WO2022212638A1

WO2022212638A1 - Prodrugs of adamts inhibitors, preparation methods and medicinal uses thereof

Info

Publication number: WO2022212638A1
Application number: PCT/US2022/022736
Authority: WO
Inventors: Peng Zhao; Jian Liu; Fengqi Zhang; Chunying Song
Original assignee: Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Priority date: 2021-04-02
Filing date: 2022-03-31
Publication date: 2022-10-06
Also published as: CN117136051A; TW202304886A

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

PRODRUGS OF AD AMTS INHIBITORS, PREPARATION METHODS AND

MEDICINAL USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application No. 63/170,371, filed on April 2, 2021, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

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

BACKGROUND OF THE DISCLOSURE

Cartilage is the highly specialized connective tissue of diarthrodial joints. Its principal function is to provide the joints the capability of load bearing and compression resistance. The main component of cartilage is extracellular matrix comprising aggrecan and collagen. The balance between production (anabolism) and degradation (catabolism) of aggrecan and collagen is shifted to catabolism in diseases such as osteoarthritis.

Osteoarthritis is the most common chronic joint disease and a leading cause of pain and disability in developed countries. It was estimated that worldwide 250 million people are currently being affected by osteoarthritis, and the prevalence is progressively rising ( Hunter et al, Lancet. 2019, 393: 1745 1759). Pain and loss of functional capacity are accompanied by an increased risk of additional disease conditions such as diabetes, cancer or cardiovascular disease {Valdes AM and Stocks J. Osteoarthritis and ageing. EurMedJ. 2018, 3:116-123). Osteoarthritis is a whole joint disease: the structural changes are found to be degradation of articular cartilage, synovitis, alterations 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, with mechanical damage, inflammation, aging, and metabolism factors being involved. Osteoarthritis is not a passive degenerative disease, but an active dynamic alteration arising from an imbalance between the repair and destruction of joint tissues {Hunter et al, Lancet. 2019, 393: 1745 1759). Currently, the pharmacological treatments available for osteoarthritis are limited to symptomatic relief of pain and inflammation. Disease-modifying drugs that arrest or slow down disease progression are not available.

Progressive loss of articular cartilage is currently viewed as an early event in osteoarthritis. Aggrecan may have a role protecting loss of collagen {Pratta et al, J Biol Chem. 2003, 278: 45539-45545). These studies suggest the critical role of aggrecan in osteoarthritis and other joint diseases. Aggrecan is a proteoglycan, possessing a core protein with covalently attached sulfated glycosaminoglycan (GAG) chains. Its core protein has three globular domains, G1 and G2 domains in the N-terminus, and G3 in the C-terminus. The extensive region between the G2 and G3 domains is heavily modified by GAG keratan sulfate (KS) and chondroitin sulfate (CS). Based on the difference in the amino acid sequence, the CS domain is further divided into two subdomains, CS1 and CS2. The GAG chains provide aggrecan with its high anionic charge. Multiple aggrecan monomers bind to hyaluronan (HA) through G1 domains, which is stabilized by a link protein, forming large supramolecular aggregates. The large aggrecan aggregates absorb water and provide the resilient properties for the cartilage ( Roughley et al., The Journal of Experimental Orthopaedics. 2014, 1: 8). A high concentration of aggrecan, a high degree of sulfation and the ability to form large aggregation is required for the normal function of cartilage.

The extended structure of aggrecan can be cleaved by proteolytic enzymes, leading to impaired normal function of cartilage. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a family of zinc ion-dependent metalloproteases. ADAMTS-4 and -5, also termed “aggrecanases”, degrade aggrecan at several specific locations in the IGD and the CS2 domain. It was demonstrated that ADAMTS-5 deficiency protects against aggrecan loss and cartilage damage in mouse osteoarthritis disease model induced by surgeries ( Glasson et al, Nature. 2005, 434: 644 648; Stanton et al, Nature. 2005, 434:648 652), implicating ADAMTS- 5 in driving cartilage loss and osteoarthritis disease severity. Some studies in human cartilage explant culture also suggested that not only ADAMTS-5, but also ADAMTS-4 are important for human osteoarthritis ( Verma et al, Journal of Cellular Biochemistry. 2011, 112: 3507-3514). These studies strongly suggest that inhibiting the enzymatic function of ADAMTS-5 and AD AMT -4 might provide a protecting role in osteoarthritis. Taken together, the role of ADAMTS-5 and/or ADAMTS-4 in cartilage degradation has been well-established. Therefore, inhibitors of ADAMTS-5 and/or ADAMTS-4 may be of therapeutic value in the treatment of arthritis. Patent applications for compounds that have been published as ADAMTS-5 and/or ADAMTS-4 inhibitors include WO2014066151A1, WO2016102347A1, WO2017211667A1, WO2017211666A1, WO2017211668A1, WO2021011720A2 and WO2021011723A1. Although numerous prodrug strategies exist to provide choices in modulating conditions for delivery of a drug molecule with various benefits, identification of prodrugs with desired properties is often difficult and not straightforward. None of the existing technologies teaches or suggests the specific prodrugs of present disclosure. SUMMARY OF THE DISCLOSURE The present disclosure, in one aspect, provides a compound of formula (I): or a pharmaceutic

