isomer A0149 (Rf = 0.3) were obtained. Then, each was separated by HPLC, purified, and lyophilized to obtain the more polar product A0149 (38.84 mg, yield: 9.05%) and the less polar product A0171 (42.95 mg, yield: 9.99%).

[0725] A0149: MS m / z (ESI): 427.1 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.25-7.09 (m,5H),6.97-6.96 (m,1H),5.03-4.99 (m,1H),4.62-4.52 (m,1H),4.42-4.30 (m,1H),4.20-3.93 (m,3H),3.85-3.70 (m,3H),3.62-3.48 (m,3H),3.30-3.22 (m,1H),3.15 (s,3H),3.01-2.79 (m,1H),2.70-2.55 (m,1H),2.27 (s,3H),1.97 (s,3H). A0171: MS m / z (ESI): 427.1 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.36-7.07 (m,5H),7.00-6.95 (m,1H),5.05-4.95 (m,1H),4.61-4.20 (m,2H),4.12-3.92 (m,3H),3.85-3.72 (m,3H),3.65-3.45 (m,3H),3.31-3.22 (m,1H),3.14 (s,3H),2.82-2.70 (m,2H),2.27 (s,3H),1.94 (s,3H).

[0726] Examples A0148 & A0169 (S,Z)-(2-(2-hydroxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,E)-(2-(2-hydroxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0727] [ka]

[0728] See Examples A0149 & A0171, 149b

[0729] [ka]

[0730] The crude product was separated by silica gel prep-TLC (EA:PE = 2:1) to give the less polar isomer A0169 (Rf = 0.25) and the more polar isomer A0148 (Rf = 0.2). These were then separated by HPLC, purified, and lyophilized to give the more polar product A0148 (61.98 mg, yield: 15.87%) and the less polar product A0169 (60.43 mg, yield: 15.39%).

[0731] A0148: MS m / z (ESI): 413.0 [M+1] + . 1 H NMR (400MHz,DMSO-d6) δ 7.22-7.09 (m,5H),6.98-6.96 (m,1H),5.08-4.95 (m,1H),4.78-4.72 (m,1H),4.62-4.12 (m,2H),4.10-3.92 (m,3H),3.75 (d,J=34.0Hz,3H),3.62-3.52 (m,3H),3.30-3.20 (m,1H),3.02-2.78 (m,1H),2.68-2.58 (m,1H),2.24 (s,3H),1.98 (s,3H). A0169: MS m / z (ESI): 413.0 [M+1] + . 1H NMR (400MHz,DMSO-d6) δ 7.21-7.09 (m,5H),6.97 (d,J=6.8Hz,1H),5.05-4.97 (m,1H),4.76-4.72 (m,1H),4.63-4.14 (m,2H),4.10-3.92 (m,3H),3.78 (s,3H),3.76-3.45 (m,3H),3.30-3.21 (m,1H),2.82-2.69 (m,2H),2.28 (s,3H),1.98 (s,3H).

[0732] Examples A0157 & A0179 (S,Z)-4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide (S,E)-4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide

[0733] [ka]

[0734] [ka]

[0735] Step 1 Methyl 4-(2,3-dimethylphenyl)-3-formylbenzoate 157a Under argon gas protection, methyl 4-bromo-3-formylbenzoate (3 g, 12.34 mmol), 2,3-dimethylphenylboronic acid (2.78 g, 18.51 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.90 g, 1.23 mmol), potassium carbonate (5.12 g, 37.02 mmol) were mixed in 1,4-dioxane (30 mL) and water (5 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated brine and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give product 157a (2.0 g, yield: 54.35%). MS m / z (ESI): 269.2 [M+1] + .

[0736] Step 2 Methyl 4-(2,3-dimethylphenyl)-3-carboxylbenzoate 157b The starting material, methyl 4-(2,3-dimethylphenyl)-3-formylbenzoate 157a (1 g, 3.73 mmol, 100% purity), was dissolved in acetonitrile (10 mL) and water (10 mL), and sodium dihydrogen phosphate monohydrate (1.54 g, 11.19 mmol), hydrogen peroxide (0.13 g, 3.73 mmol), and sodium chlorite (1.86 g, 20.52 mmol) were added. The reaction was carried out at room temperature for 16 hours. 20 ml of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the product, methyl 4-(2,3-dimethylphenyl)-3-carboxylbenzoate 157b (650 mg, yield: 61.34%). MS m / z (ESI): 285.3 [M+1] + .

[0737] Step 3 Methyl 4-(2,3-dimethylphenyl)-3-[(oxetan-3-yl)aminoformyl]benzoate 157c 157a (100 mg, 0.35 mmol) was dissolved in DMF (2 mL), and HATU (0.16 g, 0.42 mmol) and ethyl diisopropyl ether (0.18 g, 1.4 mmol) were added. The mixture was allowed to react at room temperature for 30 minutes. 3-Aminoxetane (0.031 g, 0.42 mmol) was added, and the mixture was allowed to react at room temperature for 5 hours. 20 mL of water was added, followed by extraction with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give product 157c (104 mg, yield: 87.1%). MS m / z (ESI): 340.0 [M+1] + .

[0738] Step 4 2',3'-Dimethyl-2-(oxetan-3-ylaminoformyl)-[1,1'-biphenyl]-4-carboxylic acid 157d 157c (104 mg, 0.31 mmol) was dissolved in THF (2 mL), methanol (2 mL), and water (1 mL), and lithium hydroxide hydrate (0.039 g, 0.93 mmol) was added. The reaction was allowed to proceed at room temperature for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 157d (70 mg, yield: 70.0%). MS m / z (ESI): 326.2 [M+1] + .

[0739] Step 5 (S,Z)-4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide (S,E)-4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide 157d (75 mg, 0.23 mmol) and 4 (0.036 g, 0.25 mmol) were dissolved in dichloromethane (7 mL) and DMF (3 mL), and EDCI (0.044 g, 0.23 mmol), 4-dimethylaminopyridine (0.056 g, 0.46 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 hours. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel prep-TLC (PE:EA = 1:2) to give the less polar isomer A0179 (Rf = 0.25) and the more polar isomer A0157 (Rf = 0.2), which were then separated by HPLC, purified, and lyophilized to give the more polar product A0157 (4.08 mg, yield: 3.69%) and the less polar product A0179 (0.72 mg, yield: 0.59%), respectively.

[0740] A0157: MS m / z (ESI):452.0[M+1] + . 1H NMR (400MHz,Chloroform-d) δ 8.11-8.09 (m,1H),7.72-7.65 (m,1H),7.35-7.26 (m,2H),7.25-7.22 (m,1H),7.13-7.05 (m,1H),6.06-5.88 (m,1H),5.00-4.82 (m,1H),4.74-4.69 (m,2H),4.42-4.11 (m,2H),3.98-3.74 (m,8H),2.98-2.91 (m,1H),2.70-2.65 (m,1H),2.35 (d,J=3.2Hz,3H),2.07-1.98 (m,3H). A0179: MS m / z (ESI):452.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.10-8.09 (m,1H),7.70-7.62 (m,1H),7.35-7.27 (m,2H),7.25-7.22 (m,1H),7.10-7.05 (m,1H),5.82-5.75 (m,1H),5.00-4.82 (m,1H),4.73-4.68 (m,2H),4.42-4.11 (m,2H),3.98-3.75 (m,8H),2.99-2.88 (m,1H),2.72-2.58 (m,1H),2.40-2.28 (m,3H),2.07-1.98 (m,3H).

[0741] Examples A0158 & A0180 (2S,4Z)-(2',3'-Dimethyl-2-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (2S,4E)-(2',3'-Dimethyl-2-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0742] [ka]

[0743] [ka]

[0744] Following the above synthetic route and referring to the synthetic method for compound A0157, the less polar isomer A0180 (Rf=0.25) and the more polar isomer A0158 (Rf=0.2) were obtained, which were then separated, isolated, and purified to give the more polar product A0158 (10.74 mg, yield: 6.17%) and the less polar product A0180 (9.01 mg, yield: 5.29%), respectively.

[0745] A0158: MS m / z (ESI): 465.9 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.65-7.52 (m,2H),7.37-7.33 (m,1H),7.22-7.12 (m,3H),4.98-4.87 (m,1H),4.49-4.27 (m,2H),3.95-3.72 (m,5H),3.67-3.25 (m,4H),3.12-2.58 (m,6H),2.40-2.33 (m,3H),2.15-2.03 (m,3H). A0180: MS m / z (ESI): 465.9 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.64-7.51 (m,2H),7.38-7.32 (m,1H),7.19-7.13 (m,3H),4.92-4.83 (m,1H),4.42-4.17 (m,2H),3.98-3.80 (m,5H),3.72- 3.22 (m,4H),3.18-2.50 (m,6H),2.38-2.30 (m,3H),2.15-2.02 (m,3H).

[0746] Examples A0191 & A0199 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2'-(2-methoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2'-(2-methoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0747] [ka]

[0748] See Examples A0149 & A0171, 149a

[0749] [ka]

[0750] The crude product was separated by silica gel prep-TLC (PE:EA=1:3) to give the less polar isomer A0199 (Rf=0.25) and the more polar isomer A0191 (Rf=0.2), which were then separated by HPLC, purified, and lyophilized to give the more polar product A0191 (12.1 mg, yield: 2.76%) and the less polar product A0199 (9.17 mg, yield: 2.14%).

