TW202304886A - Prodrugs of adamts inhibitors, preparation methods and medicinal uses thereof - Google Patents

Abstract

Compounds of formula (I) useful as inhibitors of ADAMTS-5 and/or ADAMTS-4, pharmaceutical compositions thereof, and use of them as therapeutic agents for the treatment of diseases involving degradation of cartilage or disruption of cartilage homeostasis, in particular osteoarthrosis and/or rheumatoid arthritis, are disclosed.

Description

Prodrug of ADAMTS inhibitor and its preparation method and medical application

The present invention relates to prodrug compounds and methods for inhibiting the function of ADAMTS-5 and/or ADAMTS-4 and their use in the treatment of diseases involving cartilage degradation or disturbance of cartilage homeostasis, such as osteoarthritis and/or rheumatoid arthritis The application.

Cartilage is the highly specialized connective tissue of the articular joint. Its main function is to provide joints with the ability to carry loads and resist compression. The major components of cartilage are the extracellular matrix comprising aggrecan and collagen. In diseases such as osteoarthritis, the balance between the production (anabolism) and degradation (catabolism) of aggrecan and collagen switches to catabolism.

Osteoarthritis is the most common chronic joint disease and a leading cause of pain and disability in developed countries. An estimated 250 million people worldwide currently suffer from osteoarthritis , with an increasing incidence ( Hunter et al ., Lancet . 2019 , 393 : 1745-1759 ). Pain and functional loss are associated with an increased risk of additional disease conditions such as diabetes , cancer or cardiovascular disease ( Valdes AM and Stocks J. Osteoarthritis and aging . Eur Med J. 2018 , 3 : 116-123 ). Osteoarthritis is a disease of the whole joint: structural changes are found as degradation of articular cartilage, arthrosis and changes in subchondral bone and other periarticular tissues ( Goldring MB and Otero M . Inflammation in osteoarthritis . Curr Opin Rheumatol . 2011 , 23 : 471 - 478 ). The pathogenesis of osteoarthritis is not very clear, involving mechanical damage, inflammation, aging and metabolic factors. Osteoarthritis is not a passive degenerative disease, but an active dynamic change caused by an imbalance between repair and damage of joint tissue ( Hunter et al., Lancet . 2019 , 393 : 1745 - 1759 ). Currently, pharmacological treatments available for osteoarthritis are limited to symptomatic relief of pain and inflammation. Disease-modifying drugs that halt or slow disease progression are not available.

Progressive loss of articular cartilage is currently considered an early event in osteoarthritis. Aggrecan may have the effect of protecting collagen loss ( Pratta et al ., J Biol Chem . 2003 , 278 : 45539-45545 ). These studies demonstrate the important role of aggrecan in osteoarthritis and other joint diseases. Aggrecan is a proteoglycan that has a core protein of covalently linked sulfated glycosaminoglycan (GAG) chains. Its core protein has three globular domains, the N-terminal G1 and G2 domains and the C-terminal G3 domain. The extended region between the G2 and G3 domains is heavily modified with GAGs keratan sulfate (KS) and chondroitin sulfate (CS). Based on differences in amino acid sequence, the CS domain is further divided into two subdomains: CS1 and CS2. The GAG chains provide aggrecan with its higher anionic charge. Multiple aggrecan monomers bind to hyaluronic acid (HA) via the G1 domain, which is stabilized by connexins, forming larger supramolecular aggregates. Larger aggrecan aggregates absorb water and provide the elastic properties of cartilage ( Roughley et al ., The Journal of Experimental Orthopaedics . 2014 , 1 : 8 ). High concentrations of aggrecan, high sulfation and ability to form larger aggregates are required for normal function of cartilage.

The extended structure of aggrecan can be cleaved by proteolytic enzymes, resulting in impairment of the normal function of cartilage. ADAMTS (Disassociating Integrins and Metalloproteases with Thrombin Motifs) are a family of zinc ion-dependent metalloproteases. ADAMTS-4 and -5 (also known as "aggrecanases") degrade aggrecan at several specific positions in the IGD and CS2 domains. ADAMTS-5 insufficiency was shown to prevent aggrecan loss and cartilage damage in a surgically induced mouse osteoarthritis disease model ( Glasson et al. , Nature . 2005 , 434 : 644-648 ; Stanton et al ., Nature . 2005 , 434 : 648-652 ), suggesting that ADAMTS-5 contributes to cartilage loss and osteoarthritic disease severity. Some studies in human cartilage explant cultures have also shown that not only ADAMTS-5, but also ADAMTS-4 are critical for human osteoarthritis ( Verma et al ., Journal of Cellular Biochemistry . 2011 , 112 : 3507-3514 ) . These studies strongly suggest that inhibition of the enzymatic function of ADAMTS-5 and ADAMT-4 may provide protection in osteoarthritis.

In summary, a role for ADAMTS-5 and/or ADAMTS-4 in cartilage degradation has been recognized. Therefore, inhibitors of ADAMTS-5 and/or ADAMTS-4 may have therapeutic value in the treatment of arthritis. Published patent applications for compounds as ADAMTS-5 and/or ADAMTS-4 inhibitors include WO2014066151A1, WO2016102347A1, WO2017211667A1, WO2017211666A1, WO2017211668A1, WO2021011720A2 and WO2021011723A1.

Although numerous prodrug strategies exist to provide options for the delivery of drug molecules with multiple benefits in regulatory situations, the identification of prodrugs with desired properties is often difficult and indirect. None of the prior art teaches or suggests the specific prodrugs of the present invention.

或其醫藥學上可接受之鹽， 其中： X ¹及X ²係相同或不同，且各自獨立地係氫或-L-R ⁰，其限制條件為X ¹及X ²兩者不皆為氫； L選自-(CQ ¹Q ²) _t-、-C(=O)O-、-C(=O)O(CQ ¹Q ²) _t-及-C(=O)S(CQ ¹Q ²) _t-； R ⁰選自-OP(=O)(OH) ₂、-OP(=O)(OH)-OP(=O)(OH) ₂、-OC(=O)Q ³、-NQ ⁶C(=O)Q ³、-OC(=O)OQ ⁴、-NQ ⁶C(=O)OQ ⁴、-OP(=O)(OQ ⁴) ₂、-OQ ⁵、-NQ ⁶Q ⁷、-O-C(=O)(CQ ¹Q ²) _t-(Cy) _s-OP(=O)(OH) ₂、-OC(=O)-NQ ⁶Q ⁷、-OC(=O)CH=CHC(=O)OH、-O-C(=O)-O-(CQ ¹Q ²) _t-OP(=O)(OH) ₂、-O-C(=O)-NH-(CQ ¹Q ²) _t-OP(=O)(OH) ₂、氫、雜環基及雜芳基； Cy係芳基或雜芳基，各自視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：烷基、烷氧基、鹵素、鹵代烷基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； Q ¹及Q ²係相同或不同的且各自獨立地選自氫、氘及烷基，其中該烷基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：烷氧基、鹵素、羥基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； Q ³選自氫、烷基、環烷基及雜環基，其中該烷基、環烷基或雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：氘、鹵素、烷基、烷氧基、鹵代烷基、羥基、羥基烷基、氰基、-NQ ⁶Q ⁷、硝基、環烷基、雜環基、芳基及雜芳基； Q ⁴及Q ⁵係相同或不同，且各自獨立地選自烷基、環烷基及雜環基，其中該烷基、環烷基或雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：氘、鹵素、烷基、烷氧基、鹵代烷基、羥基、羥基烷基、氰基、胺基、硝基、-NQ ⁶Q ⁷、-OC(=O)Q ⁸、-OC(=O)OQ ⁸、環烷基、雜環基、芳基及雜芳基； Q ⁶及Q ⁷係相同或不同，且各自獨立地選自氫、烷基、鹵代烷基、氘烷基、羥基烷基、環烷基及雜環基； Q ⁸選自烷基、鹵代烷基及氘烷基； R ¹選自氫、烷基、鹵代烷基、羥基烷基、環烷基、雜環基、芳基及雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之基團取代：鹵素、羥基、氰基、烷基、烷氧基及羥基烷基； R ^2a、R ^2b、R ^3a及R ^3b各自係相同或不同，且各自獨立地選自氫、氘、鹵素、烷基、烷氧基、羥基、鹵代烷基、鹵代烷氧基、羥基烷基、氰基、胺基、環烷基及雜環基，其中該烷基、環烷基及雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之基團取代：鹵素、烷基、烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； 或R ^2a、R ^2b、R ^3a及R ^3b中之兩者連同其所連接之碳原子形成環烷基或雜環基； R ^4a、R ^4b、R ^5a及R ^5b各自係相同或不同，且各自獨立地選自氫、氘、鹵素、烷基、烷氧基、羥基、鹵代烷基、鹵代烷氧基、羥基烷基、環烷基及雜環基； 或R ^4a、R ^4b、R ^5a及R ^5b中之兩者連同其所連接之碳原子形成環烷基或雜環基； R ^6a、R ^6b、R ^6c及R ^6d係相同或不同，且各自獨立地選自氫、鹵素、烷基、氘烷基、烷氧基、鹵代烷基、鹵代烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視情況經一或多個選自以下之基團取代：鹵素、烷基、烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； n為1或2； m為1或2； t為1或2；且 s為0或1。 In one aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X ¹ and X ² are the same or different, and are independently hydrogen or -LR ⁰ , with the limitation that both X ¹ and X ² are not hydrogen; L selected from -(CQ ¹ Q ² ) _t -, -C(=O)O-, -C(=O)O(CQ ¹ Q ² ) _t -and -C(=O)S(CQ ¹ Q ² ) _t -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OP(=O)(OH)-OP(=O)(OH) ₂ , -OC(=O)Q ³ , -NQ ⁶ C(=O)Q ³ , -OC(=O)OQ ⁴ , -NQ ⁶ C(=O)OQ ⁴ , -OP(=O)(OQ ⁴ ) ₂ , -OQ ⁵ , -NQ ⁶ Q ⁷ , -OC(=O)(CQ ¹ Q ² ) _t -(Cy) _s -OP(=O)(OH) ₂ , -OC(=O)-NQ ⁶ Q ⁷ , -OC(=O)CH=CHC (=O)OH, -OC(=O)-O-(CQ ¹ Q ² ) _t -OP(=O)(OH) ₂ , -OC(=O)-NH-(CQ ¹ Q ² ) _t - OP(=O)(OH) ₂ , hydrogen, heterocyclic group and heteroaryl group; Cy is aryl group or heteroaryl group, one or more, sometimes preferably one to five and sometimes better One to three substituents independently selected from the following substituents: alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q ¹ and Q ² are the same or different and each independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally passed through one or more, sometimes preferably one to five and sometimes More preferably one to three substituents independently selected from the following substituents are substituted: alkoxy, halogen, hydroxyl, cyano, amine, nitro, cycloalkyl, heterocyclic, aryl and ^heteroaryl ; From hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally independently replaced by one or more, sometimes preferably from one to five and sometimes more preferably from one to three Substituents selected from the following substituents: deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NQ ⁶ Q ⁷ , nitro, cycloalkyl, heterocyclyl, aryl base and heteroaryl; ^Q4 and ^Q5 are the same or different, and each independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl as appropriate through one or Multiple, sometimes preferably one to five and sometimes more preferably one to three substituents independently selected from the group consisting of deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano , amino, nitro, -NQ ⁶ Q ⁷ , -OC(=O)Q ⁸ , -OC(=O)OQ ⁸ , cycloalkyl, heterocyclyl, aryl and heteroaryl; Q ⁶ and Q ⁷ are the same or different, and each independently selected from hydrogen, alkyl, haloalkyl, deuterane radical, hydroxyalkyl, cycloalkyl and heterocyclyl; ^Q is selected from alkyl, haloalkyl and deuterated alkyl; ^R is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally replaced by one or more, sometimes preferably one to five and sometimes more preferably one to three Substituted by a group independently selected from the following groups: halogen, hydroxyl, cyano, alkyl, alkoxy and hydroxyalkyl; R ^2a , R ^2b , R ^3a and R ^3b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted by one or more, sometimes preferably one to five and sometimes more preferably one to three groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalk group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; or two of R ^2a , R ^2b , R ^3a and R ^3b together with the carbon atom to which they form Cycloalkyl or heterocyclyl; R ^4a , R ^4b , R ^5a and R ^5b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkane Oxygen, hydroxyalkyl, cycloalkyl and heterocyclyl; or two of R ^4a , R ^4b , R ^5a and R ^5b together with the carbon atoms to which they are attached form cycloalkyl or heterocyclyl; R ^6a , R ^6b , R ^6c and R ^6d are the same or different, and each independently selected from hydrogen, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, Amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally selected from one or more of the following Group substitution: halogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 1 or 2; m is 1 or 2; t is 1 or 2; and s is 0 or 1.

In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and / or other excipients.

In another aspect, the present invention also provides a method of preventing and/or treating an inflammatory condition or disease involving cartilage degradation and/or disturbance of cartilage homeostasis, comprising administering to an individual in need thereof a therapeutically effective amount of A step of compound of formula (I) or a pharmaceutically acceptable salt thereof.

The disease or condition comprises arthritis, preferably rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis, which is further preferably associated with the activity of ADAMTS-5 and/or ADAMTS-4.

Other aspects or advantages of the present invention will be better understood based on the following detailed description, examples and claims.

This application claims priority to U.S. Provisional Patent Application No. 63/170,371, filed April 2, 2021, which is hereby incorporated by reference in its entirety.

