Imine compound as well as preparation method and application thereof

Abstract

The invention relates to an imine compound as well as a preparation method and application thereof, in particular to a compound shown in a formula I which can be used for treating diseases such as premature delivery. # imgabs0 #

Description

Imine compound and its preparation method and application Technical Field

[0001] The present invention relates to the field of medicine, and in particular to an imine compound, a preparation method thereof, and an application thereof. Background Art

[0002] Oxytocin is a cyclic nonapeptide that exerts its physiological effects by binding to its specific receptors (oxytocin receptors, OTRs). Oxytocin's physiological effects are known to involve multiple aspects, including social bonding, 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 kidney function, respectively. V1b receptors are primarily expressed in the brain and pituitary gland and control the release of adrenocorticotropic hormone and β-endorphin.

[0003] Studies have shown that oxytocin plays a key role in childbirth in mammals, particularly humans. During labor, oxytocin binds to its receptors, producing strong uterine contractions that facilitate delivery. However, untimely contractions can lead to miscarriage and premature birth. Downregulating oxytocin or blocking its binding to receptors can inhibit its contractile effects on the uterus and is an important approach for combating premature birth.

[0004] Atosiban is a peptide-based oxytocin receptor antagonist that has been approved for the treatment of preterm labor. In addition, several other oxytocin receptor antagonists, such as Nolasiban, Cligosiban, and Retosiban, are currently under clinical investigation.

[0005] Patent applications WO2001072705A1, WO2002074741A1, WO2002102799A2, WO2004005249A1, WO2004076407A2, and WO2015036160A1 disclose a series of compounds that can be used as oxytocin receptor antagonists, which can be used to treat sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasm disorder, dyspareunia, premature ejaculation, prenatal delivery, delivery complications, appetite and eating disorders, benign prostatic hyperplasia, premature birth, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, intraocular hypertension, obsessive-compulsive disorder, neuropsychiatric diseases, etc.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound of Formula I that can be used as an oxytocin receptor antagonist. The compound of Formula I provided herein has improved OTR antagonistic activity. The compound of Formula I provided herein also has lower antagonistic activity against ViaR and improved OTR / V1a target selectivity.

[0008] The present disclosure provides a compound represented by formula I:

[0009] or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing;

[0010] Where X is N–OR 1 ;

[0011] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0012] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 5a ,–N(R 5c )S(O)2R 5a 、–S(O)2N(R 5a )(R 5b ),–Si(R 5a )3, –Si(R5a )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 );

[0013] R 3a For hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl or -L 1 –R 3c ;

[0014] R 3b For hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, –L 1 –R 3c 、–C(O)OR 3d ,–C(O)N(R 3d )(R 3e ),–S(O)2R 3d 、–S(O)2N(R 3d )(R 3e ),–P(O)(OR 3d )(OR 3e ),–P(O)(OR 3d )(R 3e ),–P(O)(R 3d )(R3e ), C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0015] Or, R 3a and R 3b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0016] Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and Rb are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0017] Each R 3c 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)2R 7a ,–N(R 7c )S(O)2R 7a 、–S(O)2N(R 7a )(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 );

[0018] L 2 For–[C(R 10a )(R 10b )] t –, where one of the C(R 10a )(R 10b ) part is optionally replaced by –O– or –N(R 10a )-replace;

[0019] s is 1 and t is 1; or, s is 2 and t is 1; or, s is 1 and t is 2;

[0020] R 9a and R 9b are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl; or, R 9a and R 9b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl; or, R 9a and R 3a Connect with each other to form –CH2– or –CH2CH2–;

[0021] R 10a and R 10b are independently hydrogen, halogen, cyano, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2– 6 alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl; or, R 10a and R 10b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl; or, R 10a and R 3a , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl;

[0022] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I; each ---- bond is independently a single bond or a double bond;

[0023] Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a );

[0024] Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b );

[0025] A 3 CH, C(O), N, N(R 4c ) or C(R 4c );

[0026] Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d );

[0027] A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d );

[0028] Each A 6 are independently C or N;

[0029] Each A 7 are independently C or N;

[0030] Each R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, C 2–6 Alkenyl, halogenated C2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 8a ,–N(R 8c )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 );

[0031] Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0032] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0033] Each R 2a 、R 2b and R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 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 );

[0034] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; said C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0035] Or, R 2a and R 4b Connected to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –O– or –NH–;

[0036] Each R 3d 、R 3e 、R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Substitution by one or more substituents of cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl;

[0037] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2– 6 alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl;

[0038] The number of heteroatoms in the above heterocycloalkyl, heterocycloalkenyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O, S, Si, P and Se;

[0039] The prerequisite is that at least one of the following conditions (a), (b), (c), (d) and (e) is met:

[0040] Condition (a): R 2a and R 2b are not hydrogen; and, when R 2a C 1–6 Alkyl, R 3a is hydrogen and R 3b To divide –L 1 –R 3c If the group is other than 2b Not for C 1–6 alkyl;

[0041] Condition (b): R 3a C 1–6 Alkyl or –L 1 –R 3c And R 3b for –L 1 –R 3c ; or, R 3a and R 3b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, C 3–8 Cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 Alkynyl is substituted with one or more substituents;

[0042] Condition (c): R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ; R 3b for –L 1 –R 3c ; Ring A is wherein the * end is connected to the carbonyl group in Formula I, the # end is connected to the ring B in Formula I; and R 2a is not hydrogen; wherein each A 1 are independently CH, N or C(R 4a ); each A 2 are independently CH, N or C(R 4b ); each A3 are independently CH, N or C(R 4c ); each A 4 are independently CH, N or C(R 4d );A 5 O, S, NH or N(R 4d );

[0043] Condition (d): R 3b For –CH(C 1–6 Alkyl)–OH, –CH2NHC(O)CH2OH or –CH2OCH2CH2OH;

[0044] Condition (e): R 9a and R 3a They are connected to each other to form –CH2– or –CH2CH2–.

[0045] In some embodiments, in the structure of Formula I, for

[0046] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0047] Wherein, s is 1 and t is 1; or, s is 2 and t is 1; or, s is 1 and t is 2;

[0048] X is N–OR 1 ;

[0049] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0050] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0051] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0052] R 3b for –L 1 –R 3c 、–C(O)OR 3d ,–C(O)N(R 3d )(R 3e ),–S(O)2R 3d 、–S(O)2N(R 3d )(R 3e ), C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl to form a condensed ring; wherein the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0053] Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0054] Each R 3c 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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0055] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I; each ---- bond is independently a single bond or a double bond;

[0056] Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a );

[0057] Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b );

[0058] A 3 CH, C(O), N, N(R 4c ) or C(R 4c );

[0059] Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d );

[0060] A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d );

[0061] Each A 6 are independently C or N;

[0062] Each A 7 are independently C or N;

[0063] Each R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0064] Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0065] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0066] Each R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0067] Each R 2a and R 2b are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0068] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0069] Or, R 2a and R 4b Connected to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –O– or –NH–;

[0070] The condition is that when R 2a C 1–6 Alkyl, R 3a is hydrogen and R 3b To divide –L 1 –R 3c If the group is other than 2b Not for C 1–6 alkyl;

[0071] Each R 3d 、R 3e 、R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1– 6 haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Substitution with one or more substituents of cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0072] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0073] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0074] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0075] Wherein, s is 1 and t is 1; or, s is 2 and t is 1; or, s is 1 and t is 2;

[0076] X is N–OR 1 ;

[0077] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0078] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0079] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0080] R 3b for –L 1 –R 3c ;

[0081] Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0082] Each R 3c 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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0083] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I; each ---- bond is independently a single bond or a double bond;

[0084] Each A 1 are independently CH, C(O), N, NH, O, S, N(R 4a ) or C(R 4a );

[0085] Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b );

[0086] A 3 CH, C(O), N, N(R 4c ) or C(R 4c );

[0087] Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d );

[0088] A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d );

[0089] Each A 6 are independently C or N;

[0090] Each A 7 are independently C or N;

[0091] Each R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0092] Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0093] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0094] Each R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0095] Each R 2a and R 2b are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R6a )(R 6b );

[0096] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0097] Or, R 2a and R 4b Connected to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –O– or –NH–;

[0098] Each R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Substitution with one or more substituents of cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0099] Each R 5c、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0100] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0101] In some embodiments, in the definition of Formula I, I-1, s is 1 and t is 1.

[0102] In some embodiments, in the definition of Formula I, I-1, s is 2 and t is 1.

[0103] In some embodiments, in the definition of Formula I, I-1, s is 1 and t is 2.

[0104] In some embodiments, in the definition of Formula I and I-1, Ring A is Wherein, each ---- bond is independently a single bond or a double bond, provided that an aromatic ring is formed; each A 1 are independently CH, N, NH, O, S, N(R 4a ) or C(R 4a ); each A 2 are independently CH, N, NH, O, S, N(R 4b ) or C(R 4b );A 3 CH, N, N(R 4c ) or C(R 4c ); each A 4 are independently CH, N, N(R 4d ) or C(R 4d );A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d ); each A 6 are independently C or N; each A 7 are independently C or N; R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0105] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0106] Where s is 1 and t is 1;

[0107] X is N–OR 1 ;

[0108] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0109] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0110] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0111] R 3b for –L 1 –R 3c ;

[0112] Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are each independently hydrogen or C 1–6 Alkyl; or, R a and R b, together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0113] Each R 3c 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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0114] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I;

[0115] Each A 1 are independently CH, N or C(R 4a );

[0116] Each A 2 are independently CH, N or C(R 4b );

[0117] A 3 is CH, N or C(R 4c );

[0118] Each A 4 are independently CH, N or C(R 4d );

[0119] A 5 O, S, NH or N(R 4d );

[0120] R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0121] Or, R 4a and R 4b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0122] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0123] Each R 2a 、R 2b and R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, –OR 6a ,–SR6a ,–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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0124] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0125] Each R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0126] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0127] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S;

[0128] The prerequisite is that at least one of the following conditions (a), (b), (c) and (d) is met:

[0129] Condition (a): R 2a and R 2b None of them are hydrogen;

[0130] Condition (b): R 3a Not hydrogen;

[0131] Condition (c): Ring A is wherein the * end is connected to the carbonyl group in Formula I, the # end is connected to the ring B in Formula I; and R 2a Not hydrogen;

[0132] Condition (d): R 3b For –CH(C 1–6 alkyl)–OH.

[0133] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0134] Where s is 1 and t is 1;

[0135] X is N–OR 1 ;

[0136] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0137] Each R1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0138] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0139] R 3b for –L 1 –R 3c ;

[0140] L 1 For–[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are each independently hydrogen or C 1–6 Alkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0141] R 3c for –OR 7a ,–SR 7a ,–N(R 7a )(R 7b ),–C(O)R7a 、–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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0142] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I;

[0143] Each A 1 are independently CH, N or C(R 4a );

[0144] Each A 2 are independently CH, N or C(R 4b );

[0145] A 3 is CH, N or C(R 4c );

[0146] Each A 4 are independently CH, N or C(R 4d );

[0147] A 5 O, S, NH or N(R 4d );

[0148] R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0149] Or, R 4a and R 4b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0150] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0151] Each R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0152] R 2a and R 2b are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0153] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0154] Each R 5a 、R5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0155] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0156] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0157] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0158] Where s is 1 and t is 1;

[0159] X is N–OR 1 ;

[0160] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0161] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0162] R 3a C 1–6 Alkyl or –L 1 –R 3c ;

[0163] R 3b for –L 1 –R 3c ;

[0164] Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are each independently hydrogen or C 1–6 Alkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0165] Each R 3c 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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0166] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I;

[0167] Each A 1 are independently CH, N or C(R 4a );

[0168] Each A 2 are independently CH, N or C(R 4b );

[0169] A 3 is CH, N or C(R 4c );

[0170] Each A 4 are independently CH, N or C(R 4d );

[0171] A 5 O, S, NH or N(R 4d );

[0172] R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0173] Or, R 4a and R 4b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0174] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0175] Each R 2a 、R 2b and R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, –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 )(R6b ),–S(O)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b );

[0176] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0177] Each R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0178] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0179] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0180] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0181] Where s is 1 and t is 1;

[0182] X is N–OR 1 ;

[0183] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0184] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0185] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0186] R 3bfor –L 1 –R 3c ;

[0187] L 1 For–[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are each independently hydrogen or C 1–6 Alkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0188] R 3c for –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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0189] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I;

[0190] Each A 1 are independently CH, N or C(R 4a );

[0191] Each A 2 are independently CH, N or C(R 4b );

[0192] Each A 3 are independently CH, N or C(R 4c );

[0193] Each A 4 are independently CH, N or C(R4d );

[0194] A 5 O, S, NH or N(R 4d );

[0195] R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0196] Or, R 4a and R 4b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0197] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R2c );

[0198] R 2a For halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b ).

[0199] Each R 2b and R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R6a or –S(O)2N(R 6a )(R 6b );

[0200] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0201] Each R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0202] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0203] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0204] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0205] Where s is 1 and t is 1;

[0206] X is N–OR 1 ;

[0207] R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally replaced by one or more R 1a replace;

[0208] Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 5a ,–N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b );

[0209] R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ;

[0210] R 3b For –CH(C 1–6 alkyl)–OH;

[0211] L1 For–[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are each independently hydrogen or C 1–6 Alkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0212] R 3c for –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)2R 7a ,–N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b );

[0213] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I;

[0214] Each A 1 are independently CH, N or C(R 4a );

[0215] Each A 2 are independently CH, N or C(R 4b );

[0216] A 3 is CH, N or C(R 4c );

[0217] Each A 4 are independently CH, N or C(R 4d );

[0218] A 5 O, S, NH or N(R4d );

[0219] R 4a 、R 4b 、R 4c and R 4d are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8 membered heterocycloalkyl, phenyl, 5–6 membered heteroaryl, –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)2R 8a ,–N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b );

[0220] Or, R 4a and R 4b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0221] In ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c );

[0222] Each R 2a 、R 2band R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, –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)2R 6a ,–N(R 6c )S(O)2R 6a or – S(O)2N(R 6a )(R 6b );

[0223] Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0224] Each R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents;

[0225] Each R 5c 、R 6c 、R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 hydroxyalkyl;

[0226] The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

[0227] In some embodiments, in the definition of Formula I and I-1, R 1 C 1–6 alkyl.

[0228] In some embodiments, in the definition of Formula I and I-1, R 1 It is a methyl group.

[0229] In some embodiments, in the definition of Formula I and I-1, L 1 for –[CH(R a )] n –; where n is 1, 2 or 3; R a For hydrogen, C 1–6 Alkyl or C 3–8 Cycloalkyl, the C 1–6 Alkyl, C 3–8 The cycloalkyl groups are optionally substituted with one or more hydroxy groups.

[0230] In some embodiments, in the definition of Formula I and I-1, L 1 for –[CH(R a )] n –; where n is 1, 2 or 3; R a is hydrogen or C 1–6 Alkyl, the C 1–6The alkyl group is optionally substituted with one or more hydroxy groups.

[0231] In some embodiments, in the definition of Formula I or I-1, n is 1.

[0232] In some embodiments, in the definition of Formula I and I-1, R 3c It is –OH.

[0233] In some embodiments, in the definition of Formula I and I-1, R 3a is hydrogen or C 1–6 alkyl.

[0234] In some embodiments, in the definition of Formula I and I-1, R 3a is hydrogen or methyl.

[0235] In some embodiments, in the definition of Formula I and I-1, R 3a For hydrogen.

[0236] In some embodiments, in the definition of Formula I and I-1, R 3a C 1–6 Alkyl groups, such as methyl.

[0237] In some embodiments, in the definition of Formula I and I-1, R 3b for –L 1 –R 3c , L 1 and R 3c The definition of is as described in any embodiment of the present disclosure.

[0238] In some embodiments, in the definition of Formula I and I-1, R 3b is –CH2OH, –CH(CH3)OH, –C(CH3)2OH, –CH(OH)CH2OH, –CH2CH2OH or

[0239] In some embodiments, in the definition of Formula I and I-1, R 3b for –CH2NHC(O)CH3, –CH2NHC(O)OCH3, –CH2NHC(O)CH2OH or –CH2OCH2CH2OH.

[0240] In some embodiments, in the definition of Formula I and I-1, R 3b is –CH2OH.

[0241] In some embodiments, in the definition of Formula I and I-1, R 3b is –CH(CH3)OH.

[0242] In some embodiments, in the definition of Formula I and I-1, R 3b is benzoxazolyl (e.g. ), –C(O)NHCH3, –C(O)OCH3 or For example

[0243] In some embodiments, in the definition of Formula I and I-1, R 3a is hydrogen, R 3b is –CH2OH.

[0244] In some embodiments, in the definition of Formula I and I-1, R 3a is hydrogen, R 3b is –CH(CH3)OH.

[0245] In some embodiments, in the definition of Formula I and I-1, R 3a is methyl, R 3b is –CH2OH.

[0246] In some embodiments, in the definition of Formula I and I-1, R 3a and R 3b Interconnected to form

[0247] In some embodiments, in the definition of Formula I and I-1, R 4c and R 4d are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Alkoxy, –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 ).

[0248] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Alkoxy, –OR 8a ,–SR 8a ,–N(R 8a )(R 8b ),–C(O)R 8a 、–C(O)OR8a or –C(O)N(R 8a )(R 8b ).

[0249] In some embodiments, in the definition of Formula I and I-1, R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 1–6 Alkyl is optionally independently selected from hydroxy, C 1–6 Alkyl, C 1–6 Halogenated alkyl, C 1–6 Hydroxyalkyl and C 1–6 The alkoxy group is substituted with one or more substituents.

[0250] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 Alkoxy.

[0251] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b Each is independently methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -OCH2CH2OH, -OCH2CH2OCH3, -NHCH2CH2OCH3,

[0252] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b , together with the carbon atoms connecting them, form a 3-8 membered heterocycloalkyl group; the 3-8 membered heterocycloalkyl group is optionally substituted with one or more of the aforementioned substituents (e.g., C 1–6 alkyl, carbonyl) substituted.

[0253] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b , together with the carbon atoms connecting them, form a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is optionally substituted with one or more of the aforementioned substituents (e.g., C 1–6 alkyl, carbonyl) substituted.

[0254] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b Together with the carbon atoms that connect them, The above ring is optionally substituted with one or more of the above substituents (e.g. C 1–6 alkyl, carbonyl) substituted.

[0255] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b Together with the carbon atoms that connect them,

[0256] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b Together with the carbon atoms that connect them,

[0257] In some embodiments, in the definition of Formula I and I-1, R 4a and R 4b Together with the carbon atoms that connect them,

[0258] In some embodiments, in the definition of Formula I and I-1, R 4c and R 4d are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 Alkoxy.

[0259] In some embodiments, in the definition of Formula I and I-1, R 4c and R 4d Each is independently fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or methoxy, for example fluoro.

[0260] In some embodiments, in the definition of Formula I and I-1, Ring A is A 1 is CH, N or C(R 4a ), A 2 is CH, N or C(R 4b ), A 3 is CH, N or C(R 4c ), A 4 is CH, N or C(R 4d ), A 5 O, S, NH or N(R 4d ), Ar is a 3-8 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0261] In some embodiments, in the definition of Formula I and I-1, Ring A is Among them A 1 is CH, N or C(R 4a ), A 2 is CH, N or C(R 4b ), A 3 is CH, N or C(R 4c ), A 4 is CH, N or C(R 4d );R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0262] In some embodiments, in the definition of Formula I and I-1, Ring A is Among them A 1 、A 2 、A 3 and A 4 are independently CH or N, R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0263] In some embodiments, in the definition of Formula I and I-1, Ring A is Among them A 1 is CH or C(R 4a ), A 2 is CH or C(R 4b ), A 3 is CH or C(R 4c ), A 4 is CH or C(R 4d );R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0264] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b 、R 4c and R 4d The definition of is as described in any embodiment of the present disclosure.

[0265] In some embodiments, in the definition of Formula I and I-1, Ring A is Among them A 1 、A 2 、A 3 and A 4 are each independently CH or N.

[0266] In some embodiments, in the definition of Formula I and I-1, Ring A is

[0267] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0268] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4b The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0269] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a and R 4b The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be In some embodiments, in the definition of Formula I and I-1, Ring A is In some embodiments, in the definition of Formula I and I-1, Ring A is

[0270] In some embodiments, in the definition of Formula I and I-1, Ring A is

[0271] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a The definition of is as described in any embodiment of the present disclosure.

[0272] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4b The definition of is as described in any embodiment of the present disclosure.

[0273] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b 、R4c The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0274] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b 、R 4d The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0275] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b 、R 4c 、R 4d The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0276] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0277] In some embodiments, in the definition of Formula I and I-1, Ring A is where R 4a 、R 4b The definition of is as described in any of the embodiments of the present disclosure; for example, ring A can be

[0278] In some embodiments, in the definition of Formula I and I-1, Ring A is

[0279] In some embodiments, in the definition of Formula I and I-1, R 2c is hydrogen, halogen or cyano.

[0280] In some embodiments, in the definition of Formula I and I-1, R 2c is hydrogen, fluorine or cyano, for example hydrogen or fluorine.

[0281] In some embodiments, in the definition of Formula I and I-1, G 1 In some embodiments, in the definition of formula I and I-1, G 1 For CH.

[0282] In some embodiments, in the definition of Formula I and I-1, G 2 In some embodiments, in the definition of formula I and I-1, G 2 For CH.

[0283] In some embodiments, in the definition of Formula I and I-1, G 3 is CH, C(F), C(CN) or N, such as CH or C(F). In some embodiments, in the definition of Formula I and I-1, G 3 For CH.

[0284] In some embodiments, in the definition of Formula I and I-1, R 2a For halogen, cyano, C 1–6 Alkyl or C 1–6 In some embodiments, in the definition of formula I and I-1, R 2a C 1–6 In some embodiments, R 2a Substituents, especially halogens, methyl groups, etc., can maintain or enhance the activity of the OTR target, reduce the activity of V1a, and thus improve the OTR / V1a selectivity.

[0285] In some embodiments, in the definition of Formula I and I-1, R 2a is methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, chloro or cyano. In some embodiments, in the definition of formula I and I-1, R 2a In some embodiments, in the definition of formula I and I-1, R 2a In some embodiments, in the definition of formula I and I-1, R 2a In some embodiments, in the definition of formula I and I-1, R 2a In some embodiments, in the definition of formula I and I-1, R 2a It is a cyano group.

[0286] In some embodiments, in the definition of Formula I and I-1, R 2b For hydrogen.

[0287] In some embodiments, in the definition of Formula I and I-1, R 2b C 1–6 Alkyl, cyano, C 1–6 Halogenated alkyl, C 1–6 Alkoxy or halogen.

[0288] In some embodiments, R 2bSubstituents, particularly halogen, alkyl, alkoxy, cyano, etc., can maintain or improve the activity of the OTR target, reduce the activity of V1a, and thus improve the OTR / V1a selectivity. In some embodiments, in the definition of Formula I and I-1, R 2b is methyl, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy or chlorine. In some embodiments, in the definition of formula I and I-1, R 2b In some embodiments, in the definition of formula I and I-1, R 2b In some embodiments, in the definition of formula I and I-1, R 2b In some embodiments, in the definition of formula I and I-1, R 2b In some embodiments, in the definition of formula I and I-1, R 2b In some embodiments, in the definition of formula I and I-1, R 2b It is difluoromethyl.

[0289] In some embodiments, in the definition of Formula I and I-1, R 2b and R 2a is defined as any of the following combinations (i)–(x);

[0290] (i)R 2a is methyl; R 2b is methyl;

[0291] (ii)R 2a is methyl; R 2b For chlorine;

[0292] (iii)R 2a is methyl; R 2b is cyano;

[0293] (iv)R 2a is methyl; R 2b is difluoromethyl;

[0294] (v)R 2a is methyl; R 2b is trifluoromethyl;

[0295] (vi)R 2a is methyl; R 2b is methoxy;

[0296] (vii)R 2a is chlorine; R 2b is cyano;

[0297] (viii)R 2a is cyano; R 2b is methyl;

[0298] (ix)R 2a is difluoromethyl; R 2b is cyano;

[0299] (x)R 2a is trifluoromethyl; R 2b It is a cyano group.

[0300] In some embodiments, in the definition of Formula I and I-1, R 2b and R 2a , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, for example cyclopentyl.

[0301] In some embodiments, in the definition of Formula I, I-1, The structure is

[0302] In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is In some embodiments, in the definition of Formula I, I-1, The structure is

[0303] In some embodiments, in the definition of Formula I, I-1, The structure is

[0304] In some embodiments, a compound, isotopic derivative, or pharmaceutically acceptable salt of Formula I is provided.

