CN118240002A

CN118240002A - Spiro compound, preparation method and medical application thereof

Info

Publication number: CN118240002A
Application number: CN202311780153.8A
Authority: CN
Inventors: 李心; 曾长根; 周宇航; 张礼杰; 贺峰
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2022-12-23
Filing date: 2023-12-22
Publication date: 2024-06-25

Abstract

The present disclosure relates to spiro compounds, methods for their preparation and their use in medicine. Specifically, the disclosure relates to spiro compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the spiro compounds and application of the spiro compounds as 3CL protease inhibitors in treating diseases or conditions related to 3CL protease activity. Wherein each group in the general formula (I) is defined in the specification.

Description

Spiro compound, preparation method and medical application thereof

Technical Field

The present disclosure relates to a spiro compound, a preparation method thereof and application thereof in medicine, which belongs to the field of medicine. In particular, the disclosure relates to spiro compounds represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the compounds, and use thereof as 3CL protease inhibitors in treating diseases or conditions related to 3CL protease activity.

Background

At present, research work on anti-SARS-CoV-2 medicines is actively carried out at home and abroad, and the ideal anti-SARS-CoV-2 medicines can selectively interfere with the replication cycle of SARS-CoV-2 virus, thereby inhibiting the replication process and simultaneously not affecting the normal physiological functions of host cells. Relevant hot targets include: RNA polymerase (RdRp), SARS-CoVS protein (spinous process protein), ACE2 (angiotensin converting enzyme 2), 3CL hydrolase (3 CL ^pro,M^pro), papain-like protease (PL ^pro), and the like.

Among them, 3CL ^pro, also called 3CL protease or main protease, is a cysteine hydrolase that plays an important role in the viral replication process. The polyprotein precursor generated by translation of the viral RNA after entering the host cell is mainly cleaved by 3CL protease (3 CL ^pro) and papain-like protease (PL ^pro) to form various functional proteins necessary for the virus, which are further involved in the viral RNA replication process. Thus, inhibiting the activity of 3CL ^pro would prevent viral infection and replication, while 3CL ^pro lacks homologous proteins in humans, making 3CL ^pro an ideal target for antiviral drug development. In addition, 3CL ^pro is highly conserved in all coronaviruses, and researches show that 3CL protease of SARS-CoV-2 and SARS-CoV is only 12 amino acids, the homology is as high as 96%, the substrate binding pocket part is more 100% conserved, drug resistance caused by virus mutation can be avoided, and meanwhile, the screened 3CL protease inhibitor has a certain degree of broad-spectrum anti-coronavirus capability and can be popularized to other types of coronavirus infection. At present, a number of inhibitors targeting 3CL ^pro have been reported.

The presently published patent applications for 3CL protease inhibitors include WO2021250648A1、WO2021226546A1、WO2021252644A1、WO2021212039A1、WO2021252491A1、WO2022020242A1、WO2022013684A1、WO2022208262A1 et al.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

ring D and ring H are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;

r ^d and R ^h are the same or different and are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, amino, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² are the same or different and are each independently selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

or two R ² taken together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

r ³ is selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and cycloalkyl;

r ⁴ is selected from the group consisting of a hydrogen atom, an alkyl group, and a haloalkyl group;

R ⁵ is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-(CR^j1R^j2)_jC(O)R^b、-(CR^k1R^k2)_kC(O)OR^c、-(CR^u1R^u2)_uS(O)_tR^e、-(CR^v1R^v2)_vC(O)NR^fR^g, and- (CR ^w1R^w2)_wS(O)_tNR^jR^k), wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁶、R⁷、R⁸ and R ⁹ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, and cycloalkyl;

Or R ⁶、R⁷ and the attached carbon atom, or R ⁸、R⁹ and the attached carbon atom together form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, hydroxy, hydroxyalkyl and oxo;

provided that at least one of R ⁶、R⁷ and the attached carbon atom, or R ⁸、R⁹ and the attached carbon atom, forms a ring;

R^a、R^b、R^c、R^e、R^j1、R^j2、R^k1、R^k2、R^u1、R^u2、R^v1、R^v2、R^w1 And R ^w2 are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^f、R^g、R^j and R ^k are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Or R ^f、R^g together with the attached nitrogen atom forms a cyclic group, or R ^j、R^k together with the attached nitrogen atom forms a cyclic group, said cyclic group being optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, hydroxy, hydroxyalkyl and oxo;

m is 0,1, 2, 3 or 4;

n is 1 or 2;

j is 0, 1,2,3, 4 or 5;

k is 0, 1,2,3, 4 or 5;

u is 0, 1,2,3, 4 or 5;

v is 0, 1,2,3, 4 or 5;

w is 0, 1,2,3, 4 or 5;

p is 0, 1, 2,3, 4 or 5;

q is 0,1,2,3, 4 or 5; and is also provided with

T is 0, 1 or 2.

The present disclosure provides a compound represented by the general formula (I):

Wherein:

R ¹ is

Or two R ² taken together with the carbon atom to which they are attached form cycloalkyl optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

R ⁵ is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a、-C(O)R^b、-C(O)OR^c、-S(O)_tR^e、-C(O)NR^fR^g, and-S (O) _tNR^jR^k, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one OR more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^a、R^b、R^c and R ^e are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

m is 0,1, 2, 3 or 4;

n is 1 or 2;

p is 0, 1, 2,3, 4 or 5;

q is 0,1,2,3, 4 or 5; and is also provided with

T is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1):

wherein: r ¹ to R ⁹, m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compounds of formula (I) and (I-1) or pharmaceutically acceptable salts thereof are compounds of formula (I-1-1) or (I-1-2) or pharmaceutically acceptable salts thereof:

wherein: r ¹ to R ⁹, m and n are as defined in the general formula (I).

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1), and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁸、R⁹ together with the attached carbon atom form a 3-to 8-membered cycloalkyl or a 3-to 8-membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, cyano, hydroxy, C _1-6 hydroxyalkyl, and oxo; preferably, R ⁸、R⁹ together with the carbon atom to which it is attached form a3 to 8 membered cycloalkyl group; more preferably, R ⁸、R⁹ together with the carbon atom to which it is attached forms cyclopropyl.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1), and (I-1-2), or pharmaceutically acceptable salts thereof, wherein when two R ² are attached to adjacent carbon atoms, together with the attached carbon atoms form a 3-to 6-membered cycloalkyl, optionally substituted with one or more R ^2m; or when two R ² are attached to the same carbon atom, together with the attached carbon atom form a3 to 6 cycloalkyl group, the 3 to 6 membered cycloalkyl group optionally substituted with one or more R ^2m; r ^2m are the same or different and are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1) and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ^2m is selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, R ^2m is C _1-6 alkyl; more preferably, R ^2m is methyl.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from R ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group.

In some embodiments of the present disclosure, the compounds of formula (I-1), (I-1-1), and (I-1-2), or pharmaceutically acceptable salts thereof, whereinSelected from R ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group.

In some embodiments of the present disclosure, the compounds of formula (I-1), (I-1-1), and (I-1-2), or pharmaceutically acceptable salts thereof, whereinSelected from

R ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

Wherein:

R ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

r ¹、R³ to R ⁷ are as defined in formula (I).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1) and (II), or pharmaceutically acceptable salts thereof, are compounds of formula (II-1):

Wherein: r ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II) and (II-1) or pharmaceutically acceptable salts thereof are compounds of formula (II-1-1) or (II-1-2) or pharmaceutically acceptable salts thereof:

Wherein: r ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, R ^2a and R ^2b are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, R ^2a and R ^2b are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; more preferably, R ^2a and R ^2b are the same or different and are each independently C _1-6 alkyl; further preferably, R ^2a and R ^2b are both methyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein ring D is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring D is 9 or 10 membered heteroaryl; more preferably, ring D is benzothiazolyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, whereinIs that

A is O, S, NR ^A;

r ^A is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

g ¹ is CR ^g1 or N;

G ² is CR ^g2 or N;

g ³ is CR ^g3 or N;

G ⁴ is CR ^g4 or N;