， 或其醫藥學上可接受之鹽， 其中： X ¹及X ²係相同或不同，且各自獨立地係氫或-L-R ⁰，其限制條件為X ¹及X ²兩者不皆為氫； L選自-(CQ ¹Q ²) _t-、-C(=O)O-、-C(=O)O(CQ ¹Q ²) _t-及-C(=O)S(CQ ¹Q ²) _t-； R ⁰選自-OP(=O)(OH) ₂、-OP(=O)(OH)-OP(=O)(OH) ₂、-OC(=O)Q ³、-NQ ⁶C(=O)Q ³、-OC(=O)OQ ⁴、-NQ ⁶C(=O)OQ ⁴、-OP(=O)(OQ ⁴) ₂、-OQ ⁵、-NQ ⁶Q ⁷、-O-C(=O)(CQ ¹Q ²) _t-(Cy) _s-OP(=O)(OH) ₂、-OC(=O)-NQ ⁶Q ⁷、-OC(=O)CH=CHC(=O)OH、-O-C(=O)-O-(CQ ¹Q ²) _t-OP(=O)(OH) ₂、-O-C(=O)-NH-(CQ ¹Q ²) _t-OP(=O)(OH) ₂、氫、雜環基及雜芳基； Cy係芳基或雜芳基，各自視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：烷基、烷氧基、鹵素、鹵代烷基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； Q ¹及Q ²係相同或不同的且各自獨立地選自氫、氘及烷基，其中該烷基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：烷氧基、鹵素、羥基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； Q ³選自氫、烷基、環烷基及雜環基，其中該烷基、環烷基或雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：氘、鹵素、烷基、烷氧基、鹵代烷基、羥基、羥基烷基、氰基、-NQ ⁶Q ⁷、硝基、環烷基、雜環基、芳基及雜芳基； Q ⁴及Q ⁵係相同或不同的且各自獨立地選自烷基、環烷基及雜環基，其中該烷基、環烷基或雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之取代基取代：氘、鹵素、烷基、烷氧基、鹵代烷基、羥基、羥基烷基、氰基、胺基、硝基、-NQ ⁶Q ⁷、-OC(=O)Q ⁸、-OC(=O)OQ ⁸、環烷基、雜環基、芳基及雜芳基； Q ⁶及Q ⁷係相同或不同的且各自獨立地選自氫、烷基、鹵代烷基、氘烷基、羥基烷基、環烷基及雜環基； Q ⁸選自烷基、鹵代烷基及氘烷基； R ¹選自氫、烷基、鹵代烷基、羥基烷基、環烷基、雜環基、芳基及雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之基團取代：鹵素、羥基、氰基、烷基、烷氧基及羥基烷基； R ^2a、R ^2b、R ^3a及R ^3b各自係相同或不同，且各自獨立地選自氫、氘、鹵素、烷基、烷氧基、羥基、鹵代烷基、鹵代烷氧基、羥基烷基、氰基、胺基、環烷基及雜環基，其中該烷基、環烷基或雜環基視情況經一或多個、有時較佳一至五個且有時更佳一至三個獨立地選自以下之基團取代：鹵素、烷基、烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； 或R ^2a、R ^2b、R ^3a及R ^3b中之兩者連同其所連接之碳原子形成環烷基或雜環基； R ^4a、R ^4b、R ^5a及R ^5b各自係相同或不同，且各自獨立地選自氫、氘、鹵素、烷基、烷氧基、羥基、鹵代烷基、鹵代烷氧基、羥基烷基、環烷基及雜環基； 或R ^4a、R ^4b、R ^5a及R ^5b中之兩者連同其所連接之碳原子形成環烷基或雜環基； R ^6a、R ^6b、R ^6c及R ^6d係相同或不同，且各自獨立地選自氫、鹵素、烷基、氘烷基、烷氧基、鹵代烷基、鹵代烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視情況經一或多個、有時較佳一至五個且有時更佳一至三個選自以下之基團取代：鹵素、烷基、烷氧基、羥基、羥基烷基、氰基、胺基、硝基、環烷基、雜環基、芳基及雜芳基； n為1或2； m為1或2； t為1或2；且 s為0或1。 In one aspect, the present invention provides a compound of formula (I):

, or a pharmaceutically acceptable salt thereof, wherein: X ¹ and X ² are the same or different, and each independently is hydrogen or -LR ⁰ , with the limitation that both X ¹ and X ² are not hydrogen; L is selected from -(CQ ¹ Q ² ) _t -, -C(=O)O-, -C(=O)O(CQ ¹ Q ² ) _t - and -C(=O)S(CQ ¹ Q ² ) _t -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OP(=O)(OH)-OP(=O)(OH) ₂ , -OC(=O)Q ³ , -NQ ⁶ C(=O)Q ³ , -OC(=O)OQ ⁴ , -NQ ⁶ C(=O)OQ ⁴ , -OP(=O)(OQ ⁴ ) ₂ , -OQ ⁵ , -NQ ⁶ Q ⁷ , -OC(=O)(CQ ¹ Q ² ) _t -(Cy) _s -OP(=O)(OH) ₂ , -OC(=O)-NQ ⁶ Q ⁷ , -OC(=O)CH= CHC(=O)OH, -OC(=O)-O-(CQ ¹ Q ² ) _t -OP(=O)(OH) ₂ , -OC(=O)-NH-(CQ ¹ Q ² ) _t -OP(=O)(OH) ₂ , hydrogen, heterocyclyl and heteroaryl; Cy is aryl or heteroaryl, each optionally modified by one or more, sometimes preferably one to five and sometimes more Preferably, one to three substituents independently selected from the following substituents are substituted: alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aromatic base and heteroaryl; Q ¹ and Q ² are the same or different and are independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally one or more, sometimes preferably one to five and having More preferably one to three substituents independently selected from the following substituents: alkoxy, halogen, hydroxyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q ³ selected from hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally replaced by one or more, sometimes preferably one to five and sometimes more preferably one to three Substituents independently selected from the following substituents: deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NQ ⁶ Q ⁷ , nitro, cycloalkyl, heterocyclyl, Aryl and heteroaryl; Q ⁴ and Q ⁵ are the same or different and each independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally modified by one or more, sometimes preferably one to five and sometimes more preferably one to three substituents independently selected from: deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyanide group, amino group, nitro group, -NQ ⁶ Q ⁷ , -OC(=O)Q ⁸ , -OC(=O)OQ ⁸ , cycloalkyl, heterocyclyl, aryl and heteroaryl; Q ⁶ and ^Q are the same or different and each independently selected from hydrogen, alkyl, haloalkyl, Deuteroalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl; ^Q is selected from alkyl, haloalkyl and deuteroalkyl; R ^is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally replaced by one or more, sometimes preferably one to five and sometimes better Substituted by one to three groups independently selected from the following groups: halogen, hydroxyl, cyano, alkyl, alkoxy and hydroxyalkyl; R ^2a , R ^2b , R ^3a and R ^3b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amine, cycloalkyl and heterocyclyl, wherein the alkyl, ring The alkyl or heterocyclic group is optionally substituted by one or more, sometimes preferably one to five and sometimes more preferably one to three groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; or two of R ^2a , R ^2b , R ^3a and R ^3b together with the carbon to which they are attached Atoms form a cycloalkyl or heterocyclic group; R ^4a , R ^4b , R ^5a and R ^5b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl , haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or two of R ^4a , R ^4b , R ^5a and R ^5b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; R ^6a , R ^6b , R ^6c and R ^6d are the same or different, and each independently selected from hydrogen, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally modified by one or more, Sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 substituted groups selected from: halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl , heterocyclyl, aryl and heteroaryl; n is 1 or 2; m is 1 or 2; t is 1 or 2;

In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, n is 1; and m is 1.

In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ^2a , R ^2b , R ^3a , R ^6c and R ^6d are the same or different, and are independently selected from from hydrogen, deuterium, halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl, C _{1 - 6} haloalkoxy, hydroxyl and C _{1 - 6} hydroxyalkyl; preferably , R ^2a , R ^2b , R ^3a , R ^6c and R ^6d are the same or different _{, and are each independently selected from hydrogen, halogen and C 1-6 alkyl .}

In some embodiments of the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen, deuterium, halogen , C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl, C _{1 - 6} haloalkoxy, hydroxyl and C _{1 - 6} hydroxyalkyl; preferably, R ^2a , R ^2b and R ^3a are the _same or different, and are each independently selected from hydrogen, halogen and C _1-6 alkyl _; more preferably, R ^2a , R ^2b and R ^3a are hydrogen.

In some embodiments of _the present invention, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, _R ^6c and R ^6d are the same or different, and each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl, C _{1 - 6} haloalkoxy, hydroxyl and C _{1 - 6} hydroxyalkyl; preferably, R ^6c and R ^6d are the same or different, And each independently selected from hydrogen, halogen and C _1-6 alkyl _; more preferably, R ^6c and R ^6d are _hydrogen .

其中： X ¹、X ²、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(I)中所定義。 In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein: X ¹ , X ² , R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in formula (I) above.

其中： X ¹、X ²、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(I)中所定義。 In some embodiments of the present invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof:

wherein: X ¹ , X ² , R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in formula (I) above.

In some embodiments of the present invention, in the compound of formula (I), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, R is ³ to 6 membered cycloalkyl; Preferably, R ¹ is cyclopropyl.

In some embodiments of the present invention, in the compound of formula (I), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, R ^3b is selected from hydrogen, halogen and C _{1 - 6} Alkyl; preferably, R ^3b is hydrogen.

其中： X ¹、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(I)中所定義。 In some embodiments of the present invention, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is the compound of formula (III) or a pharmaceutically acceptable salt thereof:

wherein: X ¹ , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in formula (I) above.

其中： X ¹、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(I)中所定義。 In some embodiments of the present invention, the compound of formula (I), formula (II), formula (II-1) or formula (III) or a pharmaceutically acceptable salt thereof is the compound of formula (III-1) or Pharmaceutically acceptable salts:

wherein: X ¹ , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in formula (I) above.

In some embodiments of the present invention, in the compound of formula (I), formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof, X ² is hydrogen or -LR ⁰ ; L is - CQ ¹ Q ² -; R ⁰ , Q ¹ and Q ² are as defined above in formula (I); preferably, X ² is hydrogen or -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected From -OP(=O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; Q ¹ , Q ² and Q ³ are as above Defined in formula (I); more preferably, X ² is hydrogen or -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is -OP(=O)(OH) ₂ ; and Q ¹ and Q ² is as defined above in formula (I); optimally, X ² is hydrogen.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ , Q ¹ and Q ² are as defined above in formula (I); preferably, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; Q ¹ , Q ² and Q ³ are as defined above in formula (I); more preferably, X ¹ is hydrogen or -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is -OP(=O)(OH ) ₂ ; and Q ¹ and Q ² are as defined above in formula (I).

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, Q ¹ and Q ² are the same or different, and each independently _{selected from hydrogen, deuterium and C 1-6 alkyl; and/or Q 3 is C 1-6 alkyl ;} ^preferably _{, Q 1} and ^{Q 2 are} hydrogen _; and _Q ³ is C _1-6 alkyl.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, _Each of R ^4a , R ^4b , R ^5a and R ^5b is the same or different, _and each is independently selected from hydrogen, deuterium and C _1-6 alkyl.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, Each of R ^4a and R ^4b is the same or different, and each is independently selected from hydrogen, deuterium, and C _1-6 alkyl _; preferably, _each of R ^4a and R ^4b is the same or different, and each is independently hydrogen or Deuterium; more preferably, R ^4a and R ^4b are deuterium.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, R ^4a and R ^4b are hydrogen.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, Each of R ^5a and R ^5b is the same or different, and each is independently selected from hydrogen, deuterium and C _1-6 alkyl; _preferably , _each of R ^5a and R ^5b is the same or different, and each is independently hydrogen or C _1-6 alkyl _{; more} preferably, R ^5a _is hydrogen and R ^5b is C _{1-6 alkyl} .

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, R ^5a and R ^5b are hydrogen.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, R ^4a , R ^4b , R ^5a and R ^5b are hydrogen.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, R ^4a and R ^4b _{are deuterium} ; R ^5a is hydrogen and R ^5b is C _1-6 alkyl.

In some embodiments of the present invention, in the compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof, Each of _R ^6a and R ^6b is _{the same} or different, and each _is independently _{selected from} hydrogen, halogen _, C _1-6 alkyl, C _{1-6 deuterated} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl , C _{1 - 6} haloalkoxy, hydroxyl, C _{1 - 6} hydroxyalkyl, cyano, amine, nitro, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group.

In some embodiments, each of R ^6a and R ^6b is the same _{or different} , and each is independently _{selected from} hydrogen, halogen _, C _1-6 deuterated _alkyl , C _1-6 alkyl, and C _1-6 haloalkyl.

In some embodiments, _each of R ^6a and _R ^6b is the same or _different , and each is independently selected from hydrogen, _halogen , C _1-6 alkyl and C _1-6 haloalkyl; in some preferred embodiments, R ^6a and R ^6b are each the same or different, and are each independently selected from halogen _and C _{1-6 haloalkyl ;} more preferably _, R ^6a is halogen; and R ^6b is C _1-6 haloalkyl; in some more preferred implementations In one example, R ^6a is -Cl; and R ^6b is -CF ₃ .

In some embodiments of the present invention, in the compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP( =O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; Q ¹ and Q ² are hydrogen; Q ³ is C _{1 - 6} alkyl; R ^4a , R ^4b , R ^5a and R ^5b are each the same or different, and each independently selected from hydrogen, deuterium and C _{1 - 6} alkyl; R ^6a and R ^6b are each the same or different, And _each independently selected from _hydrogen , halogen _, C _1-6 deuterated _alkyl , C _1-6 alkyl _and C _1-6 haloalkyl _.

In some embodiments of the present invention, in the compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP( =O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; Q ¹ and Q ² are hydrogen; Q ³ is C _{1 - 6} alkyl; R ^4a , R ^4b , R ^5a and R ^5b are hydrogen; R ^6a and R ^6b are each the same or different, and each independently selected from hydrogen, halogen, C _{1 - 6} alkyl and C _{1 - 6} Haloalkyl.