[0751] A0191: MS m / z (ESI):438.0[M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.64-7.62 (m,1H),7.41-7.39 (m,1H),7.34-7.26 (m,1H),7.18-7.14 (m,3H),4.92-4.82 (m,1H),4.48-4.05 (m,4H),3.98-3.78 (m,5H),3.60-3.57 (m,2H),3.26 (s,3H),2.98-2.92 (m,1H),2.67-2.63 (m,1H),2.35 (s,3H). A0199: MS m / z (ESI):438.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.64-7.61 (m,1H),7.38-7.36 (m,1H),7.34-7.26 (m,1H),7.17-7.14 (m,3H),4.92-4.82 (m,1H),4.52-4.05 (m,4H),3.98-3.68 (m,5H),3.59-3.57 (m,2H),3.26 (s,3H),2.98-2.55 (m,2H),2.35 (s,3H).

[0752] Examples A0215 & A0222 3-(6-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-methoxypyridin-3-yl)-2-methylbenzonitrile 3-(6-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-methoxypyridin-3-yl)-2-methylbenzonitrile

[0753] [ka]

[0754] [ka]

[0755] Following the above synthetic route and referring to the synthetic method for compound C0061, the less polar isomer A0222 (Rf=0.25) and the more polar isomer A0215 (Rf=0.2) were obtained, which were then separated by HPLC, purified, and lyophilized to give the more polar product A0215 (8.93 mg, yield: 6.56%) and the less polar product A0222 (7.91 mg, yield: 5.68%).

[0756] A0215: MS m / z (ESI): 395.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.73-7.57 (m,3H),7.38-7.26 (m,2H),5.20-4.75 (m,3H),4.02-3.72 (m,8H),2.97-2.91 (m,1H),2.69-2.62 (m,1H),2.35 (s,3H). A0222: MS m / z (ESI): 395.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.73-7.66 (m,2H),7.60-7.57 (m,1H),7.40-7.34 (m,2H),5.20-4.75 (m,3H),4.00-3.72 (m,8H),2.99-2.63 (m,2H),2.35 (s,3H).

[0757] Examples A0216 & A0223 3-(6-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-4-methoxypyridin-3-yl)-2-methylbenzonitrile 3-(6-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-4-methoxypyridin-3-yl)-2-methylbenzonitrile

[0758] [ka]

[0759] [ka]

[0760] Following the above synthesis route and referring to the synthesis method of compound C0061, a more polar product A0216 (5.53 mg, yield: 4.71%) and a less polar product A0223 (3.47 mg, yield: 2.68%) were obtained.

[0761] A0216: MS m / z (ESI): 395.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.26-8.20 (m,1H),7.70-7.52 (m,2H),7.39-7.35 (m,2H),4.95-4.71 (m,2H),4.26-4.21 (m,1H),3.93-3.90 (m,6H),3.80-3.72 (m,1H),3.65-3.55 (m,1H),2.96-2.82 (m,1H),2.70-2.60 (m,1H),2.34 (s,3H). A0223: MS m / z (ESI): 395.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.22-8.19 (m,1H),7.72-7.52 (m,2H),7.39-7.37 (m,2H),4.95-4.88 (m,2H),4.88-4.72 (m,1H),4.20-4.11 (m,1H),3.99-3.85 (m,6H),3.80-3.68 (m,1H),3.60-3.50 (m,1H),2.98-2.65 (m,2H),2.33 (s,3H).

[0762] Examples A0163 & A0193 (S,Z)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-2-methylbenzonitrile (S,E)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-2-methylbenzonitrile

[0763] [ka]

[0764] [ka]

[0765] Step 1 Methyl 4-bromo-2-hydroxy-3-nitrobenzoate 163b 163a (12 g, 51.94 mmol) was dissolved in concentrated sulfuric acid (30 mL) and cooled to 0°C. Concentrated nitric acid (3.6 g, 57.13 mmol) was slowly added dropwise, and the reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was poured into ice water, and a solid precipitated. The solid was collected, and the filtrate was extracted with ethyl acetate. The solids were combined and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 163b (3.0 g, yield: 18.83%). MS m / z (ESI): 275.9 [M+1] + .

[0766] Step 2 Methyl 3-amino-4-bromo-2-hydroxybenzoate 163c Under argon gas protection, 163b (2.5 g, 9.06 mmol) was dissolved in methanol (10 mL) and acetic acid (10 mL), iron powder (2.53 g, 45.3 mmol) was added, and the reaction mixture was refluxed for 2 h. Water was added to the reaction mixture, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give 163c (1 g, yield: 44.87%). MS m / z (ESI): 246.0 [M+1] + .

[0767] Step 3 Methyl 4-bromo-3-(2-chloroacetylamino)-2-hydroxybenzoate 163e 163c (200 mg, 0.81 mmol) was dissolved in chloroform (5 mL), saturated aqueous sodium bicarbonate (0.34 g, 4.05 mmol) was added, and the temperature was controlled at 0-10°C. 163d (0.11 g, 0.97 mmol) was slowly added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 4 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to give 163e (150 mg, yield: 57.22%). MS m / z (ESI): 322.0 [M+1] + .

[0768] Step 4 5-Bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid methyl ester 163f 163e (150 mg, 0.47 mmol) was dissolved in DMF (8 mL), potassium carbonate (0.26 g, 1.88 mmol) was added, and the reaction mixture was reacted at 70°C for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 163f (100 mg, yield: 67.65%). MS m / z (ESI): 286.0 [M+1]+ .

[0769] Step 5 5-Bromo-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid methyl ester 163g 163f (100 mg, 0.47 mmol) was dissolved in DMF (5 mL), potassium carbonate (0.13 g, 0.94 mmol) and iodomethane (133 mg, 0.94 mmol) were added, and the reaction mixture was allowed to react at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 163g (100 mg, yield: 95.3%). MS m / z (ESI): 300.0 [M+1] + .

[0770] Following steps 6 to 8 of the above synthetic route, and referring to the synthesis method for compound A0134, the less polar isomer A0193 (Rf = 0.25) and the more polar isomer A0163 (Rf = 0.2) were obtained. These were then separated by HPLC, purified, and lyophilized to give the more polar product A0163 (7.67 mg, yield: 5.08%) and the less polar product A0193 (30.57 mg, yield: 21.64%).

[0771] A0163: MS m / z (ESI):449.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.69 (dd,J=7.6,1.2Hz,2H),7.53-7.36 (m,2H),7.15 (dd,J=8.0,1.2Hz,1H),6.96-6.92 (m,1H),4.83-4.75 (m,1H),4.70- 4.56 (m,2H),4.30-4.18 (m,1H),4.14-4.05 (m,1H),3.97-3.91 (m,1H),3.84 (s,3H),3.81-3.76 (m,1H),3.01-2.95 (m,1H),2.73-2.62 (m,4H),2.44-2.27 (m,3H). A0193: MS m / z (ESI):449.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.70 (dd,J=7.5,1.2Hz,1H),7.50-7.36 (m,2H),7.16 (dd,J=8.0,1.2Hz,1H),6.97-6.91 (m,1H),4.82-4.76 (m,1H),4.70-4.55 (m,2H),4.30-4.02 (m,2H),3.98-3.92 (m,1H),3.86 (s,3H),3.82-3.77 (m,1H),2.98-2.82 (m,1H),2.78-2.70 (m,1H),2.64 (s,3H),2.43-2.26 (m,3H).

[0772] Examples A0162 & A0206 (S,Z)-3-(8-(2-hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-2-methylbenzonitrile (S,E)-3-(8-(2-hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-2-methylbenzonitrile

[0773] [ka]

[0774] [ka]

[0775] Step 1 5-Bromo-4-methyl-3-oxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate methyl ester 162b 163f (300 mg, 1.05 mmol) was dissolved in DMF (10 mL), potassium carbonate (440 mg, 3.15 mmol) and iodomethane (227 mg, 1.57 mmol) were added, and the reaction mixture was reacted at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a pale yellow crude product 162b (200 mg, yield: 57.20%). MS m / z (ESI): 300.1 [M+1] + .

[0776] Step 2 Methyl 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate 162c 162b (200 mg, 0.67 mmol) was dissolved in THF (10 mL), borane-tetrahydrofuran complex (1.01 mL, 1.01 mmol) was added, and the reaction was stirred at room temperature for 8 h. The reaction was quenched with methanol and concentrated to dryness to give crude 162c (180 mg). MS m / z (ESI): 286.1 [M+1] + .

[0777] Following steps 3 to 5 of the above synthetic route, and referring to the synthesis method for compound A0134, the highly polar product A0162 (14.54 mg, yield: 9.86%) and the less polar product A0206 (12.12 mg, yield: 8.27%) were obtained.

[0778] A0162: MS m / z (ESI):435.0[M+1] + . 1H NMR (400MHz,Chloroform-d) δ 7.71-7.61 (m,1H),7.59-7.46 (m,1H),7.43-7.27 (m,1H),7.03-6.94 (m,1H),6.76-6.66 (m,1H),4.78-4.72 (m,1H),4.32-4.02 (m,4H),3.87 (d,J=21.2Hz,3H),3.80-3.72 (m,1H),3.28-3.19 (m,2H),3.04-2.91 (m,1H),2.76-2.59 (m,1H),2.50-2.18 (m,7H). A0206: MS m / z (ESI):435.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.67-7.63 (m,2H),7.39-7.34 (m,1H),7.05-6.97 (m,1H),6.75-6.71 (m,1H),4.81-4.76 (m,1H),4.35-3.98 (m,4H),3.88 (d,J=18.4Hz,3H),3.80-3.70 (m,1H),3.32-3.16 (m,2H),3.01-2.94 (m,1H),2.75-2.62 (m,1H),2.46-2.28 (m,7H).

