HK40003699B - Amide derivative inhibitor and preparation method and application thereof - Google Patents

Description

Amide derivative inhibitors and their preparation method and application

Technical Field

The present invention belongs to the field of drug synthesis, and in particular relates to an amide derivative inhibitor, a preparation method and an application thereof.

Background Art

The mitosis-activated protein kinase (MAPK) signaling pathway mediates a variety of cellular functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and is a key signaling pathway for cell mitosis and apoptosis. MAPKs are divided into three major types: mitosis-activated protein kinase kinase kinase kinase (MAP3K), mitosis-activated protein kinase kinase (MAP2K), and mitosis-activated protein kinase (MAPK). MAP3K is activated in response to environmental signals, thereby activating MAP2K. MAP2K further activates MAPK, which mediates the corresponding cellular effects by phosphorylating its downstream substrates, such as transcription factors.

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitosis-activated protein kinase kinase kinase 5 (MAP3K5), is a member of the MAPK family and mediates activation of the MAPK signaling pathway. ASK1 can be activated through autophosphorylation in response to stress, including oxidative stress, endoplasmic reticulum stress, and calcium influx, thereby activating downstream MAP2Ks (such as MKK3/6 and MKK4/7). This activation further activates c-Jun N-terminal kinase (JNK) and p38 mitosis-activated protein kinase, leading to cellular effects such as apoptosis. ASK1 activation and its signaling pathways play important roles in neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmunity, and metabolic diseases.

Non-alcoholic steatohepatitis (NASH) has a high prevalence, affecting approximately 2% to 5% of patients globally and domestically. The market size is projected to reach $35 billion to $40 billion by 2025. Currently, there are no approved clinical treatments for NASH. Early-stage research targets for NASH include FXR, PPAR, and GLP. However, FXR and PPAR present significant safety concerns, while GLP is an early diabetes treatment target whose efficacy has not been validated by definitive clinical endpoints. Furthermore, as a peptide drug, it requires daily subcutaneous administration. ASK1 is emerging as a novel mechanism and target for NASH treatment. Its signaling pathway plays a key role in the development and progression of NASH by promoting liver inflammation and fibrosis. ASK1 inhibitors hold great potential for the clinical treatment of NASH and also have potential applications in other disease areas, including neurodegenerative diseases, cardiovascular disease, inflammatory, autoimmune, and metabolic diseases.

Disclosed patent applications for inhibitors that selectively inhibit ASK1 include WO2011008709, WO2016025474, WO2012003387, WO2016105453, WO2016106384 and WO2008008375, among others.

ASK1 inhibitors have good application prospects as drugs in the pharmaceutical industry. The present invention will provide a selective ASK1 inhibitor with a novel structure, and it is found that compounds with such a structure exhibit excellent effects and functions.

Summary of the Invention

The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

in:

M ₁ , M ₂ , M ₃ and M ₄ are each independently selected from N or -CR ₆ ;

X and Y are each independently selected from a bond, -NR ₇ -, -CR ₇ R ₈ -, -S(O) _m -,

Ring A is selected from aryl or heteroaryl, wherein the aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, -( _CH2 ) _nOR9 , -( _CH2 ) _nSR9 , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC (O) _OR9 , - _{( CH2} ) _nS (O _{) mR9} , -( _CH2 ) _{nNR10R11 ,} -( _CH2 ) _nC (O) _NR10R11 , - _{( CH2} ) _nC (O) _NHR10 , -( _CH2 ) _nNR10C (O _{) R9 and} -( _CH2 ) _{nNR10S (} O _{) m} is substituted by one or more substituents in R ₉ ;

_R1 is the same or different and is each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano _group , a cycloalkyl group, a heterocyclic _group , an _aryl group, _{a heteroaryl} group, -( _CH2 ) _nOR9 , -( _CH2 ) _nSR9 , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC ( _O ) _OR9 , -(CH2) _{nS (} O _{)mR9 , -} ( _CH2 ) _nNR10R11 , -( _CH2 ) _nC ( _O ) _NR10R11 , -( _CH2 ) _nC (O) _NHR10 , -(CH2)nNR10C(O) _R9 and _- ( _CH2 ) _nNR10S (O) _{mR 9} ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from a deuterium atom, an alkyl, haloalkyl, a halogen, an amino, a nitro, a cyano, a hydroxyl, an alkoxy, a haloalkoxy, a hydroxyalkyl, a cycloalkyl, a heterocyclic, aryl, _heteroaryl , -( _CH2 ) _nOR12 , -( _{CH2 ) nSR12} , _- ( _CH2 ) _nC (O) _R12 , -( _CH2 ) _nC (O) _OR12 , -( _CH2 ) _{nS (} O _{) mR12 ,} -( _CH2 ) _nNR12R13 , -( _CH2 ) _nC (O) _NR12R13 , -( _CH2 ) _nC (O) _NHR13 , _- ( _CH2 ) _nNR13C (O)R ₁₂ and -(CH ₂ ) _n NR ₁₃ S(O) _m R ₁₂ are substituted by one or more substituents;

_R2 is the same or different and is each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano _group , a cycloalkyl group, a heterocyclic _group , an _aryl group, _{a heteroaryl} group, -( _CH2 ) _nOR9 , -( _CH2 ) _nSR9 , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC ( _O ) _OR9 , -(CH2) _{nS (} O _{)mR9 , -} ( _CH2 ) _nNR10R11 , -( _CH2 ) _nC ( _O ) _NR10R11 , -( _CH2 ) _nC (O) _NHR10 , -(CH2)nNR10C(O) _R9 and _- ( _CH2 ) _nNR10S (O) _{mR 9} ;

R ₃ is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group _, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -( _{CH 2 ) n} OR ₉ , -(CH ₂ ) _n SR ₉ , -(CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) _n C(O) _{OR 9} , -(CH ₂ ) _n S(O) R 9 , -(CH ₂ ) n NR ₁₀ R ₁₁ , -(CH 2 ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

Alternatively, R ₃ and M ₃ , M ₃ and M ₄ are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, respectively, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic, aryl and heteroaryl group, -(CR ₉ R ₁₀ ) _n -, -(CH ₂ ) _n OR ₉ , -(CH ₂ ) _n SR ₉ , -(CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) _n C(O)OR ₉ , -(CH ₂ ) _n S(O) _m R ₉ , -(CH ₂ ) _n NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

Alternatively, R ₁ and X or Y, M ₁ and X or Y are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, respectively, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl, a heterocyclic, aryl and heteroaryl group, -(CR ₉ R ₁₀ ) _n -, -(CH ₂ ) _n OR ₉ , -(CH ₂ ) _n SR ₉ , -(CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) _n C(O)OR ₉ , -(CH ₂ ) _n S(O) _m R ₉ , -(CH ₂ ) _n NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

_R6 , _R7 and _R8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group _, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl _group , a heterocyclic group, an _aryl group _{, a} heteroaryl _group , -( _CH2 ) _nOR9 , -( _CH2 ) _nSR9 , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC (O) _OR9 , -( _CH2 ) _nS (O) _mR9 , _- (CH2 _{) nNR10R11} , -( _CH2 ) _nC (O) _NR10R11 , -( _CH2 ) _nC (O) _NHR10 , -(CH2) _nNR10C (O) _R9 and - _{( CH2} ) _{nNR 10} S(O) _m R ₉ ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from a deuterium atom, an alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH ₂ ) _n OR _{12 ,} -(CH 2 ) _n SR 12 , -(CH ₂ ) n C(O)R ₁₂ , -(CH ₂ ) _n C(O)OR ₁₂ , -(CH _{2 ) n} S(O) _{m R 12} , -(CH ₂ ) _n NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NHR ₁₃ , -(CH ₂ ) _n NR ₁₃ is substituted by one or more substituents selected from C(O)R ₁₂ and -(CH ₂ ) _n NR ₁₃ S(O) _m R ₁₂ ;

R ₉ is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group _, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, _- (CH ₂ ) _n OR ₁₂ , -(CH _{2 ) n} SR ₁₂ , -(CH ₂ ) _n C(O)R ₁₂ , -(CH ₂ ) n C(O)OR ₁₂ , -(CH 2 ) _n S(O) _m R 12 , -(CH ₂ ) _n NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NHR ₁₃ , -(CH ₂ ) _n NR ₁₃ C(O)R ₁₂ and -(CH ₂ ) _n NR ₁₃ S(O) _m R ₁₂ ;

R ₁₀ and R ₁₁ are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are optionally further selected from a deuterium atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, -(CH ₂ ) _{n OR 12} , -(CH ₂ ) _n SR ₁₂ , -(CH ₂ ) _n C(O)R ₁₂ , -(CH ₂ ) n C(O)OR ₁₂ , -(CH ₂ ) _n S(O) _{R 12} , -(CH ₂ ) _n NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _n C(O)NHR ₁₃ , -(CH ₂ ) _n NR ₁₃ C(O)R ₁₂ and -(CH ₂ ) _n NR ₁₃ S(O) _m R ₁₂ ;

R ₁₂ and R ₁₃ are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an ester group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

x is an integer of 0, 1, 2, 3 or 4;

y is an integer of 0, 1 or 2;

m is an integer of 0, 1 or 2; and

n is an integer of 0, 1, 2, 3, 4 or 5.

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

_R4 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a _hydroxyl group, a cyano _group , a cycloalkyl group, a heterocyclic _group , _{an aryl} group, _a heteroaryl group, -( _CH2 ) _nOR9 , -( _{CH2 ) nSR9} , -( _{CH2 ) nC} (O) _R9 , -( _CH2 ) _nC (O _{)OR9 ,} -( _CH2 ) _nS (O) _mR9 , _- ( _CH2 ) _nNR10R11 , -(CH2) _nC (O) _NR10R11 , -( _CH2 ) _nC (O)NHR10, -( _CH2 ) _nNR10C (O) _R9 and _{- (CH2)nNR10S (} O) _mR9 wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -( _CH2 ) _nOR12 , -(CH2) _nSR12 , -( _CH2 ) _nC (O) _R12 , - _{(CH2 ) nC} (O) _OR12 , -( _CH2 ) _{nS (} O) _mR12 , _- ( _CH2 ) _nNR12R13 , -( _CH2 ) _{nC (} O _{) NR12R13} , -( _CH2 ) _nC (O) _NHR13 , -( _{CH2 ) nNR13C} (O _{) R12} and -(CH2) _{n 2} ) substituted by one or more substituents in _{nNR 13} S(O) _m R ₁₂ ;

_R3 and _R4 are linked to form a heterocyclic or heteroaromatic ring, wherein the heterocyclic or heteroaromatic ring is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an _alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, _{a heterocyclic} group, _an aryl group and a heteroaryl group, - _{( CR9R10} ) _n- , -( _CH2 ) _nOR9 , -( _{CH2 ) nSR9} , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC (O) _{OR9 ,} -( _CH2 ) _{nS (} O _{) mR9} , -( _CH2 ) _nNR10R11 , -( _CH2 ) _nC (O)NR10R11, -(CH2) _nC (O) _NHR10 , -( _CH2 ) _n substituted by one or more substituents selected from NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

Alternatively, R ₃ and R ₄ are linked to form a heterocyclic or heteroaromatic ring, and any two substituents on the heterocyclic or heteroaromatic ring may form a cycloalkyl, heterocyclic, aryl and heteroaryl group, wherein the cycloalkyl, aromatic ring, heterocyclic or heteroaromatic ring group is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl, a heterocyclic, aryl and heteroaryl group, -(CR ₉ R ₁₀ ) _n -, -(CH ₂ ) _n OR ₉ , -(CH ₂ ) _n SR ₉ , -(CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) _n C(O)OR ₉ , -(CH ₂ ) _n S(O) _m R ₉ , -(CH ₂ ) _n NR ₁₀ R ₁₁ , -(CH ₂ ) _n substituted by one or more substituents selected from C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

Ring A, M ₁ , M ₂ , X, Y, R ₁ -R ₃ , x, y, m and n are as described in the general formula (I).