R ^g1、R^g2、R^g3 and R ^g4 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, amino, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts or fragments thereof (D1), wherein A is O or S, preferably S.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts or fragments thereof (D1), wherein R ^A is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts or fragments thereof (D1), wherein G ¹ is N, G ² is CR ^g2,G³ is CR ^g3,G⁴ and CR ^g4; Or G ¹ is CR ^g1,G² is N, G ³ is CR ^g3,G⁴ is CR ^g4; Or G ¹ is CR ^g1,G² is CR ^g2,G³ is N and G ⁴ is CR ^g4; Or G ¹ is CR ^g1,G², CR ^g2,G³, CR ^g3,G⁴ and N; Or G ¹ is CR ^g1,G² is CR ^g2,G³ is CR ^g3,G⁴ is CR ^g4;R^g1、R^g2、R^g3 and R ^g4 is as defined for fragment (D1).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts or fragments thereof (D1), wherein R ^g1、R^g2、R^g3 and R ^g4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, amino, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, R ^g1、R^g2、R^g3 and R ^g4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; more preferably, R ^g1、R^g2、R^g3 and R ^g4 are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts or fragments thereof (D1), wherein R ^g1、R^g2、R^g3 and R ^g4 are the same or different and are each independently a hydrogen atom or halogen; preferably, R ^g1、R^g2 and R ^g4 are both hydrogen atoms, and R ^g3 is hydrogen atom or F.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, whereinSelected from the group consisting ofP is 0,1,2,3 or 4; r ^d is as defined in formula (I); preferablyP is 0, 1,2,3 or 4; r ^d is as defined in formula (I).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, wherein R ^d is the same or different and each is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, amino, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, R ^d are the same or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; further preferably, R ^d is halogen; more preferably, R ^d is F.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein p is 0 or 1, preferably 0.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, wherein R ^d are the same or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; and/or p is 0 or 1.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein ring H is a6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring H is selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, quinolinyl, quinoxalinyl, benzotriazolyl, imidazo [1,2-a ] pyridyl, imidazo [2,1-b ] [1,3] thiazolyl, 4H-furo [3,2-b ] pyrrolyl, 4H-thieno [3,2-b ] pyrrolyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,3] triazolo [1,5-a ] pyridyl and naphthyridinyl; more preferably, ring H is phenyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, whereinIs thatR ^h and q are as defined in formula (I); preferablyForR ^h1、R^h2、R^h3、R^h4 and R ^h5 are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, amino, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl; preferably, R ^h1、R^h2、R^h3、R^h4 and R ^h5 are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; more preferably, R ^h1、R^h2、R^h3、R^h4 and R ^h5 are the same or different and are each independently a hydrogen atom or a halogen; further preferably, R ^h1、R^h3、R^h4 and R ^h5 are both hydrogen atoms and R ^h2 is halogen.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, whereinIs thatR ^h1、R^h2、R^h3、R^h4 and R ^h5 are the same or different and are each independently a hydrogen atom or a halogen; preferably, R ^h2、R^h4 and R ^h5 are both hydrogen atoms, and R ^h1 and R ^h3 are both halogen; more preferably, R ^h2、R^h4 and R ^h5 are both hydrogen atoms and R ^h1 and R ^h3 are both F.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, wherein R ^h is the same or different and each is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, amino, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, R ^h are the same or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; more preferably, R ^h is halogen; further preferably, R ^h is F or Cl; more preferably, R ^h is chloro.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein q is 0, 1 or 2, preferably 1 or 2, more preferably 1.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, R ^h are the same or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; and/or q is 0, 1 or 2.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein ring D is 9 or 10 membered heteroaryl; ring H is a6 to 10 membered aryl or a 5 to 10 membered heteroaryl.

In some embodiments of the present disclosure, the compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ isOr (b)

A and G ¹ to G ⁴ are as defined in fragment (D1) and R ^h1 to R ^h5 are as defined in fragment (H1).

In some embodiments of the present disclosure, the compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ is P is 0, 1,2,3 or 4; r ^d、R^h and q are as defined in formula (I); preferably, R ¹ is selected from More preferably, R ¹ is

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein R ³ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano and 3 to 8 membered cycloalkyl; preferably, R ³ is C _1-6 alkyl; more preferably, R ³ is tert-butyl or isopropyl; further preferably, R ³ is tert-butyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein R ⁴ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ⁴ is a hydrogen atom or C _1-6 alkyl; more preferably, R ⁴ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from the group consisting of C _1-6 alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, 5 to 10 membered heteroaryl, -OR ^a、-C(O)R^b、-C(O)OR^c、-S(O)_tR^e、-C(O)NR^fR^g and-S (O) _tNR^jR^k, wherein said C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, Hydroxy, C _1-6 hydroxyalkyl, C _1-6 alkoxyc _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, R ^a、R^b、R^c、R^e、R^f、R^g、R^j、R^k and t are as defined in formula (I); Preferably, R ⁵ is selected from the group consisting of-C (O) R ^b、-C(O)OR^c and-S (O) ₂R^e,R^b、R^c and R ^e, identical or different, And each independently is a C _1-6 alkyl or a3 to 8 membered cycloalkyl, wherein each of said C _1-6 alkyl and 3 to 8 membered cycloalkyl is independently optionally substituted with one or more halogens.

In some embodiments of the present disclosure, the compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein R ^a、R^b、R^c and R ^e are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein said C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted with a member selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, cyano, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, oxo, C _1-6 alkoxy, C _1-6 alkyl, A 3 to 8 membered cycloalkyl, a 3 to 8 membered heterocyclyl, a6 to 10 membered aryl, and a5 to 10 membered heteroaryl; Preferably, R ^a、R^b、R^c and R ^e are the same or different and are each independently selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a3 to 8 membered cycloalkyl group, wherein each of said C _1-6 alkyl group and 3 to 8 membered cycloalkyl group is independently optionally substituted with one or more halogens; More preferably, R ^a、R^b、R^c and R ^e are the same or different and are each independently C _1-6 alkyl or 3 to 8 membered cycloalkyl, wherein said C _1-6 alkyl and 3 to 8 membered cycloalkyl are each independently optionally substituted with one or more halogens.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof, wherein R ^f、R^g、R^j and R ^k are the same or different, and are each independently selected from the group consisting of a hydrogen atom, C _1-6 alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl, wherein each of said C _1-6 alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, cyano, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, Oxo, C _1-6 alkoxy C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; Preferably, R ^f、R^g、R^j and R ^k are the same or different, and are each independently selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, and a3 to 8 membered cycloalkyl group, wherein each of said C _1-6 alkyl group and 3 to 8 membered cycloalkyl group is independently optionally substituted with one or more halogens.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or pharmaceutically acceptable salts thereof are described wherein t is 2.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁶ and R ⁷ are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R ⁶ and R ⁷ are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1), and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁶、R⁷ together with the attached carbon atom form a 3-to 8-membered cycloalkyl or a 3-to 8-membered heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, cyano, hydroxy, C _1-6 hydroxyalkyl, and oxo; preferably, R ⁶、R⁷ together with the carbon atom to which it is attached form a3 to 8 membered cycloalkyl group; more preferably, R ⁶、R⁷ together with the carbon atom to which it is attached forms cyclopropyl.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1) and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁸ and R ⁹ are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, hydroxy, C _1-6 hydroxyalkyl, and 3 to 8 membered cycloalkyl; preferably, R ⁸ and R ⁹ are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1) and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁶ and R ⁷ are both hydrogen atoms; r ⁸、R⁹ together with the carbon atom to which it is attached forms cyclopropyl.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1-1) and (I-1-2), or pharmaceutically acceptable salts thereof, wherein R ⁸ and R ⁹ are both hydrogen atoms; r ⁶、R⁷ together with the carbon atom to which it is attached forms cyclopropyl.

In some embodiments of the present disclosure, the compounds of formulas (II), (II-1-1) and (II-1-2), or pharmaceutically acceptable salts thereof, wherein R ¹ isR ^d are identical or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy, p is 0 or 1; r ^h are identical or different and are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy, q is 0, 1 or 2; R ^2a and R ^2b are both methyl; r ³ is C _1-6 alkyl; r ⁴ is a hydrogen atom; R ⁵ is selected from the group consisting of-C (O) R ^b、-C(O)OR^c and-S (O) ₂R^e,R^b、R^c and R ^e, which are identical or different, and are each independently C _1-6 alkyl or 3-to 8-membered cycloalkyl, Wherein said C _1-6 alkyl and 3 to 8 membered cycloalkyl are each independently optionally substituted with one or more halo; R ⁶ and R ⁷ are each a hydrogen atom.