wherein: X¹ and X² are identical or different, and each is independently hydrogen or -L-R⁰, provided that X¹ and X² are not both hydrogen; L is selected from -(CQ¹Q²)_t-, -C(=O)O-, -C(=O)O(CQ¹Q²)_t- and -C(=O)S(CQ¹Q²)_t-; R⁰ is selected from -OP(=O)(OH)₂, -OP(=O)(OH)-OP(=O)(OH)₂, -OC(=O)Q³, -NQ⁶C(=O)Q³, -OC(=O)OQ⁴, -NQ⁶C(=O)OQ⁴, -OP(=O)(OQ⁴)₂, -OQ⁵, -NQ⁶Q⁷, -O-C(=O)(CQ¹Q²)_t-(Cy)_s- OP(=O)(OH)₂, -OC(=O)-NQ⁶Q⁷, -OC(=O)CH=CHC(=O)OH, -O-C(=O)-O-(CQ¹Q²)_t- OP(=O)(OH)₂, -O-C(=O)-NH-(CQ¹Q²)_t-OP(=O)(OH)₂, hydrogen, heterocyclyl and heteroaryl; Cy is aryl or heteroaryl, each optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three, substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q¹ and Q² are identical or different and each is independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three, substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q³ is selected from hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted 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, hydroxy, hydroxyalkyl, cyano, -NQ⁶Q⁷, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q⁴ and Q⁵ are identical or different, and each is independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ⁶Q⁷, -0C(=0)Q⁸, -0C(=0)0Q⁸, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q⁶ and Q⁷ are identical or different, and each is independently selected from hydrogen, alkyl, haloalkyl, deuterium alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

Q⁸ is selected from alkyl, haloalkyl and deuterium alkyl;

R¹ is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to five, and sometimes more preferably one to three, groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy and hydroxy alky;

R^2a, R^2b, R^3a and R^3b are each identical or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, and sometimes more preferably one to three, groups independently selected from halogen, alkyl, alkoxy, hydroxy, 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 atom(s) to which they are attached form cycloalkyl or heterocyclyl;

R^4a, R^4b, R^5a and R^5b are each identical or different, and each is 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(s) to which they are attached form cycloalkyl or heterocyclyl;

R^6a, R^6b, R^6C and R^6d are identical or different, and each is independently selected from hydrogen, halogen, alkyl, deuterium alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, hydroxy, 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 disclosure 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 disclosure also provides a method of preventing and/or treating an inflammatory condition or disease involving degradation of cartilage and/or disruption of cartilage homeostasis, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The disease or condition includes arthritis, preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis, which are further preferably related to the activity of ADAMTS-5 and/or ADAMTS-4. Other aspects or advantages of the disclosure will be better appreciated in view of the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE DISCLOSURE In one aspect, the present disclosure provides a compound of formula (I): , or a pharmaceutic

wherein: X¹ and X² are identical or different, and each is independently hydrogen or -L-R⁰, provided that X¹ and X² are not both hydrogen; L is selected from -(CQ¹Q²)_t-, -C(=O)O-, -C(=O)O(CQ¹Q²)_t- and -C(=O)S(CQ¹Q²)_t-; R⁰ is selected from -OP(=O)(OH)₂, -OP(=O)(OH)-OP(=O)(OH)₂, -OC(=O)Q³, -NQ⁶C(=O)Q³, -OC(=O)OQ⁴, -NQ⁶C(=O)OQ⁴, -OP(=O)(OQ⁴)₂, -OQ⁵, -NQ⁶Q⁷, -O-C(=O)(CQ¹Q²)_t-(Cy)_s- OP(=O)(OH)₂, -OC(=O)-NQ⁶Q⁷, -OC(=O)CH=CHC(=O)OH, -O-C(=O)-O-(CQ¹Q²)_t- OP(=O)(OH)₂, -O-C(=O)-NH-(CQ¹Q²)_t-OP(=O)(OH)₂, hydrogen, heterocyclyl and heteroaryl; Cy is aryl or heteroaryl, each optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three, substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q¹ and Q² are identical or different and each is independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three, substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q³ is selected from hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted 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, hydroxy, hydroxyalkyl, cyano, -NQ⁶Q⁷, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q⁴ and Q⁵ are identical or different and each is independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ⁶Q⁷, -0C(=0)Q⁸, -0C(=0)0Q⁸, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q⁶ and Q⁷ are identical or different and each is independently selected from hydrogen, alkyl, haloalkyl, deuterium alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