[0305] Where X is N–OR 1 ;

[0306] R 1 is -CH3;

[0307] R3a Selected from hydrogen or C 1–6 alkyl;

[0308] R 3b for –L 1 –R 3c ;

[0309] L 1 Independently –[C(R a )(R b )] n –; where n is 1; each R a and R b are each independently hydrogen, -CH3;

[0310] R 3c Independently –OR 7a ; the R 7a Selected from hydrogen or C 1–6 alkyl;

[0311] L 2 For–[C(R 10a )(R 10b )] t –

[0312] s is 1 and t is 1;

[0313] R 9a 、R 9b 、R 10a and R 10b is hydrogen;

[0314] Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to Ring B in Formula I; each ---- bond is independently a single bond or a double bond;

[0315] A 1 is CH or C(R 4a );

[0316] A 2 is CH or C(R 4b );

[0317] A 3 for CH;

[0318] A 4 for CH;

[0319] Each A 6 are independently C or N;

[0320] Each A 7 are independently C or N;

[0321] R 4aand R 4b Each independently selected from H, or R 4a and R 4b Together with the atoms that connect them,

[0322] In ring B, G 1 , G 2 and G 3 for CH;

[0323] R 2a is halogen or -CH3;

[0324] R 2b It is a cyano group.

[0325] 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:

[0326] Among them, R 1 、R 2a 、R 2b 、R 3a 、R 3b ,s,t,G 1 , G 2 , G 3 and Ring A are as defined in Formula I and I-1.

[0327] In some embodiments, in Formula I, I-1, Ia, Ib, when R 3a and R 3b When the carbon atom connected is a chiral carbon atom, it can be in R configuration, S configuration or a mixture of the two. In some embodiments, in Formula I, I-1, Ia, Ib, when R 3a and R 3b When the carbon atom to which it is attached is a chiral carbon atom, it may be in the S configuration.

[0328] In some embodiments, the compound is any one of the following compounds or a mixture thereof (eg, a mixture of Formula Ia and its stereoisomer Formula Ib):

[0329] In some embodiments, Formula I or I-1 represents the compound with the highest oxytocin receptor antagonist activity among Formula Ia and its stereoisomer Formula Ib, or a mixture of the compound with the highest oxytocin receptor antagonist activity and another compound; wherein the compound with the highest oxytocin receptor antagonist activity in the mixture is not less than the other compound. Methods for determining oxytocin receptor antagonist activity are well known in the art, such as the method disclosed in Biological Test 1 herein.

[0330] In some embodiments, Formula I or I-1 is a mixture of the more polar form of Formula Ia and its stereoisomer Formula Ib, or a mixture of the more polar form and the less polar form; wherein the content of the more polar form in the mixture is not less than the less polar form. In some embodiments, Formula I or I-1 is a mixture of the less polar form of Formula Ia and its stereoisomer Formula Ib, or a mixture of the less polar form and the more polar form; wherein the content of the less polar form in the mixture is not less than the more polar form. The relative polarity of two molecules can be determined by experimental methods known in the art; exemplary methods include silica gel thin layer chromatography, reverse phase HPLC, etc.

[0331] In some embodiments, the isotopic derivative has any of the following structures:

[0332] The present disclosure also provides a pharmaceutical composition comprising the aforementioned compound, isotope derivative or pharmaceutically acceptable salt, and pharmaceutical excipients.

[0333] The present disclosure also provides a use of the aforementioned compound, isotope derivative or pharmaceutically acceptable salt as a medicine.

[0334] The present disclosure also provides a use of the aforementioned compound, isotope derivative or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of an oxytocin receptor antagonist.

[0335] The present disclosure also provides a use of the aforementioned compound, isotope derivative or pharmaceutically acceptable salt in the preparation of a medicament for preventing and / or treating a disease or condition for which inhibition of oxytocin is known or may be shown to produce a beneficial effect.

[0336] The present disclosure also provides a method for preventing and / or treating a disease or condition for which inhibition of oxytocin is known or may be shown to have a beneficial effect, comprising administering to a subject an effective amount of a compound, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the disease or condition is sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, dyspareunia, premature ejaculation, pre-labor delivery, delivery complications, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis of the liver, renal hypertension, intraocular hypertension, obsessive-compulsive disorder, or a neuropsychiatric disorder.

[0338] In some embodiments, the disease or condition is preterm birth.

[0339] Without violating the common sense in the art, the above-mentioned implementation schemes or preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0340] The compounds of Formula I disclosed herein can be prepared by the methods of the reference examples and methods disclosed in the art. Exemplary methods are as follows:

[0341] In formula II, Y is CH(OH) or C(=N-OR 1 ); When Y is CH(OH), it can react with NH2–OR 1 The reaction forms C(=N–OR 1 ); where s, L 2 、R 9a 、R 9b 、R 1 The definition of is as described in formula I;

[0342] In Formula II, R g for Hydrogen or amino protecting group; when R g When it is an amino protecting group, the amino protecting group can be removed to form hydrogen; when R g When it is hydrogen, it can be Acylation reaction to form When R g for When Coupling formation Among them, R f can be bromine or iodine; LG can be a leaving group, such as chlorine; Ring A, R 2a 、R 2b , G 1 , G 2 , G 3 The definition of is as described in formula I;

[0343] In Formula II, R 3a” R 3a Or it can be converted into R by reactions known in the art 3a For example, when R 3a”When is hydrogen, the compound of formula II can be reacted with C 1–6 Alkyl iodides or I–L 1 –R 3c The reaction forms C 1–6 Alkyl or –L 1 –R 3c ; Among them, R 3a , L 1 and R 3c The definition of is as described in formula I;

[0344] In Formula II, R 3b” R 3b Or it can be converted into R by reactions known in the art 3b For example, in some embodiments, R 3b” It can be –COOMe, which can be reduced to –CH2OH, which can be further converted into various groups.

[0345] Definition and Description

[0346] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0347] When any variable (e.g., R) occurs more than once in a compound's structure, the definition of that variable at each occurrence is independent of each other. For example, if a group is substituted with 0–2 R, then that group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.

[0348] The term "substituted" or "substituent" refers to the replacement of a hydrogen atom in a group with a specified group. When the position of substitution is not specified, substitution can be at any position, but only if a stable or chemically feasible chemical is formed. As an example, the structure indicates that the hydrogen atoms on the benzene ring are replaced by p R a The hydrogen atoms on the pyridine ring are replaced by q R b Replaced by each R a 、R b When describing a group as being substituted by "one or more" of the substituents listed, the number of substituents can be any number that is chemically feasible, for example, the number of substituents can be 1, 2, 3 or 4.

[0349] The term "optional" or "optionally" means that the event or situation described subsequently is possible but not required, that is, the description includes instances where the event or situation occurs and instances where the event or situation does not occur. Therefore, the term "optionally substituted" means that it can be substituted or not substituted.

[0350] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0351] The term "oxo" refers to =0.

[0352] The term "amino" refers to -NH2.

[0353] The term "hydroxyl" refers to a -OH group.

[0354] The term "nitro" refers to –NO2.

[0355] The term "cyano" refers to -CN.

[0356] The term "alkyl" refers to a saturated linear or branched monovalent 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, tert-butyl.

[0357] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing at least one carbon-carbon double bond. Alkenyl groups can be linked to other structures through any carbon atom (e.g., a saturated carbon atom, a double bond carbon atom) contained therein, but only a stable or chemically feasible chemical 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 ethenyl, 1-propenyl, 2-propenyl.

[0358] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing at least one carbon-carbon triple bond. Alkynyl groups can be linked to other structures through any carbon atom (e.g., a saturated carbon atom, a triple bond carbon atom) contained therein, but only when a stable or chemically feasible chemical is formed is it permitted. 2–6 The alkynyl group may be a C2, C3, C4, C5 or C6 alkynyl group, examples of which include, but are not limited to, ethynyl.

[0359] The term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. 1–6 The alkoxy group can be C1, C2, C3, C4, C5 or C6 alkoxy, examples of which include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0360] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definitions of alkyl and halogen are as described above. 1– 6 haloalkyl can be a halogenated C1, C2, C3, C4, C5 or C6 alkyl, examples of which include but are not limited to fluoromethyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl), fluoroethyl (e.g., 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl), 1-fluoro-2-chloroethyl. In some embodiments, the C 1–6 Haloalkyl is C1, C2, C3, C4, C5 or C6 fluoroalkyl.

[0361] The term "haloalkenyl" refers to an alkenyl group substituted by one or more halogens, wherein alkenyl and halogen are as defined above. 2–6 The alkenyl group may be a halogenated C2, C3, C4, C5 or C6 alkenyl group, examples of which include but are not limited to 1-fluorovinyl, 2-fluorovinyl, 1-fluoro-2-chlorovinyl. 2–6 The alkenyl group is a fluorinated C2, C3, C4, C5 or C6 alkenyl group.

[0362] The term "haloalkynyl" refers to an alkynyl group substituted by one or more halogens, wherein the definitions of alkynyl and halogen are as described above. 2–6 The alkynyl group may be a halogenated C2, C3, C4, C5 or C6 alkynyl group. 2–6 Alkynyl is a fluorinated C2, C3, C4, C5 or C6 alkynyl.

[0363] The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxy groups, wherein the definition of alkyl is as described above. 1–6 The hydroxyalkyl group may be a C1, C2, C3, C4, C5 or C6 alkyl group substituted with one or more hydroxyl groups, examples of which include but are not limited to hydroxymethyl and hydroxyethyl.

[0364] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein the definitions of alkoxy and halogen are as described above. 1–6 The alkoxy group may be a halogenated C1, C2, C3, C4, C5 or C6 alkoxy group, examples of which include but are not limited to trifluoromethoxy. 1–6 The alkoxy group is a fluorinated C1, C2, C3, C4, C5 or C6 alkoxy group.

[0365] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (eg, fused, spiro, or bridged) cyclic hydrocarbon group. 3–8The cycloalkyl group may be a C3, C4, C5, C6, C7 or C8 cycloalkyl group, such as 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 and cyclohexyl groups.

[0366] The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic (e.g., fused, spiro, or bridged) hydrocarbon group containing at least one carbon-carbon double bond. Cycloalkenyl groups can be linked to other structures via any atom on the ring (e.g., a saturated carbon atom, a double-bonded carbon atom), but only if a stable or chemically feasible compound is formed. 3–8 The cycloalkenyl group can be a C3, C4, C5, C6, C7 or C8 cycloalkenyl group, such as 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, a C8 monocyclic or polycyclic cycloalkenyl group, examples of which include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0367] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., cyclic, spirocyclic, or bridged) cyclic group formed by carbon atoms and at least one heteroatom. In some embodiments, the heteroatoms in the heterocycloalkyl are independently selected from N, O, and S. The heterocycloalkyl group can be connected to other structures through any atom (e.g., carbon atom, heteroatom) on the ring, but only a stable or chemically feasible chemical is formed. The 3-8 membered heterocycloalkyl group herein can be a 3, 4, 5, 6, 7, or 8 membered heterocycloalkyl group, such as 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, an 8 membered monocyclic or polycyclic heterocycloalkyl group, examples of which include but are not limited to oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, and morpholinyl.

[0368] The term "heterocycloalkenyl" refers to a non-aromatic monocyclic or polycyclic (e.g., bis-cyclic, spirocyclic, or bridged) cyclic group formed by carbon atoms and at least one heteroatom, containing at least one double bond; the atoms connecting the two 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. The heterocycloalkenyl group can be connected to other structures through any atom in the ring (e.g., a saturated carbon atom, a double-bonded carbon atom, a heteroatom), but only when a stable or chemically feasible chemical compound is formed is it allowed. The 3-8 membered heterocycloalkenyl group herein can be a 3-, 4-, 5-, 6-, 7- or 8-membered heterocycloalkenyl group, such as 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, an 8-membered monocyclic or polycyclic heterocycloalkenyl group, examples of which include but are not limited to dioxolyl, dioxinyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, and dihydropyrrolyl.

[0369] The term "heteroaryl" refers to an aromatic monocyclic or condensed ring group formed by carbon atoms and at least one heteroatom. In some embodiments, the heteroatoms in the heteroaryl group are independently selected from N, O, and S. The heteroaryl group can be connected to other structures through any atom (e.g., carbon atom, heteroatom) on the ring, but only a stable or chemically feasible chemical is formed. 5-6 herein The membered heteroaryl group may be a 5-membered heteroaryl group or a 6-membered heteroaryl group, examples of which include, but are not limited to, pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), furyl (e.g., furan-2-yl, furan-3-yl), thienyl (e.g., thien-2-yl, thien-3-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), pyrazolyl (e.g., pyrazol- 1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl), pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl).

[0370] The term "pharmaceutically acceptable salt" refers to a salt of a compound formed with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compound with a sufficient amount of a pharmaceutically acceptable base in a neat solution or a suitable inert solvent. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a neat solution or a suitable inert solvent.

[0371] The term "isotopic derivative" refers to a derivative formed when an atom in a compound is replaced by an isotope of the atom. Examples of isotopes that can be incorporated into the disclosed compounds include, but are not limited to, 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 can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein. In some embodiments, the isotopic derivative is a deuterated compound, for example, a compound in which 1, 2, 3, 4, 5, or 6 hydrogen atoms are replaced by deuterium.

[0372] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of one or more biological manifestations of the disease or condition.

[0373] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0374] The term "effective amount" refers to an amount of a compound of the present disclosure that is sufficient to effectively treat or prevent a disease or condition described herein when administered to a subject. The effective amount will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0375] The term "subject" refers to any animal, preferably a mammal, most preferably a human, to which a compound or composition is to be or has been administered.

[0376] Unless otherwise indicated, the various isomers or mixtures thereof of the compounds or isotopic derivatives disclosed herein, such as tautomers, stereoisomers (e.g., geometric isomers or optical isomers) or any mixtures thereof (e.g., racemic mixtures), are all included within the scope of the present invention. Optical isomers may be enantiomers or diastereomers. These stereoisomers may be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and may also be obtained by chiral resolution by bonding or salt formation with other chiral compounds. In the stereoisomer mixtures mentioned above (e.g., mixtures of E and Z isomers, mixtures of R and S isomers), the proportion of each stereoisomer may be in the range of 5%-95% (e.g., 10%-90%, 20%-80%, 30%-70%, 40%-60%, 50%).

[0377] Various forms of the compounds, isotopic derivatives, and pharmaceutically acceptable salts disclosed herein, including various solid forms and mixtures thereof, such as crystalline forms, amorphous forms, solvates (such as hydrates), or any mixtures thereof, are all within the scope of the present invention. Beneficial effects

[0378] 1. The compounds of formula I provided by the present invention have improved OTR antagonistic activity.

[0379] 2. The compound of formula I provided by the present invention also has lower V1aR antagonistic activity and improved OTR / V1a target selectivity.

[0380] 3. The compound of formula I provided by the present invention has improved exposure AUC, half-life T 1 / 2 and clearance rate Cl.

[0381] 4. The compound of formula I provided by the present invention exhibits a lower brain tissue distribution ratio after oral administration, reducing the risk of off-target OTR antagonism in the brain. DETAILED DESCRIPTION

[0382] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0383] The starting materials and reagents in the examples are known and commercially available, or can be synthesized according to methods known in the art.

[0384] 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]dichloropalladium(II); DIEA and DIPEA represent N,N-diisopropylethylamine; HATU represents 2-(7-azabenzotriazole-1-yl)-1-nitropropane; -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DAST denotes diethylaminosulfur trifluoride; EDCI denotes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP denotes 4-dimethylaminopyridine; TsOH denotes p-toluenesulfonic acid; Pd(PPh3)4 denotes tetrakis(triphenylphosphine)palladium; Pd(dtbpf)Cl2 denotes 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride; Tf2O denotes tris(1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride); Fluoromethanesulfonic anhydride; DPPF represents 1,1'-bis(diphenylphosphino)ferrocene; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; ACN represents acetonitrile; t-BuONO represents tert-butyl nitrite; DPPP represents 1,3-bis(diphenylphosphino)propane; BF3·Et2O represents boron trifluoride etherate; t-BuOH represents tert-butyl alcohol; DMP represents Dess-Martin oxidant; BTC represents bis(trichloromethyl) carbonate; CDI denotes N,N′-carbonyldiimidazole; TBSCl denotes tert-butyldimethylsilyl chloride; LiHMDS denotes lithium bis(trimethylsilyl)amide; DEAD denotes diethyl azodicarboxylate; PPTS denotes pyridinium-1-methylbenzenesulfonate; DMK denotes acetone; NMP denotes N-methylpyrrolidone; Prep-TLC denotes preparative thin-layer chromatography; HPLC denotes high-performance liquid chromatography; rt denotes room temperature (20–30°C).

[0385] Example C0020 & C0021

[0386] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0387] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0388] first step

[0389] 1-(tert-Butyl)2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate 20b

[0390] 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-butyldimethylsilyl chloride (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 solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with 1N HCl (100 mL) and saturated brine (100 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain 20b (14 g, yield: 60.5%).

[0391] MS m / z(ESI):260.1[M+1-Boc] + .

[0392] Step 2

[0393] 1-(tert-Butyl)2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-methylpyrrolidine-1,2-dicarboxylate 20c

[0394] 20b (14 g, 36.99 mmol) was dissolved in tetrahydrofuran (200 mL). Lithium bis(trimethylsilyl)amide (11.14 g, 66.8 mmol) was added dropwise at -15°C. The mixture was allowed to react for one hour at -15°C, followed by the addition of iodomethane (9.45 g, 66.8 mmol) at -15°C. The reaction was allowed to proceed at room temperature for 16 hours. Upon completion, saturated ammonium chloride solution (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1 to 30:1) to afford 20c (2.7 g, yield: 18.6%).

[0395] MS m / z(ESI):374.1[M+1] + .

[0396] Step 3

[0397] 1-(tert-Butyl)2-methyl(2S,4R)-4-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate 20d

[0398] 20c (3.2 g, 8.57 mmol) was dissolved in tetrahydrofuran (50 mL), and tetrabutylammonium fluoride (3.36 g, 12.86 mmol) was added. The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated to remove the tetrahydrofuran. Ethyl acetate (50 mL) and water (50 mL) were then added to the residue, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 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 obtain product 20d (1.6 g, yield: 68.4%).

[0399] 1 H NMR (300MHz, DMSO-d6) δ5.13-5.10(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).

[0400] Step 4

[0401] 1-(tert-Butyl)2-methyl(S)-2-methyl-4-oxopyrrolidine-1,2-dicarboxylate 20e

[0402] 20d (1.6 g, 6.17 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin periodinane (3.92 g, 9.25 mmol) was added. 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, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), respectively. 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 afford 20e (1.2 g, yield: 71.8%).

[0403] 1 H NMR (300MHz, DMSO-d6) δ3.89 (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).

[0404] Step 5

[0405] (S)-2-Methyl-4-oxopyrrolidine-2-carboxylic acid methyl ester 20f

[0406] 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 the reaction was complete, the solvent was evaporated to obtain 20f (0.18 g, yield: 98.22%).

[0407] 1 H NMR (300MHz, DMSO-d6) δ10.80(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).

[0408] Step 6

[0409] (S)-2-Methyl-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-4-oxopyrrolidine-2-carboxylic acid methyl ester 20g

[0410] 20f (0.18 g, 1.09 mmol) was dissolved in dichloromethane (10 mL), and 4-(2-methylphenyl)benzoyl chloride (0.38 g, 1.64 mmol) and triethylamine (0.33 g, 3.27 mmol) were added. 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 = 3 / 1) to yield 20g (0.3 g, yield: 74.5%).

[0411] MS m / z(ESI):374.1[M+Na] + .

[0412] Step 7

[0413] (S,EZ)-4-(methoxyimino)-2-methyl-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 20h

[0414] Dissolve 20g (0.30g, 0.81mmol) in methanol (15mL), add methoxyamine hydrochloride (0.23g, 2.83mmol) and triethylamine (0.20g, 2.03mmol), and react at 60°C for 16 hours. After completion of the reaction, concentrate the reaction solution to remove the methanol, add ethyl acetate (20mL) to the residue, wash with water (10mL x 2), and once with saturated sodium chloride (10mL). After drying over sodium sulfate, evaporate the solvent, and purify the residue by Pre-TLC (petroleum ether / ethyl acetate = 5 / 1) to afford 20h (0.2g, yield: 61.6%).

[0415] MS m / z(ESI):381.1[M+1] + .

[0416] Step 8

[0417] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0418] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)-2-methylpyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0419] 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. The reaction was allowed to react at room temperature for 16 hours. The reaction was quenched with water, concentrated, and the residue dissolved in dichloromethane and water. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. 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 more polar isomer C0020 (Rf = 0.4). The crude product was then purified by HPLC and lyophilized to give the more polar C0020 (11.27 mg, yield: 6.3%) and the less polar C0021 (7.80 mg, yield: 4.3%).

[0420] C0020:MS m / z(ESI): 353.1[M+1] + .

[0421] 1 H NMR(400MHz, DMSO-d6)δ7.51(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).

[0422] C0021:MS m / z(ESI): 353.1[M+1] + .

[0423] 1H NMR (300MHz, DMSO-d6) δ7.53(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).

[0424] Examples C0035 & C0036

[0425] (S,E)-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0426] (S,Z)-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0427] first step

[0428] 2',3'-Dimethyl-[1,1'-biphenyl]-4-carbonyl chloride 35b

[0429] 35a (1.35 g, 5.37 mmol) was dissolved in thionyl chloride (10 mL), and the mixture was reacted at 80°C for three hours. After the reaction, the crude product 35b (1.31 g, yield: 89.7%) was obtained by direct spin drying without further treatment.

[0430] Step 2

[0431] (S)-Methyl 1-(2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-oxopyrrolidine-2-carboxylate 35d

[0432] 35b (1.31 g, 5.35 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (2.10 g, 20.79 mmol) and 35c (0.85 g, 5.94 mmol) were added at 0°C and allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution 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 afford product 35d (900 mg, yield: 38.4%).

[0433] MS m / z(ESI):351.8[M+1] + .

[0434] Step 3

[0435] (S,EZ)-methyl 1-(2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylate 35e

[0436] 35d (0.9 g, 2.56 mmol) was dissolved in methanol (10 mL). Methoxyamine hydrochloride (0.43 g, 5.12 mmol) and triethylamine (0.65 g, 6.40 mmol) were added at room temperature and allowed to react 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 (petroleum ether:ethyl acetate = 4:1 to 3:1) to afford product 35e (0.9 g, yield: 83.1%).

[0437] MS m / z(ESI):380.8[M+1] + .

[0438] Step 4

[0439] (S,Z)-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0440] (S,E)-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0441] 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. The reaction was allowed to react at room temperature for 2 hours. The reaction was quenched with water, concentrated, and the residue dissolved in dichloromethane and water. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. The crude product was separated by silica gel Prep-TLC (EA:PE = 2:1) to afford the less polar isomer C0035 (Rf = 0.5) and the more polar isomer C0036 (Rf = 0.4). Crude C0035 was purified by HPLC and lyophilized to afford C0035 (10 mg, yield: 9.3%). The crude product C0036 was purified by HPLC (FA) and lyophilized to obtain C0036 (15 mg, yield: 14.1%).

[0442] C0035:ESI-MS:m / z=353.1[M+1] + .

[0443] 1H NMR(400MHz,CD3OD-d4)δ7.60(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).

[0444] C0036:ESI-MS:m / z=353.1[M+1] + .

[0445] 1 H NMR (400MHz, CD3OD-d4) δ7.60 (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).

[0446] Example C0038 & C0038A

[0447] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0448] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0449] first step

[0450] 4-Bromo-2-methoxybenzoyl chloride 38b

[0451] 38a (1.2 g, 5.19 mmol) was dissolved in thionyl chloride (10 mL), and the mixture was reacted at 80°C for 3 hours. After the reaction, the crude product 38b (1.5 g) was obtained by direct spin drying without further treatment.

[0452] MS m / z(ESI):246.1[M+1] + .

[0453] Step 2

[0454] (S,EZ)-1-(4-bromo-2-methoxybenzoyl)-4-(methoxyimino)pyrrolidine-2-carboxylic acid methyl ester 38d

[0455] 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 nitrogen substitution, the mixture was stirred at room temperature for 20 min. Upon completion of the reaction, ethyl acetate was added, and the mixture was washed with saturated sodium chloride. The combined organic phases were dried, spin-dried, and the crude product was purified by column chromatography (PE / EA = 10:1 to 1:1) to afford 38d (1.2 g, yield: 77.7%).

[0456] MS m / z(ESI):369.1[M+1] + .

[0457] Step 3

[0458] (S,EZ)-1-(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylic acid methyl ester 38e

[0459] To a solution of 38d (200 mg, 0.52 mmol) in dioxane / water (15:1.5 mL) was added (2,3-dimethylphenyl)boronic acid (94 mg, 0.62 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (38 mg, 52 mmol). After nitrogen substitution, the mixture was reacted at 85°C for 2 hours. After cooling, the reaction solution was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spun down to dryness. 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 afford 38e (150 mg, 66.8% yield).