Table a typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by the general formula (IA):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R⁶ to R ⁹ are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1A):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R⁶ to R ⁹ are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1-1A):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R⁶ to R ⁹ are as defined in the general formula (I-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

Wherein:

The salt is preferably the hydrochloride salt;

r ¹、R⁶ and R ⁷ are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R⁶ and R ⁷ are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1-1A):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R⁶ and R ⁷ are as defined in the general formula (II-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IC):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R²、R⁶ to R ⁹, m and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1C):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R²、R⁶ to R ⁹, m and n are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1-1C):

Wherein:

The salt is preferably the hydrochloride salt;

r ¹、R²、R⁶ to R ⁹, m and n are as defined in the general formula (I-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIC):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R^2a、R^2b、R⁶ and R ⁷ are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1C):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R^2a、R^2b、R⁶ and R ⁷ are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1-1C):

Wherein:

The salt is preferably the hydrochloride salt;

R ¹、R^2a、R^2b、R⁶ and R ⁷ are as defined in the general formula (II-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIB):

Wherein:

R ⁵ is-C (O) R ^b,R^b is a 3-to 8-membered cycloalkyl, said 3-to 8-membered cycloalkyl optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, cyano, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, oxo, C _1-6 alkoxyC _1-6 alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, R ^b is 3-to 8-membered cycloalkyl, said 3-to 8-membered cycloalkyl optionally substituted with one or more halo;

R ^2a、R^2b、R³ and R ⁴ are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1B):

Wherein:

r ^2a、R^2b、R³ and R ⁴ are as defined in the general formula (II-1).

Table B typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

Reacting a compound of the general formula (IA) or a salt thereof with a compound of the general formula (IB) or a salt thereof to give a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of formula (IA) is preferably the hydrochloride salt;

R ¹ to R ⁹, m and n are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound of the general formula (I-1A) or a salt thereof with a compound of the general formula (I-1B) or a salt thereof to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the general formula (I-1A) is preferably the hydrochloride;

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof, which comprises:

Reacting a compound of the general formula (I-1-1A) or a salt thereof with a compound of the general formula (I-1B) or a salt thereof to obtain a compound of the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1-1A) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I-1-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

reacting a compound of the formula (IIA) or a salt thereof with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (II) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of formula (IIA) is preferably the hydrochloride salt;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound of the general formula (II-1A) or a salt thereof with a compound of the general formula (II-1B) or a salt thereof to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the formula (II-1A) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound of the general formula (II-1-1A) or a salt thereof with a compound of the general formula (II-1B) or a salt thereof to obtain a compound of the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the general formula (II-1-1A) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1-1).

reacting a compound of the general formula (IC) or a salt thereof with a compound of the general formula (ID) or a salt thereof to give a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (IC) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I).

Reacting a compound of the general formula (I-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1C) is preferably the hydrochloride;

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Reacting a compound of the general formula (I-1-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof to obtain a compound of the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1-1C) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I-1-1).

reacting a compound of the general formula (IIC) or a salt thereof with a compound of the general formula (ID) or a salt thereof to give a compound of the general formula (II) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (IIC) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

Reacting a compound of the general formula (II-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (II-1C) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

reacting a compound of the general formula (II-1-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof to obtain a compound of the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (II-1-1C) is preferably the hydrochloride;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formulas (I-1-1) and (I-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

Resolving the compound of the general formula (I-1) or pharmaceutically acceptable salt thereof by chiral HPLC to obtain the compounds of the general formulas (I-1-1) and (I-1-2) or pharmaceutically acceptable salt thereof,

Wherein:

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formulae (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, which comprises:

Resolving the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof by chiral HPLC to obtain the compounds of the general formulas (II-1-1) and (II-1-2) or pharmaceutically acceptable salt thereof,

Wherein:

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) as disclosed herein and shown in table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound as shown in general formulae (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting a 3CL protease.

The present disclosure further relates to the use of a compound shown in general formulae (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by a 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to the use of a compound as shown in general formulae (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of a viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a method of inhibiting a 3CL protease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder mediated by a 3CL protease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is a viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a method of treating and/or preventing a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The disclosure further relates to compounds of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The disclosure further relates to compounds of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for inhibiting 3CL protease.

The present disclosure further relates to a compound of formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting 3CL protease.

The present disclosure further relates to a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder mediated by a 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a disease or disorder mediated by a 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a compound of general formula (I), (I-1-1), (I-1-2), (II-1-1) and (II-1-2) shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of viral infection; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The 3CL protease mediated disease or condition described in the present disclosure is preferably selected from the group consisting of viral infection, chronic obstructive pulmonary disease, senile dementia, motor neuron disease, multiple sclerosis, parkinson's disease, mastocytosis, asthma, cognitive disorders, ischemic stroke and tumors; the virus is preferably coronavirus (Coronavirus), picornavirus (Picornavirus), rhinovirus (Rhinovirus), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2; the tumor is preferably gastrointestinal tumor, lymphoma, glioblastoma, pancreatic tumor, prostate cancer, liver cancer, breast cancer, colorectal cancer, lung cancer and head and neck cancer.

Preferably, the lymphomas described in the present disclosure are selected from hodgkin's disease and non-hodgkin's lymphomas (e.g., mantle cell lymphomas, diffuse large B-cell lymphomas, follicular center lymphomas, marginal zone B-cell lymphomas, lymphoplasmacytic lymphomas, and peripheral T-cell lymphomas); the lung cancer is non-small cell lung cancer (NSCLC) (e.g., lung squamous carcinoma and lung adenocarcinoma, wherein lung adenocarcinoma is preferably bronchioloalveolar carcinoma) and Small Cell Lung Cancer (SCLC); the liver cancer is hepatocellular carcinoma (HCC); the pancreatic cancer is pancreatic duct adenocarcinoma; the colorectal cancer is colon cancer and rectal cancer; the prostate cancer is hormone refractory prostate cancer.

As a general guideline, the active compounds of the present disclosure are preferably administered in unit doses, or in a manner that the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the DELTEC CADD-PLUS. TM.5400 type.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a C _1-20 alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 1 to 20 (e.g., 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a C _1-20 alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., a C _1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., a C _1-6 alkylene group). Non-limiting examples include ：-CH₂-、-CH(CH₃)-、-C(CH₃)₂-、-CH₂CH₂-、-CH(CH₂CH₃)-、-CH₂CH(CH₃)-、-CH₂C(CH₃)₂-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-, and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is defined as above having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkenyl group). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is defined as above having 2 to 12 (e.g., 2,3, 4,5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., a C _2-12 alkynyl group). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system having 3 to 20 (e.g., 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a3 to 8 membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a3 to 6 membered cycloalkyl group).

Non-limiting examples of such monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

The polycyclic cycloalkyl group includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spirocycloalkyl group. Non-limiting examples include:

The connection point can be at any position;

Etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and which has 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include:

The connection point can be at any position;

Etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 5 to 20 (e.g., 5, 6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

The connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), and having from 3 to 20 (e.g., 3,4,5, 6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocyclic group), a heterocyclic group having 4 to 6 ring atoms (i.e., a4 to 6 membered heterocyclic group), or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5 to 7 membered heterocyclic group); most preferred are heterocyclyl groups having 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl groups).

Non-limiting examples of such monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, which has 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1,2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 6 to 10 ring atoms (i.e., a 6 to 10-membered fused heterocyclic group), and still more preferably a 6-or 7-membered fused heterocyclic group. The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2,3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 6 to 10 ring atoms (i.e., a 6 to 10 membered bridged heterocyclic group), and still more preferably a 6-membered, 7-membered or 8-membered bridged heterocyclic group. The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples include:

Etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

Etc.

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaryl ring having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1,2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5 to 14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heteroaryl group) or a heteroaryl group having 9 or 10 ring atoms (i.e., a 9 or 10 membered heteroaryl group).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

Etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2, 4-Dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group for blocking or protecting the hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "methylene" refers to = CH ₂.

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bond/>, if chiral isomers are present in the chemical structureCan beOr at the same time containAndTwo configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named. /(I)

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of the lactam-lactam balance are shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as ² H (deuterium, D), ³ H (tritium ,T)、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²p、³³p、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁵I、¹²⁹I and ¹³¹ I, respectively, and the like, with deuterium being preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position of a compound of the present disclosure is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold greater than the natural abundance of deuterium (which is 0.015%), i.e., at least 15% deuterium incorporation. In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500-fold greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that it includes instances where the event or circumstance occurs or does not. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., alkenes).