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

Ring B is selected from heterocyclyl or heteroaryl;

R ₅ is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group _, a heterocyclic group, an aryl group, a heteroaryl _{group, -(CH 2 ) n OR 9 , -(CH 2 ) n SR 9 , - ( CH 2 ) n} C(O)R ₉ , -(CH ₂ ) _n C(O) _{OR 9} , -(CH ₂ ) _n S(O) m R 9 , -(CH 2 ) n NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -( _CH2 ) _nOR12 , -(CH2) _nSR12 , -( _CH2 ) _nC (O) _R12 , - _{(CH2 ) nC} (O) _OR12 , -( _CH2 ) _{nS (} O) _mR12 , _- ( _CH2 ) _nNR12R13 , -( _CH2 ) _{nC (} O _{) NR12R13} , -( _CH2 ) _nC (O) _NHR13 , -( _{CH2 ) nNR13C} (O _{) R12} and -(CH2) _{n 2} ) _n NR ₁₃ S(O) _m R ₁₂ is substituted by one or more substituents; preferably cyclopropyl;

_R is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, _{a heterocyclic} group, _{an aryl} group, _{a heteroaryl} group, -( _CR9R10 ) _n- , -( _CH2 ) _nOR9 , _- (CH2) _nSR9 , -( _CH2 ) _nC (O) _R9 , -( _CH2 ) _nC ( _O ) _{OR9 ,} -(CH2) _nS (O) _mR9 , _- ( _CH2 ) _nNR10R11 , -( _CH2 )nC(O) _NR10R11 , -(CH2) _nC (O) _NHR10 , _- ( _CH2 ) _nNR10C (O) _R9 , _and -( _CH2 ) _n 12 、-(CH 2 ) nC(O)R 12 、-(CH 2 ) nC(O)OR 12 、-(CH 2 ) nS(O) _m R 12 、-(CH 2 ) nNR ₁₂ R ₁₃ 、-(CH 2 ) nC(O)NR 12 R 13 、-(CH 2 ) nC(O)NHR 13 、-(CH ₂ ) _{nOR 12} 、-(CH ₂ ) _{nSR 12} 、-(CH ₂ ) _nC (O)R ₁₂ 、-(CH ₂ ) _nC (O)OR ₁₂ 、-(CH ₂ ) _nS (O) _m R ₁₂ 、-(CH ₂ ) _{nNR 12} R ₁₃ 、-(CH ₂ ) _nC (O)NR ₁₂ R ₁₃ 、-(CH ₂ ) _nC (O)NHR ₁₃ 、-(CH ₂ ) n _n NR ₁₃ C(O)R ₁₂ and -(CH ₂ ) _n NR ₁₃ S(O) _m R ₁₂ are substituted by one or more substituents; preferably C _1-8 alkyl, C _1-8 alkoxy, or C _1-8 cycloalkyl;

) _nR 9, -(CH 2 )nC(O)R 9, -(CH 2 )nC(O)OR 9, -(CH 2 )nS(O)R 9, -(CH 2 )nNR 10 R 11, -(CH ₂ ) _nC (O) _{NR 10} R ₁₁ , -(CH ₂ ) _nS (O)R ₉ , -(CH _{2 ) nNR 10} R ₁₁ , -( _{CH 2 ) nC (} O _{) NR 10 R 11 ,} - _{( CH 2 ) n} substituted by one or more substituents selected from C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

x-1 is an integer of 1, 2, 3 or 4; and

z is an integer of 0, 1, 2, 3, 4 or 5;

Ring A, M ₁ , M ₂ , X, Y, R ₁ to R ₅ , x, y, m and n are as described in the general formula (I).

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein: Ring A, Ring B, M ₁ , M ₂ , R ₁ , R ₂ , R ₅ , _Ra , x-1, y and z are as described in the general formula (I).

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

Ring B, R ₁ , R ₅ , _Ra , x-1 and z are as described in the general formula (I).

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VI-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

M ₅ is O, -CR ₆ or -NR ₇ ;

R ₁ is selected from hydrogen atom, C _1-8 alkyl or halogen;

_R5 is selected from _C1-8 alkyl, _C3-8 cycloalkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl or 3-6 membered heterocyclyl;

R _a are the same or different and are independently selected from hydrogen atom, cyano group, C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _1-8 haloalkyl group, C _1-8 hydroxyalkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group, -(CH ₂ ) _n OR ₉ , -(CR ₉ R ₁₀ ) _n - or -(CH ₂ ) _n C(O)R ₉ , wherein said C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, haloalkyl group, C _1-8 hydroxyalkyl group, C _1-8 alkoxy group and C _3-8 cycloalkyl group are optionally further substituted with one or _more substituents selected from hydrogen atom, deuterium atom, halogen, cyano group, hydroxyl group, C _1-8 alkyl group, C _1-8 hydroxyalkyl group or C _1-8 alkoxy group; or any two R _a substituents form a C _3-8 cycloalkyl group or C _3-8 heterocyclic group;

_R9 and _R10 are the same or different and are each independently selected from a hydrogen atom, a _C1-8 alkyl group, a _C1-8 haloalkyl group, a _C1-8 hydroxyalkyl group or a _C1-8 alkoxy group;

x-1 is an integer of 1, 2, 3 or 4;

q is 0, 1, or 2; and

z is an integer of 0, 1, 2, 3, 4 or 5.

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

o is an integer of 0, 1, 2, 3, 4 or 5; and

R ₁ , R ₅ , _Ra , x and z are as described in the general formula (VI).

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

_Ra are the same or different and are independently selected from hydrogen, cyano, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, -( _CH2 ) _nOR9 or - _{( CR9R10} ) _n- , wherein said _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy and _C3-6 cycloalkyl are optionally further substituted with one or more substituents selected from hydrogen, halogen, cyano, hydroxyl, _C1-6 alkyl _{or C1-6} alkoxy; or any two _Ra substituents may form a 3-6 membered cycloalkyl _, and

z is an integer of 0, 1, 2 or 3.

In a preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

_M5 is selected from S or CH;

_R3 is selected from the group consisting of _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 alkoxy, _C1-8 haloalkoxy, _C3-8 cycloalkyl and 3-10 membered heterocyclyl, wherein said _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 alkoxy, _C1-8 haloalkoxy, _C3-8 cycloalkyl and 3-10 membered heterocyclyl are optionally further substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, halogen, amino, hydroxyl, cyano, _C1-8 alkoxy, _C1-8 hydroxyalkyl, C3-8 cycloalkyl, _3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl;

_R4 is selected from a hydrogen atom, a _C1-8 alkyl group, a _C1-8 deuterated alkyl group, a _C1-8 alkoxy group, a _C1-8 haloalkoxy group, a _C3-8 cycloalkyl group or a 3-10 membered heterocyclic group;

or a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring formed by linking R ₃ and R ₄ , wherein the 3-10 membered heterocyclic ring or the 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group _, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, -(CR ₉ R ₁₀ ) _n -, -(CH _{2 ) n} OR ₉ , -(CH ₂ ) _n SR ₉ , -(CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) n C(O)OR 9 , -(CH ₂ ) _n S(O) _m R ₉ , -(CH ₂ ) _n NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) is substituted by one or more substituents selected from _-C (O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

R _b is selected from hydrogen atom, C _1-8 alkyl, C _1-8 deuterated alkyl or C _1-8 haloalkyl; wherein R _b can be substituted on the oxo ring or on the M ₅ ring;

p is an integer of 0, 1, 2, 3 or 4; and

q is an integer of 0 or 1.

In a more preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

R ₃ and R ₄ are linked to form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, wherein the 3-10 membered heterocyclic ring or the 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group _, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, -(CR ₉ R ₁₀ ) _n -, - _{(CH 2 ) n} OR ₉ , -(CH ₂ ) _n SR ₉ , _- (CH ₂ ) _n C(O)R ₉ , -(CH ₂ ) _n C(O)OR 9 , -(CH 2 ) _{n S} (O) R ₉ , -(CH ₂ ) _n NR ₁₀ R ₁₁ , -(CH ₂ ) _n C(O)NR ₁₀ R ₁₁ , -(CH ₂ ) _n substituted by one or more substituents selected from C(O)NHR ₁₀ , -(CH ₂ ) _n NR ₁₀ C(O)R ₉ and -(CH ₂ ) _n NR ₁₀ S(O) _m R ₉ ;

R _b is selected from a hydrogen atom, a C _1-8 alkyl group, a C _1-8 deuterated alkyl group or a C _1-8 haloalkyl group;

_R1 is selected from a hydrogen atom, a _C1-8 alkyl group, a _C1-8 deuterated alkyl group or a _C1-8 haloalkyl group;

x-1 is an integer of 0, 1, 2 or 3.

p is an integer of 0, 1, 2, 3 or 4; and

q is an integer of 0 or 1.

In a more preferred embodiment of the present invention, the compound represented by general formula (I) is a compound represented by general formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

in:

Ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group;

R _a are the same or different and are independently selected from hydrogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, -(CH ₂ ) _n OR ₉ , -(CR ₉ R ₁₀ ) _n - or -(CH ₂ ) _n C(O)R ₉ , or any two R _a substituents may form a 3-6 membered cycloalkyl;

R _b is selected from a hydrogen atom, a C _1-8 alkyl group, a C _1-8 deuterated alkyl group or a C _1-8 haloalkyl group;

_R9 and _R10 are independently selected from a hydrogen atom or a _C1-8 alkyl group;

z is an integer of 0, 1, 2, 3 or 4; and

p is 0, 1 or 2.

In a preferred embodiment of the present invention, in each of the general formulae, stereoisomers thereof or pharmaceutically acceptable salts thereof, R ₁ is selected from C _1-8 alkyl, C _3-8 cycloalkyl, 5-10 membered heteroaryl and halogen, preferably 5-6 membered heteroaryl, halogen, C _1-6 alkyl, more preferably pyrazole, fluorine atom, methyl.

In a preferred embodiment of the present invention, in the general formulae shown, stereoisomers thereof or pharmaceutically acceptable salts thereof, _Ra is selected from a hydrogen atom, a cyano group, a _C1-8 alkyl group, a _C2-8 alkenyl group, a _C2-8 alkynyl group, a _C1-8 haloalkyl group, a _C1-8 hydroxyalkyl group, a cyano- _{substituted C1-8 alkyl group, a C1-8 alkoxy group, a C3-8 cycloalkyl group, -(CH2)nOR9 , - ( CR9R10 ) n- or} -( _CH2 ) _nC ( _O ) _R9 , preferably from a hydrogen atom, a cyano group, a hydroxyl group, a C1-6 alkyl group, a _C2-6 alkenyl group, a C2-6 alkynyl group, a _{hydroxylated C1-6} alkyl group, a _C1-6 haloalkyl group, a _3-6 membered heterocyclyl group, a _C3-6 cycloalkyl group; most preferably a methyl group, an ethyl group, a vinyl group, an ethynyl group or a trifluoromethyl group.