[0460] MS m / z(ESI):410.8[M+1] + .

[0461] Step 4

[0462] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0463] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0464] To a solution of 38e (140 mg, 0.34 mmol) in tetrahydrofuran / methanol (5 / 5 mL) was slowly added LiBH4 (7.4 mg, 0.34 mmol) at 0°C under nitrogen. The mixture was stirred at room temperature for 1 hour. After cooling, the reaction solution was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. The crude product was separated by silica gel Prep-TLC (EA:PE = 2:1) to afford the less polar isomer C0038A (Rf = 0.5) and the more polar isomer C0038 (Rf = 0.4). The product was then purified by HPLC and lyophilized to afford the more polar product C0038 (9.39 mg, yield: 7.2%) and the less polar product C0038A (7.42 mg, yield: 5.7%).

[0465] C0038: MS m / z(ESI): 383.1[M+1] + .

[0466] 1 H NMR(400MHz,CD3OD-d)δ7.35-7.30(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).

[0467] C0038A: MS m / z(ESI): 383.1[M+1] + .

[0468] 1 H NMR(400MHz,CD3OD-d)δ7.35-7.32(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).

[0469] Examples C0044 & C0044A

[0470] (S,Z)-(2',3-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0471] (S,E)-(2',3-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0472] Referring to the synthesis method of compound C0038, a highly polar product C0044 (10 mg, yield: 14.20%) and a less polar product C0044A (10 mg, yield: 14.20%) were obtained.

[0473] C0044A: MS m / z(ESI): 353.1[M+1] + .

[0474] 1 H NMR(400MHz,CD3OD-d)δ7.35-7.31(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).

[0475] C0044: MS m / z(ESI): 353.1[M+1] + .

[0476] 1 H NMR(400MHz,CD3OD-d)δ7.36-7.32(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).

[0477] Examples C0045 & C0045A

[0478] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methyl-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0479] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3-methyl-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0480] Referring to the synthesis method of compound C0038, a highly polar product C0045 (15 mg, yield: 17.0%) and a less polar product C0045A (17 mg, yield: 19.3%) were obtained.

[0481] C0045: MS m / z(ESI): 367.0[M+1] + .

[0482] 1 H NMR (400MHz, CD3OD-d) δ7.36-7.31(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).

[0483] C0045A: MS m / z(ESI): 367.0[M+1] + .

[0484] 1 H NMR(400MHz,CD3OD-d)δ7.37-7.32(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).

[0485] Examples C0046 & C0046A

[0486] (S,Z)-(2',2-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0487] (S,E)-(2',2-Dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0488] Referring to the synthesis method of compound C0038, a highly 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.

[0489] C0046: MS m / z(ESI): 353.1[M+1] + .

[0490] 1 H NMR (400MHz, CD3OD-d) δ7.66-7.52(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).

[0491] C0046A: MS m / z(ESI): 353.1[M+1] + .

[0492] 1 H NMR (400MHz, CD3OD-d) δ7.47 (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).

[0493] Examples C0047 & C0047A

[0494] (S,Z)-(2,2',3'-Trimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0495] (S,E)-(2,2',3'-Trimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0496] According to the above synthesis route and referring to the synthesis method of compound C0038, the highly polar product C0047 (34.80 mg, yield: 15.0%) and the less polar product C0047A (30.80 mg, yield: 13.2%) were obtained.

[0497] C0047: MS m / z(ESI): 367.1[M+1] + .

[0498] 1 H NMR(400MHz,CD3OD-d)δ7.45(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).

[0499] C0047A: MS m / z(ESI): 367.1[M+1] + .

[0500] 1 H NMR(400MHz,CD3OD-d)δ7.46(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).

[0501] Example A0061 & A0042

[0502] (S,Z)-(5-(2,3-Dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0503] (S,E)-(5-(2,3-Dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0504] first step

[0505] 5-(2,3-Dimethylphenyl)pyrazine-2-carboxylic acid methyl ester 61c

[0506] 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. Potassium carbonate (4.81 g, 34.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.42 g, 0.58 mmol) were then added. The reaction was then allowed to react at 75°C under nitrogen for 16 hours. The mixture was then quenched by the addition of 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 to afford the crude product 61c (1.7 g, white solid, yield: 60.5%).

[0507] MS m / z(ESI):243[M+1] + .

[0508] Step 2

[0509] 5-(2,3-Dimethylphenyl)pyrazine-2-carboxylic acid 61d

[0510] Starting material 61c (1.7 g, 7.02 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water. Lithium hydroxide (0.50 g, 21.06 mmol) was then added and the reaction was allowed to proceed at 25°C for 2 hours. The pH was then adjusted to acidic by the addition of 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford product 61d (1.4 g, white solid, yield: 90.5%).

[0511] MS m / z(ESI):251[M+1] + .

[0512] Step 3

[0513] (S,EZ)-1-(5-(2,3-dimethylphenyl)pyrazine-2-carbonyl)-4-(methoxyimino)pyrrolidine-2-carboxylic acid methyl ester 61f

[0514] Starting material 61d (1.45 g, 6.35 mmol) was dissolved in 50 mL of DMF, followed by the addition of 38c (1.20 g, 6.99 mmol) and HATU (3.14 g, 8.25 mmol), followed by the slow addition of ethyldiisopropylamine (3.28 g, 25.4 mmol). The reaction was allowed to proceed at room temperature for 2 hours. 50 mL of water was then added, and the mixture was 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 resulting residue was purified by silica gel column chromatography to afford product 61f (560 mg, white solid, yield: 23.1%).

[0515] MS m / z(ESI):383.3[M+1] + .

[0516] Step 4

[0517] (S,Z)-(5-(2,3-Dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0518] (S,E)-(5-(2,3-Dimethylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0519] Raw 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. Then, 10 mL of water was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine (10 mL x 3). The organic phases were 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 yield the less polar isomer A0042 (Rf = 0.4) and the more polar isomer A0061 (Rf = 0.3). The products were then purified by HPLC and lyophilized to afford the more polar product A0061 (101.55 mg, yield: 35.8%) and the less polar product A0042 (60 mg, yield: 21.3%).

[0520] A0061: MS m / z(ESI): 355.3[M+1] + .

[0521] 1H NMR(400MHz,Chloroform-d)δ9.27(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).

[0522] A0042: MS m / z(ESI): 355.3[M+1] + .

[0523] 1 H NMR(400MHz,Chloroform-d)δ9.30-9.25(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).

[0524] Examples C0041 & C0041A

[0525] (S,Z)-(5-(3-chloro-2-methylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0526] (S,E)-(5-(3-chloro-2-methylphenyl)pyrazin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0527] Refer to the method of A0061, replace the first step raw material 61a with The highly polar product C0041 (23.5 mg, yield: 16.9%) and the less polar product C0041A (5.6 mg, yield: 4.0%) were obtained.

[0528] C0041: MS m / z(ESI): 375.1[M+1] + .

[0529] 1H NMR (400MHz, CD3OD) δ9.13-9.08(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).

[0530] C0041A: MS m / z(ESI): 375.0[M+1] + .

[0531] 1 H NMR (400MHz, CD3OD) δ9.11(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).

[0532] Synthesis of Intermediate 4

[0533] (S,EZ)-5-(Hydroxymethyl)pyrrolidin-3-one O-methyloxime hydrochloride

[0534] first step

[0535] (S,EZ)-1-(tert-butyl)-2-methyl-4-(methoxyimino)pyrrolidine-1,2-dicarboxylate

[0536] 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 allowed to react at 60°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to remove the methanol, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain 2 (14 g, yield: 88.0%), which was used directly in the next reaction.

[0537] MS m / z(ESI):216.9[M+1-56] + .

[0538] Step 2

[0539] (S,EZ)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0540] Compound 2 (14 g, 48.84 mmol) was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (150 mL), and lithium borohydride (2.13 g, 97.68 mmol) was added dropwise at room temperature. The mixture was allowed to react for 2 hours. It was observed that the starting material had not reacted completely. Then, lithium borohydride (2.13 g, 97.68 mmol) was added dropwise at room temperature. The mixture was allowed to react for another 2 hours at room temperature. After the reaction was completed, water (100 mL) and ethyl acetate (500 mL) were added to the reaction solution, 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 evaporated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 3 (10.0 g, yield: 79.6%).

[0541] MS m / z(ESI):188.9[M+1] + .

[0542] Step 3

[0543] (S,EZ)-5-(Hydroxymethyl)pyrrolidin-3-one O-methyloxime hydrochloride

[0544] Compound 3 (400 mg, 1.56 mmol) was dissolved in 4N hydrochloric acid in dioxane (4 mL) and reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to remove the solvent to obtain the crude product Compound 4 (400 mg), which was used directly in the next reaction.

[0545] MS m / z(ESI):145.0[M+1] + .

[0546] Example C0055 & C0056

[0547] (S,E)-(3'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0548] (S,Z)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0549] first step

[0550] 3'-Chloro-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 56c

[0551] To a solution of 56a (1.0 g, 4.97 mmol) in 1,4-dioxane / water (18 / 3 mL) were added 56b (1.10 g, 6.46 mmol), potassium carbonate (1.72 g, 12.42 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (365 mg, 0.5 mmol). After nitrogen purging, the mixture was reacted at 80°C for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated, and the crude product was purified by column chromatography (PE / EA = 3:1 to 1:1) to afford 56c (450 mg, 36.8% yield).

[0552] MS m / z(ESI):247.0[M+1] + .

[0553] Step 2

[0554] (S,Z)-(3'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0555] (S,E)-(3'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0556] 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 nitrogen substitution, the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once more. The organic phases were combined, washed once with brine, dried, filtered, and spin-dried to obtain the crude product. The crude product was separated by silica gel Prep-TLC (EA:PE=2:1) ​​to obtain crude large polar isomer C0056 (Rf=0.4) and crude small polar isomer C0055 (Rf=0.5). The crude product was then purified by HPLC and lyophilized to obtain large polar product C0056 (20.01 mg, yield: 8.8%) and small polar product C0055 (13.2 mg, yield: 6.0%).

[0557] C0056:MS m / z(ESI):373.1[M+1] + .

[0558] 1H NMR(400MHz,CD3OD-d)δ7.64-7.62(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).

[0559] C0055:MS m / z(ESI):373.1[M+1] + .

[0560] 1 H NMR(400MHz,CD3OD-d)δ7.64-7.62(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).

[0561] Examples C0057 & C0058

[0562] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0563] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0564] first step

[0565] 3'-Cyano-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 58b

[0566] To a solution of 58a (409.72 mg, 2.09 mmol) in methanol (20 mL) and water (10 mL) were added 4-(dihydroxyboryl)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). The atmosphere was purged with nitrogen and the mixture was allowed to react at 85°C overnight. After completion of the reaction, the methanol was removed by rotary evaporation, and the aqueous phase was extracted with ethyl acetate. The retained aqueous phase was adjusted to pH 3-4 and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporation to afford 58b (400 mg, 72.6% yield).

[0567] MS m / z(ESI):238.1[M+1] + .

[0568] Step 2

[0569] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0570] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[0571] To a solution of 58b (400 mg, 1.69 mmol) in DMF (5 mL) were added intermediate 4 (0.29 g, 2.03 mmol), triethylamine (0.51 g, 5.07 mmol), and HATU (0.96 g, 2.54 mmol). After nitrogen purging, the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spin-dried to yield the crude product. The crude product was separated by silica gel Pre-TLC (EA:PE = 5:1) to afford the less polar isomer C0057 (Rf = 0.5) and the more polar isomer C0058 (Rf = 0.4). The products were then purified by HPLC and lyophilized to afford the less polar product C0057 (34 mg, 5.6% yield) and the more polar product C0058 (22 mg, 3.6% yield).

[0572] C0057: MS m / z(ESI): 364.1[M+1] + .

[0573] 1 H NMR(400MHz,CD3OD-d4)δ7.72-7.65(m,3H),7.54-7.42(m,4H),4.81-4.74(m,1H),4.4 1-4.06(m,2H),3.91-3.67(m,4H),3.39-3.36(m,1H),2.88-2.86(m,2H),2.45(s,3H).

[0574] C0058: MS m / z(ESI): 364.1[M+1] + .

[0575] 1H NMR(400MHz,CD3OD-d4)δ7.72-7.65(m,3H),7.55-7.42(m,4H),4.76-4.74(m,1H),4.4 8-4.08(m,2H),3.88-3.67(m,4H),3.39-3.36(m,1H),3.13-2.73(m,2H),2.45(s,3H).

[0576] Examples C0059 & C0060

[0577] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanone

[0578] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanone

[0579] Following the above synthetic 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. The products were then purified by HPLC and lyophilized to give the less polar product C0059 (36 mg, yield: 9.9%) and the more polar product C0060 (27 mg, yield: 7.5%).

[0580] C0059: MS m / z(ESI): 407.1[M+1] + .

[0581] 1 H NMR(400MHz,CD3OD-d4)δ7.71-7.64(m,3H),7.47-7.40(m,4H),4.81-4.75(m,1H),4.4 3-4.01(m,2H),3.88-3.69(m,4H),3.39-3.33(m,1H),2.97-2.73(m,2H),2.33(s,3H).

[0582] C0060: MS m / z(ESI): 407.1[M+1] + .

[0583] 1H NMR(400MHz,CD3OD-d4)δ7.71-7.64(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)

[0584] Examples C0061 & C0062

[0585] (S,E)-(7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0586] (S,Z)-(7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0587] first step

[0588] Methyl 4-bromo-2,3-dihydroxybenzoate 62b

[0589] 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 a solution of 62a (5 g, 29.74 mmol) in dichloromethane (25 mL) was added dropwise over 20 minutes. The mixture was stirred at -78°C for 30 minutes and then slowly warmed to room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate / water. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by reverse phase column chromatography (acetonitrile:water = 5:95 to 45:55) to afford product 62b (1.3 g, yield: 17.7%). 1 H NMR (400MHz, CDCl3) δ11.02(s,1H),7.19(d,J=8.8Hz,1H),6.98(d,J=8.8Hz,1H),5.99(s,1H),3.87(s,3H).

[0590] Step 2

[0591] 7-Bromo-benzo[d][1,3]dioxole-4-carboxylic acid methyl ester 62c

[0592] To a solution of 62b (1.4 g, 5.67 mmol) in DMF (20 mL) was added cesium carbonate (3.69 g, 11.34 mmol). The mixture was stirred for 30 min, followed by the addition of dihydrodiiodomethane (2.43 g, 9.07 mmol). After nitrogen substitution, the mixture was stirred at 70°C for 12 h. The reaction solution was extracted with ethyl acetate / water, and the combined organic layers were washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporated to afford the product. The crude product was purified by silica gel Pre-TLC (PE:EA = 5:1) to afford 62c (500 mg, yield: 34.1%).

[0593] Step 3

[0594] 7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxole-4-carboxylic acid methyl ester 62d

[0595] To a solution of 62c (0.50 g, 1.93 mmol) in dioxane / water (10 mL / 1 mL) were 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). After nitrogen replacement, the mixture was stirred at 80°C for 3 hours. The reaction solution was extracted with ethyl acetate / water, and the combined organic layers were washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified on a reverse phase column (acetonitrile:water = 5:95 to 70:30) to afford 62d (0.30 g, yield: 54.7%).

[0596] MS m / z(ESI):285.0[M+1] + .

[0597] Step 4

[0598] 7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxole-4-carboxylic acid 62e

[0599] To a solution of 62d (200 mg, 0.67 mmol) in tetrahydrofuran / water (6 mL / 3 mL) was added lithium hydroxide monohydrate (70.2 mg, 1.68 mmol), and the reaction was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to ~2 with 1N aqueous hydrochloric acid. The reaction solution was extracted with ethyl acetate / water, and the organic layers were combined and washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by reverse phase column chromatography (acetonitrile:water = 5:95 to 50:50) to obtain product 62e (150 mg, yield: 78.9%).

[0600] MS m / z(ESI):270.9[M+1] + .

[0601] Step 5

[0602] (S,E)-(7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0603] (S,Z)-(7-(2,3-Dimethylphenyl)benzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0604] To a solution of 62e (120 mg, 0.42 mmol) in DMF (4 mL) were added intermediate 4 (91 mg, 0.63 mmol), triethylamine (108 mg, 0.84 mmol), and HATU (239 mg, 0.63 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spun down to yield the crude product. The crude product was separated by silica gel Pre-TLC (EA:PE = 2:1) to yield the less polar isomer C0061 (Rf = 0.6) and the more polar isomer C0062 (Rf = 0.55). The product was then purified by HPLC and lyophilized to yield the less polar product C0061 (6.02 mg, yield: 3.4%) and the more polar product C0062 (6.1 mg, yield: 3.4%).

[0605] C0061:MS m / z(ESI): 397.1[M+1] + .

[0606] 1 H NMR (400MHz, CD3OD) δ7.18-7.01(m,4H),6.83(d,J=8.0Hz,1H),6.07-6.02(m,2H),4.84-4.4 0(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).

[0607] C0062:MS m / z(ESI): 397.1[M+1] + .

[0608] 1H NMR(400MHz,CD3OD)δ7.18-7.00(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).

[0609] Examples C0063 & C0064

[0610] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0611] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-methoxy-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[0612] Following the above synthetic 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. The products were then purified by HPLC and lyophilized to give the less polar product C0063 (26 mg, yield: 5.0%) and the more polar product C0064 (28 mg, yield: 5.4%).

[0613] C0063: MS m / z(ESI): 383.1[M+1] + .

[0614] 1 H NMR (400MHz, CD3OD-d4) δ7.22-7.06 (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).

[0615] C0064: MS m / z(ESI): 383.1[M+1] + .

[0616] 1H NMR (400MHz, CD3OD-d4) δ7.21-7.06 (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).

[0617] Examples C0065 & C0066

[0618] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0619] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0620] first step

[0621] 3'-Methoxy-2'-methyl-[1,1'-biphenyl]-4-carboxylic acid 66b

[0622] 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 atmosphere was replaced with nitrogen three times, and the mixture was heated to 80°C under nitrogen and stirred for 17 hours. After the reaction, the methanol was removed by rotary evaporation, filtered, and the filtrate was extracted with a small amount of ethyl acetate. The aqueous phase was retained and the pH of the aqueous phase was adjusted to 3-4. The aqueous phase was extracted twice with a mixture of toluene / tetrahydrofuran (1 / 1). The organic layers were combined, dried over sodium sulfate, and concentrated to afford 66b (470 mg, 78.0% yield).

[0623] MS m / z(ESI):241.0[M+1] + .

[0624] Step 2

[0625] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0626] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(3'-methoxy-2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0627] Under nitrogen, 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 allowed to react overnight at room temperature. Water (50 mL) was added to quench the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel Pre-TLC (PE:EA = 1:1) to afford 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).

[0628] C0065: MS m / z(ESI): 369.1[M+1] + .

[0629] 1 H NMR (400MHz, CD3OD) δ7.60(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).

[0630] C0066: MS m / z(ESI): 369.1[M+1] + .

[0631] 1 H NMR (400MHz, CD3OD) δ7.59(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).

[0632] Examples A0134 & A0145

[0633] (S,Z)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0634] (S,E)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0635] first step

[0636] Methyl 4-bromo-3-difluoromethylbenzoate 134b

[0637] 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 reacted at room temperature for 16 hours. 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 purified by column chromatography (petroleum ether / ethyl acetate = 30:1) to afford 134b (400 mg, yield: 73.4%).

[0638] MS m / z(ESI):265[M+1] + .

[0639] Step 2

[0640] 2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester 134d

[0641] Referring to the synthesis method of compound A0061, 134d (200 mg, yield: 45.6%) was obtained.

[0642] MS m / z(ESI):291[M+1] + .

[0643] Step 3

[0644] 2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-carboxylic acid 134e

[0645] Referring to the synthesis method of compound A0061, crude product 134e (0.2 g, yield: 94.4%) was obtained.

[0646] MS m / z(ESI):277[M+1] + .

[0647] Step 4

[0648] (S,Z)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0649] (S,E)-(2-(Difluoromethyl)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0650] 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). DMAP (0.10 g, 0.84 mmol) and EDCI (0.081 g, 0.42 mmol) were then 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 afford the highly polar crude product A0134 (Rf = 0.4) and the less polar crude product A0145 (Rf = 0.5). The product was then purified by HPLC and lyophilized to afford the highly polar product A0134 (5.37 mg, yield: 3.7%) and the less polar product A0145 (6.82 mg, yield: 4.6%).

[0651] A0134: MS m / z(ESI): 403.0[M+1] + .

[0652] 1 H NMR(400MHz,Chloroform-d)δ7.91-7.89(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).

[0653] A0145: MS m / z(ESI): 403.0[M+1] + .

[0654] 1H NMR(400MHz,Chloroform-d)δ7.88(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).

[0655] Examples C0067 & C0068

[0656] (S,Z,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0657] (S,E,RS)-(2-(1-Hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0658] first step

[0659] (S)-7-(2'-Methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester 67b

[0660] Compound 67a (800 mg, 2.37 mmol, prepared according to the method described in 20 g) was dissolved in toluene (7 mL). Ethylene glycol (221 mg, 3.56 mmol) and p-toluenesulfonic acid hydrate (90 mg, 0.47 mmol) were added to the reaction mixture, and the mixture was reacted at 120°C for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation. Prep-TLC (PE / EA = 6 / 1) yielded product 67b (500 mg, yield: 55.3%).

[0661] MS m / z(ESI):382.0[M+1] + .

[0662] Step 2

[0663] (S)-(8-(Hydroxymethyl)-1,4-dioxo-7-azaspiro[4.4]nonan-7-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 67c

[0664] 67b (160 mg, 0.42 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). Lithium borohydride tetrahydrofuran solution (2 mol / L, 0.42 mL) was added dropwise at -10°C. After the addition was complete, the reaction was heated to room temperature and stirred for 3 hours. After completion of the reaction, water was added to quench the reaction. The reaction solution was concentrated and the residue was dissolved in dichloromethane and water. After separation, the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed once with brine, dried, filtered, and spin-dried. The crude product was added to a silica gel column and eluted with (3:1 to 1:1 PE / EA). The eluate was collected and concentrated to give the product 67c (100 mg, yield: 67.4%).

[0665] MS m / z(ESI):354.0[M+1] + .

[0666] Step 3

[0667] (S)-7-(2'-Methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carbaldehyde 67d

[0668] 67c (450 mg, 1.27 mmol) was dissolved in dichloromethane (3 mL), and Dess-Martin periodinane (539 mg, 0.14 mmol) was added. The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction, dichloromethane and water were added, and the mixture was extracted twice with dichloromethane. The combined organic phases were evaporated to remove the solvent, washed once with brine, dried, filtered, and dried. The crude product was applied to a silica gel column and eluted with PE / EA (2:1 to 1:1). The eluate was collected and concentrated to afford product 67d (350 mg, yield: 78.2%).

[0669] MS m / z(ESI):352.0[M+1] + .

[0670] Step 4

[0671] (S,RS)-(8-(1-Hydroxyethyl)-1,4-dioxo-7-azaspiro[4.4]nonan-7-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 67e

[0672] 67d (320 mg, 0.91 mmol) was dissolved in tetrahydrofuran (5 mL). 4.5 mL of a 3M solution of methylmagnesium chloride in tetrahydrofuran was added at -78°C, and the mixture was allowed to warm to room temperature and stirred for 20 minutes. After completion of the reaction, the mixture was quenched with 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 afford product 67e (180 mg, 53.8% yield).

[0673] MS m / z(ESI):368.0[M+1] + .

[0674] Step 5

[0675] (S,RS)-5-(1-hydroxyethyl)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-one 67f

[0676] Compound 67e (130 mg, 0.35 mmol) was dissolved in hydrochloric acid (2 mL) and water (20 mL) and reacted at 100°C for 1 hour. 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, and filtered. The crude product was added to a silica gel column and eluted with PE / EA (1:1 to 1:2). The eluate was collected and concentrated to afford the product 67f (75 mg, yield: 65.5%).

[0677] MS m / z(ESI):324.0[M+1] + .

[0678] Step 6

[0679] (S,E,RS)-(2-(1-Hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0680] (S,Z,RS)-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[0681] 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 reaction mixture was allowed to react at 50°C for 18 hours. The methanol was removed by rotary evaporation, and the mixture was extracted three times with dichloromethane and water. The organic phases were combined, washed once with brine, dried, filtered, and dried. The crude products were purified by silica gel Prep-TLC (PE:EA=1:3) to obtain the crude products C0067 (Rf=0.7) and C0068 (Rf=0.5). The products were then purified by HPLC and lyophilized to obtain the crude products C0067 (3.94 mg, yield: 3.6%) and C0068 (8.96 mg, yield: 8.2%).

[0682] C0067:MS m / z(ESI): 353.1[M+1] + .