[0779] Examples A0188 & A0230 (S,Z)-3-(2-(cyclopropylmethoxy)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyridin-3-yl)-2-methylbenzonitrile (S,E)-3-(2-(cyclopropylmethoxy)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyridin-3-yl)-2-methylbenzonitrile

[0780] [ka]

[0781] [ka]

[0782] Step 1 5-Bromo-6-(cyclopropylmethoxy)pyridinecarboxylic acid 188c At room temperature, 188b (6.67 g, 87.6 mmol) was slowly added to NaH (0.12 g, 5 mmol) and stirred for 10 minutes. Then, 188a (250 mg, 1.0 mmol) was added and the reaction mixture was heated at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and water (5 mL) and 2N hydrochloric acid were added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product 188c (200 mg, yield: 70.03%). MS m / z (ESI): 272.0 [M+1] + .

[0783] Following Steps 2 and 3 of the above synthetic route, and referring to the synthesis method of compound C0102, the less polar isomer A0230 (Rf = 0.25) and the more polar isomer A0188 (Rf = 0.2) were obtained. These were then separated by HPLC, purified, and lyophilized to give the more polar product A0188 (3.52 mg, yield: 1.96%) and the less polar product A0230 (7.95 mg, yield: 3.90%).

[0784] A0188: MS m / z (ESI):435.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.85-7.65 (m,2H),7.62-7.56 (m,1H),7.42 -7.32 (m,2H),4.97-4.72 (m,3H),4.30-4.18 (m,2H),3.94-3.70 (m,5H),3.10-3.04 (m,1H),2.99-2.88 (m,1H),2.70-2.58 (m,1H),2.38 (s,3H),0.90-0.85 (m,1H),0.60-0.50 (m,2H),0.30-0.20 (m,2H). A0230 :MS m / z (ESI):435.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.72-7.53 (m,3H),7.40-7.36 (m,2H),4.72 -4.54 (m,1H),4.23-4.02 (m,2H),3.93-3.78 (m,3H),3.32-3.18 (m,4H),2.95-2.53 (m,1H),2.39 (s,3H),1.90-1.83 (m,1H),1.20-1.12 (m,1H),0.60-0.50 (m,2H),0.30-0.20 (m,2H).

[0785] Examples A0190 & A0208 (S,Z)-3-(5-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-methylbenzonitrile (S,E)-3-(5-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-methylbenzonitrile

[0786] [ka]

[0787] [ka]

[0788] Step 1 Methyl 5-bromo-6-((dimethylamino)methylene)amino)pyridinecarboxylate 190b 190a (1 g, 4.33 mmol) and DMF-DMA (1.03 g, 8.66 mmol) were dissolved in toluene (20 mL), and the reaction mixture was reacted at 110° C. for 4 hours. The reaction mixture was concentrated to give a reddish-brown crude product 190b (1.0 g). MS m / z (ESI): 287.9 ​​[M+1] + .

[0789] Step 2 5-Bromo-6-(N'-hydroxymethylimidamine)picolinic acid methyl ester 190c Under argon gas protection, 190b (1.2 g, 4.19 mmol), hydroxylamine hydrochloride (0.58 g, 8.38 mmol), and sodium acetate (0.69 g, 8.38 mmol) were mixed in ethanol (12 mL), and the reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, and a white solid precipitated. It was filtered to give crude product 190c (1 g). MS m / z (ESI): 273.9 [M+1] + .

[0790] Step 3 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate methyl ester 190d 190c (1 g, 3.65 mmol) was dissolved in THF (10 mL) at room temperature, and trifluoroacetic anhydride (2.30 g, 10.95 mmol) was slowly added dropwise. The reaction mixture was then heated to 75 °C and stirred for 3 h. After completion of the reaction, the mixture was quenched at 0 °C by adding saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 190d (420 mg, yield: 44.95%). MS m / z (ESI): 255.9 [M+1] + .

[0791] Following steps 4 to 6 of the above synthetic route, and referring to the synthesis method of compound A0212, the less polar isomer A0208 (Rf = 0.25) and the more polar isomer A0190 (Rf = 0.2) were obtained. These were then separated by HPLC, purified, and lyophilized to give the more polar product A0190 (29.99 mg, yield: 17.26%) and the less polar product A0208 (28.31 mg, yield: 16.29%).

[0792] A0190: MS m / z (ESI):405.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.44 (s,1H),7.78-7.76 (m,1H),7.61-7.40 (m,3H),7.36-7.31 (m,1H),4.89-4.82 (m,1H),4.41-4.20 (m,2H),4.05-3.82 (m,5H),3.75-3.65 (m,1H),3.09-3.00 (m,1H),2.97-2.82 (m,1H),2.50-2.40 (m,3H). A0208: MS m / z (ESI):405.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 8.38 (s,1H),7.71-7.68 (m,1H),7.55-7.33 (m,3H),7.28-7.19 (m,1H),4.82-4.78 (m,1H),4.36-4.12 (m,2H),3.88-3.82 (m,1H),3.77 (s,3H),3.65-3.57 (m,1H),3.27-3.20 (m,1H),3.00-2.75 (m,2H),2.35 (s,3H).

[0793] Examples A0197 & A0197A (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile

[0794] [ka]

[0795] [ka]

[0796] Step 1 6-chloro-5-(3-cyano-2-methylphenyl)pyridinecarboxylic acid methyl ester 197c Raw materials 197a (3 g, 11.98 mmol) and 197b (3.49 g, 14.38 mmol) were dissolved in dioxane (50 mL) and water (5 mL), and sodium carbonate (3.81 g, 35.94 mmol) and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.39 g, 0.60 mmol) were added. After purging with nitrogen gas, the reaction was allowed to proceed at 100°C for 2 hours. 50 mL of water was added, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give product 197c (3.04 g, yield: 88.53%). MS m / z (ESI): 287.2 [M+1] + .

[0797] Step 2 6-chloro-5-(3-cyano-2-methylphenyl)pyridinecarboxylic acid 197d The raw material 197c (3 g, 10.46 mmol) was dissolved in tetrahydrofuran (30 mL) and water (15 mL), and lithium hydroxide hydrate (2.19 g, 52.30 mmol) was added. The reaction was allowed to proceed at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain product 197d (2.4 g, yield: 84.11%). MS m / z (ESI): 273.0 [M+1] + .

[0798] Step 3 6-chloro-5-(3-cyano-2-methylphenyl)pyridine-2-carboxylic acid tert-butyl ester 197e The starting material 197d (1.5 g, 5.50 mmol) and tert-butoxycarboxylic acid anhydride (3.00 g, 13.75 mmol) were dissolved in tert-butanol (30 mL), and DMAP (0.34 g, 2.75 mmol) was added. The reaction was carried out at 80° C. for 16 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 197e (1.3 g, yield: 71.88%). MS m / z (ESI): 329.2 [M+1] + .

[0799] Step 4 5-(3-cyano-2-methylphenyl)-6-[(2-methoxyethyl)amino]pyridine-2-carboxylic acid tert-butyl ester 197f The starting material 197e (200 mg, 0.61 mmol) and 2-methoxyethan-1-amine (0.14 g, 1.83 mmol) were dissolved in DME (5 mL). Palladium acetate (0.014 g, 0.061 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.057 g, 0.12 mmol), and cesium carbonate (0.60 g, 1.83 mmol) were added, and the reaction was heated at 100°C for 16 hours. 10 mL of water was added, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give product 197f (20 mg, yield: 8.95%). MS m / z (ESI): 368.0 [M+1] + .

[0800] Step 5 5-(3-cyano-2-methylphenyl)-6-[(2-methoxyethyl)amino]pyridine-2-carboxylic acid 197g The raw material 197f (20 mg, 0.054 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.38 g, 3.30 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to give the product 197g (15 mg, yield: 88.51%). MS m / z (ESI): 312.0 [M+1] + .

[0801] Step 6 (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile The raw material 197g (15mg, 0.048mmol) and 4 (0.014g, 0.096mmol) were dissolved in dichloromethane (1mL) and DMF (0.3mL), and EDCI (0.0092g, 0.048mmol) and DMAP (0.012g, 0.096mmol) were added, and the reaction was carried out at room temperature for 16 hours. Then, 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated by silica gel prep-TLC (EA:PE = 2:1) to give the more polar isomer A0197 (Rf = 0.25) and the less polar isomer A0197A (Rf = 0.3), which were then separated by HPLC, purified, and lyophilized to give the more polar product A0197 (4.25 mg, yield: 20.16%) and a trace amount of the less polar product A0197A.

[0802] A0197: MS m / z (ESI):438.0[M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.75-7.69 (m,1H),7.53-7.23 (m,4H),4.88-4.68 (m,1H),3.90-3.78 (m,4H),3.75-3.35 (m,6H),3.30-3.25 (m,5H),2.97-2.83 (m,1H),2.69-2.49 (m,1H),2.35 (s,3H). A0197A: MS m / z (ESI):438.0[M+1] + .

[0803] Examples A0198 & A0231 (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinepyridin-3-yl)-2-methylbenzonitrile (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinepyridin-3-yl)-2-methylbenzonitrile

[0804] [ka]

[0805] [ka]

[0806] Step 1 5-Bromo-6-(morpholin-4-yl)pyridine-2-carboxylic acid 198b 198a (190 mg, 0.80 mmol) and morpholine (0.5 mL, 4 mmol) were mixed and reacted at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give product 198b (135 mg, yield: 58.52%). MS m / z (ESI): 287.1 [M+1] + .