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

Scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

reacting a compound of the general formula (IA) or a salt thereof with a compound of the general formula (IB) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of formula (IA) is preferably the hydrochloride salt;

R ¹ to R ⁹, m and n are as defined in the general formula (I).

Scheme II

A process for the preparation of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Reacting a compound of the general formula (I-1A) or a salt thereof with a compound of the general formula (I-1B) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the general formula (I-1A) is preferably the hydrochloride;

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Scheme III

A process for the preparation of a compound of formula (I-1-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Reacting a compound of the general formula (I-1-1A) or a salt thereof with a compound of the general formula (I-1B) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1-1A) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I-1-1).

Scheme IV

A process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Reacting a compound of the general formula (IIA) or a salt thereof with a compound of the general formula (IIB) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of formula (IIA) is preferably the hydrochloride salt;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

Scheme five

A process for the preparation of a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Reacting a compound of the general formula (II-1A) or a salt thereof with a compound of the general formula (II-1B) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the formula (II-1A) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

Scheme six

A process for the preparation of a compound of formula (II-1-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Reacting a compound of the general formula (II-1-1A) or a salt thereof with a compound of the general formula (II-1B) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

the salt of the general formula (II-1-1A) is preferably the hydrochloride;

Scheme seven

reacting a compound of the general formula (IC) or a salt thereof with a compound of the general formula (ID) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (IC) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I).

Scheme eight

Reacting a compound of the general formula (I-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1C) is preferably the hydrochloride;

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Scheme nine

Reacting a compound of the general formula (I-1-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (I-1-1C) is preferably the hydrochloride;

R ¹ to R ⁹, m and n are as defined in the general formula (I-1-1).

Scheme ten

Reacting a compound of the general formula (IIC) or a salt thereof with a compound of the general formula (ID) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (IIC) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in formula (II).

Scheme eleven

Reacting a compound of the general formula (II-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (II-1C) is preferably the hydrochloride;

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

Scheme twelve

Reacting a compound of the general formula (II-1-1C) or a salt thereof with a compound of the general formula (I-1D) or a salt thereof under the action of a condensing agent under alkaline conditions to obtain a compound of the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

Wherein:

The salt of the general formula (II-1-1C) is preferably the hydrochloride;

Scheme thirteen

A process for the preparation of a compound represented by the general formulae (I-1-1) and (I-1-2) of the present disclosure or a pharmaceutically acceptable salt thereof, which comprises:

Wherein:

r ¹ to R ⁹, m and n are as defined in the general formula (I-1).

Scheme fourteen

A process for the preparation of a compound represented by the general formulae (II-1-1) and (II-1-2) of the present disclosure or a pharmaceutically acceptable salt thereof, which comprises:

Chiral HPLC resolution of the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof to obtain the compounds of the general formulas (II-1-1) and (II-1-2) or pharmaceutically acceptable salt thereof,

Wherein:

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in the general formula (II-1).

Reagents providing basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1, 8-diazabicycloundec-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; n, N-diisopropylethylamine is preferred.

Condensing agents described in the above reaction include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 2- (7-oxybenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine; preferably HATU.

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and Tetramethylsilane (TMS) as internal standard.

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS).

Waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

The high performance liquid phase was prepared by using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

The average inhibition rate of kinase and IC ₅₀ were measured by NovoStar microplate reader (BMG, germany).

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), darui chemical, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: in the n-hexane/ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for regulation.

Example 1

(1R, 2S, 5S) -N- ((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo

[3.1.0] Hexane-2-carboxamide 1 (mixture of diastereomers)

Tert-butyl ((2R) -4-chloro-3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamate 1b (mixture of diastereomers)

Methyl (2R) -2- ((tert-butoxycarbonyl) amino) -3- (-5-oxo-4-azaspiro [2.4] hept-6-yl) propionate 1a (mixture of diastereomers) (500 mg,1.6mmol, prepared as disclosed on page 1338 Example 259 of patent application "WO2021252644A 1") and chloroiodomethane (1.69 g,9.6mmol, shanghai's) were dissolved in tetrahydrofuran (10 mL), cooled to-78 ℃, a solution of 2M diisopropylaminolithium in tetrahydrofuran (6.4 mL) was added dropwise, the reaction was kept at temperature stirring for 6 hours, a solution of acetic acid (1.65 mL) in tetrahydrofuran (3.3 mL) was added at-70 ℃, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the title compound 1B was purified by silica gel column chromatography to give a mixture of diastereomers (215.40 mg) of title compound (1B).

MS m/z(ESI):331.2[M+1]

Second step (3R) -3- ((tert-Butoxycarbonyl) amino) -2-oxo-4- (5-oxo-4-azaspiro [2.4] hept-6-yl) butyl 2-oxo

2-Phenylacetate 1c (mixture of diastereomers)

Benzoic acid (95.28 mg, 634.64. Mu. Mol, shanghai) was dissolved in N, N-dimethylformamide (2.5 mL), cesium fluoride (80.42 mg,1.2 mmol) was added, a solution of compound 1B (175 mg, 529. Mu. Mol) in N, N-dimethylformamide (1.5 mL) was added after stirring reaction for 10 minutes at 65℃and the reaction was continued with stirring for 1 hour at 65℃and the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 1c (mixture of diastereomers) (222 mg, yield: 94%) as an eluting system B. MS m/z (ESI): 445.2[ M+1]

Third step ((2R) -4-hydroxy-3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester 1d (mixture of diastereomers)

Compound 1c (222 mg, 499.4. Mu. Mol) was dissolved in methanol (6 mL), potassium carbonate (3.5 mg, 25. Mu. Mol) was added, and the reaction was stirred for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 1d (mixture of diastereomers) (109 mg, yield: 69.8%).

MS m/z(ESI):313.2[M+1]

Fourth step ((2R) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester 1e (mixture of diastereomers)

Compound 1d (22 mg, 70.43. Mu. Mol) and 3-chlorophenol (15.37 mg, 119.5. Mu. Mol) were dissolved in tetrahydrofuran (0.5 mL), triphenylphosphine (31.4 mg, 119.7. Mu. Mol) and diisopropyl azodicarboxylate (21.36 mg, 105.63. Mu. Mol) were added, the reaction was stirred for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 1e (mixture of diastereomers) (10 mg, yield: 33.5%). MS m/z (ESI): 423.2[ M+1]

Fifth step

6- ((R) -2-amino-4- (3-chlorophenoxy) -3-oxobutyl) -4-azaspiro [2.4] hept-5-one hydrochloride 1f (mixture of diastereomers)

Compound 1e (10 mg, 23.6. Mu. Mol) was dissolved in methylene chloride (2 mL), 4M dioxane hydrochloride solution (1 mL) was added, the reaction was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give the crude title compound 1f (mixture of diastereomers) (8.5 mg), which was used in the next reaction without purification.

MS m/z(ESI):323.2[M+1]

Sixth step (1R, 2S, 5S) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester 1h

Crude compound (1R, 2S, 5S) -3- ((S) -2-amino-3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester hydrochloride 1g (500 mg,1.57mol, prepared by the method disclosed on page 212 Example 78 of patent application "WO 2021250648"), 1-fluorocyclopropane-1-carboxylic acid (163.2 mg,1.57mol, shanghai) were dissolved in N, N-dimethylformamide (5 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (715.5 mg,1.88 mol) and N, N-diisopropylethylamine (709.4 mg,5.5 mol) were added, and the reaction mixture was stirred for 2 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 1h (448.5 mg, 77% yield). MS m/z (ESI): 369.2[ M+1]

Seventh step (1R, 2S, 5S) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid 1i

Compound 1h (463 mg,1.26 mmol) was dissolved in water (3 mL) and tetrahydrofuran (3 mL), lithium hydroxide monohydrate (265.37 mg,6.32 mmol) was added, reacted for 1 hour at 40℃and after cooling to room temperature the pH was adjusted to 2 with 1M hydrochloric acid solution, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude title compound 1i (417 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):353.2[M-1]

Eighth step

[3.1.0] Hexane-2-carboxamide 1 (mixture of diastereomers)

Crude compound 1i (8.34 mg, 23.53. Mu. Mol) and compound 1f (7.60 mg, 23.54. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL), N, N-diisopropylethylamine (10.65 mg, 82.40. Mu. Mol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (10.74 mg, 28.24. Mu. Mol) were added, respectively, and the reaction mixture was stirred for 30 minutes, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L) ammonium bicarbonate and acetonitrile, gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound 1 (mixture of diastereomers) (2 mg, 12.8%).