[0683] 1 H NMR (400MHz, CD3OD) δ7.64-7.62(m,2H),7.43(d,J=8.0Hz,2H),7.28-7.19(m,4H),4.64-4.41(m,2H),4.2 5-4.05(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).

[0684] C0068:MS m / z(ESI): 353.1[M+1] + .

[0685] Examples A0167 & A0213

[0686] 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile

[0687] 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile

[0688] first step

[0689] 4-Bromo-7-chloro-1-methyl-1H-indazole 167b

[0690] 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 reaction continued for 40 minutes. Iodomethane (2.94 g, 20.74 mmol) was then added and the temperature was raised to 20°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL × 2), dried, and purified on a silica gel column (PE:EA = 76:24) to afford product 167b (1.67 g, 39.4% yield).

[0691] MS m / z(ESI):244.9[M+1] + .

[0692] Step 2

[0693] 7-Chloro-1-methyl-1H-indazole-4-carboxylic acid methyl ester 167c

[0694] 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 under a CO atmosphere for 5 hours. The reaction solution was directly concentrated and passed through a silica gel column (PE:EA = 3:1) to afford 167c (0.73 g, 56.9% yield).

[0695] MS m / z(ESI):224.9[M+1] + .

[0696] Step 3

[0697] 7-(3-cyano-2-methylphenyl)-1-methyl-1H-indazole-4-carboxylic acid methyl ester 167e

[0698] 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 argon for 16 hours. The reaction mixture was concentrated and purified on a silica gel column (PE:EA = 3:1) to afford 167e (0.30 g, 95.9% yield).

[0699] MS m / z(ESI):306.0[M+1] + .

[0700] Step 4

[0701] 7-(3-Cyano-2-methylphenyl)-1-methyl-1H-indazole-4-carboxylic acid 167f

[0702] 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 to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was dried and concentrated to afford 167f (0.07 g, yield: 73.4%).

[0703] MS m / z(ESI):292.1[M+1] + .

[0704] Step 5

[0705] 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile

[0706] 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-1-methyl-1H-indazol-7-yl)-2-methylbenzonitrile

[0707] 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, and the reaction was continued for 16 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with brine and 1N hydrochloric acid, and 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 crude less polar isomer A0213 (Rf = 0.4) and crude more polar isomer A0167 (Rf = 0.35). The products were then prepared, purified and freeze-dried by HPLC to obtain the highly polar product A0167 (2.14 mg, yield: 2.05%) and the less polar product A0213 (2.03 mg, yield: 1.97%).

[0708] A0167:MS m / z(ESI):418.3[M+1] + .

[0709] 1 H NMR(400MHz,Chloroform-d)δ8.11(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),4.9 7(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).

[0710] A0213:MS m / z(ESI):418.3[M+1] + .

[0711] 1H NMR(400MHz,Chloroform-d)δ8.12(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).

[0712] Examples A0173 & A0181

[0713] 2-(3-cyano-2-methylphenyl)-5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[0714] 2-(3-cyano-2-methylphenyl)-5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[0715] first step

[0716] 3-Cyano-4-(3-cyano-2-methylphenyl)benzoic acid 173c

[0717] 173a (0.25 g, 1.11 mmol), 173b (0.27 g, 1.11 mmol), Pd(dppf)Cl2 (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. The reaction mixture was filtered, concentrated, dissolved in ethyl acetate (20 mL), washed with 1N hydrochloric acid, and dried and concentrated to afford the product 173c (350 mg, crude).

[0718] MS m / z(ESI):263.0[M+1] + .

[0719] Step 2

[0720] 2-(3-cyano-2-methylphenyl)-5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[0721] 2-(3-cyano-2-methylphenyl)-5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[0722] 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, and the reaction was continued for 16 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with brine and 1N hydrochloric acid, and 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 crude less polar isomer A0181 (Rf = 0.4) and crude more polar isomer A0173 (Rf = 0.35). The products were then prepared, purified and freeze-dried by HPLC to obtain the highly polar product A0173 (36.03 mg, yield: 11.6%) and the less polar product A0181 (25.85 mg, yield: 7.25%).

[0723] A0173: MS m / z(ESI): 389.1[M+1] + .

[0724] 1 H NMR(400MHz,Chloroform-d)δ7.98(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).

[0725] A0181: MS m / z(ESI): 389.1[M+1] + .

[0726] 1H NMR(400MHz,Chloroform-d)δ7.96(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).

[0727] Examples A0183 & A0184

[0728] 3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-(3-hydroxyoxetan-3-yl)phenyl)-2-methylbenzonitrile

[0729] 3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-(3-hydroxyoxetan-3-yl)phenyl)-2-methylbenzonitrile

[0730] first step

[0731] Methyl 4-chloro-3-(3-hydroxyoxetan-3-yl)benzoate 183b

[0732] 183a (2 g, 6.75 mmol) and oxetane-3-one (1.46 g, 20.25 mmol) were dissolved in THF (10 mL). n-Butyl lithium (0.56 g, 8.78 mmol) was added dropwise at -60 to -70°C. The reaction was allowed to react for 30-60 minutes after the addition was complete. The reaction was quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL × 3), dried, concentrated, and purified on a silica gel column to afford 183b (0.55 g, yield: 33.6%). MS m / z (ESI): 225.0 [M-17+1] + In steps 2 through 4 of the above synthetic route, following the synthesis method for compound A0167, crude products of the less polar isomer A0184 (Rf = 0.4) and the more polar isomer A0183 (Rf = 0.35) were obtained. These products were then purified by HPLC and lyophilized to afford the more polar product A0183 (15.58 mg, 15.6% yield) and the less polar product A0184 (18.67 mg, 18.0% yield).

[0733] A0183:MS m / z(ESI):436.0[M+1] + .

[0734] 1 H NMR(400MHz,Chloroform-d)δ7.67(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).

[0735] A0184:MS m / z(ESI):436.0[M+1] + .

[0736] 1 H NMR(400MHz,Chloroform-d)δ7.66(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).

[0737] Example C0050 & C0051

[0738] (S,E)-(4-(2,3-dihydro-1H-inden-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0739] (S,Z)-(4-(2,3-dihydro-1H-inden-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0740] Following the above synthetic route and referring to the synthetic method of compound C0055, the less polar isomer C0050 (Rf=0.6) and the crude more polar isomer C0051 (Rf=0.4) were obtained. 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 after purification by HPLC and lyophilization, respectively.

[0741] C0050: MS m / z(ESI): 365.1[M+1] + .

[0742] 1 H NMR(400MHz,CD3OD-d4)δ7.62-7.53(m,4H),7.25-7.16(m,3H),4.83-3.68(m,7 H),3.31-3.30(m,1H),2.99-2.86(m,4H),2.88-2.86(m,2H),2.08-2.01(m,2H).

[0743] C0051: MS m / z(ESI): 365.1[M+1] + .

[0744] 1 H NMR (400MHz, CD3OD-d4) δ7.62-7.55(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).

[0745] Examples C0074 & C0075

[0746] (S,E)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dimethyl-[1,1'-biphenyl]-4-carbonitrile

[0747] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dimethyl-[1,1'-biphenyl]-4-carbonitrile

[0748] first step

[0749] 4-Bromo-2,3-dimethylbenzonitrile 74b

[0750] 74a (2 g, 6.43 mmol) was dissolved in ethylene glycol (30 mL). Potassium ferrocyanide (2.12 g, 6.43 mmol), sodium hydroxide (0.51 g, 12.86 mmol), and cuprous iodide (0.12 g, 0.64 mmol) were added and stirred at 140°C for 18 hours. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and spin-dried. The crude product was purified by column chromatography (PE / EA = 10:1) to afford 74b (0.9 g, yield: 66.6%).

[0751] MS m / z(ESI):210.0[M+1] + .

[0752] From the second to third steps of the above synthetic route, referring to the synthesis method of compound C0065, crude products C0074 (Rf = 0.4) and C0075 (Rf = 0.3) were obtained. These products were then purified by HPLC and lyophilized to obtain the less polar product C0074 (11 mg, yield: 7.3%) and the more polar product C0075 (40 mg, yield: 26.7%).

[0753] C0074: MS m / z(ESI): 378.1[M+1] + .

[0754] 1 H NMR (400MHz, CD3OD-d4) δ7.65(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).

[0755] C0075:ESI-MS:m / z=378.1[M+1] + .

[0756] 1 H NMR (400MHz, CD3OD-d4) δ7.64(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).

[0757] Examples C0082 & C0083

[0758] (S,E)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0759] (S,Z)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0760] first step

[0761] 7-Bromo-2,3-dihydro-1H-inden-4-ol 83b

[0762] 83a (1.0 g, 7.45 mmol) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere. Br2 (1.43 g, 8.94 mmol) was added dropwise under 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. The organic phase was collected and washed twice with saturated sodium bicarbonate solution. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 10:1 to 5:1) to obtain 83b (1.1 g, yield: 63.7%).

[0763] MS m / z(ESI):212.8[M+1] + .

[0764] Step 2

[0765] 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-inden-4-ol 83d

[0766] To a solution of 83b (1.0 g, 4.41 mmol) in dioxane / water (20 / 4 mL) was added 83c (860 mg, 5.73 mmol) and potassium carbonate (1.52 g, 11.03 mmol). Under nitrogen, 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (323 mg, 0.44 mmol) was added at room temperature. After nitrogen replacement, the mixture was reacted at 80°C for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated, and the crude product was isolated by column chromatography (PE:EA = 6:1 to 4:1) to afford 83d (1.2 g, crude product).

[0767] MS m / z(ESI):239.0[M+1] + .

[0768] Step 3

[0769] 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate 83e

[0770] 83d (1.2 g, 4.73 mmol) was dissolved in dichloromethane (30 mL). 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 allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was isolated by column chromatography (PE:EA = 1:0 to 5:1) to afford 83e (1.1 g, yield: 60.8%).

[0771] MS m / z(ESI):271.0[M+1] + .

[0772] Step 4

[0773] 7-(2,3-Dimethylphenyl)-2,3-dihydro-1H-indene-4-carboxylic acid 83f

[0774] 83e (700 mg, 1.85 mmol) was dissolved in acetonitrile / water (14 / 2 mL). 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. Carbon monoxide was replaced three times, and the pressure was increased to 3 MPa. The mixture was reacted at 80°C for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was separated on a C18 reverse-phase silica gel column to afford 83f (230 mg, 45.7% yield).

[0775] MS m / z(ESI):267.0[M+1] + .

[0776] Step 5

[0777] (S,Z)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0778] (S,E)-(7-(2,3-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0779] To a solution of 83f (110 mg, 0.41 mmol) in DMF were added 4 (80.0 mg, 0.55 mmol), HATU (170 mg, 0.45 mmol), and N,N-diisopropylethylamine (160 mg, 1.42 mmol), and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spin-dried to obtain the crude product. Silica gel Prep-TLC (PE:EA = 1:2) of the crude product yielded the crude less polar product C0082 (Rf = 0.4) and the more polar product C0083 (Rf = 0.3). The products were then purified by HPLC and lyophilized to afford the less polar product C0082 (10.55 mg, yield: 6.5%) and the more polar product C0083 (14.05 mg, yield: 8.6%).

[0780] C0082: MS m / z(ESI): 393.2[M+1] + .

[0781] 1 H NMR(400MHz,CD3OD-d4)δ7.25(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).

[0782] C0083: MS m / z(ESI): 393.2[M+1] + .

[0783] 1 H NMR (400MHz, CD3OD-d4) δ7.25(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).

[0784] Examples C0084 & C0085

[0785] (S,E)-(5-(2,3-Dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0786] (S,Z)-(5-(2,3-Dimethylphenyl)-6-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0787] first step

[0788] 6-Chloro-3-(2,3-dimethylphenyl)-2-(trifluoromethyl)pyridine 85b

[0789] To a solution of 85a (500 mg, 1.92 mmol) in 1,4-dioxane (20 mL) and water (2 mL) were added 1A (720 mg, 4.80 mmol), potassium carbonate (663 mg, 4.80 mmol), and Pd(dppf)Cl2 (78.40 mg, 0.096 mmol). After nitrogen replacement, the mixture was reacted at 80°C for 3 hours. After completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified on a C18 reverse phase column (acetonitrile:water = 5:95 to 70:30 gradient) to afford product 85b (300 mg, yield: 51.9%).

[0790] MS m / z(ESI):285.9[M+1] + .

[0791] Step 2

[0792] Methyl 5-(2,3-dimethylphenyl)-6-(trifluoromethyl)picolinate 85c

[0793] To a solution of 85b (200 mg, 1.92 mmol) in methanol (15 mL) were added 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). The reaction mixture was purged with a carbon monoxide balloon and allowed to react at 70°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove the methanol. The residue was added with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were 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 afford product 85c (150 mg, yield: 69.3%).

[0794] MS m / z(ESI):309.9[M+1] + .

[0795] From the third to fourth steps of the above synthetic route, referring to the synthesis method of compound C0061, crude less polar isomers C0084 (Rf=0.6) and crude more polar isomers C0084 (Rf=0.55) were obtained. These were then purified by HPLC and lyophilized to afford the less polar product C0084 (38.0 mg, yield: 12.7%) and the more polar product C0085 (26.0 mg, yield: 18.6%).

[0796] C0084: MS m / z(ESI): 422.1[M+1] + .

[0797] 1 H NMR(DMSO-d6,400MHz)δ8.18-8.09(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).

[0798] C0085: MS m / z(ESI): 422.1[M+1] + .

[0799] 1 H NMR(DMSO-d6,400MHz)δ8.16-8.11(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).

[0800] Examples A0203 & A0217

[0801] 2-Chloro-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0802] 2-Chloro-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0803] first step

[0804] 4-(2-Chloro-3-cyanophenyl)benzoic acid 203c

[0805] 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 solution was diluted with 10 mL of ethyl acetate, filtered, concentrated, and redissolved in 10 mL of ethyl acetate. The solution was washed with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated to afford 203c (150 mg, 42.0% yield).

[0806] MS m / z(ESI):257.9[M+1] + .

[0807] Step 2

[0808] 2-Chloro-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0809] 2-Chloro-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0810] 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, and the reaction was continued for 16 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with brine and 1N hydrochloric acid, and 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 afford crude less polar isomers A0217 (Rf = 0.4) and crude more polar isomers A0203 (Rf = 0.35). These products were then purified by HPLC and lyophilized to afford the more polar product A0203 (5.44 mg, yield: 3.32%) and the less polar product A0217 (3.64 mg, yield: 1.99%).

[0811] A0203: MS m / z(ESI): 384.1[M+1] + .

[0812] 1 H NMR(400MHz,Chloroform-d)δ7.72(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).

[0813] A0217: MS m / z(ESI): 384.1[M+1] + .

[0814] 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=6.0Hz,1H),7.65-7.55(m,3H),7.52-7.4 3(m,3H),4.91(brs,1H),4.55-4.17(m,2H),3.98-3.75(m,5H),3.24-2.89(m,3H).

[0815] Examples A0204 & A0218

[0816] 2-(Difluoromethyl)-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0817] 2-(Difluoromethyl)-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0818] first step

[0819] To a solution of 4 (2.00 g, 13.88 mmol) in dichloromethane (20 mL) at 0°C were added 4-formylchlorophenylboronic acid (2.21 g, 12.00 mmol) and triethylamine (3.51 g, 34.7 mmol). The mixture was reacted at room temperature for 1 hour. After the reaction, the mixture was filtered and the filtrate was washed with water (20 mL). 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 by normal silica gel column chromatography (PE:EA = 1:3) to obtain product 204c (2.81 g, yield: 80%).

[0820] Step 2

[0821] 3-Bromo-2-(difluoromethyl)benzonitrile 204b

[0822] 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 reaction was continued 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 afford 204b (130 mg, crude product).

[0823] MS m / z(ESI):231.8[M+1] + .

[0824] Step 3

[0825] 2-(Difluoromethyl)-3-(4-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0826] 2-(Difluoromethyl)-3-(4-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]phenyl)benzonitrile

[0827] 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 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with brine and 1N hydrochloric acid, and 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 crude less polar isomer A0218 (Rf = 0.4) and crude more polar isomer A0204 (Rf = 0.35). The products were then purified by HPLC and freeze-dried to obtain the highly polar product A0204 (28.55 mg, yield: 24.8%) and the less polar product A0218 (23.95 mg, yield: 21.0%).

[0828] A0204: MS m / z(ESI): 400.3[M+1] + .

[0829] 1 H NMR(400MHz,Chloroform-d)δ7.92-7.84(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).

[0830] A0218: MS m / z(ESI): 400.3[M+1] + .

[0831] 1 H NMR(400MHz,Chloroform-d)δ7.87(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).

[0832] Examples A0212 & A0221

[0833] 3-(5-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]thiophen-2-yl)-2-methylbenzonitrile

[0834] 3-(5-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]thiophen-2-yl)-2-methylbenzonitrile

[0835] Following the above synthetic route and referring to the synthesis method of compound A0167, crude products of the less polar isomer A0221 (Rf = 0.6) and the more polar isomer A0212 (Rf = 0.55) were obtained. These products were then purified by HPLC and lyophilized to afford the more polar product A0212 (9.55 mg, yield: 6.16%) and the less polar product A0221 (9.00 mg, yield: 5.61%).

[0836] A0212: MS m / z(ESI): 370.0[M+1] + .

[0837] 1 H NMR(400MHz,Chloroform-d)δ7.66(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).

[0838] A0221: MS m / z(ESI): 370.0[M+1] + .

[0839] 1 H NMR(400MHz,Chloroform-d)δ7.66(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).

[0840] Examples C0070 & C0071

[0841] (S,E)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0842] (S,Z)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0843] Following the above synthetic route and referring to the synthesis method of compound C0084, crude less polar isomer C0070 (Rf=0.6) and crude more polar isomer C0071 (Rf=0.55) were obtained. These products were then purified by HPLC and lyophilized to afford the less polar product C0070 (30.0 mg, yield: 21.4%) and the more polar product C0071 (19.0 mg, yield: 13.6%).

[0844] C0070: MS m / z(ESI): 422.0[M+1] + .

[0845] 1 H NMR (400MHz, DMSO-d6) δ8.63-8.59(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).

[0846] C0071: MS m / z(ESI): 422.1[M+1] + .

[0847] 1H NMR(DMSO-d6,400MHz)δ8.65-8.59(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).

[0848] Examples C0076 & C0077

[0849] (S,E)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyrimidin-4(3H)-one

[0850] (S,Z)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyrimidin-4(3H)-one

[0851] first step

[0852] Ethyl 1-(2,3-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate 76b

[0853] 76a (500 mg, 2.97 mmol) was dissolved in dichloromethane (30 mL). 1A (535 mg, 3.56 mmol), copper 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. After nitrogen substitution, the mixture was reacted at room temperature for 17 hours. After completion of the reaction, the insoluble solid was removed by filtration, the filtrate was evaporated to remove the solvent, water (20 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by C18 reverse column chromatography (acetonitrile:water = 5:95 to 70:30 gradient elution) to give product 76b (60 mg, yield: 7.4%).

[0854] MS m / z(ESI):273.0[M+1] + .

[0855] From the second to third steps of the above synthetic route, 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. These were then purified by HPLC and lyophilized to give the less polar product C0076 (1.9 mg, yield: 2.5%) and the more polar product C0077 (4.9 mg, yield: 6.5%).

[0856] C0076: MS m / z(ESI): 371.1[M+1] + .

[0857] 1 H NMR (400MHz, CD3OD-d4) δ8.38(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).

[0858] C0077: MS m / z(ESI): 371.1[M+1] + .

[0859] 1 H NMR (400MHz, CD3OD-d4) δ8.38(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).

[0860] Examples C0078 & C0079

[0861] (S,E)-(3'-(Difluoromethyl)-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0862] (S,Z)-(3'-(Difluoromethyl)-2'-methyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0863] first step

[0864] 1-Bromo-3-(difluoromethyl)-2-methylbenzene 78b

[0865] 78a (1 g, 5.02 mmol) was dissolved in dichloromethane (20 mL) under nitrogen. Diethylaminosulfur trifluoride (0.95 g, 5.89 mmol) was added dropwise to the reaction mixture at 0°C and allowed to react at room temperature for 16 hours. After the reaction, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The solvent was then dried to dryness to afford product 78b (500 mg, yield: 44.1%).

[0866] From the second to third steps of the above synthetic route, 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. These were then purified by HPLC and lyophilized to give the less polar product C0078 (29.0 mg, yield: 14.5%) and the more polar product C0079 (57.6 mg, yield: 28.8%).

[0867] C0078: MS m / z(ESI): 389.1[M+1] + .

[0868] 1 H NMR (400MHz, CD3OD-d4) δ7.65-7.55(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).

[0869] C0079: MS m / z(ESI): 389.1[M+1] + .

[0870] 1 H NMR (400MHz, CD3OD-d4) δ7.65-7.55(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).

[0871] Examples C0086 & C0087

[0872] (S,E)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0873] (S,Z)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0874] first step

[0875] 2-Chloro-5-(2,3-dimethylphenyl)-4-(trifluoromethyl)pyrimidine 87c

[0876] To a solution of 87a (500 mg, 1.91 mmol) in 1,4-dioxane (10 mL) were added (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). After nitrogen replacement, the mixture was reacted at 80°C for 2 hours. After completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified on a silica gel normal phase column (petroleum ether:ethyl acetate = 5:1 to 3:1 gradient elution) to afford product 87c (320 mg, yield: 57.2%).

[0877] MS m / z(ESI):286.9[M+1] + .

[0878] Step 2

[0879] 5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyrimidine-2-carboxylic acid 87d

[0880] 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. Carbon monoxide was replaced three times, and the pressure was increased to 4 MPa. The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product was isolated on a C18 reverse-phase silica gel column (acetonitrile:water = 30:70 to 75:25 gradient elution) to afford 87d (170 mg, yield: 63.3%).

[0881] MS m / z(ESI):296.9[M+1] + .

[0882] Step 3

[0883] (S,Z)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0884] (S,E)-(5-(2,3-Dimethylphenyl)-4-(trifluoromethyl)pyrimidin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0885] To a solution of 87d (170 mg, 0.52 mmol) in DMF (5 mL) were 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 for 2 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. The residue was purified by silica gel Pre-TLC (PE:EA = 2:5) to afford crude less polar isomer C0086 (Rf = 0.6) and crude more polar isomer C0087 (Rf = 0.55). The products were purified by HPLC and freeze-dried to obtain a small polar product C0086 (16.89 mg, yield: 7.73%) and a large polar product C0087 (20.29 mg, yield: 9.29%).

[0886] C0086: MS m / z(ESI): 423.1[M+1] + .

[0887] 1 H NMR (400MHz, CD3OD-d4) δ8.98-8.95(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).

[0888] C0087: MS m / z(ESI): 423.1[M+1] + .

[0889] 1H NMR (400MHz, CD3OD-d4) δ8.97(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).

[0890] Example C0090 & C0091

[0891] (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0892] (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0893] first step

[0894] (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0895] (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0896] 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). Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added under nitrogen at room temperature and allowed to react at 80°C for 3 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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 afford 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 large polar isomer was purified by HPLC and lyophilized to obtain C0091 (23.68 mg, yield: 12.8%).

[0897] C0090: MS m / z(ESI): 365.1[M+1] + .

[0898] 1 H NMR(400MHz,CD3OD-d4)δ8.58(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).

[0899] C0091: MS m / z(ESI): 365.1[M+1] + .

[0900] 1 H NMR(400MHz,CD3OD-d4)δ8.58(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).

[0901] Examples C0092 & C0093

[0902] (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0903] (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0904] first step

[0905] (S,Z)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0906] (S,E)-4-(4-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)phenyl)-3-methylpicolinonitrile

[0907] 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). Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added under nitrogen at room temperature and allowed to react at 80°C for 3 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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 afford 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 large polar isomer was purified by HPLC and lyophilized to obtain C0093 (36.68 mg, yield: 19.6%).

[0908] C0092: MS m / z(ESI): 364.1[M+1] + .

[0909] 1 H NMR (400MHz, CD3OD-d4) δ7.68-7.61(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).

[0910] C0093: MS m / z(ESI): 364.1[M+1]+.

[0911] 1 H NMR(400MHz,CD3OD-d4)δ7.6-7.61(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).

[0912] Examples C0094 & C0095

[0913] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile

[0914] (S,Z)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile

[0915] first step

[0916] (S,Z)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile

[0917] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-6-methyl-[1,1'-biphenyl]-3-carbonitrile

[0918] 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). Pd(dppf)Cl2 (38 mg, 0.052 mmol) was added under nitrogen at room temperature and allowed to react at 80°C for 3 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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 afford 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 large polar isomer was purified by HPLC and lyophilized to obtain C0095 (46.49 mg, yield: 26.82%).

[0919] C0094: MS m / z(ESI): 364.1[M+1] + .

[0920] 1 H NMR (400MHz, CD3OD-d4) δ7.67-7.59(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).