In a preferred embodiment of the present invention, in the general formulae, stereoisomers thereof or pharmaceutically acceptable salts thereof, R ₅ is selected from hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, halogen, C _3-8 cycloalkyl, 3-10 membered heterocyclic group, preferably hydrogen atom, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group; R ₅ is most preferably cyclopropyl, isopropyl, hydroxyisopropyl, tert-butyl, trifluoromethyl or

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound of each general formula, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

In a preferred embodiment of the present invention, it also relates to a method for preparing a compound of general formula (I), which is an intermediate for preparing a compound of general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

in:

Ring B is a heterocyclic group;

R _a is selected from a hydrogen atom, a cyano group, a C _1-8 alkyl group, _{a C 2-8 alkenyl} group, a C _2-8 alkynyl group, a C _1-8 haloalkyl group, a C _1-8 hydroxyalkyl group, a cyano-substituted C 1-8 alkyl group, a C _1-8 alkoxy group, a C _3-8 cycloalkyl group, -(CH ₂ ) _n OR ₉ , -(CR ₉ R ₁₀ ) _n - or -(CH ₂ ) _n C(O)R ₉ , preferably a hydrogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-6 hydroxyalkyl group, a halosubstituted C _1-6 alkyl group, a 3-6 membered heterocyclic group, a C _3-6 cycloalkyl group; most preferably a methyl group, an ethyl group, a vinyl group, an ethynyl group or a halosubstituted C _1-3 alkyl group;

z is 0, 1, 2, 3, 4 or 5.

In a preferred embodiment of the present invention, there is also provided a method for preparing a compound represented by general formula (I), which is a compound represented by general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound of general formula (IX-A) and the compound of general formula (IX) are coupled to obtain the compound of general formula (III).

In a preferred embodiment of the present invention, it also relates to a method for preparing a compound of general formula (I), which is an intermediate for preparing a compound of general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

in:

Ring C is a heterocyclyl or heteroaryl group;

R _b is selected from a hydrogen atom, a C _1-8 alkyl group, a C _1-8 deuterated alkyl group or a C _1-8 haloalkyl group; and

p is 0, 1 or 2.

In a preferred embodiment of the present invention, there is also provided a method for preparing a compound represented by general formula (I), which is a compound represented by general formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound of general formula (X-1) and the compound of general formula (X) are coupled to obtain the compound of general formula (VIII-B).

The present invention also relates to a synthesis scheme of a compound represented by the intermediate general formula (IX), its stereoisomers or pharmaceutically acceptable salts thereof.

The compound represented by the general formula (IX) is synthesized by the one-pot method according to the above scheme, wherein the definitions of the various groups are as shown in the general formula (IX).

The present invention also relates to a method for treating and/or preventing diseases with ASK1-mediated pathological characteristics, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of an ASK1 inhibitor drug.

The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders and ASK1, wherein the inflammatory disorder is preferably non-alcoholic steatohepatitis (NASH).

The present invention further relates to a method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating non-alcoholic steatohepatitis (NASH).

The present invention also relates to a method for treating, preventing and/or treating neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, and metabolic disorders, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Detailed Description of the Invention

Unless otherwise stated, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched-chain isomers thereof, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to _-CH2- , "ethylene" refers to -( _CH2 ) _2- , "propylene" refers to -( _CH2 ) _3- , "butylene" refers to -( _CH2 ) _4- , etc. The above substituents may be attached to different carbon atoms to form a carbon chain, or to a single carbon atom to form a cycloalkyl group. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; and most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Preferably, the alkoxy group containing 1 to 8 carbon atoms is used, more preferably the alkoxy group containing 1 to 6 carbon atoms is used, and most preferably the alkoxy group containing 1 to 3 carbon atoms is used. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"Alkenyl" refers to a chain alkenyl group, also known as an alkene group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms; wherein the alkenyl group can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), preferably an alkynyl containing 2 to 8 carbon atoms, more preferably an alkynyl containing 2 to 6 carbon atoms, and most preferably an alkynyl containing 2 to 3 carbon atoms. The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carboxyl" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetylene glycol.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium.

“Dppf” refers to 1,1’-bis(diphenylphosphino)ferrocene.

"HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis(trimethylsilylamide).

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically/pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

DETAILED DESCRIPTION

The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

Example

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD), and deuterated chloroform (CDCl ₃ ) as the solvents, with tetramethylsilane (TMS) as the internal standard.

Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

Example 1

Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Step 1: Preparation of 5-amino-2-fluoro-4-methylbenzonitrile

5-Bromo-4-fluoro-2-methylaniline (10.0 g, 49.0 mmol) and cuprous cyanide (8.78 g, 98.0 mmol) were mixed in NMP (50 mL) and stirred at 180°C for 1 hour under nitrogen, then at 100°C overnight. After cooling, 28 wt% aqueous ammonia solution was added, stirred for 15 minutes, and extracted three times with EtOAc. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield the title compound, 5-amino-2-fluoro-4-methylbenzonitrile (5.70 g, 78%).

MS m/z(ESI):151.1[M+H] ⁺ .

Step 2: Preparation of 5-((2-cyclopropyl-2-carbonylethyl)amino)-2-fluoro-4-methylbenzonitrile

5-Amino-2-fluoro-4-methylbenzonitrile (5.70 g, 38.0 mmol), _K₂CO₃ (6.30 g, 45.6 mmol), KI (0.630 g, 3.80 mmol), and 2-bromo-1-cyclopropylethane-1 _- one (7.43 g, 45.6 mmol) were mixed in DMF (50 mL) and stirred at 80°C under nitrogen for 90 minutes. After the reaction mixture was cooled, 2-bromo-1-cyclopropylethane-1-one (3.00 g, 18.4 mmol) and _K₂CO₃ (2.54 g, 18.4 mmol) were added, and the _mixture was stirred at 75°C for another 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction flask. After standing for 15 minutes, the mixture was filtered. The filter cake was washed with water and dried to give the title compound 5-((2-cyclopropyl-2-carbonylethyl)amino)-2-fluoro-4-methylbenzonitrile as a crude product (6.80 g, 77%).

MS m/z(ESI):233.1[M+H] ⁺ .

Step 3: Preparation of 5-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile

A solution of 5-((2-cyclopropyl-2-carbonylethyl)amino)-2-fluoro-4-methylbenzonitrile (6.80 g, 29.3 mmol) and KSCN (5.69 g, 58.6 mmol) _in acetic acid (100 mL) was stirred at 110°C for 4 hours. After cooling, the mixture was concentrated, and _CH₂Cl₂ and water were added. The organic phase was separated, and the aqueous phase was extracted once more _{with CH₂Cl₂} . The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 8.00 g of crude 5-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile, which was used directly in the next reaction.

MS m/z(ESI):274.1[M+H] ⁺ .

Step 4: Preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile

To a solution of the crude product in acetic acid (160 mL) and water (32 mL) was slowly added dropwise hydrogen peroxide (30 wt%, 10.0 mL) at 50°C. After complete addition, the mixture was stirred at the same temperature for one hour. After cooling to room temperature, _{aqueous Na₂SO₃} (20 wt%, 100 mL) was slowly added, followed by stirring for 30 minutes. The organic solvent was removed by concentration, and the aqueous phase was extracted twice with _CH₂Cl₂ . The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield the title compound, 5-(4-cyclopropyl-1H-imidazol-1 _- yl)-2-fluoro-4-methylbenzonitrile (3.3 g, 47% yield over two steps).

MS m/z(ESI):242.1[M+H] ⁺ .

Step 5: Synthesis of 6-aminomethylpicolinohydrazide

Methyl 6-aminomethyl picolinate (2.0 g, 13 mmol) was dissolved in ethanol (60 mL) at room temperature, and hydrazine hydrate (4.1 g, 66 mmol) was added. The reaction mixture was heated to 80°C and stirred at this temperature for 5 hours. After slowly cooling to room temperature, the precipitated solid was filtered and the filter cake was collected to obtain the title compound, 6-aminomethyl picolinate hydrazide (1.6 g, 80%).

MS m/z(ESI):153.2[M+H] ⁺ .

Step 6: Synthesis of 6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (300 mg, 1.97 mmol) was dissolved in 2-pentanol (5 mL) and acetic acid (1 mL), and 5-methoxy-3,4-dihydro-2H-pyrrole (195 mg, 1.97 mmol) was added. The reaction was heated to 125°C and stirred at this temperature for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to afford the title compound, 6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (360 mg, 91%).

MS m/z(ESI):202.1[M+H] ⁺ .

Step 7: Synthesis of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (1.8 g, 7.47 mmol) was dissolved in 30 mL of concentrated hydrochloric acid, heated under reflux and stirred overnight, cooled and concentrated, and dried to give 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (2 g, crude product), which was used directly in the next step.

The above 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (100 mg, the above crude product) was dissolved in thionyl chloride (5 mL) at room temperature, heated under reflux and stirred for 2 hours, cooled and concentrated under reduced pressure to obtain a light yellow solid product, which was directly used in the next reaction.

Step 8: Synthesis of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (100 mg, crude product from the previous step) in THF (5 mL) and pyridine (5 mL) was added 6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (43 mg, 0.22 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added dropwise and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the title compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (60 mg, 63%).

¹ H NMR (400MHz, CDCl ₃ )δ9.05(d,J＝15.1Hz,1H),8.34(d,J＝8.2Hz,1H),8.13-8.02(m,2H),7.88(t,J＝8.0Hz,1H),7.48(m,1H),7.20(d,J＝12.4Hz,1H),6.80 (m,1H),4.53-4.34(m,2H),3.04(t,J＝7.7Hz,2H),2.96-2.74(m,2H),2.30(s,3H),1.98-1.82(m,1H),0.90(m,2H),0.88-0.76(m,2H);

MS m/z(ESI):444.1[M+H] ⁺ .

Example 2

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)benzamide was as described in Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ9.00(d,J＝14.9Hz,1H),8.29(d,J＝0.8Hz,1H),7.99(d,J＝7.3Hz,1H),7. 92-7.90(m,1H),7.83(t,J＝7.9Hz,1H),7.43(d,J＝1.0Hz,1H),7.12(d,J＝1 2.3Hz,1H),6.73(m,1H),4.57(m,2H),3.03-3.01(m,2H),2.22(s,3H),1.8 5(m,3H),1.81(m,2H),1.74(m,2H),0.85-0.82(m,2H),0.79-0.76(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 3

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)benzamide refers to Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ8.98(d,J＝14.6Hz,1H),8.27(d,J＝8.2Hz,1H),7.99(t,J＝7.5Hz,2H),7. 81(t,J＝8.0Hz,1H),7.39(s,1H),7.12(d,J＝12.3Hz,1H),6.72(s,1H),4.41 (t,J＝6.0Hz,2H),3.00(t,J＝6.4Hz,2H),2.22(s,3H),2.03-1.95(m,2H),1 .93-1.87(m,2H),1.85-1.79(m,1H),0.88-0.79(m,2H),0.78-0.70(m,2H);

MS m/z(ESI):458.2[M+H] ⁺ .

Example 4

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide was as described in Example 1.