MS m/z(ESI):659.2[M+1]。

¹H NMR(500MHz,MeOD):δ7.30-7.22(m,1H),7.13-6.89(m,3H),5.39-5.34(m,1H),4.94(d,2H),4.64(s,1H),4.38(s,1H),4.11-4.02(m,1H),3.92(t,1H),2.96-2.87(m,1H),2.86-2.76(m,1H),2.60(s,1H),2.38(d,1H),2.06(t,3H),1.63(s,4H),1.35(s,3H),1.31(d,9H),1.07(s,3H),0.93(q,4H).

Example 2

(1R, 2S, 5S) -N- ((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0]

Hexane-2-carboxamide 2 (mixture of diastereomers)

First step (1R, 2S, 5S) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester 2b

Methyl trifluoroacetate 2a (803 mg,6.27mmol, shanghai shao) and compound 1g (400 mg,1.25 mmol) were dissolved in methanol (5 mL), N-diisopropylethylamine (811 mg,6.28 mol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure to give crude title compound 2b (480 mg), and the product was used in the next reaction without purification.

MS m/z(ESI):379.2[M+1]

Second step

Hexane-2-carboxamide 2 (mixture of diastereomers)

Using the synthetic route in example 1, the seventh starting compound 1h was replaced with compound 2b to give the title compound 2 (mixture of diastereomers) (2 mg, yield: 16%).

MS m/z(ESI):669.2[M+1]

¹H NMR(500MHz,MeOD):δ7.27(t,1H),7.07-7.00(m,1H),6.99-6.92(m,1H),6.91(d,1H),5.36(t,1H),4.94(d,2H),4.60(d,1H),4.37(s,1H),4.04(dd,1H),3.96(s,1H),2.92(s,1H),2.80(s,1H),2.60(s,1H),2.37(t,1H),2.05(d,3H),1.35(s,3H),1.31(d,9H),1.07(s,3H),0.92(t,4H).

Example 3

((2S) -1- ((1R, 2S, 5S) -2- (((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hex-3-yl) -3, 3-dimethyl-1-oxobutan-2 ]

Methyl carbamate 3 (mixture of diastereomers)

First step

(1R, 2S, 5S) -2- (((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 3b (mixture of diastereomers)

(1R, 2S, 5S) -3- (tert-Butoxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid 3a (15.81 mg, 61.92. Mu. Mol, shanghai) was dissolved in N, N-dimethylformamide (3 mL), compound 1f (22.2 mg, 61.92. Mu. Mol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (28.3 mg, 74.4. Mu. Mol) and N, N-diisopropylethylamine (28 mg, 261. Mu. Mol) were added, the reaction was stirred for 0.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid preparation chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30. Mu. M; mobile phase: aqueous phase (10 mmol/L) and acetonitrile, gradient: 30% -45%, 30 mL: 30 mL/min) to give a mixture of the title compound (11 mg, 11%).

MS m/z(ESI):560.2[M+1]

Second step

(1R, 2S, 5S) -N- ((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide hydrochloride 3c (mixture of diastereomers)

Compound 3b (3.6 mg, 6.4. Mu. Mol) was dissolved in methylene chloride (2 mL), and a 4M dioxane solution (1 mL) of hydrochloric acid was added under ice bath, and the reaction was stirred at the maintained temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 3c (mixture of diastereomers) (3 mg), which was used in the next reaction without purification. MS m/z (ESI): 460.2[ M+1]

The third step ((2S) -1- ((1R, 2S, 5S) -2- (((2S) -4- (3-chlorophenoxy) -3-oxo-1- (5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hex-3-yl) -3, 3-dimethyl-1-oxobutan-2-yl)

Methyl carbamate 3 (mixture of diastereomers)

The compound N-methoxycarbonyl-L-tert-leucine (2.46 mg,13. Mu. Mol, shanghai Shao) and the compound 3c (3.00 mg, 6.52. Mu. Mol) were dissolved in N, N-dimethylformamide (1.5 mL), N, N-diisopropylethylamine (2.95 mg, 22.82. Mu. Mol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (4.95 mg, 13.01. Mu. Mol) were added in this order and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: 30% -45% acetonitrile, flow rate: 30 mL/min) to give the title compound 3 (mixture of diastereomers) (2 mg, yield: 48.5%). MS m/z (ESI): 631.2[ M+1]

¹H NMR(500MHz,MeOD):δ7.27(s,1H),7.08-6.77(m,3H),5.48-5.38(m,1H),5.20-5.02(m,2H),4.73(d,1H),4.36(s,1H),4.01(s,1H),3.94(d,1H),3.46-3.35(m,3H),2.91(s,1H),2.80(s,1H),2.63-2.51(m,1H),2.37(s,1H),2.05(s,3H),1.35(s,3H),1.31(s,9H),1.01(d,3H),0.92(t,4H).

Example 4

(1R, 2S, 5S) -N- ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- (5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -3- ((S) -3, 3-dimethyl-2- (methylsulfonyl) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 4 (mixture of diastereomers)

First step (2R) -2- ((tert-Butoxycarbonyl) amino) -3- (5-oxo-4-azaspiro [2.4] hept-6-yl) propanoic acid 4a (mixture of diastereomers)

Compound 1a (450 mg,1.44 mmol) was dissolved in methanol (10 mL) and water (5 mL), sodium hydroxide (86.43 mg,2.16 mmol) was added at 0deg.C, stirring was continued for 1 hour, pH was adjusted to around 4 with 1M hydrochloric acid solution, the solvent was removed by concentration under reduced pressure, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude title compound 4a (mixture of diastereomers) (344 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):297.2[M-1]

The second step ((2R) -1- (methoxy (methyl) amino) -1-oxo-3- (5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 4b (mixture of diastereomers)

Crude compound 4a (34 mg,1.15 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-N-methoxyamine hydrochloride (135 mg,1.38 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (265 mg,1.38 mmol), 1-Hydroxybenzotriazole (HOBT) (210 mg,1.38 mmol) and triethylamine (408 mg,4 mmol) were added, after stirring for 16 hours, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 4B (mixture of diastereomers) (360 mg, yield: 91.4%) as a title compound by eluting system B.

MS m/z(ESI):342.2[M+1]

Third step ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- (-5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 4c (mixture of diastereomers)

Benzothiazole (570 mg,4.2 mmol) was dissolved in tetrahydrofuran (10 mL), -2.5M n-butyllithium in n-hexane (1.5 mL) was added at 78℃and after stirring at a temperature of 1 hour, compound 4B (360 mg,1.05 mmol) was added, and after stirring at a temperature of 1 hour, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 4c (mixture of diastereomers) (159 mg, yield: 36.2%).

MS m/z(ESI):416.2[M+1]

Fourth step

6- ((S) -2-amino-3- (benzo [ d ] thiazol-2-yl) -3-oxopropyl) -4-azaspiro [2.4] hept-5-one hydrochloride 4d (mixture of diastereomers)

Compound 4c (214 mg, 515. Mu. Mol) was dissolved in methylene chloride (5 mL), and a 4M dioxane solution (2 mL) of hydrochloric acid was added under ice bath to stir the reaction mixture for 60 minutes. The reaction solution was concentrated under reduced pressure to give the crude title compound 4d (mixture of diastereomers) (180 mg), which was used in the next reaction without purification.

MS m/z(ESI):316.2[M+1]

Fifth step

(1R, 2S, 5S) -3- ((S) -3, 3-dimethyl-2- (methylsulfonyl) butanoyl) -6, 6-dimethyl-3-azabicyclo

[3.1.0] Hexane-2-carboxylic acid methyl ester 4e

1G (100 mg, 354.1. Mu. Mol) of the crude compound, triethylamine (107.5 mg,1.06 mmol) was dissolved in methylene chloride (5 mL), methanesulfonyl chloride (40.6 mg, 354.1. Mu. Mol) was added under ice-bath, and the reaction was stirred at the temperature for 2 hours. Water was added to the reaction solution, extracted with methylene chloride (10 mL. Times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the crude title compound 4e (126 mg), which was used in the next reaction without purification.