[0921] C0095: MS m / z(ESI): 364.1[M+1] + .

[0922] 1H NMR(400MHz,CD3OD-d4)δ7.63-7.60(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).

[0923] Examples C0096 & C0097

[0924] (S,E)-(5-(2,3-Dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0925] (S,Z)-(5-(2,3-Dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0926] first step

[0927] (S,EZ)-(5-Bromothiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone 97b

[0928] To a solution of 97a (450 mg, 2.16 mmol) in DMF (9 mL) were added 4 (373.69 mg, 2.59 mmol), HATU (0.99 g, 2.59 mmol), and TEA (0.66 g, 6.48 mmol). After nitrogen replacement, the mixture was reacted at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate / water, and the organic layers were combined and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by reverse phase column chromatography (HO:ACN = 95:5 to 50:50) to obtain product 97b (450 mg, yield: 56.0%).

[0929] MS m / z(ESI): 333.8,335.8[M+1] + .

[0930] Step 2

[0931] (S,E)-(5-(2,3-Dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0932] (S,Z)-(5-(2,3-Dimethylphenyl)thiazol-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0933] To a solution of 97b (200 mg, 0.60 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added (2,3-dimethylphenyl)boronic acid (0.11 g, 0.72 mmol), potassium carbonate (0.25 g, 1.80 mmol), and Pd(dppf)Cl2 (0.049 g, 0.060 mmol). After nitrogen replacement, the reaction mixture was reacted at 95°C for 1 hour. The reaction mixture was extracted with ethyl acetate / water, and the organic layers were combined and washed with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 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%).

[0934] C0096: MS m / z(ESI): 360.1[M+1] + .

[0935] 1 H NMR(400MHz,CD3OD-d4)δ7.85(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).

[0936] C0097: MS m / z(ESI): 360.1[M+1] + .

[0937] 1 H NMR (400MHz, CD3OD-d4) δ7.85 (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).

[0938] Examples C0098 & C0099

[0939] 3-(7-[(2S,4E)-2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile

[0940] 3-(7-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile

[0941] first step

[0942] 7-(3-cyano-2-methylphenyl)benzo[d][1,3]dioxolane-4-carboxylic acid methyl ester 99b

[0943] To a solution of 99a (200 mg, 0.77 mmol) in dioxane (5 mL) and water (0.5 mL) were added (3-cyano-2-methylphenyl)boronic acid (140 mg, 0.87 mmol), potassium carbonate (210 mg, 1.52 mmol), and Pd(dppf)Cl2 (63 mg, 0.077 mmol). After nitrogen substitution, the mixture was reacted at 90°C for 3 hours. The reaction solution was filtered, dried, and purified by silica gel Prep-TLC (PE:EA = 5:1) to afford product 99b (150 mg, 65.8% yield).

[0944] MS m / z(ESI):296.1[M+1] + .

[0945] Step 2

[0946] 7-(3-Cyano-2-methylphenyl)benzo[d][1,3]dioxolane-4-carboxylic acid 99c

[0947] 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 at room temperature overnight. The reaction mixture was filtered through a Buchner funnel, and the filtrate was free of methanol and extracted with EA. The aqueous phase was collected, the pH of the aqueous phase was adjusted to 1-3 with hydrochloric acid, and then extracted with EA. The organic layers were combined and washed with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to afford product 99c (100 mg, yield: 65.6%).

[0948] Step 3

[0949] 3-(7-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile

[0950] 3-(7-[(2S,4E)-2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2H-1,3-benzodioxolan-4-yl)-2-methylbenzonitrile

[0951] To a solution of 4 (74 mg, 0.52 mmol) in DMF (3 mL) were added 99c (120 mg, 0.69 mmol), triethylamine (270 mg, 2.07 mmol), and HATU (390 mg, 0.43 mmol). After nitrogen purging, the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spin-dried to yield the crude product. The crude product was separated by silica gel Pre-TLC (EA:PE = 5:1) to yield the less polar isomer C0098 (Rf = 0.6) and the more polar isomer C0099 (Rf = 0.5). The crude more polar isomer was purified by HPLC and lyophilized to yield the more polar product C0099 (14.0 mg, yield: 7.97%).

[0952] C0098: MS m / z(ESI): 408.1[M+1] + .

[0953] 1 H NMR (400MHz, CD3OD-d4) δ7.72(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).

[0954] C0099: MS m / z(ESI): 408.1[M+1] + .

[0955] 1 H NMR (400MHz, CD3OD-d4) δ7.72(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,1 H),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).

[0956] Examples C0102 & C0103

[0957] (S,E)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one

[0958] (S,Z)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one

[0959] first step

[0960] 5-Bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid 102b

[0961] 102a (50 mg, 0.23 mmol) was dissolved in a mixture of water (7 mL) and methanol (1 mL). Methyl iodide (326 mg, 2.30 mmol) and potassium hydroxide (43 mg, 0.76 mmol) were added and microwave-treated at 110°C for 4 hours. After completion of the reaction, the reaction solution was concentrated to remove the methanol and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The solvent was then dried to give product 102b (33 mg, yield: 62.0%).

[0962] Step 2

[0963] 5-(2,3-Dimethylphenyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid 102c

[0964] To a mixture of 102b (700 mg, 3.02 mmol) in 1,4-dioxane (30 mL) and water (3 mL) were added (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). After nitrogen substitution, the mixture was reacted at 105°C for 16 hours. After completion of the reaction, water (20 mL) was added, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to afford product 102c (720 mg, 92.8% yield).

[0965] MS m / z(ESI):258.0[M+1] + .

[0966] Step 3

[0967] (S,E)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one

[0968] (S,Z)-3-(2,3-Dimethylphenyl)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-1-methylpyridin-2(1H)-one

[0969] To a solution of 102c (700 mg, 2.72 mmol) in DMF were added 4 (392 mg, 2.72 mmol), HATU (1551 mg, 4.08 mmol), and N,N-diisopropylethylamine (879 mg, 6.80 mmol). The reaction mixture was allowed to react 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 x 3). The combined organic phases were 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 afford the crude less polar isomer C0102 (Rf = 0.5) and the crude more polar isomer C0103 (Rf = 0.4). The products were purified by HPLC and freeze-dried to obtain a small polar product C0102 (30.0 mg, yield: 2.8%) and a large polar product C0103 (50.0 mg, yield: 4.7%).

[0970] C0102: MS m / z(ESI): 384.1[M+1] + .

[0971] 1 H NMR(400MHz,CD3OD-d4)δ7.44-7.40(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).

[0972] C0103: MS m / z(ESI): 384.1[M+1] + .

[0973] 1H NMR (400MHz, CD3OD-d4) δ7.44-7.40(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).

[0974] Examples C0108 & C0109

[0975] (S,E)-(6-(2,3-Dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0976] (S,Z)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0977] first step

[0978] 6-(2,3-Dimethylphenyl)-1,2,4-triazin-3-amine 109b

[0979] 109a (3.7 g, 21.14 mmol), (2,3-dimethylphenyl)boronic acid (4.12 g, 27.48 mmol), Pd(dtbpf)Cl2 (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 atmosphere was replaced with nitrogen three times and stirred at 25°C under nitrogen for 17 hours. 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 afford 109b (4.0 g, 94.5% yield) as a yellow solid.

[0980] MS m / z(ESI):201.0[M+1] + .

[0981] Step 2

[0982] 3-Bromo-6-(2,3-dimethylphenyl)-1,2,4-triazine 109c

[0983] 109b (4.0 g, 19.98 mmol) and copper bromide (8.9 g, 40 mmol) were added to acetonitrile (500 mL). tert-Butyl nitrite (3.09 g, 29.97 mmol) was slowly added dropwise. The mixture was heated to 30°C and stirred for 1 hour. The mixture was filtered, concentrated, and the concentrate was subjected to flash column chromatography (PE:EA = 1:1) to afford 109c (2.05 g, 38.8% yield) as a yellow oil.

[0984] MS m / z(ESI): 263.8,265.8[M+1] + .

[0985] 1 H NMR (400MHz, DMSO-d6) δ8.92 (s, 1H), 7.39-7.34 (m, 2H), 7.30 (d, J = 7.2Hz, 1H), 2.34 (s, 3H), 2.21 (s, 3H).

[0986] Step 3

[0987] 6-(2,3-Dimethylphenyl)-1,2,4-triazine-3-carboxylic acid 109d

[0988] 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 mixture 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 hours. The residue was concentrated and purified by C18 reverse-phase column chromatography (acetonitrile:water = 10:90) to afford 109d (980 mg, 56.4% yield) as a yellow solid.

[0989] MS m / z(ESI):228.1[M-1] + .

[0990] Step 4

[0991] (S,Z)-(6-(2,3-dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0992] (S,E)-(6-(2,3-Dimethylphenyl)-1,2,4-triazin-3-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[0993] 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 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel Pre-TLC (PE:EA = 1:3) to afford the crude less polar isomer C0108 (Rf = 0.6) and the crude more polar isomer C0109 (Rf = 0.5). The crude products were then purified by HPLC and lyophilized to afford the less polar product C0108 (46 mg, 5.9% yield) and the more polar product C0109 (43 mg, 5.5% yield).

[0994] C0108: MS m / z(ESI): 356.1[M+1] + .

[0995] 1 H NMR (400MHz, DMSO-d6) δ9.13-9.11(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),3.71-3.5 7(m,1H),3.39-3.27(m,1H),2.88-2.71(m,2H),2.36(s,3H),2.25-2.24(m,3H).

[0996] C0109: MS m / z(ESI): 356.1[M+1] + .

[0997] 1 H NMR(400MHz, DMSO-d6)δ9.13-9.12(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).

[0998] Examples C0014 & C0015

[0999] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone

[1000] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone

[1001] first step

[1002] 5-(o-Tolyl)pyridine-2-carboxylic acid 14c

[1003] 14a (0.74 g, 5.44 mmol) and 14b (1 g, 4.95 mmol) were dissolved in methanol (7 mL) and water (14 mL) under nitrogen. Potassium carbonate (2.26 g, 16.32 mmol) and tetrakistriphenylphosphine palladium (63 mg, 0.054 mmol) were added at room temperature under nitrogen. The reaction was allowed to proceed at 80°C for 16 hours. After the reaction was completed, the methanol was concentrated to remove the methanol. Water (10 mL) was added to the reaction solution, and the pH was adjusted to 3 with 6M hydrochloric acid. The solution was then extracted with toluene / tetrahydrofuran. The organic phase was dried over sodium sulfate, and the solvent was evaporated to afford 14c (0.7 g, yield: 58.5%).

[1004] MS m / z(ESI):214.1[M+1] + .

[1005] Step 2

[1006] 5-(o-Tolyl)pyridine-2-yl chloride 14d

[1007] 14c (0.7 g, 3.28 mmol) was dissolved in thionyl chloride (10 mL) and reacted at 80°C for 2 h. After completion of the reaction, the reaction solution was concentrated to give crude product 14d (0.43 g, yield: 50.8%).

[1008] Step 3

[1009] (S)-4-oxo-1-(5-(o-tolyl)pyridine-2-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 14e

[1010] (S)-Methyl 4-oxopyrrolidine-2-carboxylate (0.3 g, 1.47 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.52 g, 5.14 mmol) and compound 14d (0.43 g, 1.76 mmol) were added at 0°C and allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated to remove dichloromethane, and the residue was purified by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 5:1 to 3:1) to afford compound 14e (230 mg, yield: 46.3%).

[1011] MS m / z(ESI):339.0[M+1] + .

[1012] Step 4

[1013] (S,EZ)-4-(methoxyimino)-1-(5-(o-tolyl)pyridine-2-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 14f

[1014] 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. The mixture was allowed to react 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 (petroleum ether:ethyl acetate = 4:1 to 3:1 gradient elution) to afford 14f (230 mg, yield: 40.1%).

[1015] MS m / z(ESI):368.1[M+1] + .

[1016] Step 5

[1017] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone

[1018] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyridin-2-yl)methanone

[1019] 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. The reaction was allowed to react at room temperature for 2 hours. The reaction was quenched with water, concentrated, and the residue dissolved in dichloromethane and water. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. The crude product was separated by silica gel Prep-TLC (EA:PE = 2:1) to afford 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%).

[1020] C0014: MS m / z(ESI): 340.1[M+1] + .

[1021] 1 H NMR (400MHz, DMSO-d6) δ8.61-8.58(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).

[1022] C0015: MS m / z(ESI): 340.1[M+1] + .

[1023] 1 H NMR(400MHz,DMSO-d6)δ8.64-8.58(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).

[1024] Example C0012 & C0013

[1025] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyrazin-2-yl)methanone

[1026] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(5-(o-tolyl)pyrazin-2-yl)methanone

[1027] Referring to Example C0014 & C0015, 14b was replaced by The crude product was separated by silica gel Prep-TLC (EA:PE=2:1) ​​to obtain the large polar isomer C0013 (Rf=0.4, 98.17 mg, yield: 24.3%) and the small polar isomer C0012 (Rf=0.5, 75.55 mg, yield: 19.0%).

[1028] C0012: MS m / z(ESI): 341.0[M+1] + .

[1029] 1 HNMR(400MHz,DMSO-d6)δ9.07-9.01(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),4.82-4.6 4(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).

[1030] C0013: MS m / z(ESI): 341.0[M+1] + .

[1031] 1 H NMR(400MHz,DMSO-d6)δ9.09-9.02(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).

[1032] Examples C0029 & C0030

[1033] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone

[1034] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone

[1035] first step

[1036] 1-(tert-Butyl)2-methyl(S,EZ)-4-(methoxyimino)pyrrolidine-1,2-dicarboxylate 29b

[1037] To a solution of 29a (5.0 g, 20.55 mmol) in methanol (50 mL) were added methoxyamine hydrochloride (1.16 g, 24.66 mmol) and triethylamine (4.57 g, 45.21 mmol). After nitrogen replacement, the mixture was reacted at 60°C overnight. The crude product, which was directly spin-dried, was purified by silica gel column chromatography (PE:EA = 5:1) to afford 29b (3.2 g, 56.0% yield).

[1038] MS m / z(ESI):173.0[M+1-56] + .

[1039] Step 2

[1040] Methyl (S,EZ)-4-(methoxyimino)pyrrolidine-2-carboxylate 29c

[1041] 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 the reaction, the crude product 29c (2.0 g, yield: 89.0%) was obtained by direct spin drying.

[1042] MS m / z(ESI):217[M+1-56] + .

[1043] From the third to the fourth step of the above synthetic route, referring to the synthetic method of compound C0014, crude 2-(o-tolyl)thiazole-5-carbonyl chloride was obtained.

[1044] Step 5

[1045] (2S,4EZ)-4-(methoxyimino)-1-(2-(2-methylphenyl)-1,3-thiazole-5-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 29g

[1046] To a solution of 29f (400 mg, 1.68 mmol) and 29c (433.89 mg, 2.52 mmol) in DCM (10 mL) was added TEA (0.68 g, 6.72 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the crude product was spin-dried to dryness. The crude product was purified by preparative chromatography (ACN:H2O = 5:95 to 45:55) to afford 29g (400 mg, yield: 62.4%).

[1047] MS m / z(ESI):374.1[M+1] + .

[1048] Step 6

[1049] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone

[1050] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(o-tolyl)thiazol-5-yl)methanone

[1051] To a solution of 29 g (390 mg, 1.04 mmol) in THF (5 mL) and methanol (5 mL) was slowly added LiBH4 (0.023 g, 1.04 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction, water (10 mL) was added to the mixture, and the mixture was 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 obtain the crude product. The residue was purified by silica gel Pre-TLC (PE:EA = 1:3) to obtain the crude less polar isomer C0029 (Rf = 0.5) and the crude more polar isomer C0030 (Rf = 0.4). Chiral separation and purification were then performed to obtain the less polar product C0029 (15.9 mg, yield: 4.41%) and the more polar product C0030 (21.4 mg, yield: 5.87%), respectively.

[1052] C0029: MS m / z(ESI): 346.1[M+1] + .

[1053] 1 H NMR (400MHz, Chloroform-d) δ8.26 (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).

[1054] C0030: MS m / z(ESI): 346.1[M+1] + .

[1055] 1 H NMR (400MHz, Chloroform-d) δ8.29 (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).

[1056] Example C0033

[1057] (EZ)-(3-(Methoxyimino)hexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[1058] first step

[1059] (S)-4-(((Benzyloxy)carbonyl)glycyl)morpholine-3-carboxylic acid 33b

[1060] 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 hours. The reaction mixture was cooled, concentrated, and purified by C18 reverse-phase column chromatography (acetonitrile / water = 50 / 50) to afford 33b (3.06 g, yield: 62.2%) as a white solid.

[1061] MS m / z(ESI):323.1[M+H] + .

[1062] Step 2

[1063] Benzyl 3-oxohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylate 33c

[1064] 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 etherate (1.76 g, 12.42 mmol) was slowly 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 mixture was separated and extracted twice with water (100 mL). 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 afford 33c as a colorless oil (1.2 g, yield: 70.0%).

[1065] MS m / z(ESI):277.1[M+H] + .

[1066] Step 3

[1067] tert-Butyl 3-oxohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylate 33d

[1068] 33c (0.2 g, 0.72 mmol) was dissolved in methanol (10 mL). Di-tert-butyl dicarbonate (0.2 g, 0.94 mmol) and palladium on carbon (10%, 39 mg) were added under nitrogen. The atmosphere was replaced with hydrogen 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 to obtain the crude product 33d (0.1 g, yield: 57.0%).

[1069] MS m / z(ESI):243.1[M+H] + .

[1070] Step 4

[1071] tert-Butyl 3-thiohexahydro-1H-imidazo[2,1-c][1,4]oxazine-1-carboxylate 33e

[1072] 33d (0.8 g, 3.30 mmol) was dissolved in toluene (15 mL), and Lawesson's reagent (1.33 g, 3.30 mmol) was added. The mixture was heated to 50°C and allowed to react for half an hour. After completion of the reaction, solid impurities were removed by filtration, the solvent was evaporated, and the product was purified by reverse phase preparative method to afford 33e (0.6 g, yield: 62.6%).

[1073] MS m / z(ESI):259.0[M+H] + .

[1074] Step 5

[1075] Tetrahydro-1H-imidazo[2,1-c][1,4]oxazine-3(2H)-thione 33f

[1076] 33e (0.68 g, 2.63 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated to obtain 33f (0.4 g, yield: 96.0%).

[1077] MS m / z(ESI):159.0[M+H] + .

[1078] Step 6

[1079] (2'-Methyl-[1,1'-biphenyl]-4-yl)(3-thiohexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)methanone 33g

[1080] 33f (0.7 g, 4.42 mmol) was dissolved in dichloromethane (10 mL), and 2'-methyl-[1,1'-biphenyl]-4-carbonyl chloride (1.02 g, 4.42 mmol) and triethylamine (1.34 g, 13.26 mmol) were added. The reaction 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 afford 33f (1 g, yield: 56.4%).

[1081] MS m / z(ESI):353.1[M+H] + .

[1082] Step 7

[1083] (EZ)-(3-(Methoxyimino)hexahydro-1H-imidazo[2,1-c][1,4]oxazin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[1084] 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 completion of the reaction, ethyl acetate (20mL) was added to the reaction solution, and the mixture was washed with water (10mL x 2) and once with saturated sodium chloride (10mL). After drying over sodium sulfate, the solvent was evaporated and the crude product was purified by HPLC (HCOOH) and lyophilized to obtain C0033 (80mg, yield: 38.6%).

[1085] MS m / z(ESI):366.1[M+H] + .

[1086] 1 H NMR(400MHz,DMSO-d6)δ7.72-7.62(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).

[1087] Examples C0048 & C0049

[1088] (S,E)-(4-(Benzo[d][1,3]dioxolan-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1089] (S,Z)-(4-(Benzo[d][1,3]dioxolan-4-yl)phenyl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1090] Following the above synthetic route and referring to the synthesis method of 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 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%).

[1091] C0048: MS m / z(ESI): 369.1[M+1] + .

[1092] 1 H NMR (400MHz, CD3OD-d4) δ7.87-7.85(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).

[1093] C0049: MS m / z(ESI): 369.1[M+1] + .

[1094] 1H NMR (400MHz, CD3OD-d4) δ7.85(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).

[1095] Examples C0080 & C0081

[1096] (S,E)-(5-(2,3-dimethylphenyl)-3-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1097] (S,Z)-(5-(2,3-dimethylphenyl)-3-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1098] Following the above synthetic 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. The crude products were then purified by HPLC and lyophilized to give the less polar product C0080 (19.2 mg, yield: 4.29%) and the more polar product C0081 (22.69 mg, yield: 5.07%).

[1099] C0080: MS m / z(ESI): 384.1[M+1] + .

[1100] 1 H NMR(400MHz,CD3OD-d4)δ8.11-8.09(m,1H),7.54-7.52(m,1H),7.24-7.10(m,3H),4.80-4.55(m,1H),4.19-4.1 5(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).

[1101] C0081: MS m / z(ESI): 384.1[M+1] + .

[1102] 1H NMR(400MHz,CD3OD-d4)δ8.11-8.09(m,1H),7.54-7.52(m,1H),7.24-7.08(m,3H),4.69-4.50(m,1H),4.26-3.9 9(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).

[1103] Examples C0072 & C0073

[1104] (S,E)-(5-(2,3-Dimethylphenyl)-6-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1105] (S,Z)-(5-(2,3-Dimethylphenyl)-6-methoxypyridin-2-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1106] Refer to the method of C0080 & C0081, replace the first step raw material 81a with The above compound is obtained.

[1107] The crude product was separated by silica gel Prep-TLC (PE:EA=1:5) to obtain the crude less polar product C0072 (Rf=0.4) and the pure more polar product C0073 (Rf=0.3, 20 mg, yield: 18.7%). The crude less polar isomer was further purified by HPLC and lyophilized to obtain the less polar product C0072 (34.9 mg, yield: 9.72%).

[1108] C0072: MS m / z(ESI): 384.1[M+1] + .

[1109] 1 H NMR (400MHz, CD3OD-d4) δ7.64-7.18(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).

[1110] C0073: MS m / z(ESI): 384.1[M+1] + .

[1111] 1 H NMR(400MHz,CD3OD-d4)δ7.64-7.54(m,2H),7.18-7.10(m,2H),6.97-6.95(m,1H),4.83-4.7 6(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).

[1112] Examples C0110 & C0111 & C0112 & C0113

[1113] (S,S,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1114] (S,S,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1115] (S,R,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1116] (S,R,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1117] first step

[1118] Methyl (S)-7-(3'-cyano-2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylate 110b

[1119] Compound 110a (1.8 g, 4.97 mmol, prepared according to the method for 35d in Examples C0035 & C0036) was dissolved in toluene (15 mL). Ethylene glycol (463 mg, 7.46 mmol) and p-toluenesulfonic acid hydrate (331 mg, 1.74 mmol) were added to the reaction mixture, and the mixture was allowed to react at 120°C for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the product 110b (500 mg, yield: 24.8%) was obtained by column chromatography (PE / EA = 6 / 1).

[1120] MS m / z(ESI):406.8[M+1] + .

[1121] Step 2

[1122] (S)-4'-(8-(Hydroxymethyl)-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110c

[1123] 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 was heated to room temperature and stirred for 3 hours. After completion of the reaction, water was added to quench the reaction. The reaction solution was concentrated and the residue was dissolved in dichloromethane and water. After separation, the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with salt, dried, filtered, and dried. The crude product was added to a silica gel column and eluted with (PE / EA = 3:1 to 1:1). The eluate was collected and concentrated to give the product 110c (4 g, yield: 71.6%).

[1124] MS m / z(ESI):378.9[M+1] + .

[1125] Step 3

[1126] (S)-4'-(8-Formyl-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110d

[1127] 110c (4.2 g, 11.10 mmol) was dissolved in dichloromethane (200 mL), and Dess-Martin periodinane (4.71 g, 11.1 mmol) was added to the reaction mixture. The reaction was allowed to react at room temperature for 16 hours. After completion of the reaction, dichloromethane and water were added, and the mixture was extracted twice with dichloromethane. The combined organic phases were evaporated to remove the solvent, washed once with brine, dried, filtered, and dried. The crude product was applied to a silica gel column and eluted with PE / EA (2:1 to 1:1). The eluate was collected and concentrated to afford product 110d (3.5 g, yield: 83.8%).

[1128] MS m / z(ESI):376.9[M+1] + .

[1129] Step 4

[1130] (S)-4'-(8-(1-hydroxyethyl)-1,4-dioxo-7-azaspiro[4.4]nonane-7-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110e

[1131] 110d (3.5 g, 9.30 mmol) was dissolved in tetrahydrofuran (125 mL). 24.7 mL of a 3M solution of methylmagnesium chloride in tetrahydrofuran was added at -78°C, and the mixture was allowed to warm to room temperature and stirred for 20 minutes. After completion of the reaction, the mixture was quenched with 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 afford product 110e (1.5 g, 41.1% yield).