¹ H NMR (400 MHz, CDCl ₃ )δ9.08(d,J＝14.7Hz,1H),8.41-8.35(m,1H),8.13-8.07(m,1H),8.05(d,J＝7 .3Hz,1H),7.91(t,J＝8.0Hz,1H),7.48(d,J＝1.2Hz,1H),7.20(d,J＝12.3Hz,1H ),6.80(d,J＝1.2Hz,1H),5.06(s,2H),4.59(t,J＝5.2Hz,2H),4.09(t,J＝5.3H z,2H),2.30(s,3H),1.95-1.86(m,1H),0.95-0.87(m,2H),0.87-0.78(m,2H);

MS m/z(ESI):460.2[M+H] ⁺ .

Example 5

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)benzamide was as described in Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ9.01(d,J＝14.5Hz,1H),8.29(d,J＝8.3Hz,1H),7.99(t,J＝8.3Hz,2H),7.83(d,J＝8.0Hz,1H),7.42(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H) ,4.45(t,J＝5.5Hz,2H),4.27(s,2H),3.24(t,J＝5.5Hz,2H),2.33(s,1H) ,2.22(s,3H),1.84-1.82(m,1H),0.87-0.80(m,2H),0.78-0.75(m,2H);

MS m/z(ESI):459.2[M+H] ⁺ .

Example 6

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)benzamide refers to Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ8.98(d,J＝14.8Hz,1H),8.29(d,J＝8.2Hz,1H),8.01(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H), 4.49(t,J＝5.5Hz,2H),3.80(s,2H),2.83(t,J＝5.5Hz,2H),2.48(s,3H),2.22(s,3H),1.85(m,1H),0.85-0.82(m,2H),0.79-077(m,2H);

MS m/z(ESI):473.2[M+H] ⁺ .

Example 7

4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)methylpicolinamide

The preparation method of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)methylpicolinamide was as described in Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ10.16(s,1H),8.68(d,J＝5.4Hz,1H),8.49(s,1H),8.27(d,J＝2.1Hz,1H),8.01(d,J＝1.0Hz,1H),7.92-7.64(m,2H),7.63-7.41(m,2H),7. 22(d,J＝1.0Hz,1H),4.35(t,J＝7.1Hz,2H),3.08-3.04(m,2H),2.89-2.84(m,2H),1.94-1.90(m,1H),0.95-0.91(m,2H),0.87-0.84(m,2H);

MS m/z(ESI):412.2[M+H] ⁺ .

Example 8

(R)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

Step 1: Synthesis of (R)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole

Under ice-cooling, trimethyloxonium tetrafluoroborate (3.55 g, 24.0 mmol) was added portionwise to a solution of (R)-5-methylpyrrolidin-2-one (1.7 g, 17.2 mmol) in dichloromethane (40 mL). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The mixture was concentrated under reduced pressure to obtain a crude product, which was used directly in the next reaction.

MS m/z(ESI):114.1[M+H] ⁺ .

Step 2 Synthesis of (R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (2.35 g, 15.4 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL), and (R)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole (1.93 g, 17.1 mmol) was added. The reaction was heated to 125°C and stirred at this temperature for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. After column chromatography, the title compound (R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (1.62 g, 49% yield over two steps) was obtained.

¹ H NMR (400MHz, CDCl ₃ )δ7.65(m,1H),7.61-7.42(m,1H),6.54(m,1H),5.17-4.88(m,1H),3.18-2.77(m,3H),2.43-2.31(m,1H),1.53-1.37(m,3H);

MS m/z(ESI):216.1[M+H] ⁺ .

Step 3 Synthesis of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (298 mg, 1.07 mmol) in THF (10 mL) and pyridine (10 mL) was added (R)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (139 mg, 0.65 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (12 mg, 0.097 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the title compound (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide (151 mg, yield 51%).

¹ H NMR (400MHz, CDCl ₃ )δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5 .03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1. 90(m,1H),1.56(d,J=6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H);

MS m/z(ESI):458.1[M+H] ⁺ .

Example 9

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CDCl ₃ )δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5 .03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1. 90(m,1H),1.56(d,J＝6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H);

MS m/z(ESI):458.1[M+H] ⁺ .

Example 10

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

The first step is the synthesis of 5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole

Under ice-cooling, trimethyloxonium tetrafluoroborate (0.66 g, 4.45 mmol) was added portionwise to a dichloromethane solution (30 mL) of 5,5-dimethylpyrrolidin-2-one (0.36 g, 3.2 mmol). The reaction mixture was then slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The mixture was concentrated under reduced pressure to obtain a crude product that was used directly in the next reaction.

MS m/z(ESI):128.2[M+H] ⁺ .

Step 2 Synthesis of 6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (435 mg, 2.86 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL), and 5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole (404 mg, 3.2 mmol) was added. The reaction was heated to 125°C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting mixture was purified by column chromatography to afford the title compound, 6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (380 mg, 52% yield over two steps).

MS m/z(ESI):230.1[M+H] ⁺ .

Step 3 Synthesis of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (70 mg, 0.25 mmol) in THF (5 mL) and pyridine (5 mL) was added 6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (35 mg, 0.15 mmol) at room temperature, and 4-dimethylaminopyridine (4.6 mg, 0.04 mmol) was added. The reaction was heated to 45°C and stirred at this temperature for 2 hours, then quenched by the addition of water (5 mL), extracted with dichloromethane (50 mL × 2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give the title compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (39 mg, yield 54%).

¹ H NMR (400MHz, CDCl ₃ )δ9.05(d,J＝16.6Hz,1H),8.29-8.27(m,1H),8.09-7.94(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.2Hz,1H),6.73 (s,1H),3.10-2.86(m,2H),2.60-2.45(m,2H),2.22(s,3H),1.88-1.82(m,1H),1.72(s,6H),0.87-0.82(m,2H),0.78-0.75(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 11

(S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

¹ H NMR (400 MHz, CDCl ₃ )δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7 .49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m, 1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2 .82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H);

MS m/z(ESI):488.2[M+H] ⁺ .

Example 12

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

¹ H NMR (400 MHz, CDCl ₃ )δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7 .49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m, 1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2 .82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H);

MS m/z(ESI):488.2[M+H] ⁺ .

Example 13

(R)-2-Fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.22(d,J＝1.4Hz,1H),8.45(d,J＝8.2Hz,1H),8.10(t,J＝8.0Hz,1H),8.05-7.97(m,2H),7.66(s,1H),7.50(d,J＝10.9Hz,1H),5. 57-5.45(m,1H),3.47-3.36(m,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.59(d,J＝6.5Hz,3H),1.43(d,J＝6.9Hz,6H);

MS m/z(ESI):460.2[M+H] ⁺ .

Example 14

(S)-2-Fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.21(s,1H),8.55-8.30(m,1H),8.18-7.96(m,3H),7.67(s,1H),7.51(d,J＝9.8Hz,1H),5.54-5.34(m,1H) ,3.34(s,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.57(d,J＝5.8Hz,3H),1.42(d,J＝6.9Hz,6H);

MS m/z(ESI):460.2[M+H] ⁺ .

Example 15

(R)-5-(4-(tert-Butyl)-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-5-(4-(tert-butyl)-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H), 5.64(s,1H),3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J=5.5Hz,3H),1.48(s,9H);

MS m/z(ESI):474.2[M+H] ⁺ .

Example 16

(S)-5-(4-(tert-Butyl)-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-5-(4-(tert-butyl)-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H), 5.64(s,1H),3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J=5.5Hz,3H),1.48(s,9H);

MS m/z(ESI):474.2[M+H] ⁺ .

Example 17

(S)-2-Fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (S)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

MS m/z(ESI):490.2[M+H] ⁺ .

Example 18

(R)-2-Fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (R)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

MS m/z(ESI):490.2[M+H] ⁺ .

Example 19

(S)-5-(4-(tert-Butyl)-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (S)-5-(4-(tert-butyl)-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

MS m/z(ESI):504.2[M+H] ⁺ .

Example 20

(R)-5-(4-(tert-Butyl)-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of (R)-5-(4-(tert-butyl)-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide refers to Example 8.

MS m/z(ESI):504.2[M+H] ⁺ .

Example 21

(R)-2-Fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzamide

The preparation method of (R)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzamide refers to Example 8.

MS m/z(ESI):486.2[M+H] ⁺ .

Example 22

(S)-2-Fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzamide

The preparation method of (S)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzamide refers to Example 8.

MS m/z(ESI):486.2[M+H] ⁺ .

Example 23

(R)-2-Fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(oxetan-3-yl)-1H-imidazol-1-yl)benzamide

The preparation method of (R)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(oxetan-3-yl)-1H-imidazol-1-yl)benzamide refers to Example 8.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 24

(S)-2-Fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(oxetan-3-yl)-1H-imidazol-1-yl)benzamide

The preparation method of (S)-2-fluoro-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-(oxetan-3-yl)-1H-imidazol-1-yl)benzamide refers to Example 8.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 25

(R)-2-Fluoro-5-(4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-2-fluoro-5-(4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide was referred to Example 8. MS m/z (ESI): 476.2 [M+H] ⁺ .

Example 26

(S)-2-Fluoro-5-(4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-2-fluoro-5-(4-(2-hydroxypropane-2-yl)-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

MS m/z(ESI):476.2[M+H] ⁺ .

Example 27

N-(6-(7-Acetyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation of N-(6-(7-acetyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide was the same as in Example 1.

¹ H NMR (400MHz, CDCl ₃ )δ9.00(d,J＝15.0Hz,1H),8.31(m,1H),8.15-7.94(m,2H),7.84(t,J＝8.0Hz,1H),7.47-7.37(m,1H),7.14(m,1H),6.74(s,1H ),4.95(m,2H),4.62-4.44(m,2H),3.93(m,2H),2.22(s,3H),2.19(s,3H),1.85(m,1H),0.88-0.81(m,2H),0.78-0.75(m,2H);

MS m/z(ESI):501.2[M+H] ⁺ .

Example 28

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(7-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(7-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400 MHz, CD ₃ OD)δ8.20(d,J＝8.1Hz,1H),7.87(t,J＝7.9Hz,1H),7.83-7.78(m,1H),7.68-7. 62(m,2H),7.25(d,J＝11.2Hz,1H),6.96(s,1H),4.58-4.50(m,1H),4.34-4.23( m,1H),3.35-3.26(m,1H),2.94-2.86(m,1H),2.38-2.28(m,1H),2.17(s,3H),1 .84-1.77(m,1H),1.35(d,J＝7.0Hz,3H),0.81-0.77(m,2H),0.68-0.62(m,2H);

MS m/z(ESI):458.2[M+H] ⁺ .

Example 29

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(6-methoxy-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(6-methoxy-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide can be referred to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.11(s,1H),8.35(s,1H),8.11-7.90(m,3H),7.60(s,1H),7.50(d,J＝10.3Hz,1H),4.71-4.62(m,2H),3.46(s ,3H),3.39-3.35(m,2H),3.15-3.03(m,1H),2.35(s,3H),2.13-2.06(m,1H),1.19-1.13(m,2H),0.97-0.88(m,2H);

MS m/z(ESI):474.2[M+H] ⁺ .