MS m/z(ESI):361.2[M+1]

Sixth step

[3.1.0] Hexane-2-carboxylic acid 4f

The crude compound 4e (160 mg, 446.2. Mu. Mol) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL) and water (5 mL), lithium hydroxide monohydrate (37.4 mg, 892.4. Mu. Mol) was added, the reaction was stirred for 3 hours, pH was adjusted to around 4 with 1M hydrochloric acid solution, most of the solvent was removed by concentration under reduced pressure, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 4f (95 mg), which was directly used for the next reaction without purification.

MS m/z(ESI):345.2[M-1]

Seventh step

Crude compound 4f (69.86 mg, 201. Mu. Mol) and compound 4d (53 mg, 168. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL), and N, N-diisopropylethylamine (76 mg, 588. Mu. Mol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (76.7 mg, 202. Mu. Mol) were added sequentially. The reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: 30% -45% acetonitrile, flow rate: 30 mL/min) to give the title compound 4 (mixture of diastereomers) (10 mg, yield: 9.2%).

MS m/z(ESI):644.2[M+1]

¹H NMR(500MHz,MeOD):δ8.25-8.16(m,1H),8.12(dd,1H),7.69-7.57(m,2H),5.77(dd,1H),5.34(dd,1H),4.45(s,1H),3.99-3.90(m,2H),3.83(d,1H),2.90(d,3H),2.42-2.29(m,2H),2.22-2.13(m,2H),1.63-1.55(m,2H),1.12-1.01(m,15H),0.89(d,2H),0.78-0.74(m,2H).

Example 5

(1R, 2S, 5S) -N- ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- (5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo

[3.1.0] Hexane-2-carboxamide 5 (mixture of diastereomers)

Using the synthetic route in example 1, the eighth starting compound 1f was replaced with compound 4d to give the title compound 5 (mixture of diastereomers) (8 mg, yield: 8.1%).

MS m/z(ESI):652.2[M+1]。

¹H NMR(500MHz,MeOD):δ8.24(dd,1H),8.15(dd,1H),7.74(dd,1H),7.66(dd,1H),5.86-5.74(m,1H),4.64(dd,1H),4.46(s,1H),4.31(t,1H),4.07-3.96(m,1H),3.92(d,1H),2.42-2.31(m,2H),2.28-2.22(m,2H),1.77-1.71(m,2H),1.59(dd,2H),1.52-1.45(m,4H),1.07(d,9H),1.03-0.99(m,6H),0.99-0.96(m,2H).

Example 6

(1R, 2S, 5S) -N- ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- (5-oxo-4-azaspiro [2.4] hept-6-yl) propan

-2-Yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo

[3.1.0] Hexane-2-carboxamide 6 (mixture of diastereomers)

Using the synthetic route in example 4, the sixth starting compound 4e was replaced with compound 2b to give the title compound 6 (mixture of diastereomers) (3 mg, yield: 3%).

MS m/z(ESI):662.2[M+1]

¹H NMR(500MHz,MeOD):δ8.28-8.18(m,1H),8.14(t,1H),7.76-7.59(m,2H),5.84-5.74(m,1H),4.60(s,1H),4.45(s,1H),4.03(dd,1H),3.87(d,1H),3.37(d,1H),2.38(td,2H),2.28-2.23(m,2H),1.59(dd,2H),1.50(d,2H),1.27(d,3H),1.08(d,9H),0.96(s,3H),0.93-0.90(m,2H).

Example 7

(1R, 2S, 5S) -N- ((S) -4- (3-chlorophenoxy) -3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo

[3.1.0] Hexane-2-carboxamide 7-1

Or (b)

(1R, 2S, 5S) -N- ((S) -4- (3-chlorophenoxy) -3-oxo-1- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 7-2

First step

(R) -2- ((tert-Butoxycarbonyl) amino) -3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propanoic acid methyl ester 7a-1

Or (b)

(R) -2- ((tert-Butoxycarbonyl) amino) -3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propanoic acid methyl ester 7a-2

Compound 1a (19 g,60.86 mmol) was resolved by chiral column (Gilson 281, column: phenomenex Amylose-2,21.2 x 250mm,5 μm; mobile phase A: n-hexane; mobile phase B: acetonitrile: ethanol=3:1 (0.1% NH3 in EtOH), gradient ratio: A: B:50:50, flow rate: 30 mL/min) to give the title compound 7a-1 or 7a-2 (12 g, yield: 63%).

MS m/z(ESI):313.2[M+1]。

Chiral HPLC analysis: retention time 19.477 min, purity: 99% (chromatographic column: phenomenex Lux Amylose-2.150 x 4.6mm,5um; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A: B:50, flow rate: 1.0 mL/min).

¹H NMR(500MHz,CDCl₃)δ6.68(d,1H),5.56(d,1H),4.28(d,1H),3.73(d,3H),2.74(dd,1H),2.27-2.19(m,1H),2.17-2.11(m,1H),2.06(ddd,1H),1.94-1.84(m,1H),1.42(d,9H),0.86(dd,1H),0.69(ddt,3H).

Second step

(R) -6- ((S) -2-amino-4- (3-chlorophenoxy) -3-oxobutyl) -4-azaspiro [2.4] hept-5-one hydrochloride 7b-1

Or (b)

(S) -6- ((S) -2-amino-4- (3-chlorophenoxy) -3-oxobutyl) -4-azaspiro [2.4] hept-5-one hydrochloride 7b-2

Using the first to fifth steps of the synthetic route in example 1, the first starting compound 1a was replaced with compound 7a-1 or 7a-2 to give the crude title compound 7b-1 or 7b-2 (250 mg).

MS m/z(ESI):323.2[M+1]。

Third step

(1R, 2S, 5S) -N- ((S) -4- (3-chlorophenoxy) -3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 7-1

Or (b)

Crude compound 1i (166.9 mg, 470.8. Mu. Mol) and compound 7b-1 or 7b-2 (168 mg, 471. Mu. Mol) were dissolved in N, N-dimethylformamide (4 mL), N, N-diisopropylethylamine (213 mg,1.65 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (214 mg, 565.1. Mu. Mol) were added under ice-bath, respectively, and the reaction was resumed for 30 minutes under stirring, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound 7-1 or 7-2 (20 mg, 6.4%). MS m/z (ESI): 659.2[ M+1].

¹H NMR(500MHz,CD3OD):δ7.29-7.25(m,1H),7.04-6.92(m,3H),4.94(d,1H),4.74(dd,1H),4.63(d,1H),4.38(s,1H),4.04(dd,1H),3.96-3.83(m,2H),2.91(dd,1H),2.28-1.98(m,6H),1.32-1.18(m,4H),1.06(d,12H),0.94(s,3H),0.88(d,2H),0.78-0.70(m,2H).

Example 8

(1R, 2S, 5S) -N- ((S) -4- (3-chlorophenoxy) -3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 8-1

Or (b)

(1R, 2S, 5S) -N- ((S) -4- (3-chlorophenoxy) -3-oxo-1- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 8-2

First step

(1R, 2S, 5S) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid 8a

Compound 2b (176 mg, 465.1. Mu. Mol) was dissolved in water (2 mL) and tetrahydrofuran (2 mL), lithium hydroxide monohydrate (97.6 mg,2.3 mmol) was added, the reaction was stirred for 1 hour, the pH was adjusted to 2 with 1M hydrochloric acid solution, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 8a (93 mg), which was used in the next reaction without purification.

MS m/z(ESI):363.2[M-1]

Second step

Or (b)

Crude compound 8a (232.2 mg, 638.2. Mu. Mol) and compound 7b-1 or 7b-2 (228.6 mg, 638.2. Mu. Mol) were dissolved in N, N-dimethylformamide (4 mL), N, N-diisopropylethylamine (289 mg,2.2 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (29 mg, 765.8. Mu. Mol) were added, the reaction was allowed to stir at room temperature for 30 minutes, water was added to the reaction mixture, the organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid preparation chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30.150 mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, ratio: 30% -45% acetonitrile, flow rate: 30 mL/min) to give the title compound 8-2 mg or 8.8 mg, yield 25.5%.

MS m/z(ESI):669.2[M+1]。

1H NMR(500MHz,CD₃OD):δ7.27(t,1H),7.04-6.91(m,3H),4.94(d,1H),4.75(dd,1H),4.59(s,1H),4.37(s,1H),4.05(dt,1H),3.95-3.78(m,2H),2.92(dd,1H),2.34-1.96(m,6H),1.07(d,12H),0.95(s,3H),0.91-0.86(m,2H),0.73(ddd,2H).