[1132] MS m / z(ESI):392.9[M+1] + .

[1133] Step 5

[1134] (S)-4'-(2-(1-hydroxyethyl)-4-oxopyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile 110f

[1135] 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 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, and filtered. The crude product was applied to a silica gel column and eluted with PE / EA (1:1 to 1:2). The eluate was collected and concentrated to afford the product 110f (28 mg, yield: 63.0%).

[1136] MS m / z(ESI):348.9[M+1] + .

[1137] Step 6

[1138] (S,S,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1139] (S,R,E)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1140] (S,S,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1141] (S,R,Z)-4'-(2-(1-hydroxyethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1142] 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 reaction was carried out at 50 ° C for 18 hours. The reaction solution was evaporated to remove methanol, and the mixture was extracted three times with dichloromethane and water. The organic phases were combined, washed once with brine, dried, filtered and dried. The residue was purified by silica gel Pre-TLC (PE:EA=1:2) to obtain a crude less polar isomer (Rf=0.6) and a crude more polar isomer (Rf=0.5). Then, the first peak of the polar small product C0110 (30 mg, yield: 6.9%, elution time: 5.85 min) and the second peak of the polar small product C0111 (52 mg, yield: 12.0%, elution time: 7.98 min) were obtained by chiral separation. The chiral analysis method is as follows: Instrument: High-throughput semi-preparative chromatography GX-281; ​​Chromatographic column: Daicel 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;

[1143] The first peak of the highly polar product C0112 (72 mg, yield: 12.6%, elution time: 6.59 min), the second peak of the highly polar product C0113 (47 mg, yield: 10.9%, elution time: 8.42 min), the chiral analysis method is as follows: Instrument: High-throughput semi-preparative chromatography GX-281; ​​Chromatographic column: Daicel 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.

[1144] C0110:MS m / z(ESI): 378.1[M+1] + .

[1145] 1 H NMR (400MHz, CD3OD) δ7.72-7.67(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).

[1146] C0111:MS m / z(ESI): 378.1[M+1] + .

[1147] 1H NMR(400MHz,CD3OD)δ7.72-7.66(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).

[1148] C0112:MS m / z(ESI): 378.1[M+1] + .

[1149] 1 H NMR (400MHz, CD3OD) δ7.72-7.66(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).

[1150] C0113:MS m / z(ESI):378.1[M+1] + .

[1151] 1 H NMR(400MHz,CD3OD)δ7.72-7.67(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).

[1152] Example A0086

[1153] (S,EZ)-(2-(Benzo[d]oxazol-2-yl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[1154] first step

[1155] (2S,4R)-Benzyl 4-hydroxy-2-((2-hydroxyphenyl)carbamoyl)pyrrolidine-1-carboxylate 86c

[1156] 86a (9 g, 33.93 mmol) and ethyldiisopropylamine (17.54 g, 135.72 mmol) were dissolved in 100 mL of DMF, followed by the addition of HATU (16.77 g, 44.11 mmol). After a 5-minute 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 then added, and the mixture was extracted with ethyl acetate (100 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 afford the crude product 86c (5 g, yield: 41.3%).

[1157] MS m / z(ESI):357.2[M+1] + .

[1158] Step 2

[1159] Benzyl (2S,4R)-2-(benzo[d]oxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate 86d

[1160] 86c (5.3 g, 14.87 mmol) was dissolved in 50 mL of toluene, followed by the addition of toluene-4-sulfonic acid (0.51 g, 2.97 mmol). The reaction was refluxed at 110°C for 16 hours. 100 mL of water was then added, and the mixture was extracted with ethyl acetate (100 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 afford product 86d (184 mg, yield: 3.66%).

[1161] MS m / z(ESI):339.2[M+1] + .

[1162] Step 3

[1163] (3R,5S)-5-(Benzo[d]oxazol-2-yl)pyrrolidin-3-ol 86e

[1164] The starting material 86d (270 mg, 0.8 mmol) was dissolved in 5 mL of methanol, followed by the addition of wet palladium on carbon (0.085 g, 0.8 mmol). After H₂ displacement, the reaction was allowed to proceed at 25°C for 16 hours. The reaction mixture was filtered, and the filter cake was rinsed twice with methanol. The filtrate was then concentrated to afford the crude product 86e (140 mg).

[1165] MS m / z(ESI):205.2[M+1] + .

[1166] Step 4

[1167] ((2S,4R)-2-(Benzo[d]oxazol-2-yl)-4-hydroxypyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 86f

[1168] 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, followed by the addition of HATU (0.34 g, 0.90 mmol) and ethyldiisopropylamine (0.36 g, 2.76 mmol). The reaction was allowed to proceed at room temperature for 2 hours. 10 mL of water was then added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 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 afford the product 86f (140 mg, yield: 51.3%).

[1169] MS m / z(ESI):399.2[M+1] + .

[1170] Step 5

[1171] ((S)-5-(Benzo[d]oxazol-2-yl)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-one 86g

[1172] Starting material 86f (260 mg, 0.65 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of Dess-Martin reagent (0.55 g, 1.3 mmol). The reaction was then allowed to proceed at 25°C for 16 hours. The reaction was then quenched by the addition of 20 mL of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phases were washed with brine (10 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford product 86g (250 mg, 96.6% yield).

[1173] MS m / z(ESI):397.2[M+1] + .

[1174] Step 6

[1175] (S,EZ)-(2-(Benzo[d]oxazol-2-yl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone

[1176] 86g (270mg, 0.68mmol) and methoxyamine hydrochloride (0.17g, 2.04mmol) were dissolved in 2mL of tetrahydrofuran and 2mL of water. Sodium bicarbonate (0.17g, 2.04mmol) was then added and the reaction was allowed to proceed at 25°C for 5 hours. 10mL of water was then added, and the mixture was extracted with ethyl acetate (10mL x 3). The combined organic phases were washed with brine (10mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative separation to obtain product A0086 (55.67mg, yield: 96.6%).

[1177] MS m / z(ESI):426.0[M+1] + .

[1178] 1 H NMR(400MHz,Chloroform-d)δ7.78-7.62(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).

[1179] Example A0087 & A0101

[1180] [(3Z)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone

[1181] [(3E)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone

[1182] first step

[1183] 3-Oxo-7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl ester 87d

[1184] 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 min. The reaction solution was then concentrated under reduced pressure to afford the crude product 87b (125 mg).

[1185] MS m / z(ESI):170.0[M+1] + .

[1186] Step 3

[1187] 7-(2'-Methyl-[1,1'-biphenyl]-4-carbonyl)-3-oxo-7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl ester 87e

[1188] Compound 87d (125 mg, 0.74 mmol) and compound 87b (0.20 g, 0.89 mmol) were dissolved in 5 mL of tetrahydrofuran, and potassium carbonate (0.31 g, 2.22 mmol) was added. The reaction was then allowed to proceed at 25°C for 6 hours. 10 mL of water was then added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude product 87e (268 mg).

[1189] MS m / z(ESI):364.3[M+1] + .

[1190] Step 4

[1191] (EZ)-3-(methoxyimino)-7-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl ester 87f

[1192] 87e (200 mg, 0.55 mmol) was dissolved in 2 mL of tetrahydrofuran and 2 mL of water, followed by the addition of methoxyamine hydrochloride (0.18 g, 2.2 mmol) and sodium bicarbonate (0.14 g, 1.65 mmol). The reaction was allowed to proceed at 25°C for 16 hours. 10 mL of water was then added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product 87f (299 mg).

[1193] MS m / z(ESI):364.2[M+1] + .

[1194] Step 5

[1195] [(3Z)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone

[1196] [(3E)-3-(Methoxyimino)-7-(4-(2-methylphenyl)benzoyl)-7-azabicyclo[2.2.1]heptan-1-yl]methanone

[1197] 87f (100 mg, 0.25 mmol) was dissolved in 2 mL of tetrahydrofuran and the atmosphere was purged with nitrogen. Lithium borohydride (8.2 mg, 0.38 mmol) was then added and the reaction was allowed to proceed at 25°C for 16 hours. 5 mL of water was then added, and the mixture was extracted 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 yield the crude product. Silica gel Prep-TLC (EA:PE = 2:1) yielded the less polar isomer A0101 (Rf = 0.4) and the crude more polar isomer A0087 (Rf = 0.3). The residue obtained by HPLC preparation and purification after freeze-drying to obtain a highly polar product was prepared and purified to obtain a highly polar product A0087 (3.3 mg, yield: 3.5%) and a less polar product A0101 (2.94 mg, yield: 3.15%).

[1198] A0087: MS m / z(ESI): 365.0[M+1] + .

[1199] 1 H NMR(400MHz,Chloroform-d)δ7.54(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,1 H),2.27(s,3H),2.18-2.13(m,2H),1.84-1.76(m,1H),1.69-1.63(m,1H).

[1200] A0101: MS m / z(ESI): 365.0[M+1] + .

[1201] 1 H NMR(400MHz,Chloroform-d)δ7.55-7.53(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).

[1202] Examples A0130 & A0144

[1203] (S,Z)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile

[1204] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile

[1205] first step

[1206] 2'-Cyano-3'-methyl-[1,1'-biphenyl]-4-carboxylic acid 130c

[1207] Under argon, 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 afford 130c (120 mg, 44.6% yield).

[1208] MS m / z(ESI):238[M+1] + .

[1209] Step 2

[1210] (S,Z)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile

[1211] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-3-methyl-[1,1'-biphenyl]-2-carbonitrile

[1212] 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). 4-Dimethylaminopyridine (0.10 g, 0.84 mmol) and EDCI (0.081 g, 0.42 mmol) were then slowly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove dichloromethane and diluted with 20 mL of water. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with brine (20 mL × 3). The organic phases were 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 afford the less polar isomer A0144 (Rf = 0.4) and the more polar isomer A0130 (Rf = 0.3). The products were then prepared, purified and freeze-dried by HPLC to obtain a highly polar product A0130 (11.53 mg, yield: 7.15%) and a less polar product A0144 (9.14 mg, yield: 5.76%).

[1213] A0130: MS m / z(ESI): 364.0[M+1] + .

[1214] 1 H NMR(400MHz,Chloroform-d)δ7.64-7.58(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).

[1215] A0144: MS m / z(ESI): 364.0[M+1] + .

[1216] 1 H NMR(400MHz,Chloroform-d)δ7.64-7.61(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).

[1217] Examples A0131 & A0153

[1218] 5-(2,3-Dimethylphenyl)-2-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[1219] 5-(2,3-Dimethylphenyl)-2-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[1220] first step

[1221] Methyl 2-cyano-4-(2,3-dimethylphenyl)benzoate 131b

[1222] 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 under argon for 12 hours. The reaction solution was directly concentrated and purified by column chromatography to afford 131b (0.300 g, 67.8% yield).

[1223] MS m / z(ESI):266.0[M+1] + .

[1224] Step 2

[1225] 2-Cyano-4-(2,3-dimethylphenyl)benzoic acid 131c

[1226] 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 1-2 hours. The reaction mixture was adjusted to pH 3-4 with 1M hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried and concentrated to afford crude product 131c (0.210 g).

[1227] MS m / z(ESI):252.1[M+1] + .

[1228] Step 3

[1229] 5-(2,3-Dimethylphenyl)-2-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[1230] 5-(2,3-Dimethylphenyl)-2-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]benzonitrile

[1231] 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 2-12 h. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with brine (10 mL × 3). The organic phase was 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 obtain the less polar isomer A0153 (Rf=0.25) and the more polar isomer A0131 (Rf=0.2), which were then prepared and purified by HPLC and lyophilized to obtain the more polar products A0131 (9.52 mg, yield: 7.32%) and A0153 (4.51 mg, yield: 3.68%).

[1232] A0131: MS m / z(ESI): 378.3[M+1] + .

[1233] 1 H NMR(400MHz,Chloroform-d)δ7.67-7.56(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).

[1234] A0153: MS m / z(ESI): 378.3[M+1] + .

[1235] 1 H NMR(400MHz,Chloroform-d)δ7.66-7.56(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).

[1236] Examples A0137 & A0154

[1237] [(2S,4Z)-1-(5-(2,3-Dimethylphenyl)-6-(trifluoromethyl)pyrazine-2-carbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methanone

[1238] [(2S,4E)-1-(5-(2,3-Dimethylphenyl)-6-(trifluoromethyl)pyrazine-2-carbonyl)-4-(methoxyimino)pyrrolidin-2-yl]methanone

[1239] According to the above synthetic route and referring to the synthetic method of compound A0131, highly polar products A0154 (15.93 mg, yield: 11.8%) and A0137 (4.71 mg, yield: 3.48%) were obtained.

[1240] A0137: MS m / z(ESI): 423.3[M+1] + .

[1241] 1 H NMR(400MHz,Chloroform-d)δ9.48(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).

[1242] A0154: MS m / z(ESI): 423.3[M+1] + .

[1243] 1 H NMR(400MHz,Chloroform-d)δ9.49(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).

[1244] Examples A0147 & A0170

[1245] (S,Z)-(2',3'-dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1246] (S,E)-(2',3'-dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1247] Referring to the synthetic method of the first step 131b in Examples A0131 & A0153, 147a can be obtained by replacing the raw material 4-bromo-2-cyanobenzoic acid methyl ester with 4-bromo-3-hydroxybenzoic acid methyl ester.

[1248] first step

[1249] 2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-carboxylic acid methyl ester 147c

[1250] Under argon, 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 allowed to react at 100°C for 16 hours. Ethyl acetate was added to the reaction mixture, washed with water, and 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 afford 147c (290 mg, yield: 47.6%).

[1251] MS m / z(ESI):313.0[M+1] + .

[1252] Step 2

[1253] 2',3'-Dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-carboxylic acid 147d

[1254] Compound 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 hours. The pH of the reaction mixture was adjusted to 4-5 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude compound 147d (260 mg).

[1255] MS m / z(ESI):299.0[M+1] + .

[1256] Step 3

[1257] (S,Z)-(2',3'-dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1258] (S,E)-(2',3'-dimethyl-2-(oxetan-3-yloxy)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1259] 147d (260 mg, 0.52 mmol) and 4 (0.061 g, 0.36 mmol) were dissolved in DCM (3 mL) and DMF (7 mL). 4-Dimethylaminopyridine (0.13 g, 1.04 mmol) and EDCI (0.10 g, 0.52 mmol) were then slowly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove dichloromethane and diluted with 30 mL of water. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with brine (30 mL × 3). The organic phases were 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 afford the less polar isomer A0170 (Rf = 0.3) and the more polar isomer A0147 (Rf = 0.2). The products were then prepared, purified and freeze-dried by HPLC to obtain a highly polar product A0147 (60.71 mg, yield: 27.1%) and a less polar product A0170 (58.91 mg, yield: 26.0%).

[1260] A0147: MS m / z(ESI): 425.0[M+1] + .

[1261] 1 H NMR(400MHz,DMSO-d6)δ7.21-7.12(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),3.2 8-3.15(m,1H),2.98-2.72(m,1H),2.68-2.58(m,1H),2.30(s,3H),2.02(s,3H).

[1262] A0170: MS m / z(ESI): 425.0[M+1] + .

[1263] 1 H NMR(400MHz,DMSO-d6)δ7.20-7.15(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).

[1264] Examples A0149 & A0171

[1265] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(2-methoxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[1266] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2-(2-methoxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)methanone

[1267] 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. The more polar product A0149 (38.84 mg, yield: 9.05%) and the less polar product A0171 (42.95 mg, yield: 9.99%) were then prepared, purified, and lyophilized by HPLC.

[1268] A0149: MS m / z(ESI): 427.1[M+1] + .

[1269] 1H NMR(400MHz,DMSO-d6)δ7.25-7.09(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).

[1270] A0171: MS m / z(ESI): 427.1[M+1] + .

[1271] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.07(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).

[1272] Examples A0148 & A0169

[1273] (S,Z)-(2-(2-Hydroxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1274] (S,E)-(2-(2-Hydroxyethoxy)-2',3'-dimethyl-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1275] Referring to Examples A0149 & A0171, 149b was replaced by 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). The products were then purified by HPLC 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%).

[1276] A0148: MS m / z(ESI): 413.0[M+1] + .

[1277] 1 H NMR (400MHz, DMSO-d6) δ7.22-7.09(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).

[1278] A0169: MS m / z(ESI): 413.0[M+1] + .

[1279] 1 H NMR (400MHz, DMSO-d6) δ7.21-7.09(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,2 H),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).

[1280] Examples A0157 & A0179

[1281] (S,Z)-4-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide

[1282] (S,E)-4-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide

[1283] first step

[1284] Methyl 4-(2,3-dimethylphenyl)-3-formylbenzoate 157a

[1285] Under argon, 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), and 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 with saturated brine and saturated sodium bicarbonate, respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford product 157a (2.0 g, yield: 54.35%). MS m / z (ESI): 269.2 [M+1] + .

[1286] Step 2

[1287] Methyl 4-(2,3-dimethylphenyl)-3-carboxybenzoate 157b

[1288] The starting material, methyl 4-(2,3-dimethylphenyl)-3-formylbenzoate 157a (1 g, 3.73 mmol, purity 100%), was dissolved in acetonitrile (10 mL) and water (10 mL). 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 then 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 (30 mL x 3). The combined organic phases were washed with brine (30 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 afford methyl 4-(2,3-dimethylphenyl)-3-carboxybenzoate 157b (650 mg, yield: 61.34%). MS m / z(ESI):285.3[M+1] + .

[1289] Step 3

[1290] Methyl 4-(2,3-dimethylphenyl)-3-[(oxetan-3-yl)carbamoyl]benzoate 157c

[1291] 157a (100 mg, 0.35 mmol) was dissolved in DMF (2 mL), followed by the addition of HATU (0.16 g, 0.42 mmol) and ethyldiisopropylamine (0.18 g, 1.4 mmol). The reaction was allowed to proceed at room temperature for 30 minutes. 3-Oxetanamine (0.031 g, 0.42 mmol) was then added, and the reaction was allowed to proceed at room temperature for 5 hours. 20 mL of water was then added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (10 mL x 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 afford product 157c (104 mg, yield: 87.1%).

[1292] MS m / z(ESI):340.0[M+1] + .

[1293] Step 4

[1294] 2',3'-Dimethyl-2-(oxetan-3-ylcarbamoyl)-[1,1'-biphenyl]-4-carboxylic acid 157d

[1295] Compound 157c (104 mg, 0.31 mmol) was dissolved in THF (2 mL), methanol (2 mL), and water (1 mL), followed by the addition of lithium hydroxide hydrate (0.039 g, 0.93 mmol). The reaction was allowed to proceed at room temperature for 16 hours. 20 mL of water was then added, and the mixture was extracted with ethyl acetate (20 mL x 2). 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 resulting residue was purified by silica gel column chromatography to afford product 157d (70 mg, yield: 70.0%).

[1296] MS m / z(ESI):326.2[M+1] + .

[1297] Step 5

[1298] (S,Z)-4-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide

[1299] (S,E)-4-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2',3'-dimethyl-N-(oxetan-3-yl)-[1,1'-biphenyl]-2-carboxamide

[1300] 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) and 4-dimethylaminopyridine (0.056 g, 0.46 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 h. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with brine (10 mL × 3). The organic phase was 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 obtain the less polar isomer A0179 (Rf=0.25) and the more polar isomer A0157 (Rf=0.2), which were then prepared and purified by HPLC and lyophilized to obtain the more polar product A0157 (4.08 mg, yield: 3.69%) and the less polar product A0179 (0.72 mg, yield: 0.59%).

[1301] A0157:MS m / z(ESI):452.0[M+1] + .

[1302] 1 H NMR(400MHz,Chloroform-d)δ8.11-8.09(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).

[1303] A0179:MS m / z(ESI):452.0[M+1] + .

[1304] 1H NMR(400MHz,Chloroform-d)δ8.10-8.09(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),5.0 0-4.82(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).

[1305] Examples A0158 & A0180

[1306] (2S,4Z)-(2',3'-dimethyl-2-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1307] (2S,4E)-(2',3'-Dimethyl-2-(morpholine-4-carbonyl)-[1,1'-biphenyl]-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1308] According to the above synthetic route and referring to the synthetic method of compound A0157, the less polar isomer A0180 (Rf=0.25) and the more polar isomer A0158 (Rf=0.2) were obtained, and then they were prepared, separated and purified separately to obtain the more polar product A0158 (10.74 mg, yield: 6.17%) and the less polar product A0180 (9.01 mg, yield: 5.29%).

[1309] A0158: MS m / z(ESI): 465.9[M+1] + .

[1310] 1 H NMR(400MHz,Chloroform-d)δ7.65-7.52(m,2H),7.37-7.33(m,1H),7.22-7.12(m,3H),4.98-4.87(m,1H),4.4 9-4.27(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).

[1311] A0180: MS m / z(ESI): 465.9[M+1] + .

[1312] 1 H NMR(400MHz,Chloroform-d)δ7.64-7.51(m,2H),7.38-7.32(m,1H),7.19-7.13(m,3H),4.92-4.83(m,1H),4.4 2-4.17(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).

[1313] Examples A0191 & A0199

[1314] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2'-(2-methoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1315] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2'-(2-methoxyethoxy)-2-methyl-[1,1'-biphenyl]-3-carbonitrile

[1316] Referring to Examples A0149 & A0171, 149a was replaced by (Prepared by the method of 147a.) 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). Separate products were then purified by HPLC 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%).

[1317] A0191:MS m / z(ESI):438.0[M+1] + .

[1318] 1H NMR(400MHz,Chloroform-d)δ7.64-7.62(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).

[1319] A0199:MS m / z(ESI):438.0[M+1] + .

[1320] 1 H NMR(400MHz,Chloroform-d)δ7.64-7.61(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).

[1321] Examples A0215 & A0222

[1322] 3-(6-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-methoxypyridin-3-yl)-2-methylbenzonitrile

[1323] 3-(6-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-2-methoxypyridin-3-yl)-2-methylbenzonitrile

[1324] According to the above synthetic route and referring to the synthetic method of compound C0061, the small polar isomer A0222 (Rf=0.25) and the large polar isomer A0215 (Rf=0.2) were obtained, and then prepared, purified and freeze-dried by HPLC to obtain the large polar product A0215 (8.93 mg, yield: 6.56%) and the small polar product A0222 (7.91 mg, yield: 5.68%).

[1325] A0215: MS m / z(ESI): 395.0[M+1] + .

[1326] 1 H NMR(400MHz,Chloroform-d)δ7.73-7.57(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).

[1327] A0222: MS m / z(ESI): 395.0[M+1] + .

[1328] 1 H NMR(400MHz,Chloroform-d)δ7.73-7.66(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).

[1329] Examples A0216 & A0223

[1330] 3-(6-[(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-4-methoxypyridin-3-yl)-2-methylbenzonitrile

[1331] 3-(6-[(2S,4E)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl]-4-methoxypyridin-3-yl)-2-methylbenzonitrile

[1332] According to the above synthetic route and referring to the synthetic method of compound C0061, the highly polar product A0216 (5.53 mg, yield: 4.71%) and the less polar product A0223 (3.47 mg, yield: 2.68%) were obtained.

[1333] A0216: MS m / z(ESI): 395.0[M+1] + .

[1334] 1H NMR(400MHz,Chloroform-d)δ8.26-8.20(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).

[1335] A0223: MS m / z(ESI): 395.0[M+1] + .

[1336] 1 H NMR(400MHz,Chloroform-d)δ8.22-8.19(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).

[1337] Examples A0163 & A0193

[1338] (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

[1339] (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

[1340] first step

[1341] Methyl 4-bromo-2-hydroxy-3-nitrobenzoate 163b

[1342] 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. The reaction mixture was allowed to react at 0°C for 1 hour. The reaction mixture was poured into ice water, whereupon solid precipitated. The solid was collected and the filtrate was extracted with ethyl acetate. The combined solids were purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford 163b (3.0 g, yield: 18.83%).

[1343] MS m / z(ESI):275.9[M+1] + .

[1344] Step 2

[1345] Methyl 3-amino-4-bromo-2-hydroxybenzoate 163c

[1346] Under argon, 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 hours. Water was added to the reaction mixture, neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to afford 163c (1 g, yield: 44.87%).

[1347] MS m / z(ESI):246.0[M+1] + .

[1348] Step 3

[1349] Methyl 4-bromo-3-(2-chloroacetylamino)-2-hydroxybenzoate 163e

[1350] 163c (200 mg, 0.81 mmol) was dissolved in chloroform (5 mL), and saturated aqueous sodium bicarbonate (0.34 g, 4.05 mmol) was added. 163d (0.11 g, 0.97 mmol) was slowly added dropwise at a temperature controlled between 0 and 10°C. After completion, the reaction mixture was stirred at room temperature for 4 hours. Dichloromethane was added to the reaction mixture, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to afford 163e (150 mg, yield: 57.22%).