Example 30

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide can be referred to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ8.22(d,J＝8.1Hz,1H),7.88(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.64(d,J＝6.6Hz,1H),7.5 8(d,J＝1.2Hz,1H),7.27(d,J＝11.1Hz,1H),6.94(d,J＝1.1Hz,1H),4.70-4.63(m,1H),4.18-4.14( m,1H),3.13-3.07(m,1H),2.79-2.72(m,1H),2.55-2.43(m,1H),2.17(s,3H),1.82-1.77(m,1H) ,1.01-0.91(m,1H),0.81-0.74(m,2H),0.67-0.62(m,2H),0.53-0.47(m,2H),0.28-0.16(m,2H);

MS m/z(ESI):484.2[M+H] ⁺ .

Example 31

N-(6-(5'H,7'H-spiro[cyclopropane-1,6'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation method of N-(6-(5'H,7'H-spiro[cyclopropane-1,6'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide refers to Example 8.

MS m/z(ESI):470.2[M+H] ⁺ .

Example 32

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide can be referred to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ8.36-8.28(m,2H),8.00-7.86(m,2H),7.77(d,J＝5.9Hz,1H),7.37(d,J＝10.8Hz,1H),7.12(s,1H),4.3 1(s,2H),2.87(s,2H),2.29(s,3H),1.97-1.88(m,1H),1.35(s,6H),0.96-0.89(m,2H),0.80-0.74(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 33

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide can be referred to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7. 98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40- 3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2 .06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H);

MS m/z(ESI):458.2[M+H] ⁺ .

Example 34

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7. 98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40- 3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2 .06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H);

MS m/z(ESI):458.2[M+H] ⁺ .

Example 35

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7. 98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40- 3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2 .06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H);

MS m/z(ESI):458.2[M+H] ⁺ .

Example 36

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-((R)-5-((R)-1-methoxyethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

Refer to Example 8 for the preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-((R)-5-((R)-1-methoxyethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.

¹ H NMR (400MHz, CDCl ₃ )δ8.96(d,J＝15.6Hz,1H),8.31(m,1H),8.01(m,2H),7.83(t,J＝8.0Hz,1H),7.41(s,1H),7.12(d,J＝12.6Hz,1H),6.73(s, 1H),5.08(m,1H),4.03-3.92(m,1H),3.36(s,3H),2.96-2.87(m,2H),2.87-2.64(m,3H),2.21(s,3H),0.85-0.79(m,7H);

MS m/z(ESI):502.2[M+H] ⁺ .

Example 37

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

For the synthesis of (S)-5-vinylpyrrolidin-2-one, see J.Org.Chem., 2017, 82, 532–540.

MS m/z(ESI):112.2[M+H] ⁺ .

Step 1: Synthesis of (S)-5-methoxy-2-vinyl-3,4-dihydro-2H-pyrrole

Under ice-cooling, (S)-5-vinylpyrrolidin-2-one (0.26 g, 2.34 mmol) was dissolved in dichloromethane (60 mL), and trimethyloxonium tetrafluoroborate (0.48 g, 3.28 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The organic solvent was concentrated under reduced pressure to obtain a crude product that was used directly in the next reaction.

MS m/z(ESI):126.1[M+H] ⁺ .

Step 2: Synthesis of (S)-6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

6-Aminomethylpicolinohydrazide (321 mg, 2.11 mmol) was dissolved in a mixture of 2-pentanol (10 mL) and acetic acid (1 mL) at room temperature, and (S)-5-methoxy-2-vinyl-3,4-dihydro-2H-pyrrole (293 mg, 2.34 mmol) was added. The reaction mixture was heated to 125°C and stirred for 12 hours. After cooling to room temperature, the organic solvent was concentrated under reduced pressure, and saturated aqueous _NaHCO₃ (5 mL) was added. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated and separated by column chromatography to give the title compound (S)-6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (240 mg, 50% yield over two steps).

MS m/z(ESI):228.1[M+H] ⁺ .

Step 3: Synthesis of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (90 mg, 0.33 mmol) in THF (5 mL) and pyridine (5 mL) was added (S)-6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (44 mg, 0.19 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (5.9 mg, 0.048 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added dropwise and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated and then column chromatography was performed to obtain the title compound (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide (53 mg, yield 58%).

¹ H NMR (400MHz, CD ₃ OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m, 2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H) ,5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1 H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H);

MS m/z(ESI):470.1[M+H] ⁺ .

Example 38

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

Refer to Example 37 for the preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide.

¹ H NMR (400MHz, CD ₃ OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m, 2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H) ,5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1 H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H);

MS m/z(ESI):470.1[M+H] ⁺ .

Example 39

(R)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

Refer to Example 37 for the preparation of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide.

¹ H NMR (400MHz, CD ₃ OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m, 2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H) ,5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1 H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H);

MS m/z(ESI):470.1[M+H] ⁺ .

Example 40

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

Step 1: Synthesis of (S)-5-methoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole

Under ice-cooling, (S)-5-(Trifluoromethyl)pyrrolidin-2-one (0.6 g, 3.92 mmol) was dissolved in dichloromethane (40 mL), and trimethyloxonium tetrafluoroborate (0.81 g, 5.5 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ solution (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The organic solvent was concentrated under reduced pressure to obtain a crude product that was used directly in the next reaction.

MS m/z(ESI):168.2[M+H] ⁺ .

Step 2: Synthesis of (S)-6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (620 mg, 3.71 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S)-5-methoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (650 mg, 3.89 mmol) was added. The reaction was heated to 125°C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated, and the title compound (S)-6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (560 mg, 56% yield over two steps) was isolated by column chromatography.

MS m/z(ESI):270.2[M+H] ⁺ .

Step 3: Synthesis of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (100 mg, 0.36 mmol) in THF (5 mL) and pyridine (5 mL) was added (S)-6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (43 mg, 0.22 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated and separated by column chromatography to obtain the title compound (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide (51 mg, yield 62%).

¹ H NMR (400MHz, CDCl ₃ )δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H) ,6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H);

MS m/z(ESI):512.2[M+H] ⁺ .

Example 41

5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

Refer to Example 40 for the preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide.

¹ H NMR (400MHz, CDCl ₃ )δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H) ,6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H);

MS m/z(ESI):512.2[M+H] ⁺ .

Example 42

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide was performed with reference to Example 40.

¹ H NMR (400MHz, CDCl ₃ )δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H) ,6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H);

MS m/z(ESI):512.2[M+H] ⁺ .

Example 43

(S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Synthesis of tert-butyl (S)-2-formyl-5-carbonylpyrrolidine-1-carboxylate: Org. Lett. 2011, 13, 2634-2637

Step 1: Synthesis of S-ethyl (S)-5-carbonylpyrrolidine-2-methylsulfate

Under ice-cooling, (S)-5-carbonylpyrrolidine-2-carboxylic acid (20 g, 150 mmol) was dissolved in _CH₂Cl₂ (300 _mL ) and DMF (160 mL). DMAP (1.85 g, 15.0 mmol), ethanethiol (13.8 mL, 180 mmol), and DCC (40.5 g, 180 mmol) were then added sequentially. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 16 hours. Saturated aqueous _NaHCO₃ (20 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound, S-ethyl (S)-5-carbonylpyrrolidine-2-methylsulfate (18.5 g, 69%).

MS m/z(ESI):174.1[M+H] ⁺ .

Step 2: Synthesis of tert-butyl (S)-2-((ethylthio)carbonyl)-5-carbonylpyrrolidine-1-carboxylate

Under ice-cooling, S-ethyl (S)-5-carbonylpyrrolidine-2-methylsulfate (6 g, 34.6 mmol) was dissolved in MeCN (35 mL), followed by the addition of _Boc₂O (8.28 mL, 35.0 mmol) and DMAP (470 mg, 3.46 mmol). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 2 hours. Saturated aqueous _NaHCO₃ (20 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound, S-ethyl (S)-5-carbonylpyrrolidine-2-methylsulfate (7.3 g, 77%).

MS m/z(ESI):296.1[M+Na] ⁺ .

Step 3: Synthesis of tert-butyl (S)-2-formyl-5-carbonylpyrrolidine-1-carboxylate

Under ice, S-ethyl (S)-5-carbonylpyrrolidine-2-methylsulfate (1.0 g, 3.66 mmol) was dissolved in acetone (15 mL), followed by the addition of Pd/C (160 mg) and EtSiH (1.28 g, 10.98 mmol). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 1 hour. The mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure to afford an oily product (0.72 g) which was used directly in the next step.

¹ H NMR (400MHz, CDCl ₃ ) δ9.58(s,1H),4.63-4.41(m,1H),2.54-2.48(m,2H),2.28-2.15(m,1H),2.07-2.01(m,1H),1.46(s,9H);

MS m/z(ESI):214.1[M+H] ⁺ .

Step 4: Synthesis of (S)-5-carbonylpyrrolidine-2-carbaldehyde

Under ice-cooling, tert-butyl (S)-2-formyl-5-carbonylpyrrolidine-1-carboxylate (0.72 g, 3.38 mmol) was dissolved in CH ₂ Cl ₂ (10 mL), and TFA (2.5 mL) was added sequentially. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 2 hours. After concentration under reduced pressure, the crude oil (400 mg) was obtained and used directly in the next step.

MS m/z(ESI):114.1[M+H] ⁺ .

Step 5: Synthesis of (S)-5-ethynylpyrrolidin-2-one

Under ice-cooling, (S)-5-carbonylpyrrolidine-2-carbaldehyde (400 mg, crude product from the previous step) was dissolved in MeOH (15 mL), followed by the addition _{of K₂CO₃} (931 mg, 6.74 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.01 g, 4.04 mmol). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 12 hours. Saturated brine (20 mL) was added, and _the mixture was extracted with _CH₂Cl₂ (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound, (S)-5-ethynylpyrrolidin-2-one (260 mg, 71%).

¹ H NMR (400MHz, CDCl ₃ ) δ6.68 (s, 1H), 4.38-4.35 (m, 1H), 2.50-2.40 (m, 2H), 2.37 (d, J = 2.2Hz, 1H), 2.33-2.26 (m, 1H), 2.22-2.15 (m, 1H);

MS m/z(ESI):110.1[M+H] ⁺ .

Step 6: Synthesis of (S)-2-ethynyl-5-methoxy-3,4-dihydro-2H-pyrrole

Under ice-cooling, (S)-5-ethynylpyrrolidin-2-one (0.26 g, 2.38 mmol) was dissolved in _CH₂Cl₂ (10 mL) _and trimethyloxonium tetrafluoroborate (0.67 g, 4.53 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added and the mixture was extracted with _{CH₂Cl₂ (} 50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The organic solvent was concentrated under reduced pressure to obtain a crude product (315 mg) which was used directly in the next reaction.

MS m/z(ESI):124.2[M+H] ⁺ .

Step 7: Synthesis of (S)-6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (320 mg, 2.1 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S)-2-ethynyl-5-methoxy-3,4-dihydro-2H-pyrrole (315 mg, crude product from the previous step) was added. The reaction was heated to 125°C and stirred at this temperature for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous NaHCO₃ ( ₅ mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated, and the title compound, (S)-6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine, was isolated by column chromatography (362 mg, 46% yield over two steps).

MS m/z(ESI):226.2[M+H] ⁺ .