Q⁸ is selected from alkyl, haloalkyl and deuterium alkyl;

R^2a, R^2b, R^3a and R^3b are each identical or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, and sometimes more preferably one to three, groups selected from halogen, alkyl, alkoxy, hydroxy, 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 atom(s) to which they are attached form cycloalkyl or heterocyclyl;

R^4a, R^4b, R^5a and R^5b are each identical or different, and each is 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(s) to which they are attached form cycloalkyl or heterocyclyl; R^6a, R^6b, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, halogen, alkyl, deuterium alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more, sometimes preferably one to five, and sometimes more preferably one to three, groups selected from halogen, alkyl, alkoxy, hydroxy, 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 some embodiments of the disclosure, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, n is 1; and m is 1. In some embodiments of the disclosure, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, R^2a, R^2b, R^3a, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, hydroxy and C_1-6 hydroxyalkyl; preferably, R^2a, R^2b, R^3a, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, halogen and C_1-6 alkyl. In some embodiments of the disclosure, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, R^2a, R^2b and R^3a are identical or different, and each is independently selected from hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, hydroxy and C_1-6 hydroxyalkyl; preferably, R^2a, R^2b and R^3a are identical or different, and each is 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 disclosure, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, hydroxy and C_1-6 hydroxyalkyl; preferably, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, halogen and C_1-6 alkyl; more preferably, R^6c and R^6d are hydrogen. In some embodiments of the disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein:

X¹, X², R¹, 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 disclosure, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (II- 1 ), or a pharmaceutically acceptable salt thereof:

wherein:

In some embodiments of the disclosure, in the compound of formula (I), (II) or (II- 1 ), or a pharmaceutically acceptable salt thereof, R¹ is 3 to 6-membered cycloalkyl; preferably, R¹ is cyclopropyl.

In some embodiments of the disclosure, in the compound of formula (I), (II) or (II- 1 ), or a pharmaceutically acceptable salt thereof, R^3b is selected from hydrogen, halogen and Ci-₆ alkyl; preferably, R^3b is hydrogen.

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

wherein:

X¹, 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 disclosure, the compound of formula (I), (II), (II- 1 ) or (III), or a pharmaceutically acceptable salt thereof, is a compound of formula (PI-l), or a pharmaceutically acceptable salt thereof:

wherein:

In some embodiments of the disclosure, in the compound of formula (I), (II) or (II- 1 ), or a pharmaceutically acceptable salt thereof, X² is hydrogen or -L-R°; L is -CQ'Q²-; R°, Q¹ and Q² are as defined in formula (I) above; preferably, X² is hydrogen or -L-R°; L is -CQ'Q²-; R° is selected from -0P(=0)(0H)₂, -0C(=0)Q³ and -0P(=0)(0H)-0P(=0)(0H)₂; Q¹, Q² and Q³ are as defined in formula (I) above; more preferably, X² is hydrogen or -L-R°; L is -CQ'Q²-; R° is - 0P(=0)(0H)₂; and Q¹ and Q² are as defined in formula (I) above; most preferably, X² is hydrogen.

In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, X¹ is -L-R°; L is -CQ'Q²-; R°, Q¹ and Q² are as defined in formula (I) above; preferably, X¹ is -L-R°; L is -CQ'Q²-; R° is selected from - 0P(=0)(0H)₂, -0C(=0)Q³ and -0P(=0)(0H)-0P(=0)(0H)₂; Q¹, Q² and Q³ are as defined in formula (I) above; more preferably, X¹ is -L-R°; L is -CQ'Q²-; R° is -0P(=0)(0H)₂; and Q¹ and Q² are as defined in formula (I) above. In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, Q¹ and Q² are identical or different, and each is independently selected from hydrogen, deuterium and Ci-₆ alkyl; and/or Q³ is Ci-₆ alkyl; preferably, Q¹ and Q² are hydrogen; and Q³ is Ci-₆ alkyl.