[0807] Step 2 5-(3-cyano-2-methylphenyl)-6-(morpholin-4-yl)pyridine-2-carboxylic acid 198d The starting materials 198b (110 mg, 0.38 mmol) and 198c (0.12 g, 0.49 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL), and sodium carbonate (0.12 g, 1.14 mmol) and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) (24.77 mg, 0.038 mmol) were added. After purging with nitrogen gas, the reaction was allowed to proceed at 100°C for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to give product 198d (120 mg, yield: 96.86%).

[0808] Step 3 (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinepyridin-3-yl)-2-methylbenzonitrile (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinepyridin-3-yl)-2-methylbenzonitrile The starting material 197d (105 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of sodium bicarbonate (0.26 g, 3.1 mmol) in water (2 mL) was added. After reacting for 10 minutes, 4 (0.054 g, 0.37 mmol) was added dropwise at 0°C, and the reaction was continued at 25°C for 2 hours. The reaction mixture was diluted with 5 mL of ethyl acetate, washed twice with water, dried, and concentrated. The crude product was separated by silica gel prep-TLC (EA:PE=2:1) ​​to give the less polar isomer A0231 (Rf=0.25) and the more polar isomer A0198 (Rf=0.2), which were then separated by HPLC, purified, and lyophilized to give the more polar product A0198 (1.58 mg, yield: 1.14%) and the less polar product A0231 (1.8 mg, yield: 1.30%).

[0809] A0198: MS m / z (ESI): 450.0 [M+1] + . 1 H NMR (400MHz,Chloroform-d) δ 7.68-7.37 (m,5H),5.00-4.50 (m,4H),3.98-3.81 (m,4H),3.57-3.48 (m,5H),3.10-2.63 (m,5H),2.42 (s,3H). A0231: MS m / z (ESI): 450.0 [M+1] + . 1H NMR (400MHz,Chloroform-d) δ 8.06-7.37 (m,5H),5.00-3.75 (m,8H),3.56-3.30 (m,3H),3.28-3.00 (m,2H),3.22-2.60 (m,5H),2.42 (s,3H).

[0810] Common intermediate A (S)-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)boronic acid

[0811] [ka]

[0812] Step 1 7-Bromobenzo[d][1,3]dioxolane-4-carboxylate methyl ester A-2 Diiodomethane (9.02 g, 33.68 mmol) and cesium carbonate (16.88 g, 51.82 mmol) were added to a solution of A-1 (6.40 g, 25.91 mmol) in N,N-dimethylformamide (150 mL). The atmosphere was purged with nitrogen gas, and the mixture was reacted at 70 °C for 3 hours. After completion of the reaction, the reaction mixture was filtered to remove the cesium carbonate. The filter cake was washed with ethyl acetate. Water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine (50 mL × 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified using a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 5:95 to 50:50) to obtain product A-2 (2.2 g, yield: 32.78%). MS m / z (ESI): 260.0 [M+1] + .

[0813] Step 2 7-Bromobenzo[d][1,3]dioxole-4-carboxylic acid A-3 Sodium hydroxide (734 mg, 18.35 mmol) was added to a solution of A-2 (950 mg, 3.67 mmol) in tetrahydrofuran (10 mL) / methanol (5 mL) / water (5 mL), and the reaction mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated to remove the methanol, and ethyl acetate (100 mL) was added to the residue. The pH was adjusted to 3 with 1N HCl, and then extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to give product A-3 (800 mg, yield: 89.03%). MS m / z (ESI): 244.0 [M-1] + .

[0814] Step 3 (S,EZ)-(7-bromobenzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone A-4 A solution of A-3 (1.7 g, 6.49 mmol) in N,N-dimethylformamide (50 mL) was added with triethylamine (2.69 g, 20.82 mmol), 4 (1.5 g, 8.33 mmol), and HATU (3.17 g, 8.33 mmol), and the reaction mixture was incubated at room temperature for 90 minutes. After completion of the reaction, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was then evaporated, and the residue was purified using a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 5:95 to 60:40) to obtain product A-4 (2.38 g, yield: 92.42%). MS m / z (ESI): 372.2 [M+1] + .

[0815] Step 4 (S,EZ)-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxol-4-yl)boronic acid A A-4 (1.60 g, 4.31 mmol), bis(pinacolato)diboron (1.97 g, 7.76 mmol), and potassium acetate (1.27 g, 12.93 mmol) were dissolved in 1,4-dioxane (30 mL). After purging with nitrogen gas, Pd(dppf)Cl2 (320 mg, 0.44 mmol) was added at room temperature and reacted at 80 °C for 4 hours. After the reaction was complete, the mixture was poured into a mixed solvent of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The residue was purified on a C18 reverse-phase silica gel column (eluted with a gradient of acetonitrile:water = 15:85 to 60:40) to give A (650 mg, yield: 44.87%). MS m / z (ESI): 337.0 [M+1] + .

[0816] Examples C0117 & C0118 (S,E)-(7-(3-(difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(7-(3-(difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0817] [ka]

[0818] [ka]

[0819] Step 1 3-Difluoromethyl-2-methylbenzenepinacolatodiboron 118b To a solution of 118a (150 mg, 0.68 mmol) in 1,4-dioxane (8 mL), bis(pinacolato)diboron (0.35 g, 1.36 mmol), potassium carbonate (0.20 g, 2.04 mmol), and Pd(dppf)Cl2 (0.050 g, 0.068 mmol) were added. After purging with nitrogen gas, the mixture was reacted at 75 °C for 3 h. After completion of the reaction of the raw materials was monitored by TLC, the mixture was directly subjected to the next step without further workup.

[0820] Step 2 (S,E)-(7-(3-(difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone (S,Z)-(7-(3-(difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone To the reaction solution of 118b, A-4 (200 mg, 0.54 mmol), Pd(dppf)Cl2 (0.044 g, 0.054 mmol), potassium carbonate (0.22 g, 1.62 mmol), and water (1 mL) were added. After purging with nitrogen gas, the reaction solution was reacted at 95 °C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3) and dried over sodium sulfate. The solvent was then evaporated, and the residue was purified by silica gel prep-TLC (PE:EA = 1:5) to obtain the crude less polar isomer C0117 (Rf = 0.6) and the crude more polar isomer C0118 (Rf = 0.55). Next, each was separated and purified by HPLC, and after lyophilization, the less polar product C0117 was obtained. (2.0 mg, yield: 0.86%) and the more polar product C0118 (2.0 mg, yield: 0.86%).

[0821] C0117:MS m / z (ESI):433.1[M+1] + . 1H NMR (400MHz,CD3OD-d4) δ 7.57-7.56 (m,1H),7.41-7.34 (m,2H),7.11-6.84 (m,3H),6.09-6.04 (m,2H),4.72-4.14 (m,3H),3.87-3.31 (m,5H),2.95-2.30 (m,2H),2.23 (s,3H).

[0822] C0118:MS m / z (ESI):433.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.57-7.56 (m,1H),7.40-7.34 (m,2H),7.11-6.84 (m,3H),6.10-6.05 (m,2H),4.72-4.16 (m,3H),3.87-3.31 (m,5H),3.12-2.66 (m,2H),2.30 (s,3H).

[0823] Examples C0120 & C0121 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone

[0824] [ka]

[0825] [ka]

[0826] Step 1 (S,Z)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone (S,E)-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone Following the above synthetic route and referring to the synthetic method for compound A0204, the less polar isomer C0120 (20 mg, yield: 31.9%) and the more polar isomer C0121 (22 mg, yield: 35.1%) were obtained.

[0827] C0120:MS m / z (ESI):379.1[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.08 (s,1H),7.81-7.79 (dd,J=8.0,0.8Hz,1H),7.70-7.69 (m,2H),7.59-7.57 (m,2H),7.28-7.20 (m,2H),4.77-4.71 (m,8H),3.63 (s,3H),2.93-2.86 (m,2H). C0121: MS m / z (ESI): 379.1 [M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.08 (s,1H),7.81-7.79 (dd,J=8.0,0.8Hz,1H),7.70-7.68 (m,2H),7.59-7.57 (m,2H),7.27-7.20 (m,2H),4.78-3.79 (m,8H),3.63 (s,3H),3.35-3.30 (m,1H),2.97-2.65 (m,2H).

[0828] Examples C0122 & C0123 (S,E)-6-Fluoro-3-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)-2-methylbenzonitrile (S,Z)-6-Fluoro-3-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)-2-methylbenzonitrile

[0829] [ka]

[0830] [ka]

[0831] Step 1 After dissolving 122a (1 g, 7.40 mmol) in trifluoromethanesulfonic acid (15 mL), NBS (1.32 g, 7.40 mmol) was slowly added at 0 °C, the temperature was returned to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give product 122b (1.45 g, yield: 91.55%).

[0832] Following Steps 2 and 3 of the above synthetic route, and referring to the synthesis method for compound C0117, crude less polar isomer C0122 (Rf=0.4) and crude more polar isomer C0123 (Rf=0.3) were obtained. These were then separated and purified by HPLC, and lyophilized to give less polar isomer C0122 (5 mg, yield: 1.8%) and more polar isomer C0123 (10 mg, yield: 3.5%).

[0833] C0122: MS m / z (ESI): 426.1 [M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.63-7.58 (m,1H),7.27 (t,J=8.4Hz,1H),7.06 (d,J=8.4Hz,1H),6.87 (d,J=8.4Hz,1H),6.12-6.07 (m,2H),4.74-3.70 (m,8H),2.90-2.85 (m,2H),2.46 (s,3H). C0123: MS m / z (ESI): 426.1 [M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 7.64-7.60 (m,1H),7.27 (t,J=9.2Hz,1H),7.06 (d,J=8.4Hz,1H),6.87 (d,J=8.0Hz,1H),6.13-6.07 (m,2H),4.71-4.14 (m,4H),3.88-3.69 (m,4H),3.13-2.65 (m,2H),2.47 (s,3H).