特戊酸( S)-(4-(3-(5-氯-6-(三氟甲基)異吲哚啉-2-基)-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲酯 3 4

特戊酸(( S)-4-(3-(( R)-5-氯-1-甲基-6-(三氟甲基)異吲哚啉-2-基-3,3- d ₂ )-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲酯 4 5

磷酸二氫( S)-(4-(3-(5-氯-6-(三氟甲基)異吲哚啉-2-基)-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲酯 5 6

磷酸二氫(( S)-4-(3-(( R)-5-氯-1-甲基-6-(三氟甲基)異吲哚啉-2-基-3,3- d ₂ )-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲酯 6 表B. 可基於本發明製備之其他化合物包括但不限於：

In some embodiments of the present invention, in the compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP( =O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; Q ¹ and Q ² are hydrogen; Q ³ is C _{1 -6} alkyl; R ^4a and _R ^4b are deuterium; R ^5a and R ^5b are each _the same or different, and each independently is hydrogen or C _1-6 alkyl; R ^6a and R ^6b are _each the same or different, and each independently selected from halogen and _{C 1-6 haloalkyl .} Table A. Exemplary compounds of the invention include, but are not limited to: instance number structure and name 3

Pivalic acid ( S )-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl -2,5-dioxoimidazolidin-1-yl) methyl ester 3 4

Pivalic acid (( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidin-1-yl)methyl ester 4 5

Dihydrogen phosphate ( S )-(4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-cyclopropyl -2,5-dioxoimidazolidin-1-yl) methyl ester 5 6

Dihydrogen phosphate (( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidin-1-yl)methyl ester 6 Table B. Other compounds that can be prepared based on the present invention include, but are not limited to:

其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫；且 L、R ¹、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a、R ^6b、R ^6c、R ^6d、n及m各自如式(I)中所定義。 In another aspect, the present invention provides a compound of formula (IA) or a salt thereof:

Wherein: R ^t is alkyl; preferably, R ^t is C _{1 - 6} alkyl; X ² is hydrogen; and L, R ¹ , R ^2a , R ^{2b , R 3a ,} R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , n and m are each as defined in formula (I).

其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II)中所定義。 In another aspect, the present invention provides a compound of formula (IIA) or a salt thereof:

Wherein: R ^t is alkyl; preferably, R ^t is C _{1 - 6} alkyl; X ² is hydrogen; and L, R ¹ , R ^3b , R ^{4a , R 4b ,} R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II).

其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II-1)中所定義。 In another aspect, the present invention provides a compound of formula (II-1A) or a salt thereof:

Wherein: R ^t is alkyl; preferably, R ^t is C _{1 - 6} alkyl; X ² is hydrogen; and L, R ¹ , R ^3b , R ^{4a , R 4b ,} R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II-1).

其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III)中所定義。 In another aspect, the present invention provides a compound of formula (IIIA) or a salt thereof:

wherein: R ^t is an alkyl group; preferably, R ^t is _{a C 1-6 alkyl} group; and _L , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as in formula (III) above defined.

其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III-1)中所定義。 本發明之例示性中間化合物包括但不限於： 實例編號 結構及名稱 5a

( S)-((4-(3-(5-氯-6-(三氟甲基)異吲哚啉-2-基)-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲基)磷酸二-三級丁酯 5a 6c

((( S)-4-(3-(( R)-5-氯-1-甲基-6-(三氟甲基)異吲哚啉-2-基-3,3- d ₂ )-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲基)磷酸二-三級丁酯 6c In another aspect, the present invention provides a compound of formula (III-1A) or a salt thereof:

wherein: R ^t is an alkyl group; preferably, R ^t is a C _{1 - 6} alkyl group; and L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as above formula (III-1 ) as defined in . Exemplary intermediate compounds of the invention include, but are not limited to: instance number structure and name 5a

( S )-((4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-cyclopropyl-2 ,5-dioxoimidazolidin-1-yl)methyl)di-tertiary-butyl phosphate 5a 6c

((( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3- d ₂ )- 3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolidin-1-yl)methyl)di-tertiary butyl phosphate 6c

移除式(IA)化合物或其鹽之R ^t，得到式(I)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a、R ^6b、R ^6c、R ^6d、n及m各自如式(I)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

R ^t of the compound of formula (IA) or its salt is removed to obtain the compound _of formula (I) or its pharmaceutically acceptable salt, wherein: _R ^t is an alkyl group; preferably, R ^t is a C _1-6 alkane base; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , n and m are each as defined in formula (I).

移除式(IIA)化合物或其鹽之R ^t，得到式(II)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

R ^t of the compound of formula (IIA) or its salt is removed to obtain the compound _of formula (II) or its pharmaceutically acceptable salt, wherein _: R ^t is an alkyl group; preferably, R ^t is a C _1-6 alkane base; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II).

移除式(II-1A)化合物或其鹽之R ^t，得到式(II-1)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II-1)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

R ^t of the compound of formula (II-1A) or its salt is removed to obtain the compound of formula (II-1) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _1-6 alkyl; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP( ₌ O) ₍ OH) ₂ ; and L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II-1).

移除式(IIIA)化合物或其鹽之R ^t，得到式(III)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

R ^t of the compound of formula (IIIA) or its salt is removed to obtain the compound _of formula (III) or its pharmaceutically acceptable salt, wherein _: R ^t is an alkyl group; preferably, R ^t is a C _1-6 alkane base; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as above formula (III ) as defined in .

移除式(III-1A)化合物或其鹽之R ^t，得到式(III-1)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III-1)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

R ^t of the compound of formula (III-1A) or its salt is removed to obtain the compound of formula (III-1) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _1-6 alkyl; X ¹ is -LR ⁰ , wherein R ⁰ _is -OP( ₌ O)(OH) ₂ ; and L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as above Defined in formula (III-1).

使式(IB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(I)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a、R ^6b、R ^6c、R ^6dn及m各自如式(I)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound of formula (IB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (I) or its pharmaceutically acceptable salt, wherein: R ^w is halogen; preferably, R ^w is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^2a , R ^2b , R 3a , R ^3b , R ^4a , R ^{4b ,} R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d n and m are each as defined in formula (I).

使式(IIB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(II)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound of formula (IIB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (II) or its pharmaceutically acceptable salt, wherein: R ^w is halogen; preferably, R ^w is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each of the above formula ( as defined in II).

使式(II-1B)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(II-1)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II-1)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound of formula (II-1B) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (II-1) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen; preferably, R ^W is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each As defined above in formula (II-1).

使式(IIIB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(III)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰；且 R ⁰、L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound of formula (IIIB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (III) or its pharmaceutically acceptable salt, wherein: R ^w is halogen; preferably, R ^w is Cl; X ¹ is -LR ⁰ ; and R ⁰ , L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (III).

使式(III-1B)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(III-1)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰；且 R ⁰、L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III-1)中所定義。 In another aspect, the present invention provides a method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound of formula (III-1B) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (III-1) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen; preferably, R ^w is Cl; X ¹ is -LR ⁰ ; and R ⁰ , L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (III-1).

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or a compound selected from Table A or Table B A compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and/or other excipients.

The present invention also provides a method of inhibiting ADAMTS-5 and/or ADAMTS-4, which comprises administering a therapeutically effective amount of formula (I), formula (II), formula (II-1), formula ( III) or a compound of formula (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound.

The present invention also provides a method of preventing or treating an inflammatory condition or disease involving cartilage degradation and/or disturbing cartilage homeostasis, which comprises administering a therapeutically effective amount of formula (I), formula (II) to an individual in need thereof. ), formula (II-1), formula (III) or formula (III-1) compound, or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound .

The present invention also provides a method for preventing or treating arthritis, which comprises administering a therapeutically effective amount of formula (I), formula (II), formula (II-1), formula (III) or formula ( III-1) A compound, or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound; preferably, wherein the arthritis is selected from rheumatoid arthritis arthritis, psoriatic arthritis, osteoarthritis, and hypertrophic arthritis.

In another aspect, the present invention also relates to a compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or a compound selected from Table A or Table Use of the compound of B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for the manufacture of a medicament for inhibiting ADAMTS-5 and/or ADAMTS-4.

In another aspect, the present invention also relates to a compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or a compound selected from Table A or Table Use of the compound of B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for the manufacture of prophylaxis and/or treatment of inflammatory diseases involving cartilage degradation and/or disturbance of cartilage homeostasis medicines for symptoms or diseases.

In another aspect, the present invention also relates to a compound of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or a compound selected from Table A or Table The use of the compound of B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for the manufacture of a drug for preventing and/or treating arthritis; preferably, the arthritis is selected from From rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

The present invention further relates to compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or compounds selected from Table A or Table B, or pharmaceutically An acceptable salt, or a pharmaceutical composition containing the compound, which is used as a medicine.

The present invention also relates to compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or compounds selected from Table A or Table B, or pharmaceutically An acceptable salt, or a pharmaceutical composition containing the compound, which is used for inhibiting ADAMTS-5 and/or ADAMTS-4.

The present invention also relates to compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or compounds selected from Table A or Table B, or pharmaceutically Acceptable salts, or combinations in pharmaceutical compositions containing the compounds for the prevention and/or treatment of inflammatory conditions or diseases involving cartilage degradation and/or diseases that interfere with cartilage homeostasis.

The present invention also relates to compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or compounds selected from Table A or Table B, or pharmaceutically An acceptable salt, or a combination of pharmaceutical compositions containing the compound, which is used for the prevention and/or treatment of arthritis; preferably, wherein the arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis Arthropathy and hypertrophic arthritis.

In the present invention, wherein inflammatory conditions, diseases involving cartilage degradation and/or disturbance of cartilage homeostasis and arthritis are preferably ADAMTS-5 and/or ADAMTS-4 mediated.

The phrase "inflammatory condition" refers to the group of conditions including, but not limited to: rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic respiratory diseases (eg asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven disease conditions (e.g., complications following bypass surgery or Contributing to chronic endotoxic conditions such as chronic cardia failure) and related diseases involving cartilage, such as that of the joints. In particular it refers to rheumatoid arthritis, osteoarthritis, allergic respiratory diseases (eg asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease. More particularly rheumatoid arthritis, and osteoarthritis (OA). Most specifically it refers to osteoarthritis (OA).

"Diseases involving cartilage degradation and/or disturbance of cartilage homeostasis" includes conditions such as: osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis , reactive arthritis, reflex sympathetic dystrophy, reflex sympathetic dystrophy, achondroplasia, Paget's disease, Tietze syndrome or costochondritis, muscle fibers Pain, osteochondritis, neuropathic or neuropathic arthritis, arthropathy, sarcoidosis, amyloidosis, joint deformities, periodic diseases, rheumatoid spondylitis, e.g. osteoarthritic deformity endemic, Meniere's disease Endemic forms of arthritis of (Mseleni disease) and Handigodu disease; degenerative diseases caused by fibromuscular pain, systemic lupus erythematosus, scleroderma and ankylosing spondylitis; and in particular, refers to osteoarthritis (OA ).

The pharmaceutical compositions of the present invention can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present invention can be formulated in a variety of dosage forms for oral, buccal, intranasal, parenteral (eg intravenous, intramuscular or subcutaneous), rectal administration, inhalation or insufflation administration. The compounds of the invention may also be formulated as sustained release dosage forms.

Dosages of the compounds or compositions used in the present invention will vary with the severity of the disease, the body weight of the patient and the relative efficacy of the compounds. As a general guide, however, the active compound is preferably presented in a unit dose or in a form which the patient can self-administer in a single dose. The unit dosage form of a compound or composition of this invention may be presented as a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation. Suitable unit doses may be from 0.1 mg to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present invention may contain one or more excipients selected from the following components: fillers (diluents), adhesives, wetting agents, disintegrating agents or excipients. Depending on the method of administration, the compositions may contain from 0.1% to 99% by weight of active compound.

Suitable dosage forms include, but are not limited to, troches, dragees, 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 the preparation of pharmaceutical compositions. Such compositions may contain one or more additives selected from sweetening agents, flavoring agents, coloring agents and preservatives in order to provide a pleasant and palatable pharmaceutical preparation. Tablets contain the active ingredient together with pharmaceutically acceptable nontoxic excipients which are suitable for the manufacture of tablets. Such excipients may be inert excipients, granulating agents, disintegrating agents and lubricants. The lozenge can be uncoated or coated by means of known techniques to mask the taste of the drug or to delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period of time. For example, water soluble taste-masking materials can be used.

Oral formulations can also be presented as soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or the active ingredient is mixed with a water-soluble carrier.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing, or wetting agents and can be naturally occurring phospholipids. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions may be formulated by suspending the active ingredient in vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as previously described may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids. Sweeteners may be used. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

Pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. Injectable solutions or microemulsions can be introduced into the bloodstream of a subject by local bolus injection. Alternatively, it may be advantageous to administer solutions or microemulsions in such a way as to maintain a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, continuous intravenous delivery devices may be employed. An example of such a device is the Deltec CADD-PLUS. TM. 5400 Intravenous Syringe Pump.

Pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents as have been described above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in an acceptable nontoxic parenteral diluent or solvent. In addition, sterile, fixed oils are readily employed as a solvent or suspending medium, and fatty acids are also used in the preparation of injectables.

Compounds of the invention may be administered in the form of suppositories for rectal administration. Such 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 where it will melt in the rectum to release the drug.

For buccal administration, the composition may be formulated as a lozenge or buccal lozenge by known methods.

For intranasal administration or administration by inhalation, the active compounds of the invention are propelled using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Delivery is conveniently in the form of a solution or suspension released from a pump spray container which is squeezed or drawn by the patient, or in the form of an aerosol spray released from a pressurized container or nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or sprayer can contain a solution or suspension of the active compound. Capsules or cartridges (eg, made of gelatin) for use in an inhaler or insufflator may be formulated containing the powder mix of the invention and a suitable powder base such as lactose or starch.

Those skilled in the art are well aware that the dosage of a drug depends on a variety of factors including, but not limited to, the activity of the particular compound, age, body weight, general health, behavior, the patient's diet, time of administration, route of administration, excretion rate, drug combination, and similar factors. Additionally, optimal treatment can be verified by traditional treatment regimens, such as mode of treatment, daily dosage of the compound or type of pharmaceutically acceptable salt thereof. definition

Unless otherwise stated, the terms used in this specification and claims have the meanings described below.