Example 9

(1R, 2S, 5S) -N- ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 9-1

Or (b)

(1R, 2S, 5S) -N- ((2S) -1- (benzo [ d ] thiazol-2-yl) -1-oxo-3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 9-2

First step

(R) -6- ((S) -2-amino-3- (benzo [ d ] thiazol-2-yl) -3-oxopropyl) -4-azaspiro [2.4] hept-5-one hydrochloride 9a-1

Or (b)

(S) -6- ((S) -2-amino-3- (benzo [ d ] thiazol-2-yl) -3-oxopropyl) -4-azaspiro [2.4] hept-5-one hydrochloride 9a-2

Using the first to fourth steps of the synthetic route in example 4, the first starting compound 1a was replaced with compound 7a-1 or 7a-2 to give the crude title compound 9a-1 or 9a-2 (421 mg).

MS m/z(ESI):316.2[M+1]。

Second step

Or (b)

Crude compound 9a-1 or 9a-2 (205.2 mg, 650.8. Mu. Mol) and compound 8a (308.2 mg, 846. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL), N, N-diisopropylethylamine (336.4 mg,2.6 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (297 mg, 781. Mu. Mol) were added, the reaction was resumed for 30 minutes with stirring at room temperature, water was added to the reaction solution, extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (Waters-2545, column YMC TRIART-Exrs C; 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: 30% -45% acetonitrile, flow rate: 30 mL/min) to give the title compound 9-2.9-1 mg (73.17%).

MS m/z(ESI):662.2[M+1]。

¹H NMR(500MHz,CD₃OD):δ8.26-8.17(m,1H),8.12(dd,1H),7.63(m,2H),5.84-5.74(m,1H),4.59(s,1H),4.44(s,1H),4.01(dd,1H),3.86(d,1H),2.40-2.29(m,2H),2.26-2.15(m,2H),1.58(dd,1H),1.49(d,1H),1.06(m,10H),1.03-0.92(m,6H),0.87(m,2H),0.79-0.75(m,2H).

Example 10

(1R, 2S, 5S) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -N- ((S) -1- (5-fluorobenzo [ d ] thiazol-2-yl) -1-oxo-3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 10-1

Or (b)

(1R, 2S, 5S) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -N- ((S) -1- (5-fluorobenzo [ d ] thiazol-2-yl) -1-oxo-3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 10-2

First step

(S) -2- ((tert-Butoxycarbonyl) amino) -3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propanoic acid 10a-1

Or (b)

(S) -2- ((tert-Butoxycarbonyl) amino) -3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propanoic acid 10a-2

Compound 7a-1 or 7a-2 (8.2 g,26.25 mmol) was dissolved in methanol (100 mL), aqueous sodium hydroxide (1.47 g,36.75 mmol) was added dropwise under ice bath (50 mL) and the reaction was allowed to react at a temperature for 1 hour, the reaction solution was adjusted to pH 2 with 1M hydrochloric acid solution, the solvent was removed by concentration under reduced pressure, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude title compound 10a-1 or 10a-2 (7.43 g) which was used directly in the next reaction without purification.

MS m/z(ESI):297.1[M-1]

Second step

(S) -1- (methoxy (methyl) amino) -1-oxo-3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 10b-1

Or (b)

(S) -1- (methoxy (methyl) amino) -1-oxo-3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 10b-2

The crude compound 10a-1 or 10a-2 (7.43 g,24.9 mmol) was dissolved in N, N-dimethylformamide (60 mL), N-methyl-N-methoxyamine hydrochloride (2.92 g,29.93 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.73 g,29.88 mmol), 1-Hydroxybenzotriazole (HOBT) (4.04 g,29.89 mmol) and triethylamine (6.55 g,64.75 mmol) were added under ice-bath, the reaction mixture was concentrated under reduced pressure after stirring at room temperature for 16 hours, water (100 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 10B-1 or 10B-2 (4.35 g, yield: 51.1%).

MS m/z(ESI):342.2[M+1]

Third step

(S) -1- (5-Fluorobenzo [ d ] thiazol-2-yl) -1-oxo-3- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 10c-1

Or (b)

(S) -1- (5-Fluorobenzo [ d ] thiazol-2-yl) -1-oxo-3- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) propan-2-yl) carbamic acid tert-butyl ester 10c-2

2-Bromo-5-fluorobenzothiazole (761.3 mg,3.28mmol, shanghai taitant) was dissolved in tetrahydrofuran (10 mL), -a 2.5M n-butyllithium solution in n-hexane (1.3 mL) was added at 78℃and after stirring at a temperature of 1 hour, a solution of compound 10B-1 or 10B-2 (320 mg, 937.3125. Mu. Mol) in tetrahydrofuran (3 mL) was added, after stirring at a temperature of 1 hour, the reaction mixture was quenched by adding saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound 10c-1 or 10c-2 (513 mg, yield: 126%) by purification of the residue by silica gel column chromatography with elution system B. MS m/z (ESI): 434.2[ M+1]

Fourth step

(R) -6- ((S) -2-amino-3- (5-fluorobenzo [ d ] thiazol-2-yl) -3-oxopropyl) -4-azaspiro [2.4] hept-5-one hydrochloride 10d-1

Or (b)

(S) -6- ((S) -2-amino-3- (5-fluorobenzo [ d ] thiazol-2-yl) -3-oxopropyl) -4-azaspiro [2.4] hept-5-one hydrochloride 10d-2

Compound 10c-1 or 10c-2 (313 mg,1.1834 mmol) was dissolved in dichloromethane (7 mL), 4M dioxane hydrochloride solution (3 mL) was added under ice bath, and the reaction was allowed to warm to room temperature with stirring for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 10d-1 or 10d-2 (435 mg), which was used in the next reaction without purification.

MS m/z(ESI):334.2[M+1]

Fifth step

Or (b)

Crude compound 10d-1 or 10d-2 (390 mg,1.18 mmol) and compound 8a (430.6 mg,1.18 mmol) were dissolved in N, N-dimethylformamide (7 mL), N, N-diisopropylethylamine (534.6 mg,4.1 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (539.2 mg,1.41 mmol) were added separately under ice-bath, the reaction was resumed for 30 min with stirring at room temperature, water was added to the reaction solution, the organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid preparation chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30 x 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: 30% -45% acetonitrile, flow rate: 30 mL/min) to give compound 10-1 or 10-2 mg (4.7 mg, yield: 7%).

MS m/z(ESI):680.2[M+1]。

¹H NMR(500MHz,CD₃OD):δ8.17(dd,1H),7.97(dd,1H),7.49-7.44(m,1H),5.76(dd,1H),4.59(s,1H),4.44(s,1H),4.02(dd,1H),3.87(d,1H),2.39-2.30(m,2H),2.25-2.18(m,2H),1.60(dd,1H),1.48(d,1H),1.35(s,1H),1.08(s,9H),1.02(s,3H),0.97(s,3H),0.91-0.78(m,4H).

Example 11

(1R, 2S, 5S) -N- ((S) -4- (2, 4-difluorophenoxy) -3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 11-1

Or (b)

(1R, 2S, 5S) -N- ((S) -4- (2, 4-difluorophenoxy) -3-oxo-1- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide 11-2

First step

(S) -4-hydroxy-3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester

11a-1

Or (b)

(S) -4-hydroxy-3-oxo-1- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester

11a-2

Using the first to third steps of the synthetic route in example 1, the first step starting compound 1a was replaced with compound 7a-1 or 7a-2 to give the title compound 11a-1 or 11a-2 (3.15 g, yield: 76.2%).

MS m/z(ESI):313.2[M+1]。

Second step

(S) -4- (2, 4-difluorophenoxy) -3-oxo-1- ((R) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester 11b-1

Or (b)

(S) -4- (2, 4-difluorophenoxy) -3-oxo-1- ((S) -5-oxo-4-azaspiro [2.4] hept-6-yl) butan-2-yl) carbamic acid tert-butyl ester 11b-2

Compound 11a-1 or 11a-2 (150 mg, 480.2. Mu. Mol) and 2, 4-difluorophenol (106.2 mg, 816.3. Mu. Mol, shanghai taitant) were dissolved in tetrahydrofuran (3.5 mL), triphenylphosphine (214.2 mg, 816.3. Mu. Mol) and diisopropyl azodicarboxylate (145.6 mg, 720.3. Mu. Mol) were added under ice bath, the reaction mixture was stirred at room temperature for 1 hour with natural recovery, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 11b-1 or 11b-2 (100 mg, yield: 33.5%).