[0834] Examples C0126 & C0127 (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile

[0835] [ka]

[0836] [ka]

[0837] Step 1 3-Bromo-2-(trifluoromethyl)benzamide 127b 127a (500 mg, 1.86 mmol) and HATU (780 mg, 2.05 mmol) were dissolved in DMF (8 mL), and triethylamine (750 mg, 7.44 mmol) and ammonium chloride (200 mg, 3.72 mmol) were added at room temperature. The mixture was then reacted for 2 hours at room temperature. After the reaction was completed, the mixture was filtered, and the filtrate was purified on a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 15:85 to 60:40) to obtain product 127b (350 mg, yield: 70.26%). MS m / z (ESI): 268.8 [M+1]+ .

[0838] Step 2 3-Bromo-2-(trifluoromethyl)benzonitrile 127c 127b (330 mg, 1.23 mmol) was dissolved in DMF (8 mL), triethylamine (190 mg, 1.88 mmol) was added at room temperature, and trifluoroacetic anhydride (390 mg, 1.86 mmol) was added dropwise at 0 °C under nitrogen gas protection, followed by reaction at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified using a C18 reverse-phase column (eluted with a gradient of acetonitrile:water = 20:80 to 70:30) to obtain product 127c (150 mg, yield: 48.73%). MS m / z (ESI): 250.1 [M+1] + .

[0839] Step 3 (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile 204c (120 mg, 0.41 mmol), 127c (100 mg, 0.40 mmol), and potassium carbonate (145 mg, 1.05 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL). Pd(dppf)Cl2 (30 mg, 0.041 mmol) was added under nitrogen gas protection at room temperature and the mixture was reacted at 80 °C for 2 h. After the reaction was completed, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. The residue was purified by silica gel Prep-TLC (PE:EA=1:4) to give the less polar isomer C0126 (Rf=0.6, 26.32 mg, yield: 13.53%) and the more polar isomer C0127 (Rf=0.50, 46.55 mg, yield: 25.67%).

[0840] C0127:MS m / z (ESI):418.0[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.04 (d,J=7.6Hz,1H),7.85 (t,J=7.6Hz,1H),7.71 (d,J=7.2Hz,1H),7.64 (d,J=7.6Hz,2H),7.44 (d,J=8.0Hz,2H),4.76-4.03 (m,3H),3.90-3.38 (m,5H),3.07-2.84 (m,1H),2.77-2.63 (m,1H). C0126:MS m / z (ESI):418.0[M+1] + . 1 H NMR (400MHz,CD3OD-d4) δ 8.04 (d,J=7.6Hz,1H),7.85 (t,J=7.6Hz,1H),7.70 (d,J=8.0Hz,1H),7.64 (d,J=7.6Hz,2H),7.43 (d,J=8.0Hz,2H),4.83-4.00 (m,3H),3.95-3.36 (m,5H),2.98-2.77 (m,2H).

[0841] Examples C0132 & C0133 (S,E)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylbenzonitrile (S,Z)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylbenzonitrile

[0842] [ka]

[0843] [ka]

[0844] Following the above synthesis route and referring to the synthesis method of compound C0061, a more polar product C0133 (54 mg, yield: 12.2%) and a less polar product C0132 (38 mg, yield: 8.6%) were obtained.

[0845] C0132: MS m / z (ESI): 422.1 [M+1] + . 1 H NMR (300MHz,DMSO-d6) δ 7.84-7.82 (m,1H),7.56-7.45 (m,2H),6.96-6.90 (m,1H),6.81 (dd,J=7.8,2.7Hz,1H),5.01-4.98 (m,1H),4.51-4.28 (m,5H),4.08-3.96 (m,2H),3.84-3.80 (m,3H),3.59-3.58 (m,1H),3.27-3.26 (m,1H),2.87-2.74 (m,2H),2.33 (s,3H). C0133: MS m / z (ESI): 422.1 [M+1] + . 1H NMR (400MHz,DMSO-d6) δ 7.80 (d,J=7.6Hz,1H),7.55-7.42 (m,2H),6.92-6.89 (m,1H),6.78 (dd,J=6.4,1.6Hz,1H),4.97-4.93 (m,1H),4.48-4.24 (m,5H),4.09-3.86 (m,2H),3.81-3.73 (m,3H),3.55-3.51 (m,1H),3.27-3.15 (m,1H),2.91-2.84 (m,1H),2.69-2.56 (m,1H),2.30 (s,3H).

[0846] Examples C0039 & C0040 (S,Z)-3-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one (S,E)-3-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one

[0847] [ka]

[0848] [ka]

[0849] Step 1 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-pyrrolidine-1,2-dicarboxylate 39b 39a (10 g, 40.77 mmol), tert-butyldimethylsilyl chloride (12.29 g, 81.54 mmol), and imidazole (6.94 g, 101.93 mmol) were dissolved in DMF (50 mL). The mixture was purged with nitrogen and stirred at room temperature overnight. After cooling, the reaction mixture was poured into a mixture of ethyl acetate and water. After layering, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was loaded onto a silica gel column and eluted with PE / EA (10:1). The eluate was collected and rotary evaporated to give 39b (13.5 g, 87.5% yield). 1 H NMR (400MHz,CDCl3) δ 4.43-4.31 (m,2H),3.74-3.72 (m,3H),3.62-3.59 (m,1H),3.42-3.30 (m,1H),2.19-2.15 (m,1H),2.03-1.98 (m,1H),1.46-1.41 (m,9H),0.92 (s,6H),0.059 (s,6H).

[0850] Step 2 1-(tert-butyl) 2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(cyanomethyl)pyrrolidine-1,2-dicarboxylate 39c LiHMDS (7.35 g, 43.94 mmol) was added dropwise to 39b (7.9 g, 21.97 mmol) and potassium iodide (0.36 g, 2.20 mmol) in THF (100 mL) at 0 °C under nitrogen gas protection. After stirring for 20 min, the mixture was cooled to -78 °C. 2-Bromoacetonitrile (5.27 g, 43.94 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction mixture was gradually warmed to room temperature and allowed to react overnight at room temperature. After the reaction was complete, the mixture was poured into a mixed solvent of ethyl acetate and water. The aqueous phase was extracted once more after layering. The combined organic phases were washed once with brine, dried, filtered, and rotary evaporated. The crude product was loaded onto a silica gel column and eluted with PE / EA (50:1 to 5:1). The eluate was collected and rotary evaporated to give 39c (2.0 g, yield: 20.5%). 1 H NMR (400MHz,CDCl3) δ 4.45-4.07 (m,1H),3.63-3.53 (m,3H),3.26-3.12 (m,2H),2.95-2.91 (m,1H),2.37-2.28 (m,1H),2.11-2.02 (m,1H),1.31-1.24 (m,9H),0.79-0.76 (m,9H),0.01-0.00 (m,6H).

[0851] Step 3 (2S,4R)-2-(cyanomethyl)-4-hydroxypyrrolidine-2-carboxylate methyl ester 39d 39c (2.0 g, 5.02 mmol) was dissolved in a solution of hydrochloric acid in dioxane (10 mL). The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was directly rotary evaporated to give crude product 39d (1.0 g). MS m / z (ESI): 185.1 [M+1] + .

[0852] Step 4 (2S,4R)-2-(cyanomethyl)-4-hydroxy-1-(4-(2-methylphenyl)benzoyl)pyrrolidine-2-carboxylic acid methyl ester 39f Triethylamine (1.65 g, 16.29 mmol) was added to a solution of 39d (1 g, 5.43 mmol) and 39e (1.88 g, 8.14 mmol) in DCM (20 mL). After purging with nitrogen gas, the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was extracted with dichloromethane / water, and the combined organic phases were washed with saturated NaCl solution. The combi...