"Alkyl" refers to a saturated aliphatic hydrocarbon group including C ₁ -C ₂₀ straight chain and branched chain groups. Preferably the alkyl group is an alkyl group having 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7 _, 8, 9, 10 _, 11 and 12) carbon atoms (i.e., C _1-12 alkane base). In some embodiments, it is sometimes preferred that the _alkyl group is an alkyl group having 1 to 8 carbon atoms (ie, a C _{1 -8} alkyl group). Representative examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl Base, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-di Methylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethyl Hexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl -3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and branched chain isomers thereof. In some embodiments, sometimes preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms (i.e., C _{1 -6} alkyl) and _sometimes more preferably 1 to 4 carbon atoms Lower alkyl (ie, C _{1 - 4} alkyl). Representative examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl base, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. . Alkyl groups can be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more substituents, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 independently selected from the following groups Group: halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, hetero Aryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and pendant oxy.

"Alkenyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2- butenyl or 3-butenyl, etc.; preferably C _{2 - 20} alkenyl, more preferably C _{2 - 12} (for example including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 And 12 carbon) alkenyl, and sometimes more preferably C _{2 - 6} alkenyl, and sometimes even more preferably C _{2 - 4} alkenyl. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of halogen, alkoxy, alkynyl, Alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, Cycloalkylthio, heterocyclic thio and pendant oxy.

"Alkynyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl , 2-butynyl or 3-butynyl, etc., preferably C _{2 - 20} alkynyl, more preferably C _{2 - 12} (such as including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) alkynyl, and sometimes preferably C _{2 - 6} alkynyl, and sometimes even more preferably C _{2 - 4} alkynyl. Alkynyl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkoxy, alkyl Sulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkyl Thio and Heterocyclic Thio.

"Alkylene" means a saturated straight or branched chain divalent aliphatic hydrocarbon group derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Straight chain or branched chain groups contain 1 to 20 carbon atoms, preferably 1 to 12 (for example including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atoms ) carbon atoms, sometimes more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-Propyl (-CH(CH ₂ CH ₃ )-), 1,2-Propyl (-CH ₂ CH(CH ₃ )-), 1,3-Propyl (-CH ₂ CH ₂ CH ₂ -) and 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. Alkylene groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkoxy, Alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cyclo Alkylthio and heterocyclic thio.

"Alkenylene" means an alkylene group as defined above having at least two carbon atoms and at _{least one} carbon-carbon double bond, preferably a C _{2 -20} alkenylene group, more preferably a C _{2 -12} ( For example, including 2, 3, 4, 5, 6 _, 7, 8, 9, 10, 11 and 12 carbons) alkenylene, sometimes _more preferably _C2-6 alkenylene, and sometimes even more preferably C _{2 - 4} alkenyl. Non-limiting examples of alkenylene include, but are not limited to _, -CH=CH-, -CH= _CHCH2- , -CH= _CHCH2CH2- , _-CH2CH = _CHCH2- , and the like. Alkenylene groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of alkynyl, alkoxy, alkyl Sulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkyl Thio and Heterocyclic Thio.

"Cycloalkyl" means having from 3 to 20 carbon atoms, preferably from 3 to 12 (e.g. including 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) carbon atoms (i.e. 3 to 12 membered cycloalkyl), more preferably 3 to 10 carbon atoms, sometimes more preferably 3 to 8 (eg 3, 4, 5, 6, 7 or 8) carbon atoms (ie 3 to 8 membered cycloalkane groups) and sometimes even more preferably saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon groups of 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Trienyl, cyclooctyl, etc. Multicyclic cycloalkyls include cycloalkyls having spiro, fused or bridged rings.

。 "Spirocycloalkyl" refers to a 5 to 20 membered polycyclic group having rings joined through a common carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds. Preferably, the spirocycloalkyl group is 6 to 14 membered (e.g. including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), and more preferably 7 to 10 membered (e.g. 7, 8 , 9 and 10 members). According to the number of shared spiro atoms, spirocycloalkyl is divided into single spirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, and preferably refers to single spirocycloalkyl or dispirocycloalkyl, more preferably 3 Member/5 member, 3 member/6 member, 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member or 5 member/6 member single spirocycloalkyl. Representative examples of spirocycloalkyl groups include, but are not limited to, the following groups:

.

。 "Fused cycloalkyl" means a 5 to 20 membered polycyclic hydrocarbon group in which each ring in the system shares adjacent pairs of carbon atoms with another ring, wherein one or more rings may contain one or more double bonds. Preferably, the fused cycloalkyl group is 6 to 14 members (such as including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), more preferably 7 to 10 (such as 7, 8, 9 and 10) members. According to the number of member rings, fused cycloalkyl groups are divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and preferably refer to bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3 people/5 people, 3 people/6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people /3-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered bicyclic fused cycloalkyl group. Representative examples of fused cycloalkyl groups include, but are not limited to, the following groups:

.

。 "Bridged cycloalkyl" means a 5 to 20 membered polycyclic hydrocarbon group in which every two rings in the system share two unlinked carbon atoms. Rings may have one or more double bonds. Preferably, the bridged cycloalkyl group is 6 to 14 members (e.g. including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons) and more preferably 7 to 10 (e.g. 7, 8, 9 and 10) members. According to the number of member rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged Cycloalkyl. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following groups:

.

Cycloalkyl groups may also include the cycloalkyl groups described above fused to a ring of an aryl, heteroaryl, or heterocyclyl group, wherein the ring bonded to the parent structure is a cycloalkyl group. Representative examples include, but are not limited to, indenyl, tetrahydronaphthalene, benzocycloheptyl, and the like. Cycloalkyl groups are optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of: alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, Heterocycle, cycloalkylthio, heterocyclethio and pendant oxy.

"Heterocyclyl" means a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic group having one or more heteroatoms selected from N, O and S as ring atoms, wherein sulfur is optionally oxidized , forming S(=O) or S(=O) ₂ , but excluding -OO-, -OS- or -SS-. Preferably, the heterocyclyl is 3 to 12 membered (ie 3 to 12 membered heterocyclyl) having 1 to 4 (eg 1, 2, 3 or 4) heteroatoms; more preferably 1 to 3 heterocyclyls 3 to 10 (eg 3, 4, 5, 6, 7, 8, 9 and 10) members of atoms (ie 3 to 10 membered heterocyclyl); more preferably 6 to 10 members with 1 to 3 heteroatoms (ie 6 to 10 membered heterocyclyl); most preferably 5 to 6 membered (ie 5 to 6 membered heterocyclyl) with 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperolyl, morpholinyl, sulfo-morpholinyl, homopiperidinyl, and the like. Polycyclic heterocyclic groups include heterocyclic groups having spiro, fused or bridged rings.

。 "Spiroheterocyclyl" means a 5- to 20-membered polycyclic heterocyclyl group having rings connected through a common carbon atom (called the spiro atom), wherein the rings have one or more rings selected from N, O and S Heteroatoms as ring atoms in which sulfur is optionally oxidized to form S(=O) or S(=O) ₂ , but excluding -OO-, -OS- or -SS-, where one or more rings may contain One or more double bonds. Preferably, the spiroheterocyclyl is 6 to 14 members (e.g. comprising 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (e.g. 7, 8 , 9 and 10) members. According to the number of shared spiro atoms, spiroheterocyclyl is divided into single spiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl, and preferably refers to single spiroheterocyclyl or dispiroheterocyclyl, more preferably 3 Member/5 member, 3 member/6 member, 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member or 5 member/6 member monospiro heterocyclyl. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:

.

。 "Fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclyl in which each ring in the system shares adjacent pairs of carbon atoms with another ring, one or more of which may contain one or more bis bond, and wherein the rings have one or more heteroatoms selected from N, O and S as ring atoms, wherein sulfur is optionally oxidized to form S(=O) or S(=O) ₂ , but does not include- OO-, -OS-, or -SS-. Preferably, the fused heterocyclyl is 6 to 14 members (for example including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (for example 7, 8, 9 and 10) members. According to the number of member rings, fused heterocyclic groups are divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered Members/5 members, 3 members/6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 6 members/ 3-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered bicyclic fused heterocyclic group. Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups:

.

。 "Bridged heterocyclyl" means a 5 to 14 membered polycyclic heterocyclyl in which two unlinked carbon atoms are shared between each two rings in the system, the rings may have one or more double bonds, and the rings may have one or more a heteroatom selected from N, O and S as ring atoms, wherein sulfur is optionally oxidized to form S(=O) or S(=O) ₂ , excluding -OO-, -OS- or -SS-. Preferably, the bridging heterocyclyl is 6 to 14 members (e.g. comprising 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (e.g. 7, 8 , 9 and 10) members. According to the number of member rings, bridged heterocyclic groups are divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and preferably refer to bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups Ring base. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

.

等。 The ring of the heterocyclyl group includes the above-mentioned heterocyclyl group fused to a ring of an aryl group, a heteroaryl group or a cycloalkyl group, wherein the ring bonded to the parent structure is a heterocyclyl group. Representative examples include, but are not limited to, the following groups:

wait.

A heterocyclyl group is optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, Alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl Oxy, cycloalkylthio and heterocyclicthio.

。 "Aryl" means a 6 to 14 membered full carbon monocyclic or polycyclic fused ring ("fused" ring system means that each ring in the system shares adjacent pairs of carbon atoms with another ring in the system) group and It has a fully conjugated π electron system. Preferred aryl groups are 6 to 10 membered (ie 6 to 10 membered aryl), such as phenyl and naphthyl, most preferably phenyl. Aryl includes the aryl groups described above fused to a ring of a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring bonded to the parent structure is an aryl group. Representative examples include, but are not limited to, the following groups:

.

Aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, Alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl Oxy, cycloalkylthio and heterocyclicthio.

。 "Heteroaryl" refers to having 1 to 4 (such as 1, 2, 3 and 4) heteroatoms selected from O, S and N as ring atoms and having 5 to 14 (such as including 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms) ring atom aryl systems (i.e. 5 to 14 membered heteroaryl) in which sulfur is optionally oxidized to form S(=O) or S(= O) ₂ , but not including -OO-, -OS- or -SS-. Preferably the heteroaryl is 5 to 10 membered (eg 5, 6, 7, 8, 9 and 10) (i.e. 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e. 5 to 6 membered heteroaryl). aryl) such as thiadiazolyl, pyrazolyl, oxazolyl, oxdiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N -alkylpyrrole group, pyrimidinyl, pyrimidyl, imidazolyl, tetrazolyl and the like. Heteroaryl includes the aforementioned heteroaryls fused to a ring of aryl, heterocyclyl, or cycloalkyl, wherein the ring bonded to the parent structure is a heteroaryl. Representative examples include, but are not limited to, the following groups:

.

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, Alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl Oxy, cycloalkylthio and heterocyclicthio. "Alkoxy" means an -O-(alkyl) group in which alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups, sometimes preferably 1 to 5 and sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkynyl, alkane Oxygen, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy group, cycloalkylthio group and heterocyclethio group.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups contain a monovalent residue derived from the removal of one hydrogen atom from a parent ring atom, or a monovalent residue derived from the removal of two hydrogen atoms from the same or different ring atoms of the parent Derived divalent residues, namely "divalent cycloalkyl group", "divalent heterocyclic group", "aryl extended group" and "heteroaryl extended group".

"Bond" means a covalent bond using the "-" symbol.

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

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

"Hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

"Hydroxy" means an -OH group.

"Thiol" refers to a -SH group.

"Alkylthio" means an alkyl-S- group in which alkyl is as defined above.

"Haloalkylthio" means a haloalkyl-S- group in which haloalkyl is as defined above.

"Cycloalkoxy" means cycloalkyl-O-, wherein cycloalkyl is as defined above.

"Heterocyclyloxy" means heterocyclyl-O-, wherein heterocyclyl is as defined above.

"Cycloalkylthio" means cycloalkyl-S-, wherein cycloalkyl is as defined above.

"Heterocyclylthio" means heterocyclyl-S-, wherein heterocyclyl is as defined above.

"Halogen" means a fluorine, chlorine, bromine or iodine atom.

"Amino" refers to a _-NH2 group.

"Cyano" refers to a -CN group.

"Nitro" refers to a _-NO2 group.

"Pendant oxygen" refers to the =O group.

"Carboxy" means a -C(O)OH group.

"Carboxylate" means -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O) O-group, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present invention may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but differ in the arrangement of their atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-mirror isomers, diastereoisomers, ( D )- and ( L )-isomers, tautomers, hindered isomers, conformational isomers and mixtures thereof (such as mixtures of racemates and diastereomers). Substituents in compounds of the invention may have additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present invention. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, and ( D )- and ( L )-isomers can be synthesized via chirality, Prepared by chiral reactants or other known techniques. Isomers of the compounds of the present invention can be prepared by asymmetric synthesis or chiral additives, or when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), with a suitable optically active Acids or bases form diastereomeric salts and subsequent isolation of the diastereomers by conventional methods known in the art affords the pure isomers. Additionally, separation of enantiomers from diastereomers is usually accomplished by chromatography.

」表示非特定構形，即，若化學結構中存在對掌性異構體，則鍵「

」可為「

」或「

」或含有「

」或「

」構形兩者。本發明化合物可以不同互變異構形式存在，且所有此類形式均包括於本發明之範疇內。術語「互變異構體」或「互變異構體形式」係指平衡存在且易於自一種異構體轉換成另一種異構體之結構性異構體。其包括所有可能的互變異構體，亦即，呈一種異構體之形式或呈互變異構體之混合物的任意比例的形式。非限制性實例包括酮烯醇、亞胺烯胺、內醯胺內醯亞胺等。內醯胺內醯亞胺平衡之實例如下：

。 In the chemical structures of the compounds described in the present invention, the bond "

"Indicates a non-specific configuration, that is, if there is an enantiomer in the chemical structure, the bond"

" can be "

"or"

" or contain "

"or"

"Construct both. The compounds of the present invention may exist in different tautomeric forms and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily converted from one isomer to another. It includes all possible tautomers, ie in the form of one isomer or in a mixture of tautomers in any proportion. Non-limiting examples include ketoenols, imineenamines, lactamyl imines, and the like. An example of a lactam lactimine equilibrium is as follows:

.

。 For example, pyrazolyl should be understood as including any one of the following two structures or a mixture of two tautomers:

.

All tautomeric forms are within the scope of the invention and the names of the compounds do not exclude any tautomers.