MS m/z(ESI):425.2[M+1]

Third step

(R) -6- ((S) -2-amino-4- (2, 4-difluorophenoxy) -3-oxobutyl) -4-azaspiro [2.4] hept-5-one hydrochloride

11c-1

Or (b)

(S) -6- ((S) -2-amino-4- (2, 4-difluorophenoxy) -3-oxobutyl) -4-azaspiro [2.4] hept-5-one hydrochloride

11c-2

Compound 11b-1 or 11b-2 (100 mg, 235.6. Mu. Mol) was dissolved in methylene chloride (2 mL), 4M dioxane hydrochloride solution (0.5 mL) was added, the reaction was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give crude title compound 11c-1 or 11c-2 (85 mg), the product was used in the next reaction without purification.

MS m/z(ESI):325.2[M+1]

Fourth step

Or (b)

Crude compound 11c-1 or 11c-2 (85 mg, 236. Mu. Mol) and compound 8a (85.4 mg, 234.3. Mu. Mol) were dissolved in N, N-dimethylformamide (3 mL), N, N-diisopropylethylamine (106 mg, 820.1. Mu. Mol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (106.9 mg, 281.1. Mu. Mol) were added under ice-bath, respectively, and the reaction was resumed for 30 minutes with stirring at room temperature, water was added to the reaction mixture, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC TRIART-Exrs C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile at a gradient ratio of 30% -45%, flow rate: 30 mL/min) to give title compound 11-1 or 2 (39.24 mg, yield: 24%).

MS m/z(ESI):671.2[M+1]。

¹H NMR(500MHz,CD₃OD):δ7.10-7.01(m,2H),6.88(d,1H),4.97(d,2H),4.59(s,1H),4.38(s,1H),4.04(dd,2H),3.87(d,1H),2.93(s,1H),2.14(ddt,6H),1.14-1.04(m,12H),0.96(s,3H),0.77-0.64(m,4H).

Biological evaluation

The present disclosure is explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: detection of antiviral Activity based on HCoV-OC43 Virus Compounds

Experimental materials:

Reagent name	Goods number #)	Suppliers (suppliers)
			Huh-7 cells	ATCC CCL-171	ATCC
HCoV-OC43 virus	ATCC VR-759	ATCC
			Fetal bovine serum, FBS	35-081-CV	Corning
Penicillin-Streptomycin double-antibody solution	15140-122	Gibco
			Cell culture Medium MEM	11095-080	Gibco
DPBS	21-031-CV	Corning
			TrypLE ^TM Express enzyme (1×)	12605-010	Gibco
CellTiter-Glo	G7573	Promega

Instrument:

Instrument name	Suppliers (suppliers)
		Desk type centrifugal machine	Thermo fisher
CO ₂ incubator	ESCO
		Biological safety cabinet	ESCO
Cell counter TC20	Bio-Rad
		Multifunctional enzyme labeling instrument	TECAN

The experimental steps are as follows:

Huh-7 cells were seeded into 96-well plates at a density of 1X 10 ⁵/mL, with 0.1mL of cell suspension added per well. After Huh-7 cells were grown to form monolayers in 96-well cell culture plates, cells were infected with 100TCID50 HCoV-OC43 virus. Compounds to be tested were semi-logarithmically diluted in 96-well V-base plates with DMSO and added to 96-well plates Huh-7 cells. The plates with added virus and compound were incubated in a 5% CO ₂ incubator at 37 ℃. After 5-6 days, 100. Mu.L of cell lysate was added to each well and lysed for 30min. Luciferase substrate and cell lysate were mixed at 1:1, placing the mixture into an enzyme-labeled instrument to detect fluorescent signals, and evaluating the inhibition effect of the compound on HCoV-OC43 virus according to the cell activity result.

Inhibitory Activity of the Compounds of Table 1 against HCoV-OC43 Virus

Compounds of formula (I)	EC₅₀(μM)
		1	0.08
2	0.09
		7-1 Or 7-2	0.04
8-1 Or 8-2	0.03
		10-1 Or 10-2	0.07
11-1 Or 11-2	0.04

Conclusion: the compound disclosed by the disclosure has good inhibition effect on HCoV-OC43 virus.

Test example 2: detection of antiviral Activity based on HcoV-229E Virus Compounds

Experimental materials:

Reagent name	Goods number #)	Suppliers (suppliers)
			MRC-5 cells	ATCC CCL-171	ATCC
Hcov-229E virus	ATCC VR-740	ATCC
			Fetal bovine serum, FBS	35-081-CV	Corning
Penicillin-Streptomycin double-antibody solution	15140-122	Gibco
			Cell culture Medium MEM	11095-080	Gibco
DPBS	21-031-CV	Corning
			TrypLE ^TM Express enzyme (1×)	12605-010	Gibco
CellTiter-Glo	G7573	Promega

Instrument:

Instrument name	Suppliers (suppliers)
		Desk type centrifugal machine	Thermo fisher
CO2 incubator	ESCO
		Biological safety cabinet	ESCO
Cell counter TC20	Bio-Rad
		Multifunctional enzyme labeling instrument	TECAN

The experimental steps are as follows:

MRC-5 cells were seeded into 96-well plates at a density of 1X 10 ⁵/mL, 0.1mL of cell suspension was added to each well, and incubated in a 5% CO ₂ incubator at 37 ℃. After MRC-5 cells were grown to form monolayers in 96-well cell culture plates, cells were infected with 100TCID50 HcoV-229E virus. Compounds to be tested were semi-logarithmically diluted in 96-well V-base plates with DMSO and added to 96-well plates of MRC-5 cells. The plates with added virus and compound were incubated in a 5% CO ₂ incubator at 37 ℃. After 4 days, 100. Mu.L of cell lysate was added to each well and lysed for 30min. Luciferase substrate and cell lysate were mixed at 1:1, placing the mixture into an enzyme-labeled instrument to detect fluorescent signals, and evaluating the inhibition effect of the compound on HcoV-229E virus according to the cell activity result.

Inhibitory Activity of the Compounds of Table 2 against HcoV-229E Virus

Conclusion: the compound disclosed has good inhibition effect on HCoV-229E virus.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

Wherein:

R ¹ is

m is 0,1, 2, 3 or 4;

n is 1 or 2;

j is 0, 1,2,3, 4 or 5;

k is 0, 1,2,3, 4 or 5;

u is 0, 1,2,3, 4 or 5;

v is 0, 1,2,3, 4 or 5;

w is 0, 1,2,3, 4 or 5;

p is 0, 1, 2,3, 4 or 5;

q is 0,1,2,3, 4 or 5; and is also provided with

T is 0, 1 or 2.

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹、R³ to R ⁷ are as defined in claim 1.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in claim 2.

4. A compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound of the formula (II-1-1) or (II-1-2) or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹、R^2a、R^2b、R³ to R ⁷ are as defined in claim 2.

5. A compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring D is 9 or 10 membered heteroaryl; ring H is a6 to 10 membered aryl or a 5 to 10 membered heteroaryl.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ¹ isP is 0,1, 2, 3 or 4; r ^d、R^h and q are as defined in claim 1.

7. A compound of formula (I) according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^2b are the same or different and are each independently C _1-6 alkyl; preferably, R ^2a and R ^2b are both methyl.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-6 alkyl.

9. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ⁴ is a hydrogen atom.

10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from-C (O) R ^b、-C(O)OR^c and-S (O) ₂R^e,R^b、R^c and R ^e, which are the same or different, and are each independently C _1-6 alkyl or 3 to 8 membered cycloalkyl, wherein said C _1-6 alkyl and 3 to 8 membered cycloalkyl are each independently optionally substituted by one or more halogens.

11. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ⁶ and R ⁷ are both hydrogen atoms.

12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ^d is the same or different and each is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; and/or p is 0 or 1.

13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ^h is the same or different and each is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; and/or q is 0, 1 or 2.

14. A compound of general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

15. A compound of the general formula (IA):

Wherein:

R ¹、R⁶ to R ⁹ are as defined in claim 1.

16. A compound or salt thereof selected from the following compounds:

17. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

Wherein:

R ¹ to R ⁹, m and n are as defined in claim 1.

18. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for inhibiting a 3CL protease.

20. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections; the virus is preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.