[1351] MS m / z(ESI):322.0[M+1] + .

[1352] Step 4

[1353] 5-Bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid methyl ester 163f

[1354] 163e (150 mg, 0.47 mmol) was dissolved in DMF (8 mL), and potassium carbonate (0.26 g, 1.88 mmol) was added. The reaction mixture was incubated at 70°C for 2 hours. Ethyl acetate was added to the reaction mixture, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to afford 163f (100 mg, yield: 67.65%).

[1355] MS m / z(ESI):286.0[M+1] + .

[1356] Step 5

[1357] 5-Bromo-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid methyl ester 163g

[1358] 163f (100 mg, 0.47 mmol) was dissolved in DMF (5 mL), and potassium carbonate (0.13 g, 0.94 mmol) and iodomethane (133 mg, 0.94 mmol) were added. 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 afford 163f (100 mg, 95.3% yield).

[1359] MS m / z(ESI):300.0[M+1] + .

[1360] Steps 6 to 8 of the above synthetic route, following the synthesis method for compound A0134, yielded the less polar isomer A0193 (Rf = 0.25) and the more polar isomer A0163 (Rf = 0.2). These products were then purified and lyophilized by HPLC to afford the more polar product A0163 (7.67 mg, 5.08% yield) and the less polar product A0193 (30.57 mg, 21.64% yield).

[1361] A0163:MS m / z(ESI):449.0[M+1] + .

[1362] 1H NMR(400MHz,Chloroform-d)δ7.69(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).

[1363] A0193:MS m / z(ESI):449.0[M+1] + .

[1364] 1 H NMR(400MHz,Chloroform-d)δ7.70(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).

[1365] Examples A0162 & A0206

[1366] (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

[1367] (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

[1368] first step

[1369] 5-Bromo-4-methyl-3-oxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid methyl ester 162b

[1370] 163f (300 mg, 1.05 mmol) was dissolved in DMF (10 mL), and potassium carbonate (440 mg, 3.15 mmol) and iodomethane (227 mg, 1.57 mmol) were added. 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 afford a pale yellow crude product 162b (200 mg, 57.20% yield).

[1371] MS m / z(ESI):300.1[M+1] + .

[1372] Step 2

[1373] Methyl 5-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate 162c

[1374] 162b (200 mg, 0.67 mmol) was dissolved in THF (10 mL), and borane-tetrahydrofuran complex (1.01 mL, 1.01 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was quenched with methanol and concentrated to dryness to afford crude product 162c (180 mg).

[1375] MS m / z(ESI):286.1[M+1] + .

[1376] From the third to the fifth steps of the above synthetic route, referring to the synthetic method of compound A0134, a highly polar product A0162 (14.54 mg, yield: 9.86%) and a less polar product A0206 (12.12 mg, yield: 8.27%) were obtained.

[1377] A0162:MS m / z(ESI):435.0[M+1] + .

[1378] 1 H NMR(400MHz,Chloroform-d)δ7.71-7.61(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,1 H),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).

[1379] A0206:MS m / z(ESI):435.0[M+1] + .

[1380] 1 H NMR(400MHz,Chloroform-d)δ7.67-7.63(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).

[1381] Examples A0188 & A0230

[1382] (S,Z)-3-(2-(cyclopropylmethoxy)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyridin-3-yl)-2-methylbenzonitrile

[1383] (S,E)-3-(2-(cyclopropylmethoxy)-6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)pyridin-3-yl)-2-methylbenzonitrile

[1384] first step

[1385] 5-Bromo-6-(cyclopropylmethoxy)picolinic acid 188c

[1386] At room temperature, 188b (6.67 g, 87.6 mmol) was slowly added with NaH (0.12 g, 5 mmol), stirred for 10 minutes, and then 188a (250 mg, 1.0 mmol) was added. The reaction mixture was allowed to react 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 afford crude product 188c (200 mg, yield: 70.03%).

[1387] MS m / z(ESI):272.0[M+1] + .

[1388] From the second to third steps of the above synthetic route, following 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 products were then purified and lyophilized by HPLC to yield the more polar product A0188 (3.52 mg, yield: 1.96%) and the less polar product A0230 (7.95 mg, yield: 3.90%).

[1389] A0188:MS m / z(ESI):435.0[M+1] + .

[1390] 1 H NMR(400MHz,Chloroform-d)δ7.85-7.65(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).

[1391] A0230:MS m / z(ESI):435.0[M+1] + .

[1392] 1 H NMR(400MHz,Chloroform-d)δ7.72-7.53(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).

[1393] Examples A0190 & A0208

[1394] (S,Z)-3-(5-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-methylbenzonitrile

[1395] (S,E)-3-(5-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-methylbenzonitrile

[1396] first step

[1397] Methyl 5-bromo-6-((dimethylamino)methylene)amino)picolinate 190b

[1398] 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 h. The reaction mixture was concentrated to give a reddish-brown crude product 190b (1.0 g).

[1399] MS m / z(ESI):287.9[M+1] + .

[1400] Step 2

[1401] 5-Bromo-6-(N′-hydroxymethylimido)picolinic acid methyl ester 190c

[1402] Under argon, 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 stirred at 50°C for 4 h. The reaction mixture was cooled to room temperature, whereupon a white solid precipitated, which was filtered to afford crude product 190c (1 g).

[1403] MS m / z(ESI):273.9[M+1] + .

[1404] Step 3

[1405] 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester 190d

[1406] 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 hours. After completion, the reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0°C. The mixture was extracted with ethyl acetate (20 mL x 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 afford 190d (420 mg, yield: 44.95%).

[1407] MS m / z(ESI):255.9[M+1] + .

[1408] Steps 4 to 6 of the above synthetic route, following the synthesis method for compound A0212, yielded the less polar isomer A0208 (Rf = 0.25) and the more polar isomer A0190 (Rf = 0.2). These products were then purified and lyophilized by HPLC to yield the more polar product A0190 (29.99 mg, 17.26% yield) and the less polar product A0208 (28.31 mg, 16.29% yield).

[1409] A0190:MS m / z(ESI):405.0[M+1] + .

[1410] 1 H NMR(400MHz,Chloroform-d)δ8.44(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).

[1411] A0208:MS m / z(ESI):405.0[M+1] + .

[1412] 1 H NMR(400MHz,Chloroform-d)δ8.38(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).

[1413] Example A0197 & A0197A

[1414] (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile

[1415] (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile

[1416] first step

[1417] Methyl 6-chloro-5-(3-cyano-2-methylphenyl)picolinate 197c

[1418] Starting 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). 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 then added. After nitrogen displacement, the reaction was allowed to proceed at 100°C for 2 hours. Then, 50 mL of water was added, and the mixture was 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 to afford the crude product, which was then purified by column chromatography to afford product 197c (3.04 g, yield: 88.53%).

[1419] MS m / z(ESI):287.2[M+1] + .

[1420] Step 2

[1421] 6-Chloro-5-(3-cyano-2-methylphenyl)picolinic acid 197d

[1422] The starting material 197c (3 g, 10.46 mmol) was dissolved in tetrahydrofuran (30 mL) and water (15 mL), followed by the addition of lithium hydroxide hydrate (2.19 g, 52.30 mmol). The reaction was allowed to proceed at room temperature for 16 hours. 50 mL of water was then added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and 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 afford the product 197d (2.4 g, yield: 84.11%).

[1423] MS m / z(ESI):273.0[M+1] + .

[1424] Step 3

[1425] tert-Butyl 6-chloro-5-(3-cyano-2-methylphenyl)pyridine-2-carboxylate 197e

[1426] The starting material 197d (1.5 g, 5.50 mmol) and tert-butyloxycarbonyl 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 then allowed to proceed at 80°C for 16 hours. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford the product 197e (1.3 g, yield: 71.88%).

[1427] MS m / z(ESI):329.2[M+1] + .

[1428] Step 4

[1429] tert-Butyl 5-(3-cyano-2-methylphenyl)-6-[(2-methoxyethyl)amino]pyridine-2-carboxylate 197f

[1430] The starting material 197e (200 mg, 0.61 mmol) and 2-methoxyethane-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 then added. The reaction was continued at 100°C for 16 hours. Then, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine (10 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 197f (20 mg, yield: 8.95%).

[1431] MS m / z(ESI):368.0[M+1] + .

[1432] Step 5

[1433] 5-(3-cyano-2-methylphenyl)-6-[(2-methoxyethyl)amino]pyridine-2-carboxylic acid 197g

[1434] The starting 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 afford the product 197g (15 mg, yield: 88.51%).

[1435] MS m / z(ESI):312.0[M+1] + .

[1436] Step 6

[1437] (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile

[1438] (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-((2-methoxyethyl)amino)pyridin-3-yl)-2-methylbenzonitrile

[1439] The starting materials 197 g (15 mg, 0.048 mmol) and 4 (0.014 g, 0.096 mmol) were dissolved in dichloromethane (1 mL) and DMF (0.3 mL), and then EDCI (0.0092 g, 0.048 mmol) and DMAP (0.012 g, 0.096 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 hours. Then 10 mL of water was added, extracted with ethyl acetate (5 mL × 3), the organic phases were combined, and the organic phases were washed with brine (5 mL × 3). The organic phase was 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 obtain the large polar isomer A0197 (Rf = 0.25) and the small polar isomer A0197A (Rf = 0.3). They were then prepared, purified, and lyophilized by HPLC to obtain the large polar product A0197 (4.25 mg, yield: 20.16%) and a trace amount of the small polar product A0197A.

[1440] A0197:MS m / z(ESI):438.0[M+1] + .

[1441] 1 H NMR(400MHz,Chloroform-d)δ7.75-7.69(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).

[1442] A0197A:MS m / z(ESI): 438.0[M+1] + .

[1443] Example A0198 & A0231

[1444] (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinopyridin-3-yl)-2-methylbenzonitrile

[1445] (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinopyridin-3-yl)-2-methylbenzonitrile

[1446] first step

[1447] 5-Bromo-6-(morpholin-4-yl)pyridine-2-carboxylic acid 198b

[1448] Compound 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 then concentrated under reduced pressure to afford compound 198b (135 mg, 58.52% yield).

[1449] MS m / z(ESI):287.1[M+1] + .

[1450] Step 2

[1451] 5-(3-Cyano-2-methylphenyl)-6-(morpholin-4-yl)pyridine-2-carboxylic acid 198d

[1452] 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). 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 then added. After nitrogen substitution, the reaction was allowed to proceed at 100°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography to afford product 198d (120 mg, 96.86% yield).

[1453] Step 3

[1454] (S,Z)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinopyridin-3-yl)-2-methylbenzonitrile

[1455] (S,E)-3-(6-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-morpholinopyridin-3-yl)-2-methylbenzonitrile

[1456] Starting material 197d (105 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL), and a 2 mL aqueous solution of sodium bicarbonate (0.26 g, 3.1 mmol) was added. After 10 minutes of reaction, 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 solution 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 afford the less polar isomer A0231 (Rf = 0.25) and the more polar isomer A0198 (Rf = 0.2). These products were then purified by HPLC and lyophilized to afford the more polar product A0198 (1.58 mg, yield: 1.14%) and the less polar product A0231 (1.8 mg, yield: 1.30%).

[1457] A0198: MS m / z(ESI): 450.0[M+1] + .

[1458] 1 H NMR (400MHz, Chloroform-d) δ7.68-7.37(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).

[1459] A0231: MS m / z(ESI): 450.0[M+1] + .

[1460] 1 H NMR (400MHz, Chloroform-d) δ8.06-7.37(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).

[1461] Common intermediate A

[1462] (S)-(7-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)boronic acid

[1463] first step

[1464] 7-Bromobenzo[d][1,3]dioxolane-4-carboxylic acid methyl ester A-2

[1465] To a solution of A-1 (6.40 g, 25.91 mmol) in N,N-dimethylformamide (150 mL) were added diiodomethane (9.02 g, 33.68 mmol) and cesium carbonate (16.88 g, 51.82 mmol). After nitrogen replacement, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the cesium carbonate was removed by filtration, and the filter cake was washed with ethyl acetate. Water (50 mL) was added to the filtrate, and the product was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over sodium sulfate, and the solvent was evaporated. The residue was purified on a C18 reverse phase column (acetonitrile:water = 5:95 to 50:50 gradient) to afford product A-2 (2.2 g, yield: 32.78%).

[1466] MS m / z(ESI):260.0[M+1] + .

[1467] Step 2

[1468] 7-Bromobenzo[d][1,3]dioxole-4-carboxylic acid A-3

[1469] To a solution of A-2 (950 mg, 3.67 mmol) in tetrahydrofuran (10 mL) / methanol (5 mL) / water (5 mL) was added sodium hydroxide (734 mg, 18.35 mmol). 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. Ethyl acetate (100 mL) was added to the residue, and the pH was adjusted to ~3 with 1N HCl. The residue was then extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to yield product A-3 (800 mg, yield: 89.03%).

[1470] MS m / z(ESI):244.0[M-1] + .

[1471] Step 3

[1472] (S,EZ)-(7-bromobenzo[d][1,3]dioxol-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone A-4

[1473] To a solution of A-3 (1.7 g, 6.49 mmol) in N,N-dimethylformamide (50 mL) were added triethylamine (2.69 g, 20.82 mmol), 4 (1.5 g, 8.33 mmol), and HATU (3.17 g, 8.33 mmol). The reaction mixture was allowed to react at room temperature for 90 minutes. After completion of the reaction, water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by C18 reverse-phase column chromatography (gradient elution with acetonitrile:water = 5:95 to 60:40) to obtain product A-4 (2.38 g, yield: 92.42%).

[1474] MS m / z(ESI):372.2[M+1] + .

[1475] Step 4

[1476] (S,EZ)-(7-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxol-4-yl)boronic acid A

[1477] A-4 (1.60 g, 4.31 mmol), pinacol diboronate (1.97 g, 7.76 mmol), and potassium acetate (1.27 g, 12.93 mmol) were dissolved in 1,4-dioxane (30 mL). After nitrogen replacement, Pd(dppf)Cl2 (320 mg, 0.44 mmol) was added at room temperature and allowed to react at 80°C for 4 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and spin-dried. The residue was purified on a C18 reverse-phase silica gel column (gradient elution with acetonitrile:water = 15:85 to 60:40) to yield A (650 mg, yield: 44.87%).

[1478] MS m / z(ESI):337.0[M+1] + .

[1479] Examples C0117 & C0118

[1480] (S,E)-(7-(3-(Difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1481] (S,Z)-(7-(3-(Difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1482] first step

[1483] 3-Difluoromethyl-2-methylphenylboronic acid pinacol ester 118b

[1484] To a solution of 118a (150 mg, 0.68 mmol) in 1,4-dioxane (8 mL) were added pinacol diboronate (0.35 g, 1.36 mmol), potassium carbonate (0.20 g, 2.04 mmol), and Pd(dppf)Cl2 (0.050 g, 0.068 mmol). After nitrogen substitution, the mixture was reacted at 75°C for 3 h. After the reaction was complete, the raw material was monitored by TLC and directly used in the next step without post-treatment.

[1485] Step 2

[1486] (S,E)-(7-(3-(Difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1487] (S,Z)-(7-(3-(Difluoromethyl)-2-methylphenyl)benzo[d][1,3]dioxolan-4-yl)(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)methanone

[1488] To the reaction solution of 118b were added 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). After nitrogen substitution, 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 organic phases were combined and washed with saturated brine (10 mL × 3). After drying over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel Prep-TLC (PE:EA=1:5) to obtain crude less polar isomer C0117 (Rf=0.6) and crude more polar isomer C0118 (Rf=0.55). These were then purified by HPLC and lyophilized to obtain the less polar product C0117 (2.0 mg, yield: 0.86%) and the more polar product C0118 (2.0 mg, yield: 0.86%).

[1489] C0117: MS m / z(ESI): 433.1[M+1] + .

[1490] 1H NMR(400MHz,CD3OD-d4)δ7.57-7.56(m,1H),7.41-7.34(m,2H),7.11-6.84(m,3H),6.0 9-6.04(m,2H),4.72-4.14(m,3H),3.87-3.31(m,5H),2.95-2.30(m,2H),2.23(s,3H).

[1491] C0118: MS m / z(ESI): 433.1[M+1] + .

[1492] 1 H NMR(400MHz,CD3OD-d4)δ7.57-7.56(m,1H),7.40-7.34(m,2H),7.11-6.84(m,3H),6.1 0-6.05(m,2H),4.72-4.16(m,3H),3.87-3.31(m,5H),3.12-2.66(m,2H),2.30(s,3H).

[1493] Examples C0120 & C0121

[1494] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone

[1495] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone

[1496] first step

[1497] (S,Z)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone

[1498] (S,E)-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidin-1-yl)(4-(1-methyl-1H-indazol-7-yl)phenyl)methanone

[1499] According to the above synthesis route and referring to the synthesis method of 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.

[1500] C0120: MS m / z(ESI): 379.1[M+1] +.

[1501] 1 H NMR(400MHz,CD3OD-d4)δ8.08(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).

[1502] C0121: MS m / z(ESI): 379.1[M+1] + .

[1503] 1 H NMR (400MHz, CD3OD-d4) δ8.08 (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).

[1504] Examples C0122 & C0123

[1505] (S,E)-6-Fluoro-3-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)-2-methylbenzonitrile

[1506] (S,Z)-6-Fluoro-3-(7-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)benzo[d][1,3]dioxolan-4-yl)-2-methylbenzonitrile

[1507] first step

[1508] 122a (1 g, 7.40 mmol) was dissolved in trifluoromethanesulfonic acid (15 mL), and NBS (1.32 g, 7.40 mmol) was slowly added at 0°C. The mixture was allowed to return to room temperature and 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 afford product 122b (1.45 g, 91.55% yield).

[1509] From the second to third steps of the above synthetic route, referring to the synthesis method of compound C0117, crude less polar isomer C0122 (Rf = 0.4) and crude more polar isomer C0123 (Rf = 0.3) were obtained. These were then purified by HPLC and lyophilized to afford less polar isomer C0122 (5 mg, yield: 1.8%) and more polar isomer C0123 (10 mg, yield: 3.5%).

[1510] C0122: MS m / z(ESI): 426.1[M+1] + .

[1511] 1 H NMR (400MHz, CD3OD-d4) δ7.63-7.58(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).

[1512] C0123: MS m / z(ESI): 426.1[M+1] + .

[1513] 1 H NMR (400MHz, CD3OD-d4) δ7.64-7.60(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).

[1514] Examples C0126 & C0127

[1515] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile

[1516] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile

[1517] first step

[1518] 3-Bromo-2-(trifluoromethyl)benzamide 127b

[1519] 127a (500 mg, 1.86 mmol) and HATU (780 mg, 2.05 mmol) were dissolved in DMF (8 mL). Triethylamine (750 mg, 7.44 mmol) and ammonium chloride (200 mg, 3.72 mmol) were added at room temperature and allowed to react for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was purified on a C18 reverse phase column (gradient elution with acetonitrile:water = 15:85 to 60:40) to afford product 127b (350 mg, yield: 70.26%).

[1520] MS m / z(ESI):268.8[M+1] + .

[1521] Step 2

[1522] 3-Bromo-2-(trifluoromethyl)benzonitrile 127c

[1523] 127b (330 mg, 1.23 mmol) was dissolved in DMF (8 mL). Triethylamine (190 mg, 1.88 mmol) was added at room temperature under nitrogen. Trifluoroacetic anhydride (390 mg, 1.86 mmol) was added dropwise at 0°C. The mixture was allowed to react for 4 hours. After completion of the reaction, the reaction solution was concentrated and the residue was purified on a C18 reverse phase column (gradient elution with acetonitrile:water = 20:80 to 70:30) to afford product 127c (150 mg, yield: 48.73%).

[1524] MS m / z(ESI):250.1[M+1] + .

[1525] Step 3

[1526] (S,Z)-4'-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile

[1527] (S,E)-4'-(2-(Hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-carbonitrile

[1528] Compound 204c (120 mg, 0.41 mmol), compound 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 at room temperature and allowed to react at 80°C for 2 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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%).

[1529] C0127: MS m / z(ESI): 418.0[M+1] + .

[1530] 1 H NMR (400MHz, CD3OD-d4) δ8.04(d,J=7.6Hz,1H),7.85(t,J=7.6Hz,1H),7.71(d,J=7.2Hz,1H),7.64(d,J=7.6 Hz, 2H), 7.44 (d, J = 8.0 Hz, 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).

[1531] C0126: MS m / z(ESI): 418.0[M+1] + .

[1532] 1 H NMR (400MHz, CD3OD-d4) δ8.04(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).

[1533] Examples C0132 & C0133

[1534] (S,E)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylbenzonitrile

[1535] (S,Z)-3-(8-(2-(hydroxymethyl)-4-(methoxyimino)pyrrolidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylbenzonitrile

[1536] According to the above synthesis route and referring to the synthesis method of compound C0061, a highly polar product C0133 (54 mg, yield: 12.2%) and a less polar product C0132 (38 mg, yield: 8.6%) were obtained.

[1537] C0132: MS m / z(ESI): 422.1[M+1] + .

[1538] 1 H NMR(300MHz,DMSO-d6)δ7.84-7.82(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).

[1539] C0133: MS m / z(ESI): 422.1[M+1] + .

[1540] 1 H NMR(400MHz, DMSO-d6)δ7.80(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).

[1541] Examples C0039 & C0040

[1542] (S,Z)-3-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one

[1543] (S,E)-3-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one

[1544] first step

[1545] 1-(tert-Butyl)2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-pyrrolidine-1,2-dicarboxylate 39b

[1546] 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). After nitrogen substitution, the mixture was stirred at room temperature overnight. The reaction mixture was cooled and poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once. The combined organic phases were washed once with brine, dried, filtered, and spun down to dryness. The crude product was applied to a silica gel column and eluted with PE / EA (10:1). The eluate was collected and rotary evaporated to afford 39b (13.5 g, 87.5% yield).

[1547] 1 H NMR (400MHz, CDCl3) δ4.43-4.31(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).

[1548] Step 2

[1549] 1-(tert-Butyl)2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(cyanomethyl)pyrrolidine-1,2-dicarboxylate 39c

[1550] To 39b (7.9 g, 21.97 mmol) and potassium iodide (0.36 g, 2.20 mmol) dissolved in THF (100 mL) at 0°C under nitrogen was added dropwise LiHMDS (7.35 g, 43.94 mmol). The mixture was stirred for 20 minutes and then 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 solution was gradually warmed to room temperature and allowed to react overnight. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted once more. The combined organic phases were washed once with brine, dried, filtered, and spun down to dryness. The crude product was applied to a silica gel column and eluted with PE / EA (50:1 to 5:1). The eluate was collected and rotary evaporated to afford 39c (2.0 g, 20.5% yield).

[1551] 1 H NMR (400MHz, CDCl3) δ4.45-4.07(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).

[1552] Step 3

[1553] (2S,4R)-2-(cyanomethyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester 39d

[1554] 39c (2.0 g, 5.02 mmol) was dissolved in dioxane hydrochloride solution (10 mL). The mixture was reacted at room temperature for 1 hour. After the reaction, the reaction mixture was directly dried to obtain crude product 39d (1.0 g).

[1555] MS m / z(ESI):185.1[M+1] + .

[1556] Step 4

[1557] (2S,4R)-2-(cyanomethyl)-4-hydroxy-1-(4-(2-methylphenyl)benzoyl)pyrrolidine-2-carboxylic acid methyl ester 39f

[1558] To a solution of 39d (1 g, 5.43 mmol) and 39e (1.88 g, 8.14 mmol) in DCM (20 mL) was added triethylamine (1.65 g, 16.29 mmol). After nitrogen substitution, the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was extracted with dichloromethane / water, and the organic layers were combined and washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, 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 dried to afford the product 39f (900 mg, 39.4% yield).

[1559] MS m / z(ESI):379.0[M+1] + .

[1560] Step 5

[1561] (2S,4R)-2-(2-aminoethyl)-4-hydroxy-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester 39g

[1562] Under nitrogen, to a solution of 39f (500 mg, 1.32 mmol) in methanol (20 mL) and water (0.2 mL) was added cobalt chloride (1.88 g, 7.92 mmol) and NaBH4 (0.20 g, 5.28 mmol). The mixture was reacted at -20°C to 0°C for 4 hours. After completion of the reaction, the reaction mixture was quenched with water, filtered through a Buchner funnel, and the residue was spin-dried at 45°C to give the crude product 39g (500 mg).

[1563] MS m / z(ESI):383.0[M+1] + .