"Optional/optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes circumstances in which the event or circumstance may or may not occur. For example, "the heterocyclic group is optionally substituted with an alkyl group" means that an alkyl group may be present but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by the corresponding number of substituents. Those skilled in the art can determine whether substitutions are possible or impossible, either experimentally or theoretically, without undue effort. For example, a combination of an amine or hydroxyl group with free hydrogen and a carbon atom with an unsaturated bond such as an alkene can be unstable.

"Pharmaceutical composition" refers to one or more of the compounds described in the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs together with physiologically/pharmaceutically acceptable carriers and excipients A mixture of other chemical components of the excipient. The purpose of a pharmaceutical composition is to facilitate the administration to an organism of a compound which facilitates the absorption of the active ingredient and thus exhibits biological activity.

"Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has corresponding biological activity.

Salts can be prepared during the final isolation and purification of the compounds, or separately by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium, potassium, lithium, calcium, magnesium, or ammonium hydroxide; organic ammonium hydroxides, such as Tetramethylammonium or tetraethylammonium hydroxide, and organic bases, such as various organic amines, including but not limited to methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N , N -dimethylaniline, N -methylpiperidine and N -methylmorpholine.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen disulfide; and organic acids such as p-toluenesulfonic acid, salicylic acid, Tartaric acid, ditartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Lactic acid, oxalic acid, brosylic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids.

"Prodrug" refers to a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active parent compound.

As used herein, the term "pharmaceutically acceptable" means, within the scope of sound medical judgment, a drug that satisfies a reasonable benefit/risk ratio and is suitable for use in contact with a patient's tissue without undue toxicity, irritation, allergic reaction, or other problem or complication. diseases, and those compounds, materials, compositions and/or dosage forms that are effective for their intended use.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit, such as a sustained reduction in viral load. When applied to an individual active ingredient administered alone, the term refers to that ingredient only. When applied to a combination, the term refers to combined amounts of the active ingredients that produce a therapeutic effect, whether administered in combination sequentially or simultaneously.

The terms "treat/treating/treatment" or similar terms mean: (i) inhibiting a disease, disorder or condition, i.e. arresting its development; and (ii) alleviating the disease, disorder or condition, i.e., Promoting regression of a disease, disorder and/or condition. In addition, the compounds of the present invention may be used in their prophylactic role to prevent the occurrence of a disease, disorder or condition in an individual who may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed with it.

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

As used herein, the term "individual" or "patient" refers to a human or mammal including, but not limited to, dogs, cats, horses, cows, monkeys, or the like.

When the term "about" is applied to a parameter such as pH, concentration, temperature or the like, it indicates that the parameter may vary by ±10%, and sometimes preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, values are generally given for purposes of illustration only and not limitation.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms making up such compounds. Unnatural proportions of isotopes can be defined as ranging from amounts found in nature to amounts consisting of 100% of the atom in question. For example, compounds may incorporate radioactive isotopes such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C); or non-radioactive isotopes such as deuterium (D) or carbon-13 ( ^13C ). Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may have additional uses including, but not limited to, as diagnostic and/or imaging reagents or as cytotoxic/radiotoxic therapeutic agents.

In the compounds of the present invention, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen according to its naturally abundant isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium," that position is understood to have an abundance at least 3000 times greater than the natural abundance of deuterium, which is 0.015%. Deuterium (ie, incorporates at least 45% deuterium). Example compounds have a deuterium abundance that is at least 1000 times greater than the natural abundance of deuterium (i.e., incorporates at least 15% deuterium), at least 2000 times greater than the natural abundance of deuterium (i.e., incorporates at least 30% deuterium) ), at least 3000 times greater than the natural abundance of deuterium (i.e., incorporate at least 45% deuterium), at least 3340 times greater than the natural abundance of deuterium (i.e., incorporate at least 50.1% deuterium), than the natural abundance of deuterium At least 3500 times more abundant (i.e., incorporate at least 52.5% deuterium), at least 4000 times greater than the natural abundance of deuterium (i.e., incorporate at least 60% deuterium), at least 4500 times greater than the natural abundance of deuterium (i.e., incorporate at least 67.5% deuterium), at least 5000 times greater than the natural abundance of deuterium (i.e., incorporate at least 75% deuterium), at least 5,500 times greater than the natural abundance of deuterium (i.e., incorporate at least 82.5% deuterium), at least 6000 times greater than the natural abundance of deuterium (i.e., incorporate at least 90% deuterium), at least 6333.3 times greater than the natural abundance of deuterium (i.e., incorporate at least 95% deuterium), At least 6466.7 times greater than the natural abundance of deuterium (i.e., incorporate at least 97% of deuterium), at least 6600 times greater than the natural abundance of deuterium (i.e., incorporate at least 99% of deuterium), than the natural abundance of deuterium A deuterium abundance that is at least 6633.3 times greater (ie, incorporates at least 99.5% deuterium) or higher. resolve resolution

The compounds disclosed in this application are or can be prepared according to the following synthetic schemes: plan 1

在酸性條件下，移除式(IA)化合物或其鹽之R ^t，得到式(I)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a、R ^6b、R ^6c、R ^6d、n及m各自如式(I)中所定義。 方案2 A preparation method of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under acidic conditions, the R ^t of the compound of formula (IA) or its salt is removed to obtain the compound of formula (I) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _{1 - 6} alkyl; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , n and m are each as defined in formula (I). Scenario 2

在酸性條件下，移除式(IIA)化合物或其鹽之R ^t，得到式(II)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II)中所定義。 方案3 A preparation method of a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under acidic conditions, R ^t of the compound of formula (IIA) or its salt is removed to obtain the compound of formula (II) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _{1 - 6} alkyl; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II). Option 3

在酸性條件下，移除式(II-1A)化合物或其鹽之R ^t，得到式(II-1)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ²係氫； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II-1)中所定義。 方案4 A preparation method of a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under acidic conditions, remove the R ^t of the compound of formula (II-1A) or its salt to obtain the compound of formula (II-1) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably , R ^t is C _{1 - 6} alkyl; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II-1). Option 4

在酸性條件下，移除式(IIIA)化合物或其鹽之Rt，得到式(III)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III)中所定義。 方案5 A preparation method of a compound of formula (III) or a pharmaceutically acceptable salt, which comprises the following steps:

Under acidic conditions, the Rt of the compound of formula (IIIA) or its salt is removed to obtain the compound of formula (III) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _1-6 alkyl; X ¹ is -LR ⁰ , wherein R ⁰ _is -OP( ₌ O)(OH) ₂ ; and L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as above Defined in formula (III). Option 5

在酸性條件下，移除式(III-1A)化合物或其鹽之Rt，得到式(III-1)化合物或其醫藥學上可接受之鹽， 其中： R ^t係烷基；較佳地，R ^t係C _{1 - 6}烷基； X ¹係-L-R ⁰，其中R ⁰係-OP(=O)(OH) ₂；且 L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III-1)中所定義。 方案6 A preparation method of a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under acidic conditions, the Rt of the compound of formula (III-1A) or its salt is removed to obtain the compound of formula (III-1) or its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group; preferably, R ^t is C _{1 - 6} alkyl; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (III-1). Option 6

在鹼性條件下，使式(IB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(I)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a、R ^6b、R ^6c、R ^6d、n及m各自如式(I)中所定義。 方案7 A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under basic conditions, the compound of formula (IB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (I) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen; preferably , R ^w is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^2a , R ^{2b , R 3a} , R ^3b , R ^4a , ^{R 4b ,} R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , n and m are each as defined in formula (I). Option 7

在鹼性條件下，使式(IIB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(II)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II)中所定義。 方案8 A method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under basic conditions, the compound of formula (IIB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (II) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen; preferably , R ^w is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^3b , R ^{4a , R 4b} , R ^5a , ^{R 5b ,} R ^6a and R ^6b are each as defined above in formula (II). Option 8

在鹼性條件下，使式(II-1B)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(II-1)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰； X ²係氫或-L-R ⁰；且 R ⁰、L、R ¹、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(II-1)中所定義。 方案9 A method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under basic conditions, the compound of formula (II-1B) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (II-1) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen ; Preferably, R ^w is Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (II-1). Option 9

在鹼性條件下，使式(IIIB)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(III)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰；且 R ⁰、L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III)中所定義。 方案10 A method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under basic conditions, the compound of formula (IIIB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (III) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen; preferably , R ^w is Cl; X ¹ is -LR ⁰ ; and R ⁰ , L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined above in formula (III). Scheme 10

在鹼性條件下，使式(III-1B)化合物或其鹽與R ⁰-L-R ^w化合物反應，得到式(III-1)化合物或其醫藥學上可接受之鹽， 其中： R ^w係鹵素；較佳地，R ^w係Cl； X ¹係-L-R ⁰；且 R ⁰、L、R ^4a、R ^4b、R ^5a、R ^5b、R ^6a及R ^6b各自如上文式(III-1)中所定義。 A method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under basic conditions, the compound of formula (III-1B) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (III-1) or its pharmaceutically acceptable salt, wherein: R ^w is a halogen ; preferably, R ^w is Cl; X ¹ is -LR ⁰ ; and R ⁰ , L, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as in the above formula (III-1) defined.

Reactants that provide acidic conditions in the above synthetic schemes include, but are not limited to, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrogen Chloric acid and nitric acid, preferably acetic acid or trifluoroacetic acid.

The reactants providing alkaline conditions in the above synthesis schemes include organic bases and inorganic bases. Organic bases include, but are not limited to, triethylamine, pyridine, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tertiary butoxide or tertiary Potassium butoxide; inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably sodium hydroxide.

The reaction is preferably carried out in one or more solvents, including but not limited to acetic acid, trifluoroacetic acid, methanol, ethanol, butanol, dimethyl ether, acetonitrile, petroleum ether, n-hexane, toluene, tetrahydrofuran, dichloromethane, di Methylidene, 1,4-dioxane, water, N , N -dimethylformamide, N , N -dimethylacetamide, 1,2-dibromoethane and mixtures thereof. example

The following examples are used to illustrate the present invention, but these examples should not be considered as limiting the scope of the present invention. If the specific conditions of the experimental method are not specified in the examples of the present invention, they are generally consistent with the known conditions or the suggested conditions of the raw material and product manufacturers. Reagents not assigned a specific source were commercially available, conventional reagents.

The structure of each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR chemical shifts (δ) ^{are given in 10 −6 (} ppm). NMR was determined by Bruker AVANCE-300, AVANCE-400 or AVANCE-500 machines. The solvents were deuterated dimethylsulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD).

High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 150×4.6 mm chromatography column), Waters 2695-2996 high pressure liquid chromatography spectrometer (Gimini C18 150×4.6 mm chromatography tube column) or Shimadzu UFLC equipped with Xbridge C18 (5μm 150×4.6mm) column.

Chiral high-performance liquid chromatography (HPLC) was determined on LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.) or Waters-UPC² instrument.

MS by SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, model: LC-20AD, LCMS-2020), Waters UPLC- QDa or Agilent Agilent6120 equipped with Xbridge C18 (5μm 50×4.6mm) column was used for determination.

The thin layer silica gel plate used in thin layer chromatography is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The dimensions of the plates used in TLC are from 0.15 mm to 0.2 mm and in thin layer chromatography for product purification from 0.4 mm to 0.5 mm.

Column chromatography generally uses Yantai Huanghai 200 to 300 mesh silica gel as a carrier.

Known starting materials of the present invention can be prepared by conventional synthetic methods in the prior art or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Dari chemical Company, Fisher Scientific Or Combi-Blocks etc.

Unless otherwise stated in the Examples, the following reactants were placed under argon or nitrogen atmosphere.

The term "argon atmosphere" or "nitrogen atmosphere" means that the reaction flask was fitted with a balloon with 1 L of argon or nitrogen.

Unless otherwise stated in the examples, the solutions used in the following reactions refer to aqueous solutions.

Unless otherwise stated in the Examples, the reaction temperature for the following reactions is room temperature.

Unless otherwise stated, the reaction temperature in the reaction refers to room temperature, and the room temperature ranges from 20°C to 30°C.

The reaction process was monitored by LC-MS or thin layer chromatography (TLC), and the developing solvent system included: A: dichloromethane and methanol, B: hexane and ethyl acetate. The solvent volume ratio is adjusted according to the polarity of the compound. The eluting system used to purify the compound by column chromatography, thin layer chromatography and flash chromatography (Combi Flash ) includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent can be adjusted according to the polarity of the compound, and sometimes a small amount of a basic reactant such as ammonia or an acidic reactant such as acetic acid can be added.

By Shimadzu (LC-20AD, SPD20A) preparative HPLC (Phenomenex Gemini-NX 5 μM C18 21.2×100mm column), Waters 2767 equipped with Sunfire Pre C18 (10 μm 19×250mm) column or equipped with Xbridge Pre Waters 2767-QDa instrument with C18 (10 μm 19×250 mm) column, using water/MeOH or water/CH ₃ CN elusion system with optional additives such as HCOOH, TFA, NH ₄ HCO ₃ to purify the final compound .

Flash chromatography was performed on systems from Teledyne ISCO or Agela Technologies.