Claims

1. Formula I: 【Chemistry 1】 or an isotopic derivative thereof, or a pharmaceutically acceptable salt of either of the foregoing, X is N-OR １ and R １ is hydrogen or C １-６ is an alkyl group, １-６ The alkyl group may optionally be one or more R １ａ is replaced by Each R １ａ are independently a halogen, a cyano group, a nitro group, an oxo group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, C ３-８ Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR ５ａ , -SR ５ａ , -N(R ５ａ ) (R ５ｂ ), -C(O)R ５ａ , -OC(O)R ５ａ , -C(O)OR ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ｃ ) C(O)R ５ａ , -N(R ５ｃ )C(O)N(R ５ａ ) (R ５ｂ ), -S(O) ２ R ５ａ , -N(R ５ｃ ) S (O) ２ R ５ａ , -S(O) ２ N (R ５ａ ) (R ５ｂ ), -Si(R ５ａ ) ３ , -Si(R ５ａ ) ２ (OR ５ｂ ), -OSi(R ５ａ ) ３ , -Si(R ５ａ ) (OR ５ｂ ) ２ , -OP(O)(OR ５ａ ) (OR ５ｂ ), -P(O)(OR ５ａ ) (OR ５ｂ ), -OP(O)(OR ５ａ ) (R ５ｂ ), -P(O)(OR ５ａ ) (R ５ｂ ), -OP(O)(R ５ａ ) (R ５ｂ ) or -P(O)(R ５ａ ) (R ５ｂ ) and R ３ａ is hydrogen, halogen, cyano group, nitro group, C １-６ Alkyl group, C １-６ Haloalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, C ３-８ a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, or -L １ -R ３ｃ and R ３ｂ is hydrogen, halogen, cyano group, nitro group, C １-６ Alkyl group, C １-６ Haloalkyl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, -L １ -R ３ｃ , -C(O)OR ３ｄ , -C(O)N(R ３ｄ ) (R ３ｅ ), -S(O) ２ R ３ｄ , -S(O) ２ N (R ３ｄ ) (R ３ｅ ), -P(O)(OR ３ｄ ) (OR ３ｅ ), -P(O)(OR ３ｄ ) (R ３ｅ ), -P(O)(R ３ｄ ) (R ３ｅ ), C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a condensed ring formed with a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; Or, R ３ａ and R ３ｂ together with the carbon atoms attached thereto, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group and the 3- to 8-membered heterocycloalkenyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; Each L １ are independently -[C(R ａ ) (R ｂ )] ｎ -, where n is 1, 2, or 3, and each R ａ and R ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R ａ and R ｂ together with the carbon atoms attached thereto, ３-８ Forms a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C １-６ Alkyl group, C ３-８ The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; Each R ３ｃ is independently, -OR ７ａ , -SR ７ａ , -N(R ７ａ )(R ７ｂ ), -C(O)R ７ａ , -OC(O)R ７ａ , -C(O)OR ７ａ , -C(O)N(R ７ａ )(R ７ｂ ), -N(R ７ｃ )(C(O)R ７ａ , -N(R ７ｃ )(C(O)N(R ７ａ )(R ７ｂ ), -S(O) ２ R ７ａ , -N(R ７ｃ )(S(O) ２ R ７ａ , -S(O) ２ N(R ７ａ )(R ７ｂ ), -Si(R ７ａ ) ３ , -Si(R ７ａ )(O R ２ ), -O Si(R ７ｂ )(O R ７ａ ), -Si(R ３ )(O R ７ａ )(O R ７ｂ ), -O P(O)(O R ２ )(O R ７ａ )(O R ７ｂ ), -P(O)(O R ７ａ )(O R ７ｂ ), -O P(O)(O R ７ａ )(R ７ｂ ), -P(O)(O R ７ａ )(R ７ｂ ), -O P(O)(R ７ａ )(R ７ｂ ) or -P(O)(R ７ａ )(R ７ｂ ), and L ２ is -[C(R １０ａ ) (R １０ｂ )] ｔ -, where one C(R １０ａ ) (R １０ｂ ) moiety is optionally —O— or —N(R １０ａ ) - is replaced by s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2; R ９ａ and R ９ｂ are each independently hydrogen, halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group or halo C ２-６ an alkynyl group, or R ９ａ and R ９ｂ together with the atoms bonded to them, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ forms a cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group, or R ９ａ and R ３ａ are bonded to each other to form -CH ２ -or-CH ２ CH ２ - Forms R １０ａ and R １０ｂ are each independently hydrogen, halogen, a cyano group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group or halo C ２-６ an alkynyl group, or R １０ａ and R １０ｂ together with the carbon atoms attached thereto, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ forms a cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group, or R １０ａ and R ３ａ together with the atoms bonded to them, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ forming a cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group, Ring A is 【Chemistry 2】 wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each --- bond is independently a single bond or a double bond; Each A １ are independently CH, C(O), N, NH, O, S, N(R ４ａ ) or C(R ４ａ ) and Each A ２ are independently CH, C(O), N, NH, O, S, N(R ４ｂ ) or C(R ４ｂ ) and A ３ is CH, C(O), N, N(R ４ｃ ) or C(R ４ｃ ) and Each A ４ are independently CH, C(O), N, N(R ４ｄ ) or C(R ４ｄ ) and A ５ are CH, N, O, S, NH, C(R ４ｄ ) or N(R ４ｄ ) and Each A ６ are independently C or N; Each A ７ are independently C or N; Each R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are each independently a halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, C ３-８ Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR ８ａ , -SR ８ａ , -N(R ８ａ ) (R ８ｂ ), -C(O)R ８ａ , -OC(O)R ８ａ , -C(O)OR ８ａ , -C(O)N(R ８ａ ) (R ８ｂ ), -N(R ８ｃ ) C(O)R ８ａ , -N(R ８ｃ )C(O)N(R ８ａ ) (R ８ｂ ), -S(O) ２ R ８ａ , -N(R ８ｃ ) S (O) ２ R ８ａ , -S(O) ２ N (R ８ａ ) (R ８ｂ ), -Si(R ８ａ ) ３ , -Si(R ８ａ ) ２ (OR ８ｂ ), -OSi(R ８ａ ) ３ , -Si(R ８ａ ) (OR ８ｂ ) ２ , -OP(O)(OR ８ａ ) (OR ８ｂ ), -P(O)(OR ８ａ ) (OR ８ｂ ), -OP(O)(OR ８ａ ) (R ８ｂ ), -P(O)(OR ８ａ ) (R ８ｂ ), -OP(O)(R ８ａ ) (R ８ｂ ) or -P(O)(R ８ａ ) (R ８ｂ ) and Or, R ４ａ and R ４ｂ together with the atoms bonded to them, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; In ring B, G １ , G ２ and G ３ are each independently N or C(R ２ｃ ) and Each R ２ａ , R ２ｂ and R ２ｃ are each independently hydrogen, halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, C ３-８ Cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, -OR ６ａ , -SR ６ａ , -N(R ６ａ ) (R ６ｂ ), -C(O)R ６ａ , -OC(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) (R ６ｂ ), -N(R ６ｃ ) C(O)R ６ａ , -N(R ６ｃ )C(O)N(R ６ａ ) (R ６ｂ ), -S(O) ２ R ６ａ , -N(R ６ｃ ) S (O) ２ R ６ａ , -S(O) ２ N (R ６ａ ) (R ６ｂ ), -Si(R ６ａ ) ３ , -Si(R ６ａ ) ２ (OR ６ｂ ), -OSi(R ６ａ ) ３ , -Si(R ６ａ ) (OR ６ｂ ) ２ , -OP(O)(OR ６ａ ) (OR ６ｂ ), -P(O)(OR ６ａ ) (OR ６ｂ ), -OP(O)(OR ６ａ ) (R ６ｂ ), -P(O)(OR ６ａ ) (R ６ｂ ), -OP(O)(R ６ａ ) (R ６ｂ ) or -P(O)(R ６ａ ) (R ６ｂ ) and Or, R ２ｂ and R ２ａ or R ２ｃ together with the carbon atoms attached thereto, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; Or, R ２ａ and R ４ｂ are bonded to each other to form -(CH ２ ) ｐ -, p is 2, 3 or 4, and one or two CH ２ the moiety is optionally replaced with —O— or —NH—; Each R ３ｄ , R ３ｅ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, 3- to 8-membered heterocycloalkenyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ a condensed ring formed with a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein １-６ Alkyl group, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group, the 3- to 8-membered heterocycloalkenyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group, halo C ２-６ Alkynyl group, C ３-８ substituted with one or more substituents independently selected from a cycloalkenyl group, a 3- to 8-membered heterocycloalkenyl group, a phenyl group, and a 5- to 6-membered heteroaryl group; Each R ５ｃ , R ６ｃ , R ７ｃ and R ８ｃ are each independently hydrogen, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl group or halo C ２-６ is an alkynyl group, the number of heteroatoms in the heterocycloalkyl group, heterocycloalkenyl group, and heteroaryl group is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, S, Si, P, or Se; As a prerequisite, at least one of the following conditions (a), (b), (c), (d), and (e) is satisfied: Condition (a): R ２ａ and R ２ｂ are not hydrogen, and R ２ａ is C １-６ is an alkyl group, and R ３ａ is hydrogen, and R ３ｂ Ga-L １ -R ３ｃ When R is a group other than ２ｂ is C １-６ Not an alkyl group, Condition (b): R ３ａ is C １-６ Alkyl group or -L １ -R ３ｃ , R ３ｂ -L １ -R ３ｃ or R ３ａ and R ３ｂ together with the carbon atoms attached thereto, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ A cycloalkenyl group or a 3- to 8-membered heterocycloalkenyl group is formed, ３-８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, C ３-８ The cycloalkenyl group and the 3- to 8-membered heterocycloalkenyl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ２-６ Alkenyl group, halo C ２-６ Alkenyl group, C ２-６ Alkynyl groups and halo C ２-６ substituted with one or more substituents independently selected from alkynyl groups; Condition (c): R ３ａ is hydrogen, C １-６ Alkyl group or -L １ -R ３ｃ and R ３ｂ -L １ -R ３ｃ and ring A is 【Transformation 3】 wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and R ２ａ is not hydrogen, where each A １ are independently CH, N, or C(R ４ａ ), and each A ２ are independently CH, N, or C(R ４ｂ ), and each A ３ are independently CH, N, or C(R ４ｃ ), and each A ４ are independently CH, N, or C(R ４ｄ ) and A ５ is O, S, NH or N(R ４ｄ ) and Condition (d): R ３ｂ is -CH(C １-６ alkyl group)-OH, 【Chemistry 4】 -CH ２ NHC(O)CH ２ OH or -CH ２ OCH ２ CH ２ OH, Condition (e): R ９ａ and R ３ａ are bonded to each other to form -CH ２ -or-CH ２ CH ２ or an isotopic derivative thereof, or a pharmaceutically acceptable salt of either of the foregoing.