Step 8: Synthesis of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

At room temperature, (S)-6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (80 mg, 0.36 mmol) was added to a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (220 mg, 0.79 mmol) in THF (25 mL) and pyridine (35 mL), followed by the addition of 4-dimethylaminopyridine (15 mg, 0.12 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated and separated by column chromatography to give the title compound (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (122 mg, yield 73%).

¹ H NMR (400 MHz, CDCl ₃ )δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7 .0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1 H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz ,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H);

MS m/z(ESI):468.2[M+H] ⁺ .

Example 44

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Refer to Example 43 for 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide.

¹ H NMR (400 MHz, CDCl ₃ )δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7 .0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1 H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz ,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H);

MS m/z(ESI):468.2[M+H] ⁺ .

Example 45

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Refer to Example 43 for (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide.

¹ H NMR (400 MHz, CDCl ₃ )δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7 .0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1 H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz ,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H);

MS m/z(ESI):468.2[M+H] ⁺ .

Example 46

(S)-N-(6-(5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation method of (S)-N-(6-(5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.1 7-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H);

MS m/z(ESI):469.1[M+H] ⁺ .

Example 47

(R)-N-(6-(5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation method of (R)-N-(6-(5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.1 7-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H);

MS m/z(ESI):469.1[M+H] ⁺ .

Example 48

(S)-N-(6-(5-(Cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation method of (S)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6Hz,1H),5 .80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H), 2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H);

MS m/z(ESI):483.2[M+H] ⁺ .

Example 49

(S)-N-(6-(5-(Cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide

The preparation method of (R)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6Hz,1H),5 .80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H), 2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H);

MS m/z(ESI):483.2[M+H] ⁺ .

Example 50

(S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

Refer to Example 8 for the preparation of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.

¹ H NMR (400 MHz, CDCl ₃ )δ9.06(d,J＝15.6Hz,1H),8.28-8.16(m,1H),8.04(d,J＝7.2Hz,1H),7.79-7. 65(m,2H),7.42(t,J＝4.0Hz,1H),7.19(d,J＝12.2Hz,1H),6.79(s,1H),4.97- 4.83(m,1H),4.47(m,1H),4.05-3.87(m,1H),3.30-3.15(m,1H),3.00-2.75( m,3H),2.29(s,3H),1.94-1.75(m,2H),0.94-0.86(m,2H),0.86-0.70(m,2H);

MS m/z(ESI):474.1[M+H] ⁺ .

Example 51

(S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

Step 1: Synthesis of (S)-2-(fluoromethyl)-5-methoxy-3,4-dihydro-2H-pyrrole

Under ice-cooling, (S)-5-(Fluoromethyl)pyrrolidin-2-one (0.7 g, 6.0 mmol) was dissolved in dichloromethane (60 mL), and trimethyloxonium tetrafluoroborate (1.24 g, 8.4 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The organic solvent was concentrated under reduced pressure to obtain a crude product that was used directly in the next reaction.

MS m/z(ESI):132.2[M+H] ⁺ .

Step 2: Synthesis of (S)-6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (900 mg, 6.0 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S)-2-(fluoromethyl)-5-methoxy-3,4-dihydro-2H-pyrrole (783 mg, 6.0 mmol) was added. The reaction was heated to 125°C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated, and column chromatography was performed to obtain the title compound, (S)-6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (430 mg, 55% yield over two steps).

¹ H NMR (400MHz, CDCl ₃ )δ7.69(m,1H),7.66-7.51(m,1H),6.60-6.47(m,1H),5.21-5.04(m,1H),4.94 (m,0.5H),4.82(m,1H),4.70(m,0.5H),3.20-2.92(m,3H),2.85-2.70(m,1H);

MS m/z(ESI):234.2[M+H] ⁺ .

Step 3: Synthesis of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (390 mg, 1.4 mmol) in THF (15 mL) and pyridine (15 mL) was added (S)-6-(5-(Fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (195 mg, 0.84 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (26 mg, 0.21 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then quenched by the addition of water (5 mL), extracted with dichloromethane (50 mL × 2), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (179 mg, yield 45%).

¹ H NMR (400 MHz, CDCl ₃ )δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8. 0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m ,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87 (m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H);

MS m/z(ESI):476.2[M+H] ⁺ .

Example 52

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

Refer to Example 51 for the preparation of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide.

¹ H NMR (400 MHz, CDCl ₃ )δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8. 0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m ,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87 (m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H);

MS m/z(ESI):476.2[M+H] ⁺ .

Example 53

(R)-2-Chloro-5-(4-cyclopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-2-chloro-5-(4-cyclopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27- 6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H);

MS m/z(ESI):474.1[M+H] ⁺ .

Example 54

(S)-2-Chloro-5-(4-cyclopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-2-chloro-5-(4-cyclopropyl-1H-imidazol-1-yl)-4-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 8.

¹ H NMR (400MHz, CD ₃ OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27- 6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H);

MS m/z(ESI):474.1[M+H] ⁺ .

Example 55

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Step 1: Preparation of (S)-(5-carbonylpyrrolidin-2-yl)methyl 4-methylbenzenesulfonate

At room temperature, (S)-5-(Hydroxymethyl)pyrrolidin-2-one (5.0 g, 43.5 mmol), p-toluenesulfonyl chloride (13.3 g, 71.7 mmol), and triethylamine (13.2 g, 130.6 mmol) were dissolved in dichloromethane (60 mL) in sequence. The mixture was reacted at room temperature overnight. Dichloromethane (80 mL) was added to dilute the mixture, and the mixture was washed with 1N HCl. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain (S)-(5-carbonylpyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (8.3 g, yield: 71%).

¹ H NMR (400MHz, CDCl ₃ )δ7.79(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),6.26(s,1H),4.06-4.03(m, 1H),3.97-3.84(m,2H),2.46(s,3H),2.36-2.19(m,3H),1.83-1.72(m,1H);

MS m/z(ESI):270.1[M+H] ⁺ .

Step 2: Preparation of (R)-5-ethylpyrrolidin-2-one

Under ice bath conditions, cuprous iodide (1.06 g, 5.6 mmol) was dissolved in tetrahydrofuran (6 mL), the atmosphere was replaced with nitrogen three times, and methyl lithium (7.4 mL, 11.1 mmol) was added dropwise. The reaction was stirred at 0°C for 45 min, cooled to -20°C, and a solution of (S)-(5-carbonylpyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (500 mg, 1.9 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction system. Stirring was continued at -20°C for 45 min, then the temperature was gradually raised to room temperature and the reaction was allowed to proceed overnight. Saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain (R)-5-ethylpyrrolidin-2-one (185 mg, yield: 86%).

¹ H NMR (400MHz, CD ₃ OD)δ3.54-3.45(m,1H),2.24-2.19(m,2H),2.18-2.09(m,1H),1.66-1.57(m,1H),1.53-1.43(m,1H),1.42-1.32(m,1H),0.84(t,J=7.5Hz,3H);

MS m/z(ESI):114.2[M+H] ⁺ .

Step 3: Preparation of (R)-2-ethyl-5-methoxy-3,4-dihydro-2H-pyrrole

Under an ice bath, trimethyloxonium tetrafluoroborate (226 mg, 1.59 mmol) was added portionwise to a solution of (R)-5-ethylpyrrolidin- ₂ -one (180 mg, 1.59 mmol) in dichloromethane (10 mL). The reaction was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The mixture was concentrated under reduced pressure to obtain a crude product that was used directly in the next reaction.

MS m/z(ESI):128.2[M+H] ⁺ .

Step 4: Synthesis of 6-aminomethylpicolinohydrazide

Methyl 6-aminomethyl picolinate (2.0 g, 13 mmol) was dissolved in ethanol (60 mL) at room temperature, and hydrazine hydrate (4.1 g, 66 mmol) was added. The reaction mixture was heated to 80°C and stirred at this temperature for 5 hours. After slowly cooling to room temperature, the precipitated solid was filtered and the filter cake was collected to obtain the title compound, 6-aminomethyl picolinate hydrazide (1.6 g, 80%).

MS m/z(ESI):153.2[M+H] ⁺ .

Step 5: Preparation of (R)-6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (243 mg, 1.59 mmol) was dissolved in 2-pentanol (5 mL) and acetic acid (2 mL), and (R)-2-ethyl-5-methoxy-3,4-dihydro-2H-pyrrole (202 mg, 1.59 mmol) was added. The reaction was heated to 125°C and stirred at this temperature for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the title compound, (R)-6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (70 mg, 19% yield).

MS m/z(ESI):230.2[M+H] ⁺ .

Step 6: Synthesis of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride

The above 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (154 mg, 0.594 mmol) was dissolved in thionyl chloride (5 mL) at room temperature, heated under reflux and stirred for 2 hours, cooled and concentrated under reduced pressure to obtain a light yellow solid product which was directly used in the next reaction.

Step 7: Preparation of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (165 mg, 0.594 mmol) in THF (6 mL) and pyridine (4 mL) was added (R)-6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine (68 mg, 0.297 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (15 mg, 0.119 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the title compound (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (26 mg, 19% yield).

¹ H NMR (400MHz, CDCl ₃ )δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz, 1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.0 8-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1 H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 56

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

The preparation method of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide refers to Example 55.

¹ H NMR (400MHz, CDCl ₃ )δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz, 1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.0 8-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1 H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 57

(S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-isopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-isopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide was carried out with reference to Example 8.

¹ H NMR (400 MHz, CDCl ₃ )δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H) ),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m ,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H),2.22(s,3H),1.85 (m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H);

MS m/z(ESI):486.2[M+H] ⁺ .

Example 58

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-isopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

The preparation of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(5-isopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-methylbenzamide was carried out with reference to Example 8.

¹ H NMR (400 MHz, CDCl ₃ )δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H) ),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m ,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H),2.22(s,3H),1.85 (m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H);

MS m/z(ESI):486.2[M+H] ⁺ .

Example 59

(R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (R)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 55.

¹ H NMR (400MHz, CDCl ₃ )δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H ),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89 (m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.6 3(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H);

MS m/z(ESI):486.2[M+H] ⁺ .

Example 60

(S)-5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide

The preparation method of (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)benzamide refers to Example 55.

¹ H NMR (400MHz, CDCl ₃ )δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H ),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89 (m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.6 3(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H);

MS m/z(ESI):486.2[M+H] ⁺ .

Example 61

5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

Step 1: Synthesis of 5-methoxy-4-azaspiro[2.4]hept-4-ene

Under ice-cooling, trimethyloxonium tetrafluoroborate (3.55 g, 24.0 mmol) was added portionwise to a solution of 4-azaspiro[2.4]heptane-5-one (1.7 g, 17.2 mmol) in dichloromethane (60 mL). The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 5 hours. Saturated aqueous _NaHCO₃ (5 mL) was then added and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and glacial acetic acid (5 mL) was added. The mixture was concentrated under reduced pressure to obtain a crude product which was used directly in the next reaction.

MS m/z(ESI):126.2[M+H] ⁺ .

Step 2: Synthesis of 6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-amine

At room temperature, 6-aminomethylpicolinohydrazide (500 mg, 4.5 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and 5-methoxy-4-azaspiro[2.4]hept-4-ene (930 mg, 6.3 mmol) was added. The reaction was heated to 125°C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Saturated aqueous _NaHCO₃ (5 mL) was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration of the organic solvent, the title compound, 6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-amine, was isolated by column chromatography (515 mg, 50% yield over two steps).