步驟 14-環丙基-4-側氧基丁酸三級丁酯 Int - 1 - 2 The following abbreviations are used in this application: DIPEA is N , N -diisopropylethylamine, HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium 3-oxide hexafluorophosphate DCM is dichloromethane, DMF is N , N -dimethylformamide, DMSO is dimethylsulfoxide, EtOAc is ethyl acetate, TBAI is iodine Tetrabutylammonium chloride, TFA is trifluoroacetic acid, Prep HPLC is preparative high performance liquid chromatography, NMR is proton nuclear magnetic resonance, MS is mass spectrometry, wherein (+) refers to generally endowing M+1 (or M+H) absorption The positive mode, where M = molecular weight. Experimental Procedure Intermediate 1 ( Int - 1 ) ( S )-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl) propanoic acid Intermediate 1 ( Int - 1 )

Step 1 Tertiary butyl 4-cyclopropyl-4-oxobutyrate Int - 1 - 2

A solution of LDA (15.28 g, 142.66 mmol , 71.43 mL) in THF (50 mL) was cooled to -78 °C, then cyclopropylmethyl ketone Int - 1-1 (10 g, 118.88 mmol) was added dropwise in Solution in THF (10 mL). The resulting solution was warmed to 20 °C and stirred for 30 minutes. The reaction mixture was then cooled again to -78 °C, and tert-butyl 2-bromoacetate (23.19 g, 118.88 mmol) in THF (10 mL) was added slowly. The reaction was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with saturated NH ₄ Cl (50 mL, aq), the mixture was extracted with EtOAc (50 mL×3), the organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated, The crude title compound Int - 1 - 2 was obtained (22 g, 110.97 mmol, 93.34% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.83 (t, 2H), 2.50 (t, 2H), 1.97-1.92 (m, 1H), 1.45 (s, 9H), 1.06-1.01 (m, 2H) , 0.91-0.86 (m, 2H). Step 2 (±)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid tertiary butyl ester Int - 1 - 3

A mixture of Int - 1-2 (8.2 g, 41.36 mmol), ammonium carbonate ( 33.78 g, 351.56 mmol), sodium cyanide (5.07 g, 103.40 mmol), EtOH ( 50 mL) and water (50 mL) was sealed and Heat to 80°C for 18 hours. The reaction mixture was cooled and poured into a mixture of EtOAc (100 mL) and water (100 mL), the layers were separated and the aqueous layer was extracted with EtOAc (100 mL x 3). The organic solutions were combined and washed _with brine, dried over _Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane = 1/2) to give the title compound Int - 1 - 3 (5.7 g, 21.24 mmol, 51.36% yield). ¹ H NMR (400 MHz, DMSO- d6 ): δ 10.61 (s, 1H), 7.66 (s, 1H), 2.29-2.08 (m, 2H), 1.93-1.88 (m, 2H), 1.29 (s, 9H) ), 1.09-1.02 (m, 1H), 0.47-0.26 (m, 3H), 0.11-0.04 (m, 1H). Step 3 and Step 4 ( S )-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid Int - 1

步驟1 5-胺基-2-溴-4-(三氟甲基)苯甲酸 1b A solution of Int - 1 - 3 (7.2 g, 26.83 mmol) in HCl/dioxane (4M, 50 mL) was stirred at room temperature for 4 hours and concentrated. The resulting solid was triturated in MeCN (30 mL) for 1 h and filtered to afford pure racemic target Int − 1 − 4 as a white solid. By SFC (using chiral column CHIRALPAK AD-H 10 μm 2.5*25 cm; flow rate/detection: 70 g/min; detector wavelength: 214 nm; mobile phase A: supercritical CO ₂ ; mobile Phase B: methanol) chiral separation of the solid afforded the title compound Int - 1 (2 g, 9.42 mmol, 35.12% yield). ¹ H NMR (400 MHz, DMSO- d6 ): δ 12.20 (s, 1H), 10.63 (s, 1H), 7.71 (s, 1H), 2.32-2.09 (m, 2H), 1.99-1.87 (m, 2H ), 1.11-1.03 (m, 1H), 0.48-0.27 (m, 3H), 0.12-0.05 (m, 1H). Chiral HPLC: 98.04% ee, Rt: 2.918 min. LCMS: MS m/z (ESI): 213.1 [M+1]. Example 1 ( S )-5-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine -2,4-Dione 1

Step 1 5-Amino-2-bromo-4-(trifluoromethyl)benzoic acid 1b

To a solution of 3-amino-4-(trifluoromethyl)benzoic acid 1a (1 g, 4.87 mmol) in DMF (20 mL) was added NBS (870 mg, 4.89 mmol). The mixture was stirred at room temperature for 2 hrs, the resulting mixture was poured into ice water (20 mL) and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over Na ₂ SO ₄ (s) and filtered. The filtrate was concentrated to obtain crude 1b (1 g, 3.52 mmol, 72.22% yield). Step 2 Methyl 5-amino-2-bromo-4-(trifluoromethyl)benzoate 1c

To a solution of 1b (1 g, 3.52 mmol) in MeOH (10 mL) was added _H2SO4 (18 M, 0.7 mL) dropwise _. After stirring the mixture at 75 °C overnight, the mixture was cooled to room temperature and poured into ice water (20 mL), the mixture was extracted with EtOAc (50 mL). The organic portion was dried over _{Na2SO4 (} s) and filtered. The filtrate was concentrated to obtain crude 1c (1 g, 3.36 mmol, 95.29% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.57 (s, 1H), 7.21 (s, 1H), 6.11 (brs, 2H), 3.85 (s, 3H). Step 3 Methyl 5-amino-2-methyl-4-(trifluoromethyl)benzoate 1d

酸(methyl boronic acid)(1 g，16.71 mmol)。在N ₂氛圍下在130℃下攪拌混合物隔夜之後，將混合物冷卻至室溫且過濾。濃縮濾液且藉由矽膠層析管柱純化殘餘物，獲得 1d(500 mg，2.14 mmol，63.91%產率)。 LCMS: MS m/z (ESI):234.1 [M+H] ⁺。 步驟4 5-氯-2-甲基-4-(三氟甲基)苯甲酸甲酯 1e To a solution of 1c (1 g, 3.36 mmol) in DMF (10 mL) was added Pd(PPh ₃ ) ₄ (430 mg, 372.11 μmol), K ₃ PO ₄ (2.2 g, 10.36 mmol) and methyl

Methyl boronic acid (1 g, 16.71 mmol). After stirring the mixture at 130 °C overnight under _N2 atmosphere, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography column to obtain 1d (500 mg, 2.14 mmol, 63.91% yield). LCMS: MS m/z (ESI): 234.1 [M+H] ⁺ . Step 4 Methyl 5-chloro-2-methyl-4-(trifluoromethyl)benzoate 1e

Concentrated HCl (2 mL) was added to a solution of 1d (2.0 g, 8.58 mmol) in acetone (20 mL), and the mixture was stirred at room temperature for 20 min. The mixture was cooled to -5 to 0 °C, a solution of _NaNO2 (600 mg, 8.70 mmol) in _H2O (2.5 mL) was added dropwise and the mixture was stirred at ambient temperature for 30 min. CuCl (849.11 mg, 8.58 mmol) was added portionwise at 0°C and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into 1N HCl (50 mL) and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography to obtain 1e (1.3 g, 5.15 mmol, 60.00% yield). Step 5 Methyl 2-bromo-5-chloro-4-(trifluoromethyl)benzoate 1f

To a solution of le (1.3 g, 5.15 mmol) in _CCl4 (20 mL) was added NBS (1.10 g, 6.18 mmol) and AIBN (25.35 mg, 154.38 μmol) and the mixture was heated to 70 °C and stirred overnight. The mixture was cooled to room temperature and filtered, the filter cake was washed with CCl ₄ , and the filtrate was concentrated in vacuo to afford crude If (1.9 g, 5.73 mmol, 111.37% yield). Step 6 6-Chloro-5-(trifluoromethyl)isoindolin-1-one 1g

To a solution of If (1.9 g, 5.73 mmol) in MeOH (10 mL) was added _NH3 /MeOH (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc=1:1) to obtain 1 g (920 mg, 3.91 mmol, 68.14% yield). LCMS: MS m/z (ESI): 236.0 [M+H] ⁺ . Step 7 5-Chloro-6-(trifluoromethyl)isoindoline 1h

To a solution of 1 g (570 mg, 2.42 mmol) in THF (5 mL) was added BH ₃ /THF (167.36 mg, 12.10 mmol, 15 mL) and the mixture was stirred at 60° C. overnight. The reaction was cooled to room temperature and quenched with methanol. The mixture was adjusted to pH 1-2 with 1M HCl. The mixture was then heated to 45°C and stirred for 30 minutes. After cooling to room temperature, the mixture was adjusted to pH 7-8 with 1 M NaOH. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by prep-TLC (DCM:MeOH=10:1) to afford 1h (10 mg, 45.13 μmol, 1.87% yield). ¹ HNMR (400 MHz, DMSO- d6 ): δ 7.78 (s, 1H), 7.65 (s, 1H), 4.16 (br, 2H), 4.14 (br, 2H). LCMS: MS m/z (ESI): 222.1 [M+H] ⁺ . Step 8 ( S )-5-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-5-cyclopropylimidazolidine -2,4-Dione 1

步驟1 5-胺基-4-(三氟甲基)-2-乙烯基-苯甲酸甲酯 2b To a solution of 1 h (10 mg, 45.12 μmol) in DMF (2 mL) was added TEA (50 μL), Int - 1 (10 mg, 47.12 μmol) and HATU (17.16 mg, 45.12 μmol). The reaction mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The crude product was purified by prep-HPLC to afford compound 1 (5 mg, 12.03 μmol, 26.65% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.63 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 4.85 (d, 2H), 4.67 (d, 2H), 2.46-2.22 (m, 2H), 2.03-1.98 (m, 2H), 1.15-1.08 (m, 1H), 0.49-0.31 (m, 3H), 0.15-0.08 (m, 1H) . ¹⁹ F NMR (376.5 MHz, DMSO- d ₆ ): δ -60.86. LCMS: MS m/z (ESI): 416.4 [M+H] ⁺ . Example 2 (5 S )-5-(3-(5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-side Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione 2 ( mixture of diastereomers )

Step 1 5-Amino-4-(trifluoromethyl)-2-vinyl-benzoic acid methyl ester 2b

To a solution of 1c (5.45 g, 18.29 mmol) and potassium vinyltrifluoroborate (2.45 g, 18.29 mmol) in dioxane (50 mL) and water (10 mL) was added Pd(dppf)Cl ₂ (1.34 g, 1.83 mmol) and K ₂ CO ₃ (6.35 g, 45.71 mmol). The resulting mixture was evacuated and refilled with _N2 3 times. The resulting mixture was stirred at 80°C for 16 hours. The mixture was diluted with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2b (3.56 g, 14.52 mmol, 79.40% yield). LCMS: MS m/z (ESI): 246.1 [M+H] ⁺ . Step 2 Methyl 5-amino-2-ethyl-4-(trifluoromethyl)benzoate 2c

To a solution of 2b (3.56 g, 14.52 mmol) in MeOH (20 mL) was added Pd/C (1.55 g, 1.45 mmol, 285.48 μL, 10% purity). The resulting mixture was evacuated and refilled with _H2 . The resulting mixture was stirred at room temperature for 16 hours and LCMS indicated the reaction was complete. The mixture was filtered and the filter cake was washed with MeOH, the filtrate was concentrated under reduced pressure to obtain the title compound 2c (3.45 g, 13.96 mmol, 96.12% yield). LCMS: MS m/z (ESI): 248.1 [M+H] ⁺ . Step 3 Methyl 5-chloro-2-ethyl-4-(trifluoromethyl)benzoate 2d

To a solution of 2c (3.36 g, 13.59 mmol) in acetone (34 mL) was added HCl (3.36 mL). The resulting mixture was stirred at room temperature for 20 minutes. After cooling the mixture to 0 °C, a solution of _NaNO2 (1.88 g, 27.18 mmol) in water (5 mL) was added. CuCl (1.48 g, 14.95 mmol) was then added in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into 1 M HCl (60 mL), the aqueous phase was extracted with EtOAc (100 mL×3), the combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane/EtOAc=50/1) to obtain the title compound 2d (2.23 g, 8.36 mmol, 61.53% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.99 (s, 1H), 7.87 (s, 1H), 3.88 (s, 3H), 2.92 (q, 2H), 1.17 (t, 3H). Step 4 (±)-Methyl 2-(1-bromoethyl)-5-chloro-4-(trifluoromethyl)benzoate 2e

To a solution of 2d (2.23 g, 8.36 mmol) in _CCl4 (35 mL) was added AIBN (412.00 mg, 2.51 mmol) and NBS (1.64 g, 9.20 mmol). The resulting mixture was stirred at 80°C for 16 hours. Filter the mixture. The solid was washed with DCM and the filtrate was concentrated in vacuo to afford crude title compound 2e (2.5 g, 7.24 mmol, 86.51% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.17 (s, 1H), 8.04 (s, 1H), 6.08 (q, 1H), 3.92 (s, 3H), 2.05 (d, 3H). Step 5 (±)-6-Chloro-3-methyl-5-(trifluoromethyl)isoindolin-1-one 2f

To a solution of 2e (2.5 g, 7.24 mmol) in MeOH (10 mL) was added _NH3 /MeOH (7 M, 30 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by Prep-HPLC to obtain the title compound 2f (1.18 g, 4.73 mmol, 65.34% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.11 (brs, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 4.71 (q, 1H), 1.42 (d, 3H). ¹⁹ F NMR (376.5 MHz, DMSO- d ₆ ): δ -60.99. LCMS: MS m/z (ESI): 250.0 [M+H] ⁺ . Step 6 (±)-5-Chloro-1-methyl-6-(trifluoromethyl)isoindoline-3,3- d ₂ 2g

To a solution of 6-chloro-3-methyl-5-(trifluoromethyl)isoindolin-1- one 2f (800 mg, 3.20 mmol) in THF (10 mL) was added BD ₃ (1M in in THF, 64 mL, 64 mmol). After the addition, the reaction was stirred (in a sealed tube) at 60°C for 10 hours. The reaction was quenched with MeOH (10 mL) followed by HCl (6 M, 20 mL). The reaction was then stirred at 80°C for 8 hours. 2 N NaOH was added to adjust the pH to 7 and extracted with EtOAc, the combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% MeOH/DCM to afford the desired product 2 g for the next step. LCMS: MS m/z (ESI): 238.1 [M+H] ⁺ . Step 7 (5 S )-5-(3-(5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-side Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione 2 ( mixture of diastereomers )