2. The compound has the structure shown in I-1, 【Transformation 5】 where s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2; X is N-OR １ and R １ is hydrogen or C １-６ is an alkyl group, １-６ The alkyl group may optionally be one or more R １ａ is replaced by Each R １ａ are independently a halogen, a cyano group, a nitro group, an oxo group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ５ａ , -SR ５ａ , -N(R ５ａ ) (R ５ｂ ), -C(O)R ５ａ , -OC(O)R ５ａ , -C(O)OR ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ｃ ) C(O)R ５ａ , -N(R ５ｃ )C(O)N(R ５ａ ) (R ５ｂ ), -S(O) ２ R ５ａ , -N(R ５ｃ ) S (O) ２ R ５ａ or -S(O) ２ N (R ５ａ ) (R ５ｂ ) and R ３ａ is hydrogen, C １-６ Alkyl group or -L １ -R ３ｃ and R ３ｂ -L １ -R ３ｃ , -C(O)OR ３ｄ , -C(O)N(R ３ｄ ) (R ３ｅ ), -S(O) ２ R ３ｄ , -S(O) ２ N (R ３ｄ ) (R ３ｅ ), C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C ３-８ a condensed ring formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; Each L １ are independently -[C(R ａ ) (R ｂ )] ｎ -, where n is 1, 2, or 3, and each R ａ and R ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R ａ and R ｂ together with the carbon atoms attached thereto, ３-８ Forms a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C １-６ Alkyl group, C ３-８ The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; Each R ３ｃ are independently -OR ７ａ , -SR ７ａ , -N(R ７ａ ) (R ７ｂ ), -C(O)R ７ａ , -OC(O)R ７ａ , -C(O)OR ７ａ , -C(O)N(R ７ａ ) (R ７ｂ ), -N(R ７ｃ ) C(O)R ７ａ , -N(R ７ｃ )C(O)N(R ７ａ ) (R ７ｂ ), -S(O) ２ R ７ａ , -N(R ７ｃ ) S (O) ２ R ７ａ or -S(O) ２ N (R ７ａ ) (R ７ｂ ) and Ring A is 【Transformation 6】 wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each --- bond is independently a single bond or a double bond; Each A １ are independently CH, C(O), N, NH, O, S, N(R ４ａ ) or C(R ４ａ ) and Each A ２ are independently CH, C(O), N, NH, O, S, N(R ４ｂ ) or C(R ４ｂ ) and A ３ is CH, C(O), N, N(R ４ｃ ) or C(R ４ｃ ) and Each A ４ are independently CH, C(O), N, N(R ４ｄ ) or C(R ４ｄ ) and A ５ are CH, N, O, S, NH, C(R ４ｄ ) or N(R ４ｄ ) and Each A ６ are independently C or N; Each A ７ are independently C or N; Each R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are each independently a halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ８ａ , -SR ８ａ , -N(R ８ａ ) (R ８ｂ ), -C(O)R ８ａ , -OC(O)R ８ａ , -C(O)OR ８ａ , -C(O)N(R ８ａ ) (R ８ｂ ), -N(R ８ｃ ) C(O)R ８ａ , -N(R ８ｃ )C(O)N(R ８ａ ) (R ８ｂ ), -S(O) ２ R ８ａ , -N(R ８ｃ ) S (O) ２ R ８ａ or -S(O) ２ N (R ８ａ ) (R ８ｂ ) and Or, R ４ａ and R ４ｂ together with the atoms bonded to them, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; In ring B, G １ , G ２ and G ３ are each independently N or C(R ２ｃ ) and Each R ２ｃ are independently hydrogen, halogen, cyano group, nitro group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ６ａ , -SR ６ａ , -N(R ６ａ ) (R ６ｂ ), -C(O)R ６ａ , -OC(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) (R ６ｂ ), -N(R ６ｃ ) C(O)R ６ａ , -N(R ６ｃ )C(O)N(R ６ａ ) (R ６ｂ ), -S(O) ２ R ６ａ , -N(R ６ｃ ) S (O) ２ R ６ａ or -S(O) ２ N (R ６ａ ) (R ６ｂ ) and Each R ２ａ and R ２ｂ are each independently a halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ６ａ , -SR ６ａ , -N(R ６ａ ) (R ６ｂ ), -C(O)R ６ａ , -OC(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) (R ６ｂ ), -N(R ６ｃ ) C(O)R ６ａ , -N(R ６ｃ )C(O)N(R ６ａ ) (R ６ｂ ), -S(O) ２ R ６ａ , -N(R ６ｃ ) S (O) ２ R ６ａ or -S(O) ２ N (R ６ａ ) (R ６ｂ ) and Or, R ２ｂ and R ２ａ or R ２ｃ together with the carbon atoms attached thereto, ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; Or, R ２ａ and R ４ｂ are bonded to each other to form -(CH ２ ) ｐ -, p is 2, 3 or 4, and one or two CH ２ the moiety is optionally replaced with —O— or —NH—; As a condition, R ２ａ is C １-６ is an alkyl group, and R ３ａ is hydrogen, and R ３ｂ Ga-L １ -R ３ｃ When R is a group other than ２ｂ is C １-６ Not an alkyl group, Each R ３ｄ , R ３ｅ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, ３-８ The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C ３-８ a condensed ring formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein １-６ Alkyl group, C ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ３-８ substituted with one or more substituents independently selected from a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group; Each R ５ｃ , R ６ｃ , R ７ｃ and R ８ｃ are each independently hydrogen, C １-６ Alkyl group, C １-６ haloalkyl group or C １-６ is a hydroxyalkyl group, 2. The compound, isotopic derivative, or pharmaceutically acceptable salt of claim 1, wherein the number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S.

3. The compound has the structure shown in formula I-1: 【Transformation 7】 where s is 1 and t is 1, or s is 2 and t is 1, or s is 1 and t is 2; X is N-OR １ and R １ is hydrogen or C １-６ is an alkyl group, １-６ The alkyl group may optionally be one or more R １ａ is replaced by Each R １ａ are independently a halogen, a cyano group, a nitro group, an oxo group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ５ａ , -SR ５ａ , -N(R ５ａ ) (R ５ｂ ), -C(O)R ５ａ , -OC(O)R ５ａ , -C(O)OR ５ａ , -C(O)N(R ５ａ ) (R ５ｂ ), -N(R ５ｃ ) C(O)R ５ａ , -N(R ５ｃ )C(O)N(R ５ａ ) (R ５ｂ ), -S(O) ２ R ５ａ , -N(R ５ｃ ) S (O) ２ R ５ａ or -S(O) ２ N (R ５ａ ) (R ５ｂ ) and R ３ａ is hydrogen, C １-６ Alkyl group or -L １ -R ３ｃ and R ３ｂ -L １ -R ３ｃ and Each L １ are independently -[C(R ａ ) (R ｂ )] ｎ -, where n is 1, 2, or 3, and each R ａ and R ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, or R ａ and R ｂ together with the carbon atoms attached thereto, ３-８ Forms a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, wherein the C １-６ Alkyl group, C ３-８ The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; Each R ３ｃ are independently -OR ７ａ , -SR ７ａ , -N(R ７ａ ) (R ７ｂ ), -C(O)R ７ａ , -OC(O)R ７ａ , -C(O)OR ７ａ , -C(O)N(R ７ａ ) (R ７ｂ ), -N(R ７ｃ ) C(O)R ７ａ , -N(R ７ｃ )C(O)N(R ７ａ ) (R ７ｂ ), -S(O) ２ R ７ａ , -N(R ７ｃ ) S (O) ２ R ７ａ or -S(O) ２ N (R ７ａ ) (R ７ｂ ) and Ring A is 【Transformation 8】 wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each --- bond is independently a single bond or a double bond; Each A １ are independently CH, C(O), N, NH, O, S, N(R ４ａ ) or C(R ４ａ ) and Each A ２ are independently CH, C(O), N, NH, O, S, N(R ４ｂ ) or C(R ４ｂ ) and A ３ is CH, C(O), N, N(R ４ｃ ) or C(R ４ｃ ) and Each A ４ are independently CH, C(O), N, N(R ４ｄ ) or C(R ４ｄ ) and A ５ are CH, N, O, S, NH, C(R ４ｄ ) or N(R ４ｄ ) and Each A ６ are independently C or N; Each A ７ are independently C or N; Each R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are each independently a halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ８ａ , -SR ８ａ , -N(R ８ａ ) (R ８ｂ ), -C(O)R ８ａ , -OC(O)R ８ａ , -C(O)OR ８ａ , -C(O)N(R ８ａ ) (R ８ｂ ), -N(R ８ｃ ) C(O)R ８ａ , -N(R ８ｃ )C(O)N(R ８ａ ) (R ８ｂ ), -S(O) ２ R ８ａ , -N(R ８ｃ ) S (O) ２ R ８ａ or -S(O) ２ N (R ８ａ ) (R ８ｂ ) and Or, R ４ａ and R ４ｂ together with the atoms bonded to them, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; In ring B, G １ , G ２ and G ３ are each independently N or C(R ２ｃ ) and Each R ２ｃ are independently hydrogen, halogen, cyano group, nitro group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ６ａ , -SR ６ａ , -N(R ６ａ ) (R ６ｂ ), -C(O)R ６ａ , -OC(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) (R ６ｂ ), -N(R ６ｃ ) C(O)R ６ａ , -N(R ６ｃ )C(O)N(R ６ａ ) (R ６ｂ ), -S(O) ２ R ６ａ , -N(R ６ｃ ) S (O) ２ R ６ａ or -S(O) ２ N (R ６ａ ) (R ６ｂ ) and Each R ２ａ and R ２ｂ are each independently a halogen, a cyano group, a nitro group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, a 5- to 6-membered heteroaryl group, -OR ６ａ , -SR ６ａ , -N(R ６ａ ) (R ６ｂ ), -C(O)R ６ａ , -OC(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) (R ６ｂ ), -N(R ６ｃ ) C(O)R ６ａ , -N(R ６ｃ )C(O)N(R ６ａ ) (R ６ｂ ), -S(O) ２ R ６ａ , -N(R ６ｃ ) S (O) ２ R ６ａ or -S(O) ２ N (R ６ａ ) (R ６ｂ ) and Or, R ２ｂ and R ２ａ or R ２ｃ together with the carbon atoms attached thereto, ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ substituted with one or more substituents independently selected from alkoxy groups; Or, R ２ａ and R ４ｂ are bonded to each other to form -(CH ２ ) ｐ -, p is 2, 3 or 4, and one or two CH ２ the moiety is optionally replaced with —O— or —NH—; Each R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ are each independently hydrogen, C １-６ Alkyl group, C ３-８ a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, ３-８ The cycloalkyl group, 3- to 8-membered heterocycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group may optionally be joined by another C ３-８ a condensed ring formed with a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group, wherein １-６ Alkyl group, C ３-８ The cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy group, halo C １-６ Alkoxy group, C ３-８ substituted with one or more substituents independently selected from a cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group; Each R ５ｃ , R ６ｃ , R ７ｃ and R ８ｃ are each independently hydrogen, C １-６ Alkyl group, C １-６ haloalkyl group or C １-６ is a hydroxyalkyl group, 3. The compound, isotopic derivative, or pharmaceutically acceptable salt of claim 1 or 2, wherein the number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S.