In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, R^4a, R^4b, R^5a and R^5b are each identical or different, and each is independently selected from hydrogen, deuterium and Ci-₆ alkyl.

In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, R^4a and R^4b are each identical or different, and each is independently selected from hydrogen, deuterium and Ci-₆ alkyl; preferably, R^4a and R^4b are each identical or different, and each is independently hydrogen or deuterium; more preferably, R^4a and R^4b are deuterium.

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

In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, R^5a and R^5b are each identical or different, and each is independently selected from hydrogen, deuterium and Ci-₆ alkyl; preferably, R^5a and R^5b are each identical or different, and each is independently hydrogen or Ci-₆ alkyl; more preferably, R^5a is hydrogen and R^5b is Ci-₆ alkyl.

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

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

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

In some embodiments of the disclosure, in the compound of formula (I), (II), (II- 1 ), (III) or (III- 1 ), or a pharmaceutically acceptable salt thereof, R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, Ci-₆ alkyl, Ci-₆ deuterium alkyl, Ci-₆ alkoxy, Ci-₆ haloalkyl, Ci-₆ haloalkoxy, hydroxy, Ci-₆ hydroxyalkyl, cyano, amino, nitro, 3 to 6- membered cycloalkyl and 3 to 6-membered heterocyclyl. In some embodiments, R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, C_1-6 deuterium alkyl, C_1-6 alkyl and C_1-6 haloalkyl. In some embodiments, R^6a and R^6b are each identical 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 identical or different, and each is independently selected from halogen and C_1-6 haloalkyl; further preferably, R^6a is halogen; and R^6b is C_1-6 haloalkyl; in some more preferred embodiments, R^6a is -Cl; and R^6b is -CF₃. In some embodiments of the disclosure, in the compound of formula (III), or a pharmaceutically acceptable salt thereof, X¹ is -L-R⁰; L is-CQ¹Q²-; R⁰ is selected from - OP(=O)(OH)₂, -OC(=O)Q³ and -OP(=O)(OH)-OP(=O)(OH)₂; Q¹ and Q² are hydrogen; Q³ is C_1-6 alkyl; R^4a, R^4b, R^5a and R^5b are each identical or different, and each is independently selected from hydrogen, deuterium and C_1-6 alkyl; R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, C_1-6 deuterium alkyl, C_1-6 alkyl and C_1-6 haloalkyl. In some embodiments of the disclosure, in the compound of formula (III), or a pharmaceutically acceptable salt thereof, X¹ is -L-R⁰; L is-CQ¹Q²-; R⁰ is selected from - OP(=O)(OH)₂, -OC(=O)Q³ and -OP(=O)(OH)-OP(=O)(OH)₂; Q¹ and Q² are hydrogen; Q³ is C_1-6 alkyl; R^4a, R^4b, R^5a and R^5b are hydrogen; R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, C_1-6 alkyl and C_1-6 haloalkyl. In some embodiments of the disclosure, in the compound of formula (III), or a pharmaceutically acceptable salt thereof, X¹ is -L-R⁰; L is-CQ¹Q²-; R⁰ is selected from - OP(=O)(OH)₂, -OC(=O)Q³ and -OP(=O)(OH)-OP(=O)(OH)₂; Q¹ and Q² are hydrogen; Q³ is C_1-6 alkyl; R^4a and R^4b are deuterium; R^5a and R^5b are each identical or different, and each is independently hydrogen or C_1-6 alkyl; R^6a and R^6b are each identical or different, and each is independently selected from halogen and C_1-6 haloalkyl. Table A. Exemplified compounds of the disclosure include, but are not limited to: Example Structure and Name

Table B. Other compounds that can be prepared based on the present disclosure include, but are not limited to:

In another aspect, this disclosure provides a compound of formula (IA) or a salt thereof:

wherein: R¹ is alkyl; preferably, R¹ is Ci-₆ alkyl;

X² is hydrogen; and

L, R¹, 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).

In another aspect, this disclosure provides a compound of formula (IIA) or a salt thereof:

wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl;

X² is hydrogen; and

L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II). In another aspect, this disclosure provides a compound of formula (II-l A) or a salt thereof:

wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl;

X² is hydrogen; and

L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II- 1).

In another aspect, this disclosure provides a compound of formula (IIIA) or a salt thereof:

wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl; and

L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III).