To a solution of ( S )-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid Int - 1 (680 mg, 3.2 mmol) in DMF (10 mL) EDCI (920 mg, 4.8 mmol) and HATU (1.83 g, 4.8 mmol) were added to . After stirring for 10 minutes, 2 g of isoindoline collected from the previous step was added. The reaction was stirred at ambient temperature for 3 hours. LCMS showed the reaction was complete. The reaction was directly purified on reverse phase HPLC to give the desired product 2 (1.10 g, 79.6% yield over two steps). ¹ H NMR (400 MHz, CD ₃ OD,) : 7.76 (s, 1 H), 7.63-7.60 (m, 1 H), 5.57-5.53 (m, 1 H), 2.59-2.40 (m, 2 H) , 2.28-2.19 (m, 2H), 1.56-1.50 (m, 3H), 1.28-1.21 (m, 1H), 0.62-0.58 (m, 1H), 0.49-0.41 (m, 3H) . LCMS: MS m/z (ESI): 432 [M+H] ⁺ . Example 2-1 and Example 2-2 ( S )-5-(3-(( R )-5-chloro-1-methyl- 6- ( trifluoromethyl )isoindoline-2 - yl-3 ,3- d ₂ )-3-oxopropyl)-5-cyclopropylimidazolidine- 2,4 -dione 2-1 ( S )-5-(3-(( S ) -5-chloro -1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-oxopropyl)-5-cyclopropylimidazolidine-2, 4 - diketone 2-2

2 (1.10 g) was separated by SFC to obtain two diastereomers 2 - 1 (325 mg, yield 29.5%) and 2 - 2 (415 mg, yield 37.7%). Compound 2 - 1 : ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.63 (br s, 1H), 7.89 (d, 1H), 7.73-7.78 (m, 1H), 5.30 - 5.16 (m, 1H) , 4.23 (d, 1H), 2.37 - 2.27 (m, 2H), 1.99 (dq, 2H), 1.50-1.55 (m, 1H), 1.43 (dd, 3H), 1.11 (td, 1H), 0.49 - 0.30 (m, 3H). LCMS: MS m/z (ESI): 432.3 [M+H] ⁺ . Chiral HPLC (1% DEA in EtOH/hexane 60/40, 1.0 mL/min, 35°C, CHIRALPAK IG, 150*4.6mm, 5μm): Rt: 4.594 min, de: 100%. Compound 2-2 : ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.53 (br s, 1H), 7.89 (d, 1H), 7.80 - 7.66 (m, 1H), 5.30 - 5.12 (m, 1H) , 4.23 (d, 1H), 2.44 - 2.36 (m, 1H), 2.31 - 2.20 (m, 1H), 2.05 - 1.95 (m, 2H), 1.51-1.54 (m, 1H), 1.44 (dd, 3H) , 1.11 (td, 1H), 0.50 - 0.29 (m, 3H). LCMS: MS m/z (ESI): 432.3 [M+H] ⁺ . Chiral HPLC (1% DEA in EtOH/hexane 60/40, 1.0 mL/min, 35°C, CHIRALPAK IG, 150*4.6mm, 5μm): Rt: 10.931 min, de: 100%. Example 3 pivalic acid ( S )-(4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-ring Propyl-2,5-dioxoimidazolidin-1-yl)methyl ester 3

To ( S )-5-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-5-cyclopropane at 0°C To a solution of imidazolidine-2,4-dione 1 (66 mg, 0.16 mmol) in DMF (5 mL) was added 1 N aqueous NaOH (0.3 mL). After stirring at this temperature for 10 minutes, chloromethyl pivalate (48 mg, 0.32 mmol) was added. The reaction was slowly warmed to ambient temperature and stirred for 12 hours. The reaction was directly applied to reverse phase preparative HPLC using 10%-60% _CH3CN / _H2O as eluent to give the desired product 3 (75 mg, 88.6% yield). ¹ H NMR (400MHz, CDCl ₃ ) : δ 7.78 (d, 1H), 7.62 (d, 1H), 5.50 (d, 2H), 4.90-4.49 (m, 4H), 2.52-2.49 (m, 1H), 2.43-2.38 (m, 1H), 2.30-2.27 (m, 2H), 1.32-1.30 (m, 1H), 1.20 (s, 9H), 0.64-0.60 (m, 1H), 0.47-0.43 (m, 2H ), 0.35-0.32 (m, 1H). LCMS: m/z (ESI) : 530.1 [M+H] ⁺ . Example 4 pivalic acid (( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidin-1-yl)methyl ester 4

步驟1 ( S)-((4-(3-(5-氯-6-(三氟甲基)異吲哚啉-2-基)-3-側氧基丙基)-4-環丙基-2,5-二側氧基咪唑啶-1-基)甲基)磷酸二-三級丁酯 5a To a solution of compound 2-1 ( 120 mg, 0.28 mmol) in DMF (10 mL) was added 1N aqueous NaOH (0.6 mL) at 0°C . After stirring for 10 minutes, chloromethyl pivalate (168 mg, 1.12 mmol) was added. The reaction was slowly warmed to ambient temperature and stirred for 12 hours. The reaction was purified on reverse phase prep-HPLC using 10%-60% _CH3CN / _H2O as eluent to give the desired product 4 (40 mg, 26.2% yield). ¹ H NMR (400MHz, CDCl ₃ ) : δ 7.76 (s, 1H), 7.60 (s, 1H), 5.50 (m, 2H), 5.32 (m, 1H), 2.48-2.13 (m, 4H), 1.55 ( s, 3H), 1.21 (s, 9H), 1.30 (m, 1H), 0.62 (m, 1H), 0.42 (m, 2H), 0.32 (m, 1H). LCMS: m/z (ESI) : 546.1 [M+H] ⁺ . Example 5 dihydrogen phosphate ( S )-(4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-ring Propyl-2,5-dioxoimidazolidin-1-yl)methyl ester 5

Step 1 ( S )-((4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-cyclopropyl -2,5-Dioxoimidazolidin-1-yl)methyl)di-tertiary butyl phosphate 5a

To a suspension of 1 (166 mg, 0.40 mmol) in THF (1 mL) was added 0.2N aqueous NaOH (2.0 mL). The reaction mixture became clear and was stirred at room temperature for 10 minutes. Solvent was removed in vacuo. Then DMF (2 mL) and _K2CO3 (94 mg, 0.68 mmol) were added, followed by di-tert-butyl (chloromethyl)phosphate (0.14 mL _, 0.54 mmol). The reaction mixture was stirred at 45°C for 16 hours. LC-MS showed about 70% conversion. EtOAc (100 mL) was added, and the organic phase was washed by brine (40 mL). The organic solvent was dried over anhydrous Na ₂ SO ₄ and purified by silica gel chromatography eluting with hexane/EtOAc to afford the crude product 5a which was used directly in the next step. LCMS: m/z (ESI) : 638.2 [M+H] ⁺ . Step 2 dihydrogen phosphate ( S )-(4-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-4-cyclo Propyl-2,5-dioxoimidazolidin-1-yl)methyl ester 5

步驟1 ( S)-5-(3-(( R)-5-氯-1-甲基-6-(三氟甲基)異吲哚啉-2-基-3,3- d ₂ )-3-側氧基丙基)-5-環丙基-3-((甲硫基)甲基)咪唑啶-2,4-二酮 6a To crude compound 5a (0.40 mmol from previous step) was added a mixture of AcOH/ _H2O (0.60/0.15 mL). The mixture was heated at 60°C for 1.5 hours. The reaction mixture was then carefully neutralized to pH = 7.0 by 2N aqueous _Na2CO3 at 0 °C _. The resulting mixture was purified by preparative HPLC using 0.5% _NH4HCO3 in 10%-30% _CH3CN and _H2O as eluents to give the desired product 5 after _{lyophilization} (53 mg over 2 steps 25.2% yield). ¹ H NMR ( 400 MHz , methanol - d ₄ ) : δ 7.70 (d, 1H), 7.54 (d, 1H), 5.18 (d, 1H), 5.11 (t, 1H), 4.83 (d, 2H), 4.68 (d, 2H), 2.45 - 2.32 (m, 2H), 2.28 - 2.04 (m, 2H), 1.24 - 1.12 (m, 1H), 0.48 (dt, 1H), 0.39 - 0.16 (m, 3H). ³¹ P NMR (400 MHz, CD ₃ OD) : δ -0.50. ¹⁹ F NMR ( 376.5 MHz, CD ₃ OD) : δ -63.6. LCMS: m/z (ESI) : 526.1 [M+H] ⁺ . Example 6 Dihydrogen Phosphate (( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidin-1-yl)methyl ester 6

Step 1 ( S )-5-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3- d ₂ )- 3-oxopropyl)-5-cyclopropyl-3-((methylthio)methyl)imidazolidine-2,4-dione 6a

To a solution of compound 2-1 ( 500 mg, 1.02 mmol) in DMF (12 mL) was added NaOH ( 82 mg, 2.04 mmol) and TBAI (754 mg, 2.04 mmol) at 0°C. After the addition, it was warmed to ambient temperature and stirred for 30 minutes. (Chloromethyl)(methyl)sulfane (394 mg, 4.08 mmol) was then added. The reaction was stirred at ambient temperature for one hour and treated with water and ethyl acetate (40+120 mL). The organic layer was collected and purified by silica gel chromatography eluting with 75% EtOAc/ _CH2Cl2 to give the desired product 6a (250 mg, _71.0 % yield). LCMS: m/z (ESI) : 492.1 [M+H] ⁺ . Step 2 ( S )-5-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3- _d2 )- 3-oxopropyl)-3-(chloromethyl)-5-cyclopropylimidazolidine-2,4-dione 6b

To a solution of 6a (250 mg, 0.51 mmol) in _CH2Cl2 (20 mL) was added triethylamine hydrochloride (210 _mg , 1.53 mmol ₎ followed by sulfonyl chloride (IN in _CH2Cl2 , 0.77 mL, 0.77 mmol). After the addition, the reaction was stirred at ambient temperature for 2 hours. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the resulting crude mixture 6b was used directly in the next step. LCMS: m/z (ESI) : 480.1 [M+H] ⁺ . Step 3 ((( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidine-1-yl)methyl)phosphoric acid di-tertiary butyl ester 6c

To a solution of 6b (0.51 mmol from previous step) in acetonitrile (20 mL) was added potassium di-tert-butylphosphate (228 mg, 0.92 mmol) followed by _NaHCO3 (10 mg, 0.1 mmol). After the addition, the reaction was stirred at 75°C for 12 hours. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with ₉₀ % EtOAc/ _CH2Cl2 to afford the desired product 6c (301 mg, 90% over 2 steps). ¹ H NMR (400MHz, CD ₃ OD) : δ 7.75 (s, 1H), 7.62 (s, 1H), 5.30 (d, 2H), 4.72-4.70 (m, 1H), 2.52-2.48 (m, 2H) , 2.37-2.34 (m, 2H), 1.53 (s, 3H), 1.49 (s, 9H), 1.26 (s, 9H), 1.41-1.38 (m, 1H), 0.62-0.58 (m, 1H), 0.48 -0.41 (m, 3H). LCMS: m/z (ESI) : 654.1 [M+H] ⁺ . Step 4 Dihydrogen phosphate (( S )-4-(3-(( R )-5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3- d ₂ )-3-oxopropyl)-4-cyclopropyl-2,5-two-oxoimidazolidin-1-yl)methyl ester 6

A solution of 6c (255 mg, 0.41 mmol) in a mixture of _CH3CN /water/TFA=2/2/1 (50 mL) was stirred at ambient temperature for 16 hours. LC-MS showed the reaction was complete. It was directly applied to reverse phase preparative HPLC using 10%-30% CH ₃ CN and H ₂ O containing 0.5% NH ₄ HCO ₃ as eluent, and the desired product 6 was obtained after lyophilization (221 mg, 99.5 %Yield). ¹ H NMR (400MHz, CD ₃ OD) : δ 7.72 (s, 1H), 7.69 (s, 1H), 5.32-5.28 (m, 2H), 5.24-5.20 (m, 1H), 2.56-2.43 (m, 2H), 2.28-2.24 (m, 2H), 1.53 (s, 3H), 1.30-1.27 (m, 1H), 0.58-0.55 (m, 1H), 0.46-0.36 (m, 3H). ³¹ P NMR (400MHz, CD ₃ OD) : δ -1.5. ¹⁹ F NMR ( 376.5 MHz, CD ₃ OD) : δ -63.6. LCMS: m/z (ESI) : 542.1 [M+H] ⁺ . biological analysis

The present invention will be further described with reference to the following test examples, but these examples should not be construed as limiting the scope of the present invention. Test Example 1 : In Vitro Fluorescence Analysis of ADAMTS - 4 or ADAMTS - 5 Activity

The FRET (fluorescence resonance energy transfer) peptide is cleaved by recombinant ADAMTS-4 or ADAMTS-5 protein into two separate fragments, resulting in an enhanced fluorescent signal that is quantified. The peptide is 5-FAM-TEGEARGSVILLK(5-TAMRA)K-NH2 custom-made from ANASPEC. ADAMTS-4 recombinant protein (Cat. No. 4307-AD) and ADAMTS-5 recombinant protein (Cat. No. 2198-AD) were purchased from R&D Systems.

Assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM _CaCl2 , 0.1% CHAPS and 5% glycerol was prepared. A volume of 2.5 µL of assay buffer containing compound was dispensed into a 384-well plate, and 2.5 µL of ADAMTS-4 or ADAMTS-5 protein was added (final concentration in the reaction was 10 nM). Compounds and proteins were pre-incubated for 15 minutes at room temperature. Subsequently, 5 µL of substrate was added to each well. The final substrate concentrations of ADAMTS-4 and ADAMTS-5 were 15 µM and 8 µM, respectively. After 3 hours of incubation at 37°C, the fluorescent signal in each well was measured on a TECAN disc reader (excitation, 490 nm; emission, 520 nm). ANALYSE information:

Data were entered into GraphPad Prism, and _IC50 values were calculated using the function "log(inhibitor) vs. response - variable slope (four parameters)". (See Table 1). Table 1. _IC50 values of exemplary compounds in the FRET-peptide enzymatic assay instance number ADAMTS-4 (IC ₅₀ , nM) ADAMTS-5 (IC ₅₀ , nM) 1 42 25 2-1 18 31 3 >10000 >10000 4 >10000 >10000 5 >10000 >10000 6 >10000 >10000

Conclusion: The parent compound 1 and the parent compound 2-1 in the present invention have significant inhibitory effect on the enzymatic activity of ADAMTS-4 and ADAMTS-5. Its prodrug molecules 3, 4, 5 and 6 do not have any enzymatic activity towards ADAMTS-4 and ADAMTS-5. Test Example 2. In Vitro ELISA ( Enzyme-Linked Immunosorbent Assay ) of ADAMTS - 5 Activity

In this assay, the enzymatic activity of the recombinant ADAMTS-5 protein (cat. no. 2198-AD, R&D Systems) was analyzed by the protein substrate, aggrecan IGD protein. The aggrecan IGD protein is a polypeptide linking human aggrecan globular domains 1 and 2 (T331-G458) expressed in E. coli to a C-terminal His-tag (Cat. No. 30411000, BIOTEZ ) . The enzymatic product ARGSVIL-peptide was detected using an ELISA kit from BioTEZ (cat. no. 30510111).

Assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM _CaCl2 , 0.1% CHAPS and 5% glycerol was prepared. Recombinant ADAMTS-5 protein was diluted to 0.3 nM in assay buffer. Transfer 10 µL of buffer and 10 µL of compound solution to each well of a 96-well plate and incubate at room temperature for 15 minutes. Substrate aggrecan-IGD was diluted to 100 nM with assay buffer and 20 µL was added to each well. The plate was incubated at 37°C for 45 minutes. After incubation, the newly produced epitope ARGSVIL-peptide was measured using the aggrecanase activity ELISA assay kit according to the manufacturer's instructions. Subsequently, 100 µL of stop solution was added and the absorbance of each well was read at 450 nM on a TECAN disk reader using 620 nM as a reference. ANALYSE information:

A standard curve for ELISA analysis was generated in GraphPad Prism using the sigmoid 4PL function and corresponding peptide concentrations were calculated from the standard curve. _IC50 values were calculated using the function "log(inhibitor) vs response - variable slope (four parameters)". (See Table 2). Table 2. _IC50 values of exemplary compounds from the aggrecan-IGD enzyme assay instance number ADAMTS-5 (IC ₅₀ , nM) 1 92 2-1 13

Conclusion: The parent compound 1 and the parent compound 2-1 of the present invention have significant inhibitory effect on the enzymatic activity of ADAMTS-5. Test example 3. The Fassif solubility test of compound among the present invention 3.1 preparation reference solution

An appropriate amount of the compound to be tested was weighed and dissolved in DMSO to obtain a 10 mM stock solution. Accurately measure 10 μL stock solution and 990 μL organic solvent (DMSO:acetonitrile:ethanol = 1:1:1 (v/v/v) mixture) into a 2 mL vial and mix well. This 100 μM clear sample solution was used as a reference solution. 3.2 Preparation of test compound Fassif solution

1 mg of test sample was dissolved in 900 μL of FaSSIF solution and mixed vigorously. Two such solutions were prepared in parallel and shaken in a 37°C water bath for 24 hours. The solution was then centrifuged at 4000 rpm for 30 minutes, and the supernatant layer was transferred to HPLC for analysis. 3.3. Data processing

Solubility (μM)=sample peak area/reference peak area*reference concentration (μM)*sample solution dilution factor. The average of two measurements was used as the final solubility. (See Table 3). Table 3. Solubility analysis of compounds of the present invention example Solubility (µM ) (Fassif) 1 64 2-1 22.2 3 194 4 156 5 1884.8 6 2008.3

Conclusion: Prodrug molecules 3, 4, 5 and 6 have enhanced Fassif solubility when compared with their parent compound 1 and parent compound 2-1, respectively. Test Example 4. Pharmacokinetic analysis instrument API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra-high performance liquid chromatography system, Shimadzu, Japan. Chromatography conditions: Column: Welch Xtimate C18 1.8μm 30×2.1mm Mobile phase A: 0.5% formic acid, 5 mM ammonium acetate in water (gradient elution) Mobile phase B: 0.5% formic acid, 5 mM ammonium acetate in 95% acetonitrile/water solution Medium (gradient elution) column temperature: 35°C Preparation of test samples

25 μL of plasma samples were mixed with 50 μL of internal standard solution (100 ng/mL) and 200 μL of CH ₃ CN precipitant, and the solution was vortexed for 5 minutes, followed by centrifugation for 10 minutes (4000 rpm). Sample 8 μL of the supernatant layer for LC/MS/MS analysis. process

In the Sprague Dawley rat PK study, groups of animals (N=4, 2 males and 2 females) were fasted overnight. The intragastric administration (ig) group received the drug by oral gavage. Serial blood samples (0.2 mL) were collected from the orbit at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours in dipotassium ethylenediaminetetraacetic acid (K2 EDTA) blood collection tubes, Plasma was then obtained by centrifugation at 4°C (10,000 rpm) for 1 minute. For the intravenous administration (iv) group, serial blood samples were collected from the orbit at time points - 5 minutes, 5 minutes, 15 minutes, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, 24.0 hours ( 0.2 mL) into a dipotassium ethylenediaminetetraacetic acid (K2 EDTA) blood collection tube. Plasma samples were isolated within 1 hour and stored at -20°C until analysis by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The entire procedure from blood collection to centrifugation was performed under ice conditions. Two hours after the administration, the rats were fed with chow. ANALYSE information

Pharmacokinetic parameters were obtained by non-compartmental analysis of plasma concentration (determined by LC/MS/MS) versus time data. Record the peak concentration (C _max ) and the time of C _max directly according to the experimental observation. The area under the curve (AUC _{0 −t )} was calculated from time zero to the last sampling time using a combination of linear and log trapezoidal summations. result

Rat ig PK results are shown in Table 4. Table 4. The rat PK result of example 2-1 and prodrug example 6 Example 2-1, ig 80 mpk Example 6, ig 100 mpk (mole is equal to example 2-1, ig 80 mpk) formula 5%DMSO+20%PEG400+70% (10%TPGS+ 5%1%HPMCK100LV) detected compound Parent Drug Compound 2-1 Prodrug Example 6 Parent Drug Compound 2-1 C _max (ng/ml) 6294 3.24 22725 AUC _0-t (ng/ml*h) 79643 37.5 330444

Conclusions: Prodrug molecule 6 can be almost fully converted to its parent compound 2-1 by oral administration in rats. In a rat ig 100 mpk PK study, a much higher parent drug exposure was observed for Example 6 when compared to the same dose of Example 2-1. Abbreviations : C _max : maximum serum concentration; PEG400: polyethylene glycol 400; HPMC K100LV: hydroxypropylmethylcellulose (HPMC) K100LV; TPGS: D-alpha-tocopheryl polyethylene glycol 1000 succinate.

The foregoing embodiments and examples are provided for illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on the disclosure and can be made without departing from the spirit and scope of the disclosure. All documents cited are hereby incorporated by reference in their entirety without admission as prior art.

Claims (22)

A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein: X ¹ and X ² are the same or different, and are independently hydrogen or -LR ⁰ , with the limitation that both X ¹ and X ² are not hydrogen; L selected from -(CQ ¹ Q ² ) _t -, -C(=O)O-, -C(=O)O(CQ ¹ Q ² ) _t -and -C(=O)S(CQ ¹ Q ² ) _t -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OP(=O)(OH)-OP(=O)(OH) ₂ , -OC(=O)Q ³ , -NQ ⁶ C(=O)Q ³ , -OC(=O)OQ ⁴ , -NQ ⁶ C(=O)OQ ⁴ , -OP(=O)(OQ ⁴ ) ₂ , -OQ ⁵ , -NQ ⁶ Q ⁷ , -OC(=O)(CQ ¹ Q ² ) _t -(Cy) _s -OP(=O)(OH) ₂ , -OC(=O)-NQ ⁶ Q ⁷ , -OC(=O)CH=CHC (=O)OH, -OC(=O)-O-(CQ ¹ Q ² ) _t -OP(=O)(OH) ₂ , -OC(=O)-NH-(CQ ¹ Q ² ) _t - OP(=O)(OH) ₂ , hydrogen, heterocyclyl and heteroaryl; Cy is aryl or heteroaryl, each optionally substituted by one or more substituents independently selected from the following: alkyl, Alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Q ^{and Q} are the same or different, and each independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of alkoxy, halogen, hydroxyl, cyano, amine, nitro, Cycloalkyl, heterocyclyl, aryl and heteroaryl; ^Q3 is selected from hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally modified by one or more Substituents independently selected from the following substituents: deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NQ ⁶ Q ⁷ , nitro, cycloalkyl, heterocyclyl , aryl and heteroaryl; Q ⁴ and Q ⁵ are the same or different, and are each independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl as the case may be One or more substituents independently selected from the following substituents: deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NQ ⁶ Q ⁷ , - OC(=O)Q ⁸ , -OC(=O)OQ ⁸ , cycloalkyl, heterocyclyl, aryl and heteroaryl; Q ⁶ and Q ⁷ are the same or different, and each independently selected from hydrogen, Alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl; ^Q is selected from alkyl, haloalkyl and deuteroalkyl; ^R is selected from hydrogen, alkyl, haloalkyl, hydroxyalk group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein the Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalkane R ^2a , R ^2b , R ^3a and R ^3b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, hydroxyalkyl , cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more groups independently selected from the following groups: halogen, alkyl, alkane Oxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two of R ^2a , R ^2b , R ^3a , and R ^3b together with The carbon atoms connected to it form a cycloalkyl group or a heterocyclic group; R ^4a , R ^4b , R ^5a and R ^5b are each the same or different, and each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy , hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or two of R ^4a , R ^4b , R ^5a and R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or Heterocyclyl; R ^6a , R ^6b , R ^6c and R ^6d are the same or different, and each independently selected from hydrogen, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally Substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and hetero aryl; n is 1 or 2; m is 1 or 2; t is 1 or 2; The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1; and m is 1. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^2a , R ^2b , R ^3a , R ^6c and R ^6d are the same or different, and each independently selected from hydrogen, halogen and C _{1 - 6} alkyl groups. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

Wherein: X ¹ , X ² , R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in Claim 1. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein: X ¹ , X ² , R ¹ , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in Claim 1. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 3 to 6 membered cycloalkyl group. The compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

Wherein: X ¹ , R ^4a , R ^4b , R ^5a , R ^5b , R ^6a and R ^6b are each as defined in Claim 1. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X ² is hydrogen or -LR ⁰ ; L is -CQ ¹ Q ² -; and R ⁰ , Q ¹ and Q ² as defined in Claim 1; preferably, X ² is hydrogen or -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OC(= O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; and Q ¹ , Q ² and Q ³ are as defined in claim 1. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; and R ⁰ , Q ¹ and Q ² are as As defined in Claim 1; preferably, X ¹ is -LR ⁰ ; L is -CQ ¹ Q ² -; R ⁰ is selected from -OP(=O)(OH) ₂ , -OC(=O)Q ³ and -OP(=O)(OH)-OP(=O)(OH) ₂ ; and Q ¹ , Q ² and Q ³ are as defined in claim 1. _The compound according to any one of claim items 1 to ₉ , or a pharmaceutically acceptable salt thereof, wherein ^Q1 and ^Q2 are the same or different, and each independently selected from hydrogen, deuterium and _C1-6 alkyl and/or Q ³ is C _{1 - 6} alkyl. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ^4a , R ^4b , R ^5a and R ^5b are each the same or different, and each independently selected from hydrogen, deuterium and C _{1 - 6} alkyl. _A compound as claimed in any one of claims 1 to ₁₁ , or a pharmaceutically acceptable salt thereof, wherein R ^6a and R ^6b are each the same or different, and each independently selected from hydrogen, halogen, C _1-6 alkane radical, C _{1 - 6} deuterated alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl, C _{1 - 6} haloalkoxy, hydroxyl, C _{1 - 6} hydroxyalkyl, cyano, amino, nitro radical, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group; preferably, each of R ^6a and R ^6b is the same or different, and each independently selected from hydrogen, halogen, C _{1 - 6} deuterated alkyl , C _{1 - 6} alkyl and C _{1 - 6} haloalkyl. A compound selected from the group consisting of:

, or a pharmaceutically acceptable salt thereof. As the compound of claim 13, or a pharmaceutically acceptable salt, wherein the compound is selected from:

. A compound of formula (IA), or a salt thereof:

Wherein: R ^t is alkyl, preferably C _1-6 alkyl; X ² is _hydrogen ; and _L , R ¹ , R ^2a , R ^2b , R 3a , R ^3b , R ^4a , R ^4b , R ^{5a ,} R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , n and m are each as defined in claim 1. The compound as claimed in item 15, or a salt thereof, wherein the compound is selected from:

. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in item 1, comprising the following steps:

R ^t of the compound of formula (IA) or its salt is removed to obtain the compound _of formula (I) or _its pharmaceutically acceptable salt, wherein: R ^t is an alkyl group, preferably a C _1-6 alkyl group; X ² is hydrogen; X ¹ is -LR ⁰ , wherein R ⁰ is -OP(=O)(OH) ₂ ; and L, R ¹ , R ^2a , R ^{2b , R 3a} , R ^3b , R ^4a , ^{R 4b ,} R ^5a , R ^5b , R ^6a , R ^6b , R ^6c , R ^6d , m and n are each as defined in claim 1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in item 1, comprising the following steps:

The compound of formula (IB) or its salt is reacted with the compound of R ⁰ -LR ^w to obtain the compound of formula (I) or its pharmaceutically acceptable salt, wherein: R ^w is halogen, preferably Cl; X ¹ is -LR ⁰ ; X ² is hydrogen or -LR ⁰ ; and R ⁰ , L, R ¹ , R ^2a , R ^2b , R 3a , R ^3b , R ^4a , R ^4b , R ^5a , R ^5b , ^{R 6a ,} R ^6b , R ^6c , R ^6d , m and n are each as defined in claim 1. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of inhibiting ADAMTS-5 and/or ADAMTS-4, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 to an individual in need, or Such as the pharmaceutical composition of claim item 19. A method of preventing or treating an inflammatory condition or disease involving cartilage degradation and/or interfering with cartilage homeostasis comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14 to a subject in need thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in item 19. A method for preventing or treating arthritis, comprising administering a therapeutically effective amount of the compound according to any one of Claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the compound according to Claim 19 to an individual in need A pharmaceutical composition; preferably, wherein the arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.