4. R ２ｂ is C １-６ Alkyl group, cyano group, C １-６ Haloalkyl group, C １-６ 4. The compound, isotope derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R is an alkoxy group or halogen, preferably a methyl group, a cyano group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, or chlorine.

5. R ２ａ is a halogen, a cyano group, C １-６ Alkyl group or C １-６ The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that the haloalkyl group is preferably a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorine group or a cyano group.

6. R ２ｂ and R ２ａ together with the carbon atoms attached thereto, ３-８ A compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that it forms a cycloalkyl group, preferably a cyclopentyl group.

7. R ２ｂ and R ２ａ is defined as any one of the following combinations (i) to (x): (i) R ２ａ is a methyl group, and R ２ｂ is a methyl group, (ii) R ２ａ is a methyl group, and R ２ｂ is chlorine, (iii) R ２ａ is a methyl group, and R ２ｂ is a cyano group, (iv) R ２ａ is a methyl group, and R ２ｂ is a difluoromethyl group, (v) R ２ａ is a methyl group, and R ２ｂ is a trifluoromethyl group, (vi) R ２ａ is a methyl group, and R ２ｂ is a methoxy group, (vii) R ２ａ is chlorine, and R ２ｂ is a cyano group, (viii) R ２ａ is a cyano group, and R ２ｂ is a methyl group, (ix) R ２ａ is a difluoromethyl group, and R ２ｂ is a cyano group, (x) R ２ａ is a trifluoromethyl group, and R ２ｂ The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein is a cyano group.

8. G １ is CH or C(F), and G ２ is CH or C(F), and G ３ is CH, C(F), C(CN) or N, preferably G １ is CH, and G ２ is CH, and G ３ The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein is CH. 【Request Item 9】 【Chemistry 9】 The structural part is 【Chemistry 10】 4. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein:

10. Ring A is 【Chemistry 11】 and A １ is CH, N or C(R ４ａ ) and A ２ is CH, N or C(R ４ｂ ) and A ３ is CH, N or C(R ４ｃ ) and A ４ is CH, N or C(R ４ｄ ) and A ５ is O, S, NH or N(R ４ｄ 10. The compound, isotopic derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein Ar is a 3- to 8-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group.

11. Ring A is 【Chemistry 12】 10. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein:

12. R ４ａ and R ４ｂ are each independently a halogen, a cyano group, or C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Alkoxy group, -OR ８ａ , -SR ８ａ , -N(R ８ａ ) (R ８ｂ ), -C(O)R ８ａ , -C(O)OR ８ａ or -C(O)N(R ８ａ ) (R ８ｂ ), and preferably R ４ａ and R ４ｂ are each independently a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, or —OCH ２ CH ２ OH, -OCH ２ CH ２ OCH ３ , -NHCH ２ CH ２ OCH ３ , 【Chemistry 13】 or R ４ａ and R ４ｂ together with the carbon atoms attached to them, 【Chemistry 14】 and the ring optionally comprises a halogen, a hydroxy group, an amino group, a cyano group, an oxo group, C １-６ Alkyl group, C １-６ Haloalkyl group, C １-６ Hydroxyalkyl group, C １-６ Alkoxy groups and haloC １-６ 12. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 11, substituted with one or more substituents independently selected from alkoxy groups.

13. R ４ｃ and R ４ｄ are each independently a halogen, a cyano group, or C １-６ Alkyl group, C １-６ haloalkyl group or C １-６ is an alkoxy group, preferably R ４ｃ and R ４ｄ are each independently fluorine, chlorine, a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, or a methoxy group.

14. Ring A is 【Chemistry 15】 where A １ , A ２ , A ３ and A ４ are each independently CH or N, 【Chemistry 16】 13. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein:

15. Ring A is 【Chemistry 17】 [Chemistry 18] 10. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein:

16. R ３ａ is hydrogen or C １-６ 16. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein the compound is an alkyl group.

17. R ３ｂ -L １ -R ３ｃ and L １ is -[CH(R ａ )] ｎ -, where n is 1, 2 or 3, and R ３ｃ is —OH, and R ａ is hydrogen or C １-６ is an alkyl group, １-６ The alkyl group is optionally substituted with one or more hydroxy groups, preferably R ３ｂ is -CH ２ OH, -CH(CH ３ )OH, -C(CH ３ ) ２ OH, -CH(OH)CH ２ OH, -CH ２ CH ２ OH or 【Chemistry 19】 17. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein:

18. R ３ａ and R ３ｂ are combined with each other 【Chemistry 20】 16. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein

19. 19. The compound, isotopic derivative or pharmaceutically acceptable salt of any one of claims 1 to 18, wherein s is 1 and t is 1.

20. R １ is C １-６ is an alkyl group, preferably R １ 20. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein is a methyl group.

21. R ３ｂ is a benzoxazolyl group, —C(O)NHCH ３ , -C(O)OCH ３ or 【Chemistry 21】 17. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1, 2 and 4 to 16, wherein: 【Request Item 22】 【Chemistry 22】 X is N-OR １ and R １ is -CH ３ and R ３ａ is hydrogen or C １-６ alkyl groups, R ３ｂ -L １ -R ３ｃ and L １ are independently -[C(R ａ ) (R ｂ )] ｎ -, where n is 1 and each R ａ and R ｂ are each independently hydrogen, —CH ３ and R ３ｃ are independently -OR ７ａ and R ７ａ is hydrogen or C １-６ alkyl groups, L ２ is -[C(R １０ａ ) (R １０ｂ )] ｔ - and s is 1, t is 1, R ９ａ , R ９ｂ , R １０ａ and R １０ｂ is hydrogen, Ring A is 【Chemistry 23】 wherein the * end is bonded to the carbonyl group in formula I, the # end is bonded to ring B in formula I, and each --- bond is independently a single bond or a double bond; A １ is CH or C(R ４ａ ) and A ２ is CH or C(R ４ｂ ) and A ３ is CH, A ４ is CH, Each A ６ are independently C or N; Each A ７ are independently C or N; R ４ａ and R ４ｂ are each independently selected from H, or R ４ａ and R ４ｂ together with the atoms bonded to them, 【Chemistry 24】 Forming In ring B, G １ , G ２ and G ３ is CH, R ２ａ is a halogen or -CH ３ and R ２ｂ 2. The compound of formula I according to claim 1, an isotopic derivative or a pharmaceutically acceptable salt thereof, wherein: is a cyano group.

23. The compound is a compound represented by the following formula Ia, or its stereoisomer represented by formula Ib, or a mixture of formula Ia and formula Ib: 【Chemistry 25】 Here, R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , s, t, G １ , G ２ , G ３ and ring A are defined as defined in any one of claims 1 to 22, the compound, isotopic derivative or pharmaceutically acceptable salt thereof.

24. A compound, an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein said compound is 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 or a stereoisomeric mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. A pharmaceutical composition comprising a compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 24, and a pharmaceutical excipient.

26. Use of the compound, isotopic derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, or a pharmaceutical composition containing the same, in the manufacture of an oxytocin receptor antagonist, or use of the compound, isotopic derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, or a pharmaceutical composition containing the same, in the inhibition of oxytocin receptors.

27. Use of a compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 24 in the manufacture of a medicament for the prevention and / or treatment of a disease or condition in which inhibition of oxytocin is known to have or may exhibit a beneficial effect, or use of a compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 24 for the prevention and / or treatment of a disease or condition in which inhibition of oxytocin is known to have or may exhibit a beneficial effect, or use of a compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 24 in the prevention and / or treatment of a disease or condition in which inhibition of oxytocin is known to have or may exhibit a beneficial effect.

28. 28. The use according to claim 27, wherein the disease or condition is sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, dyspareunia disorder, premature ejaculation, preterm birth, obstetric complications, appetite and eating disorders, benign prostatic hyperplasia, premature birth, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder and behavioral or neuropsychiatric disorders, preferably the disease or condition is premature birth.

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