[1564] Step 6

[1565] (3R,5S)-3-Hydroxy-1-(4-(2-methylphenyl)benzoyl)-1,7-diazaspiro[4.4]nonan-6-one 39h

[1566] Under nitrogen, sodium hydroxide (0.42 g, 10.48 mmol) was added to a solution of 39 g (500 mg, 1.31 mmol) in methanol (30 mL). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate / water. The organic layers were combined and washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford 39h (220 mg, yield: 38.4%).

[1567] MS m / z(ESI):351.0[M+1]+ .

[1568] Step 7

[1569] 1-(4-(2-methylphenyl)benzoyl)-1,7-diazaspiro[4.4]nonane-3,6-dione 39i

[1570] Under nitrogen, DMP (290.11 mg, 0.68 mmol) was added to a solution of 39h (200 mg, 0.57 mmol) in DCM (10 mL). The reaction was allowed to react overnight at room temperature. After completion, the reaction solution was extracted with ethyl acetate / water, and the combined organic layers were washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (EA:MeOH = 20:1) to afford product 39i (110 mg, yield: 52.5%).

[1571] MS m / z(ESI):348.8[M+1] + .

[1572] Step 8

[1573] (S,E)-3-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one

[1574] (S,Z)-3-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)-1,7-diazaspiro[4.4]nonan-6-one

[1575] To a solution of 39i (110 mg, 0.32 mmol) in methanol (15 mL) were added methoxyamine (0.080 g, 0.96 mmol) and triethylamine (0.097 g, 0.96 mmol). After nitrogen replacement, the mixture was reacted at room temperature overnight. After completion of the reaction, the reaction solution was extracted with ethyl acetate / water, and the organic layers were combined and washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated to obtain the crude product. The crude product was separated by silica gel Pre-TLC (EA:PE = 2:1) to afford the less polar isomer C0039 (Rf = 0.5) and the more polar isomer C0040 (Rf = 0.4). The crude less polar isomer was purified by HPLC and lyophilized to afford the less polar product C0039 (28.2 mg, yield: 23.5%). The crude large polar isomer C0040 (Rf=0.4) was purified by HPLC and lyophilized to obtain the large polar product C0040 (36.1 mg, yield: 30.2%).

[1576] C0039:MS m / z(ESI): 378.1[M+1] + .

[1577] 1 H NMR(400MHz, CD3OD-d)δ7.61(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),7.30-7.19(m,4H),4.39-4.30(m,2H), 3.84(s,3H),3.59-3.55(m,1H),3.45-3.39(m,1H),3.05-3.00(m,2H),2.95-2.87(m,1H),2.28-2.23(m,4H).

[1578] C0040:MS m / z(ESI): 378.1[M+1] + .

[1579] 1 H NMR(400MHz, CD3OD-d)δ7.62(d,J=8.4Hz,2H),7.42(d,J=8.0Hz,2H),7.29-7.19(m,4H),4.41-4.31(m,2H), 3.81(s,3H),3.59-3.55(m,1H),3.46-3.39(m,1H),3.05-2.92(m,2H),2.88-2.85(m,1H),2.30-2.27(m,4H).

[1580] Examples C0009 & C0010

[1581] (S,Z)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)benzamide

[1582] (S,E)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)benzamide

[1583] first step

[1584] (S,EZ)-2-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)isoindole-1,3-dione 10b

[1585] 10a (500 mg, 1.48 mmol) and isoindole-1,3-dione 10b (290 mg, 1.97 mmol) were dissolved in tetrahydrofuran (12 mL). Triphenylphosphine (390 mg, 1.48 mmol) and diethyl azodicarboxylate (260 mg, 1.48 mmol) were added sequentially at room temperature. The mixture was allowed to react for 16 hours. After completion of the reaction, the reaction solution was concentrated, dissolved in dichloromethane and water, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (70 mL x 3), dried, and spin-dried to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1 to pure EA) to obtain 10c (630 mg, yield: 82.08%).

[1586] MS m / z(ESI):468.1[M+1] + .

[1587] Step 2

[1588] (S,EZ)-(2-(Aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl)(2'-methyl-[1,1'-biphenyl]-4-yl)methanone 10d

[1589] 10c (620 mg, 1.19 mmol) was dissolved in ethanol (7 mL) and tetrahydrofuran (7 mL). Hydrazine hydrate (240 mg, 4.79 mmol) was added at room temperature. The reaction was allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, dissolved in dichloromethane and water, and the pH was adjusted to 7-8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (70 mL × 2). The organic phases were dried and spin-dried to obtain a crude product. The crude product was purified by reverse-phase column chromatography (H2O / ACN = 1:2) to obtain 10d (190 mg, yield: 44.8%).

[1590] MS m / z(ESI):338.1[M+1] + .

[1591] Step 3

[1592] (S,Z)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)benzamide

[1593] (S,E)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)benzamide

[1594] 10d (60 mg, 0.17 mmol) and benzoic anhydride (45 mg, 1.12 mmol) were dissolved in ethyl acetate (2 mL), and saturated sodium carbonate solution (0.5 mL) was added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was poured into a mixture of ethyl acetate and water. After separation, the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with brine (70 mL × 2), dried, filtered, and spin-dried. The crude product was purified by silica gel TLC (PE:EA = 1:3) and lyophilized to obtain the more polar isomer C0010 (Rf = 0.6, 33.19 mg, yield: 43.6%) and the less polar isomer C0009 (Rf = 0.7, 13.51 mg, yield: 16.8%).

[1595] C0010:MS m / z(ESI): 342.1[M+1] + .

[1596] 1 H NMR (400MHz, CD3OD-d) δ8.69-8.57(m,1H),7.79-7.73(m,2H),7.61-7.50(m,3H),7.48-7.22(m,8H),4.86(t,J=3.2Hz,1H),4. 39-4.35(m,1H),4.14-3.93(m,1H),3.81-3.62(m,3H),3.61-3.23(m,2H),3.14-2.75(m,1H),2.67-2.63(m,1H),2.24(s,3H).

[1597] C0009:MS m / z(ESI): 342.1[M+1] + .

[1598] 1 H NMR (400MHz, CD3OD-d) δ8.69-8.57(m,1H),7.79(m,2H),7.60-7.50(m,3H),7.49-7.22(m,8H),4.89-4.80(m,1H ),4.47-4.35(m,1H),4.22-3.97(m,1H),3.90-3.75(s,3H),3.51-3.22(m,2H),2.83-2.76(m,2H),2.24(s,3H).

[1599] Examples C0003 & C0006

[1600] (S,E)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1601] (S,Z)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1602] first step

[1603] (S,Z)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1604] (S,E)-N-((4-(Methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1605] EZ mixture 10d (60 mg, 0.18 mmol) and triethylamine (20.04 mg, 0.20 mmol) were dissolved in dichloromethane (10 mL), cooled to 0°C, and acetic anhydride (20.21 mg, 0.20 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL), the layers were separated, dried, concentrated, and purified by preparative silica gel thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1.5) to afford the highly polar product C0003 (Rf = 0.4, 15 mg, yield: 21.7%) and the less polar product C0006 (Rf = 0.5, 12 mg, yield: 17.6%).

[1606] C0003:MS m / z(ESI): 380.1[M+1] + .

[1607] 1 H NMR (400MHz, DMSO-d6) δ8.07-7.98(m,1H),7.61-7.52(m,2H),7.43(d,J=7.6Hz,2H),7.33-7.25(m,4H),4.69-4.28(m,1H),4.38-4.35( m,1H),4.11-3.91(m,1H),3.82-3.69(m,3H),3.38-3.25(m,1H),2.97-2.77(m,2H),2.54-2.41(m,1H),2.25(s,3H),1.80-1.65(m,3H).

[1608] C0006:MS m / z(ESI): 380.1[M+1] + .

[1609] 1H NMR (400MHz, CD3OD) δ7.88-7.83(m,1H),7.64-7.62(m,1H),7.45-7.41(m,2H),7.30-7.21(m,4H),4.93-4.52(m,1H) ,4.40-4.07(m,2H),3.86-3.75(m,3H),3.73-3.47(m,2H),3.04-2.73(m,2H),2.28-2.26(m,3H),2.22-1.85(m,3H).

[1610] Examples C0004 & C0007

[1611] Methyl (S,E)-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)carbamate

[1612] Methyl (S,Z)-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)carbamate

[1613] Referring to Examples C0003 & C0006, replace the starting acetic anhydride with methyl chloroformate. The crude product was separated by silica gel Prep-TLC (PE:EA = 1:3) to afford the highly polar product C0004 (Rf = 0.3, 10 mg, yield: 10.2%) and the less polar product C0007 (Rf = 0.4, 12 mg, yield: 12.5%).

[1614] C0004:MS m / z(ESI): 396.1[M+1] + .

[1615] 1 H NMR (400MHz, DMSO-d6) δ7.62-7.53(m,2H),7.43-7.39(m,3H),7.33-7.23(m,4H),4.75-4.68(m,1H),4.38-4.27(m,1H),4.0 5-3.89(m,1H),3.82-3.72(m,3H),3.54-3.40(m,3H),3.24-2.85(m,2H),2.84-2.67(m,1H),2.56-2.49(m,1H),2.25(s,3H).

[1616] C0007:MS m / z(ESI): 396.1[M+1] + .

[1617] 1H NMR(400MHz,DMSO-d6)δ7.86-7.21(m,9H),4.71-4.32(m,2H),4.12-3.98(m,1H),3.77-3 .69(m,3H),3.62-3.54(m,3H),3.41-3.26(m,2H),2.84-2.65(m,2H),2.25-2.23(m,3H).

[1618] Examples C0005 & C0008

[1619] (S,E)-2-Hydroxy-N-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1620] (S,Z)-2-Hydroxy-N-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1621] first step

[1622] (S,Z)-2-Hydroxy-N-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1623] (S,E)-2-Hydroxy-N-((4-(methoxyimino)-1-(2'-methyl-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-2-yl)methyl)acetamide

[1624] EZ mixture 10d (96 mg, 0.28 mmol), 2-hydroxyacetic acid (21.3 mg, 0.28 mmol), and 4-dimethylaminopyridine (10.3 mg, 0.084 mmol) were dissolved in dichloromethane (3 mL). EDCI (59.0 mg, 0.31 mmol) was added and stirred at room temperature for 17 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL), the layers separated, dried, and concentrated. The crude product was purified by silica gel Prep-TLC (DCM:EA = 1:3) to afford the highly polar product C0005 (Rf = 0.3, 25.0 mg, yield: 21.2%) and the less polar product C0008 (Rf = 0.4, 8 mg, yield: 6.7%).

[1625] C0005:MS m / z(ESI): 396.1[M+1] + .

[1626] 1H NMR (400MHz, DMSO-d6) δ8.04-7.96(m,1H),7.59(d,J=7.2Hz,2H),7.42(d,J=7.2Hz,2H),7.31-7.24(m,4H),5.43(t,J=5.2Hz,1H),4.80-4. 75(m,1H),4.36-4.32(m,1H),4.10-3.91(m,1H),3.81-3.63(m,5H),3 .39-3.32(m,1H),3.09-2.76(m,2H),2.59-2.55(m,1H),2.25(s,3H).

[1627] C0008:MS m / z(ESI): 396.1[M+1] + .

[1628] 1 H NMR (400MHz, CD3OD) δ7.63(d,J=8.4Hz,2H),7.43(d,J=8.0Hz,2H),7.31-7.21(m,4H),5.00-4.85(m,1H),4 .70-4.39(m,1H),4.25-4.07(m,1H),3.98-3.85(m,5H),3.58-3.42(m,2H),2.90-2.80(m,2H),2.27(s,3H).

[1629] Examples C0017 & C0018

[1630] (S,Z)-(2-((2-Hydroxyethoxy)methyl)-4-(methoxyimino)pyrro...

Claims

1. A compound of formula I: or an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; in, X is N–OR 1 ; R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally substituted with one or more R 1a replace; Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 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 ); R 3a For hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl or -L 1 –R 3c ; R 3b For hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, –L 1 –R 3c , –C(O)OR 3d , –C(O)N(R 3d )(R 3e ),–S(O)2R 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, 3-8 membered heterocycloalkyl, C 3–8 cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl to form a condensed ring; wherein the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; Or, R 3a and R 3b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally independently selected from halogen, hydroxy , amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; 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)2R 7a 、–N(R 7c )S(O)2R 7a 、–S(O)2N(R 7a )(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 ); L 2 For –[C(R 10a )(R 10b )] t –, one of the C(R 10a )(R 10b ) part is optionally replaced by –O– or –N(R 10a )-replace; 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 independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl; or, R 9a and R 9b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl; or, R 9a and R 3a Connect with each other to form –CH2– or –CH2CH2–; R 10a and R 10b are independently hydrogen, halogen, cyano, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2– 6-alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl; or, R 10a and R 10b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl; or, R 10a and R 3a , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl; Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to the ring B in Formula I; 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 ); Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ); A 3 CH, C(O), N, N(R 4c ) or C(R 4c ); Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ); A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d ); 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 independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 8a , –N(R 8c )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 ); Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; Ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c ); Each R 2a , R 2b and R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, –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)2R 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 ); Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; Or, R 2a and R 4b Connect to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –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 independently hydrogen, C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl to form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo Base, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl, halo C 2–6 Alkynyl, C 3–8 Substitution with one or more substituents of cycloalkenyl, 3-8 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl; Each R 5c , R 6c , R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 2–6 Alkenyl, halogenated C 2– 6-alkenyl, C 2–6 Alkynyl or halo C 2–6 Alkynyl; The number of heteroatoms in the above heterocycloalkyl, heterocycloalkenyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O, S, Si, P and Se; The prerequisite is that at least one of the following conditions (a), (b), (c), (d) and (e) is met: Condition (a): R 2a and R 2b are not hydrogen; and, when R 2a C 1–6 Alkyl, R 3a is hydrogen and R 3b To divide –L 1 –R 3c If it is a group other than 2b Not for C 1–6 alkyl; Condition (b): R 3a C 1–6 Alkyl or –L 1 –R 3c And R 3b For –L 1 –R 3c or, R 3a and R 3b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl or 3-8 membered heterocycloalkenyl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3–8 Cycloalkenyl and 3-8 membered heterocycloalkenyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 2–6 Alkenyl, halogenated C 2–6 Alkenyl, C 2–6 Alkynyl and halo C 2–6 The alkynyl group is substituted with one or more substituents; Condition (c): R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ; R 3b For –L 1 –R 3c ; Ring A is Wherein the * end is connected to the carbonyl group in Formula I, the # end is connected to the ring B in Formula I; and, R 2a is not hydrogen; wherein each A 1 are independently CH, N or C(R 4a ); each A 2 are independently CH, N or C(R 4b ); each A 3 are independently CH, N or C(R 4c ); each A 4 are independently CH, N or C(R 4d );A 5 O, S, NH or N(R 4d ); Condition (d): R 3b For –CH(C 1–6 Alkyl)–OH, –CH2NHC(O)CH2OH or –CH2OCH2CH2OH; Condition (e): R 9a and R 3a They are connected to each other to form –CH2– or –CH2CH2–.

2. The compound, isotope derivative or pharmaceutically acceptable salt according to claim 1, characterized in that: The compound has the structure shown in Formula I-1: Wherein, 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 ; R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally substituted with one or more R 1a replace; Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 5a , –N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b ); R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ; R 3b For –L 1 –R 3c , –C(O)OR 3d , –C(O)N(R 3d )(R 3e ),–S(O)2R 3d , –S(O)2N(R 3d )(R 3e ), C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3– 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl to form a condensed ring; wherein the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Each R 3c Independently for –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)2R 7a , –N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b ); Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to the ring B in Formula I; 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 ); Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ); A 3 CH, C(O), N, N(R 4c ) or C(R 4c ); Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ); A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d ); 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 independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 8a , –N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b ); Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c ); Each R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 6a , –N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b ); Each R 2a and R 2b are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 6a , –N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b ); Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Or, R 2a and R 4b Connect to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –O– or –NH–; The condition is that when R 2a C 1–6 Alkyl, R 3a is hydrogen and R 3b To divide –L 1 –R 3c If it is a group other than 2b Not for C 1–6 alkyl; Each R 3d , R 3e , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl to form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1– 6 haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Substitution with one or more substituents of cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; Each R 5c , R 6c , R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 Hydroxyalkyl; The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

3. The compound, isotope derivative or pharmaceutically acceptable salt according to claim 1 or 2, characterized in that: The compound has the structure shown in Formula I-1: Wherein, 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 ; R 1 is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally substituted with one or more R 1a replace; Each R 1a are independently halogen, cyano, nitro, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 5a , –N(R 5c )S(O)2R 5a or –S(O)2N(R 5a )(R 5b ); R 3a For hydrogen, C 1–6 Alkyl or –L 1 –R 3c ; R 3b For –L 1 –R 3c ; Each L 1 Independently –[C(R a )(R b )] n –; where n is 1, 2 or 3; each R a and R b are independently hydrogen, C 1–6 Alkyl, C 3– 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; or, R a and R b , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl or 3-8 membered heterocycloalkyl; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl and 3-8 membered heterocycloalkyl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Each R 3c Independently for –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)2R 7a , –N(R 7c )S(O)2R 7a or –S(O)2N(R 7a )(R 7b ); Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to the carbonyl group in Formula I 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 ); Each A 2 are independently CH, C(O), N, NH, O, S, N(R 4b ) or C(R 4b ); A 3 CH, C(O), N, N(R 4c ) or C(R 4c ); Each A 4 are independently CH, C(O), N, N(R 4d ) or C(R 4d ); A 5 CH, N, O, S, NH, C(R 4d ) or N(R 4d ); 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 independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 8a , –N(R 8c )S(O)2R 8a or –S(O)2N(R 8a )(R 8b ); Or, R 4a and R 4b , together with the atoms connecting them, form C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Ring B, G 1 , G 2 and G 3 Each independently is N or C(R 2c ); Each R 2c are independently hydrogen, halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 6a , –N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b ); Each R 2a and R 2b are independently halogen, cyano, nitro, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 3–8 Cycloalkyl, 3–8-membered heterocycloalkyl, phenyl, 5–6-membered heteroaryl, –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)2R 6a , –N(R 6c )S(O)2R 6a or –S(O)2N(R 6a )(R 6b ); Or, R 2b and R 2a or R 2c , together with the carbon atoms that connect them, form C 3–8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents; Or, R 2a and R 4b Connect to form –(CH2) p –, p is 2, 3 or 4, wherein one or two CH2 moieties are optionally replaced by –O– or –NH–; Each R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are independently hydrogen, C 1–6 Alkyl, C 3–8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally with another C 3–8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl to form a condensed ring; wherein the C 1–6 Alkyl, C 3–8 Cycloalkyl, 3-8 membered heterocyclic ring Alkyl, phenyl and 5-6 membered heteroaryl are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy, halogenated C 1–6 Alkoxy, C 3–8 Substitution with one or more substituents of cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; Each R 5c , R 6c , R 7c and R 8c are independently hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 Hydroxyalkyl; The number of heteroatoms in the above heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O and S.

4. The compound, isotope derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: R 2b C 1–6 Alkyl, cyano, C 1–6 Haloalkyl, C 1–6 Alkoxy or halogen; preferably methyl, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy or chloro.

5. The compound, isotope derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that: R 2a For halogen, cyano, C 1–6 Alkyl or C 1–6 Haloalkyl; preferably methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, chloro or cyano.

6. The compound, isotope derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: R 2b and R 2a , together with the carbon atoms that connect them, form C 3–8 Cycloalkyl, preferably cyclopentyl.

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

8. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 7, characterized in that: G 1 is CH or C(F); G 2 is CH or C(F); G 3 is CH, C(F), C(CN) or N; preferably G 1 CH; G 2 CH; G 3 For CH.

9. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: The structure part is 10. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: Ring A is A 1 is CH, N or C(R 4a ), A 2 is CH, N or C(R 4b ), A 3 is CH, N or C(R 4c ), A 4 is CH, N or C(R 4d ), A 5 O, S, NH or N(R 4d ), Ar is a 3- to 8-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group.

11. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: Ring A is 12. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 11, characterized in that: R 4a and R 4b are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Alkoxy, –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 ); preferably R 4a and R 4b Each is independently methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, –OCH2CH2OH, –OCH2CH2OCH3, –NHCH2CH2OCH3, or R 4a and R 4b Together with the carbon atoms that connect them, The above rings are optionally independently selected from halogen, hydroxy, amino, cyano, oxo, C 1–6 Alkyl, C 1–6 Haloalkyl, C 1–6 Hydroxyalkyl, C 1–6 Alkoxy and halogenated C 1–6 The alkoxy group is substituted with one or more substituents.

13. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 12, characterized in that: R 4c and R 4d are independently halogen, cyano, C 1–6 Alkyl, C 1–6 Haloalkyl or C 1–6 Alkoxy; preferably R 4c and R 4d Each is independently fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or methoxy.

14. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 12, characterized in that: Ring A is Among them A 1 , A 2 , A 3 and A 4 are independently CH or N, 15. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: Ring A is 16. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 15, characterized in that: R 3a is hydrogen or C 1–6 alkyl.

17. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 16, characterized in that: R 3b For –L 1 –R 3c ; L 1 =CH(R a )] n –; where n is 1, 2 or 3; R 3c is –OH; R a is hydrogen or C 1–6 Alkyl, the C 1–6 The alkyl group is optionally substituted with one or more hydroxy groups; preferably R 3b is –CH2OH, –CH(CH3)OH, –C(CH3)2OH, –CH(OH)CH2OH, –CH2CH2OH or 18. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 15, characterized in that: R 3a and R 3b Interconnected 19. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 18, characterized in that: s is 1 and t is 1.

20. The compound, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 19, characterized in that: R 1 C 1–6 Alkyl; preferably R 1 It is methyl.

21. The compound, isotopic derivative or pharmaceutically acceptable salt of any one of claims 1, 2 and 4-16, characterized in that: R 3b is benzoxazolyl, –C(O)NHCH3, –C(O)OCH3 or 22. The compound of formula I, its isotopic derivative or pharmaceutically acceptable salt as claimed in claim 1, in, X is N–OR 1 ; R 1 is -CH3; R 3a Selected from hydrogen or C 1–6 alkyl; R 3b For –L 1 –R 3c ; L 1 Independently –[C(R a )(R b )] n –; where n is 1; each R a and R b are each independently hydrogen, -CH3; R 3c Independently for –OR 7a ; said R 7a Selected from hydrogen or C 1–6 alkyl; L 2 For –[C(R 10a )(R 10b )] t – s is 1 and t is 1; R 9a , R 9b , R 10a and R 10b is hydrogen; Ring A is Wherein the * end is connected to the carbonyl group in Formula I, and the # end is connected to the ring B in Formula I; each ---- bond is independently a single bond or a double bond; A 1 is CH or C(R 4a ); A 2 is CH or C(R 4b ); A 3 for CH; A 4 for CH; Each A 6 are independently C or N; Each A 7 are independently C or N; R 4a and R 4b Each independently selected from H, or R 4a and R 4b Together with the atoms that connect them, Ring B, G 1 , G 2 and G 3 for CH; R 2a is halogen or -CH3; R 2b It is cyano.

23. The compound, isotopic derivative or pharmaceutically acceptable salt of claim 1, wherein: The compound is a compound represented by the following formula Ia, or a compound represented by its stereoisomer formula Ib, or a mixture of formula Ia and formula Ib: Among them, R 1 , R 2a , R 2b , R 3a , R 3b ,s,t,G 1 , G 2 , G 3 and Ring A is as defined in any one of claims 1-22.

24. A compound, an isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is any of the following compounds or a mixture of stereoisomers thereof:

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

26. Use of a compound, isotope derivative or pharmaceutically acceptable salt as described in any one of claims 1 to 24, or a pharmaceutical composition containing the same in the preparation of an oxytocin receptor antagonist; or use of a compound, isotope derivative or pharmaceutically acceptable salt as described in any one of claims 1 to 24, or a pharmaceutical composition containing the same in inhibiting an oxytocin receptor.

27. Use of a compound, isotopic derivative or pharmaceutically acceptable salt as claimed in any one of claims 1 to 24 in the preparation of a medicament for preventing and / or treating a disease or condition for which inhibition of oxytocin is known or can be shown to have a beneficial effect; or use of a compound, isotopic derivative or pharmaceutically acceptable salt as claimed in any one of claims 1 to 24 in the prevention and / or treatment of a disease or condition for which inhibition of oxytocin is known or can be shown to have a beneficial effect; or use of a compound, isotopic derivative or pharmaceutically acceptable salt as claimed in any one of claims 1 to 24 in the prevention and / or treatment of a disease or condition for which inhibition of oxytocin is known or can be shown to have a beneficial effect.

28. The use according to claim 27, characterized in that The disease or condition is sexual dysfunction, hyposexual disorder, sexual arousal disorder, orgasmic disorder, dyspareunia, premature ejaculation, pre-natal delivery, delivery complications, appetite and eating disorders, benign prostatic hyperplasia, premature birth, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder or neuropsychiatric disease; preferably, the disease or condition is premature birth.

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