¹ H NMR (400MHz, CDCl ₃ )δ7.60-7.44(m,2H),6.57-6.47(m,1H),4.31(s,2H),3.21-3.05(m,2H),2.79-2.67(m,2H),2.13-2.05(m,2H),0.86-0.79(m,2H);

MS m/z(ESI):228.2[M+H] ⁺ .

Step 3: 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo]) ...

Synthesis of [2,1-c][1,2,4]triazol-3'-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide

To a solution of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride (80 mg, 0.29 mmol) in THF (5 mL) and pyridine (5 mL) was added 6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-amine (39 mg, 0.17 mmol) at room temperature, followed by the addition of 4-dimethylaminopyridine (5.3 mg, 0.043 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours, then water (5 mL) was added and extracted with dichloromethane (50 mL×2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was concentrated and separated by column chromatography to give the title compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (51 mg, yield 63%).

¹ H NMR (400MHz, CDCl ₃ )δ9.05(d,J＝16.6Hz,1H),8.33-8.31(m,1H),8.09(d,J＝7.4Hz,1H),8.06 -7.99(m,1H),7.86(t,J＝8.0Hz,1H),7.46(s,1H),7.21(d,J＝12.6Hz,1H), 6.80(s,1H),3.17(t,J＝7.6Hz,2H),2.80(t,J＝7.8Hz,2H),2.30(s,3H),2. 19-2.05(m,2H),1.98-1.84(m,1H),1.00-0.87(m,4H),0.87-0.78(m,2H);

MS m/z(ESI):470.2[M+H] ⁺ .

Example 62

N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methylbenzamide

The preparation of N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-2-fluoro-5-(4-isopropyl-1H-imidazol-1-yl)-4-methylbenzamide was carried out according to Example 61.

¹ H NMR (400MHz, CDCl ₃ )δ9.06(d,J＝16.6Hz,1H),8.31(m,1H),8.05(m,2H),7.86(t,J＝8.0Hz,1H),7.57(s,1H),7.22(d,J＝12.4Hz,1H),6.77(s,1H), 3.17(t,J＝7.6Hz,2H),2.99(m,1H),2.80(t,J＝7.8Hz,2H),2.31(s,3H),2.19-2.12(m,2H),1.33(d,J＝6.8Hz,6H),0.98(m,2H);

MS m/z(ESI):472.2[M+H] ⁺ .

Example 63

6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-methylisoindolin-1-one

Step 1: Preparation of methyl 5-amino-2-cyano-4-methylbenzoate

Methyl 5-amino-2-bromo-4-methylbenzoate (900 mg, 3.69 mmol) and CuCN (657 mg, 7.38 mmol) were mixed in NMP (10 mL), stirred at 180°C for 2 hours, cooled, added with water, filtered, and dried over a filter cake to give the title compound, methyl 5-amino-2-cyano-4-methylbenzoate (1.5 g), which was used directly in the next step.

MS m/z(ESI):191.1[M+H] ⁺ .

Step 2: Preparation of 6-amino-5-methylisoindolin-1-one

The crude product was dissolved in methanol (20 mL), and Raney Ni (approximately 100 mg) was added. The mixture was stirred overnight under a _H₂ atmosphere (2-3 atm) at room temperature. The catalyst was removed by filtration through celite, and the filtrate was concentrated and purified by column chromatography to obtain the title compound, 6-amino-5-methylisoindolin-1-one (800 mg, crude product).

MS m/z(ESI):163.1[M+H] ⁺ .

Step 3: Preparation of 6-((2-cyclopropyl-2-carbonylethyl)amino)-5-methylisoindolin-1-one

6-Amino-5-methylisoindolin-1-one (370 mg, 2.28 mmol), 2-bromo-1-cyclopropylethane-1-one (409 mg, 2.51 mmol), KI (38.0 mg, 0.228 mmol), and _K₂CO₃ (378 _mg , 2.74 mmol) were mixed in DMF (5 mL) and stirred at 55°C for 2 hours. After cooling, water was added to the mixture, and the mixture was extracted twice with dichloromethane. The combined organic phases were washed three times with saturated brine, dried, and the organic solvent removed under reduced pressure. The crude product was used directly in the next step.

MS m/z(ESI):245.1[M+H] ⁺ .

Step 4: Preparation of 6-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-5-methylisoindolin-1-one

The crude product from the third step was dissolved in AcOH (10 mL), and KSCN (442 mg, 4.56 mmol) was added to the solution, followed by stirring at 120° C. for 2 h. After cooling, the reaction solution was concentrated, and the crude product was used directly in the next step.

MS m/z(ESI):286.1[M+H] ⁺ .

Step 5: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylisoindolin-1-one

The crude product from step 4 was dissolved in a mixture of AcOH (10 mL) and water (2 mL) with stirring. Hydrogen peroxide (30 wt%, 10.0 g, 87.8 mmol) was slowly added dropwise at 50°C. After the addition was complete, stirring was continued at the same temperature for 1 hour. The reaction mixture was cooled, and a 20 wt% aqueous solution _{of Na₂SO₃} (30 mL) was slowly added. The mixture was stirred at room temperature for 30 minutes. The organic solvent was removed under reduced pressure, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to yield the title compound, 6-(4-cyclopropyl-1H-imidazol-1-yl)-5-methylisoindolin-1-one (180 mg, 42% yield over five steps).

MS m/z(ESI):254.1[M+H] ⁺ .

Step 6: Preparation of 3-(6-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

The preparation of 3-(6-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole was carried out by referring to the fifth and sixth steps of Example 1.

MS m/z(ESI):221.1[M+H] ⁺ .

Step 7: Preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-methylisoindolin-1-one

6-(4-Cyclopropyl-1H-imidazol-1-yl)-5-methylisoindolin-1-one (50 mg, 0.197 mmol), 2-chloro-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine (48 mg, 0.22 mmol), and cesium carbonate (86 mg, 0.30 mmol) were mixed in 1,4-dioxane (4 mL) and deoxygenated with nitrogen for 5 minutes. Pd ₂ (dba) ₃ (18 mg, 0.02 mmol) was added, and deoxygenated with nitrogen for another 5 minutes. Xantphos (23 mg, 0.04 mmol) was then added, and deoxygenation with nitrogen was continued for another 5 minutes. The mixture was then stirred at 120°C for two days. The mixture was cooled, concentrated, and partitioned between dichloromethane and water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated and purified by preparative thin-layer chromatography to give the title compound 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-5-methylisoindolin-1-one (43 mg, yield: 50%).

¹ H NMR (400MHz, CDCl ₃ )δ8.63(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.84(t,J＝8.0Hz,1H),7.76(s,1H),7.48(s,1H),6.84(s, 1H),5.08(s,2H),4.48(t,J＝7.2Hz,2H),2.88(m,2H),2.35(s,3H),1.93(m,1H),0.91(m,2H),0.85(m,2H);

MS m/z(ESI):438.2[M+H] ⁺ .

Example 64

6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-5-methylisoindolin-1-one

Refer to Example 63 for the preparation of 6-(4-cyclopropyl-1H-imidazol-1-yl)-2-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]-3'-yl)pyridin-2-yl)-5-methylisoindolin-1-one.

¹ H NMR (400MHz, CDCl ₃ )δ8.70(d,J＝8.0Hz,1H),7.95(d,J＝7.2Hz,1H),7.87(t,J＝8.0Hz,1H),7.78(s,1H),7.56(s,1H),7.49(s,1H),6.63(s ,1H),5.13(s,2H),3.19(t,J＝7.6Hz,2H),2.80(t,J＝7.6Hz,2H),2.35(s,3H),1.93(m,3H),1.01(m,2H),0.88(m,4H);

MS m/z(ESI):464.2[M+H] ⁺ .

Example 65

(S)-6-(4-cyclopropyl-1H-imidazol-1-yl)-5-methyl-2-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)isoindolin-1-one

Refer to Example 63 for the preparation of (S)-6-(4-cyclopropyl-1H-imidazol-1-yl)-5-methyl-2-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)isoindolin-1-one.

¹ H NMR (400MHz, CDCl ₃ )δ8.67(d,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H),7.85(t,J＝8.0Hz,1H),7.77(s,1H),7.56(s,1H),7.50(s,1H),6.84(s,1H),5 .58(m,1H),5.10(d,J＝13.2Hz,1H),4.91(d,J＝13.2Hz,1H),3.19(m,2H),3.00(m,2H),2.35(s,3H),1.94(m,1H),0.90(m,4H);

MS m/z(ESI):506.2[M+H] ⁺ .

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

1. Testing ASK1 Enzyme Experiment

In this experiment, the fluorescence resonance energy transfer (TR-FRET) method was used to test the inhibitory effect of the compound on ASK1 kinase activity, and the half-maximal inhibitory concentration IC ₅₀ of the compound on ASK1 kinase activity was obtained.

1) Add 1-5 μL of ASK1 enzyme solution to a 384-well plate to a final enzyme concentration of 0.2-20 nM.

2) Add 1 to 5 μL of the compound solution diluted in a gradient.

3) Add 1-5 μL of substrate mixture containing a final concentration of substrate peptide of 100-5000 nM and a final concentration of ATP of 100-1000 μM.

4) Incubate at room temperature for 0.5 to 5 hours.

5) Add 10 μL of EDTA and the detection solution containing the labeled antibody and incubate at room temperature for 2 to 24 hours.

6) Measure the fluorescence signal values of approximately 615 nm and 665 nm in each well using a microplate reader.

7) Calculate the inhibition rate based on the fluorescence signal value.

8) The IC ₅₀ of the compound was obtained by curve fitting based on the inhibition rate at different concentrations.

The enzymatic activities of the compounds of the present invention are shown in Table 1.

Table 1 Enzymatic activities of the compounds in the examples of the present invention

The compounds in the above examples can significantly inhibit the enzymatic activity of ASK1 kinase. Some compounds show a potent inhibitory effect on ASK1 kinase, with the _IC50 of kinase enzyme activity inhibition being less than 10 nM. These compounds have great application potential as effective inhibitors of ASK1 for the treatment of NASH.

2. Mouse PK Analysis

The mouse pharmacokinetic test of the preferred embodiment of the present invention was conducted using Balb/c male mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).

Administration: Single oral administration.

Dosage: 5 mg/10 ml/kg.

Preparation prescription: 0.5% CMC-Na, ultrasonically dissolved.

Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.

Sample processing:

1) Collect 0.1 mL of blood from the orbital cavity, place in a K ₂ EDTA tube, centrifuge at 1000-3000×g for 5-20 minutes at room temperature to separate the plasma, and store at -80°C.

2) Add 160uL of acetonitrile to 40uL of plasma sample for precipitation, mix and centrifuge at 500-2000×g for 5-20 minutes.

3) Take 100 μL of the supernatant solution after treatment and perform LC/MS/MS analysis to determine the concentration of the test compound.

LC-MS/MS analysis:

Liquid phase conditions: Shimadzu LC-20AD pump

Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

Flow rate: 0.8 mL/min

Elution time: 0-3.5 minutes gradient elution

Pharmacokinetics:

The main parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are shown in Table 2 below:

Table 2

From the results of the mouse pharmacokinetic experiment in the table, it can be seen that the compounds of the present invention exhibit good metabolic properties, with both exposure AUC and maximum blood concentration _Cmax performing well.

3. Effects of the compounds of the present invention on ALT and AST levels in mice with non-alcoholic steatohepatitis induced by HFD (high-fat diet) + _CCl4

1. Experimental purpose:

The purpose of this test example is to detect whether the compound of the present invention can downregulate the levels of ALT and AST in the serum of mice with non-alcoholic steatohepatitis.

2. Experimental materials and instruments:

Using ALT/GPT test kit: Nanjing Jiancheng Technology Co., Ltd.

Aspartate aminotransferase (AST/GOT) test kit: Nanjing Jiancheng Technology Co., Ltd.

96-well plate: Corning;

BioTek Synergy H1 microplate reader: BioTek, USA

3. Experimental steps:

After 3-7 days of adaptive feeding in an SPF (specific pathogen-free) barrier, C57BL/6 mice were switched to HFD feed for feeding for 8 weeks. On the fifth week of HFD feeding, the HFD-induced mice were randomly divided according to the animal weight and orally administered _CCl4 twice a week for induction for 4 weeks. Oral administration began on the day of _CCl4 modeling, with a frequency of once a day for 28 consecutive days. The vehicle control group was given the vehicle corresponding to the test article, with a dosage volume of 10mL/kg. 48 hours after the last administration of _CCl4 , the mice were euthanized with _CO2 , and non-anticoagulated venous blood was collected from the heart. The whole blood was placed at room temperature for at least 30 minutes, centrifuged at 4 degrees and 5000 rpm for 5 minutes, and the serum was separated and divided into two portions, placed in 1.5mL EP tubes, and stored at -80℃ for later use.

Serum ALT and AST levels in mice were measured using alanine aminotransferase (ALT/GPT) and aspartate aminotransferase (AST/GOT) test kits. Preheat the ALT (or AST) assay matrix in a 37°C incubator. Add 20 μL of the matrix solution to a 96-well plate. Add 5 μL of serum to the assay wells. Mix thoroughly, seal the plate with sealing film, and incubate in a 37°C incubator for 30 minutes. Prepare an ALT (or AST) standard curve by adding 25 μL of the solution to a 96-well plate. Add 20 μL of plasma to a control well. Add 20 μL of 2,4-dinitrophenylhydrazine solution to each well. Mix thoroughly, seal the plate with sealing film, and incubate in a 37°C incubator for 20 minutes. Add 200 μL of 0.4 M NaOH solution to each well and shake on a plate shaker for 15 minutes. Read the plate at a wavelength of 510 nm using the OD detection program on a BioTek Synergy H1 instrument. Calculate the absolute OD value based on the OD value of each well. Absolute OD value = OD value of the test well - OD value of the control well. Substitute the absolute OD value into the standard curve to determine the ALT (or AST) content in the sample. Samples outside the calibration curve range should be diluted to the appropriate concentration and retested.

Data processing: (% ALT reduction rate) = (vehicle control group - test compound) / vehicle control group × 100%;

(% AST reduction rate) = (vehicle control group - test compound) / vehicle control group x 100%.

4. Experimental results:

ALT (U/L) reduction rate (%) AST (U/L) reduction rate (%) Vehicle control group - - GS-4997 40% 35% Example 10 50% Example 15 54% Example 37 57% Example 40 50% Example 43 65% Example 55 56% Example 61 50% Example 64 51% Example 65 46%

5. Experimental conclusion:

The compound of the present invention shows a good effect in downregulating the levels of ALT and AST in the serum of mice with non-alcoholic steatohepatitis.

Claims (23)

1. Compounds of general formula (III), their stereoisomers or pharmaceutically acceptable salts thereof: in: _M1 and _M2 are each independently selected from N or _-CR6 ; _R6 is selected from hydrogen atom, deuterium atom, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy or _C1-3 haloalkoxy; X and Y are each independently selected from the key, -NR ₇ -, R ₇ is selected from hydrogen atom, deuterium atom or _C1-3 alkyl; Ring A is selected from phenyl or pyridinyl; Cycle B is selected from 3-8 membered heterocyclic groups; _R1 is selected from hydrogen atom, 5-6 membered heteroaryl, halogen or _C1-8 alkyl; Alternatively, _R1 and X or Y can be linked to form a 5-membered heterocyclic group; _R2 may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy or _C1-3 haloalkoxy; R ₅ is selected from hydrogen atom, _C1-8 alkyl, halo- _C1-8 alkyl, hydroxy- _C1-8 alkyl, _C1-8 alkoxy, halo- _C1-8 alkoxy, halogen, _C3-8 cycloalkyl, 3-10 membered heterocyclic group; _Ra may be the same or different, each independently selected from cyano, _C1-8 alkyl, _C2-8 alkenyl, _C2-8 ynyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy, _C3-8 cycloalkyl, -( _CH2 ) _nOR9 or -( _CH2 ) _nC (O) _{R9 ,} wherein the _C1-8 alkyl, _C2-8 alkenyl, _C2-8 ynyl, _haloC1-8 alkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy and _C3-8 cycloalkyl may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, _C1-8 alkyl, _C1-8 hydroxyalkyl or _C1-8 alkoxy; or any two _Ra substituents form a _C3-8 cycloalkyl or _C3-8 heterocyclic group; R ₉ is selected from hydrogen atom, _C1-8 alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl or _C1-8 alkoxy; Alternatively, any two _Ra substituents on ring B can form a _C3-8 cycloalkyl group; n is 0, 1, 2, 3, 4 or 5; x-1 is 1, 2, 3, or 4; y is 0, 1, or 2; and z can be 1, 2, 3, 4 or 5. 2. The compound according to claim 1, wherein it is a compound of general formula (IV), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ring A, ring B, _M1 , _M2 , _R1 , _R2 , _R5 , _Ra , x-1, y, and z are as described in claim 1. 3. The compound according to claim 2, wherein it is a compound of general formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Rings B, _R1 , _R5 , _Ra , x-1, and z are as described in claim 2. 4. The compound according to claim 3, wherein it is a compound of general formula (VI-A), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: _M5 is O, _-CR6 , or _-NR7 ; _R1 is selected from hydrogen atoms, _C1-8 alkyl groups, or halogens; _R5 is selected from _C1-8 alkyl, _C3-8 cycloalkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl or 3-6 membered heterocyclic groups; _Ra may be the same or different, each independently selected from cyano, _C1-8 alkyl, _C2-8 alkenyl, _C2-8 ynyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy, _C3-8 cycloalkyl, -( _CH2 ) _nOR9 or -( _CH2 ) _nC (O) _{R9 ,} wherein the _C1-8 alkyl, _C2-8 alkenyl, _C2-8 ynyl, _haloC1-8 alkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy and _C3-8 cycloalkyl may optionally be further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, _C1-8 alkyl, _C1-8 hydroxyalkyl or _C1-8 alkoxy; or any two _Ra substituents form a _C3-8 cycloalkyl or _C3-8 heterocyclic group; R ₉ is selected from hydrogen atom, _C1-8 alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl or _C1-8 alkoxy; x-1 is 1, 2, 3, or 4; q is 0, 1, or 2; and z can be 1, 2, 3, 4 or 5. 5. The compound according to claim 1, wherein it is a compound of general formula (VI), its stereoisomer, or a pharmaceutically acceptable salt thereof: o is an integer of 0, 1, 2, 3, 4, or 5; and _R1 , _R5 , _Ra , x-1, and z are as described in claim 1. 6. The compound according to claim 1, wherein it is a compound of general formula (VII), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ra _may be the same or different, each independently selected from cyano, _C1-6 alkyl, _{C2-6 alkenyl, C2-6 ynyl} , _C1-6 haloalkyl, _C1-6 alkoxy, _C3-6 cycloalkyl or -( _CH2 ) _{n OR9} , wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, _C1-6 alkoxy and _C3-6 cycloalkyl may optionally be further substituted by one or more substituents selected from halogen, cyano, hydroxyl, _C1-6 alkyl or _C1-6 alkoxy; Alternatively, any two _Ra substituents can form a 3-6 membered cycloalkyl group, and z is an integer of 1, 2, or 3. 7. The compound according to claim 1, wherein it is a compound of general formula (VIII-A), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ring C is a 5-membered heterocyclic group; _Ra may be the same or different, and each can be independently selected from cyano, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, -( _CH2 ) _nOR9 or -( _CH2 ) _nC (O _{) R9} , or any two _Ra substituents can form a 3-6 membered cycloalkyl; _Rb is selected from hydrogen atoms, _C1-8 alkyl, _C1-8 deuterated alkyl, or _C1-8 haloalkyl; _R9 is selected from hydrogen atoms or _C1-8 alkyl groups; z is 1, 2, 3, or 4; and p is 0, 1, or 2. 8. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _R1 is selected from pyrazole, fluorine atom or methyl. 9. The compound according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that _Ra is selected from cyano, hydroxy, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, halo-C1-6 alkyl, _3-6 heterocyclic or _C3-6 cycloalkyl. 10. The compound according to claim 9, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that _Ra is selected from methyl, ethyl, vinyl, ethynyl or trifluoromethyl. 11. The compound according to any one of claims 1-5, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that _R5 is selected from hydrogen atom, _C1-6 alkyl, hydroxy- _C1-6 alkyl, halo- _C1-6 alkyl, 3-6 membered heterocyclic group or _C3-6 cycloalkyl. 12. The compound according to any one of claims 1-5, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that _R5 is selected from cyclopropyl, isopropyl, hydroxyisopropyl, tert-butyl, trifluoromethyl, or... 13. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 14. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 15. A compound of general formula (IX), its stereoisomer, or a pharmaceutically acceptable salt thereof, in: Ring B is a 3-8 membered heterocyclic group; Ra _is selected from cyano, _C1-8 alkyl, _C2-8 alkenyl, _C2-8 ynyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, cyano _- substituted _C1-8 alkyl, _C1-8 alkoxy, _C3-8 cycloalkyl, -( _CH2 ) _nOR9 or -( _CH2 ) _nC (O) _R9 ; R ₉ is selected from hydrogen atom, _C1-8 alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl or _C1-8 alkoxy; n is 0, 1, 2, 3, 4 or 5; z can be 1, 2, 3, 4 or 5. 16. The compound according to claim 15, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that _Ra is selected from cyano, hydroxy, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 hydroxyalkyl, halo- _C1-6 alkyl, 3-6 heterocyclic or _C3-6 cycloalkyl. 17. The compound of claim 15, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _Ra is selected from methyl, ethyl, vinyl, ethynyl or halogenated _C1-3 alkyl. 18. A method for preparing a compound of formula (III) according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound of general formula (IX-A) and the compound of general formula (IX) are coupled to obtain the compound of general formula (III). 19. A compound of general formula (X), its stereoisomer, or a pharmaceutically acceptable salt thereof, in: Ring C is a 5-membered heterocyclic group; _Rb is selected from _C1-8 alkyl, _C1-8 deuterated alkyl, or _C1-8 haloalkyl; and p is 1 or 2. 20. A method for preparing a compound of general formula (VIII-B) according to claim 7, its stereoisomers, or pharmaceutically acceptable salts thereof, comprising the following steps: The compound of general formula (X-1) and the compound of general formula (X) are coupled to give the compound of general formula (VIII-A). 21. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 14, in the preparation of an ASK1 inhibitor medicament. 22. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders, and ASK1. 23. The application according to claim 22, wherein the inflammatory disorder is non-alcoholic steatohepatitis (NASH).