In another aspect, this disclosure provides a compound of formula (III- 1 A) or a salt thereof:

wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl; and L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III-1). Exemplified intermediate compounds of the disclosure include, but are not limited to: Example S^{tructure and Name}

In another aspect, this disclosure provides a process of preparing the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising a step of:

la (I) or a pharmaceutically acceptable salt thereof, wherein: R^t is alkyl; preferably, R^t is C_1-6 alkyl; X² is hydrogen; X¹ is -L-R⁰, wherein R⁰ is -OP(=O)(OH)₂; and L, R¹, 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). In another aspect, this disclosure provides a process of preparing the compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising a step of: R^4a R^{4a O} O R¹ R^4b ^O _R ¹ O R^4b ^6a

la (II) or a pharmaceutically acceptable salt thereof, wherein: R^t is alkyl; preferably, R^t is C_1-6 alkyl; X² is hydrogen; X¹ is -L-R⁰, wherein R⁰ is -OP(=O)(OH)₂; and L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II). In another aspect, this disclosure provides a process of preparing the compound of formula (II-1), or a pharmaceutically acceptable salt thereof, comprising a step of:

of formula (II-1) or a pharmaceutically acceptable salt thereof, wherein: R^t is alkyl; preferably, R^t is C_1-6 alkyl; X² is hydrogen; X¹ is -L-R⁰, wherein R⁰ is -OP(=O)(OH)₂; and L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II-1). In another aspect, this disclosure provides a process of preparing the compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising a step of:

la (III) or a pharmaceutically acceptable salt thereof, wherein: R^t is alkyl; preferably, R^t is C_1-6 alkyl; X¹ is -L-R⁰, wherein R⁰ is -OP(=O)(OH)₂; and L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III). In another aspect, this disclosure provides a process of preparing the compound of formula (III-1), or a pharmaceutically acceptable salt thereof, comprising a step of:

of formula (III-1) or a pharmaceutically acceptable salt thereof, wherein: R^t is alkyl; preferably, R^t is C_1-6 alkyl; X¹ is -L-R⁰, wherein R⁰ is -OP(=O)(OH)₂; and L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III-1). In another aspect, this disclosure provides a process of preparing the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (IB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°;

X² is hydrogen or -L-R°; and

R°, L, R¹, 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). In another aspect, this disclosure provides a process of preparing the compound of formula

(II), or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (IIB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°;

X² is hydrogen or -L-R°; and

R°, L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II). In another aspect, this disclosure provides a process of preparing the compound of formula

(II-l), or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (II- IB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (II- 1) or a pharmaceutically acceptable salt thereof, wherein: R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°;

X² is hydrogen or -L-R°; and

R°, L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II- 1).

In another aspect, this disclosure provides a process of preparing the compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (MB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°; and

R°, L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III).

In another aspect, this disclosure provides a process of preparing the compound of formula (III- 1 ), or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (III-1B) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (PI-1) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°; and

R°, L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (IP-1).

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

The present disclosure also provides a method of inhibiting ADAMTS-5 and/or ADAMTS- 4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II- 1), (III) or (III-l), 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 disclosure also provides a method of preventing or treating an inflammatory condition, or diseases involving degradation of cartilage and/or involving disruption of cartilage homeostasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II- 1), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound.

The present disclosure also provides a method of preventing or treating arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II- 1), (III) or (III-l), 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, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.

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

In another aspect, the present disclosure also relates to use of a compound of formula (I), (II), (II- 1 ), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for preventing and/or treating inflammatory conditions or diseases involving degradation of cartilage and/or involving disruption of cartilage homeostasis.

In another aspect, the present disclosure also relates to use of a compound of formula (I), (II), (II-l), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for preventing and/or treating arthritis; preferably, wherein the arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.

The present disclosure further relates to the compound of formula (I), (II), (II- 1 ), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for use as a medicament.

The present disclosure also relates to the compound of formula (I), (II), (II- 1 ), (III) or (III- 1), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for use in inhibiting ADAMTS-5 and/or ADAMTS-4.

The present disclosure also relates to the combination of the compound of formula (I), (II), (II-l), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for use in preventing and/or treating inflammatory conditions or diseases involving degradation of cartilage and/or diseases disruption of cartilage homeostasis.

The present disclosure also relates to the combination of the compound of formula (I), (II), (II-l), (III) or (III-l), or a compound selected from table A or table B, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound, for use in preventing and/or treating arthritis; preferably, wherein the arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.

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

The phrase “inflammatory conditions” refers to the group of conditions including, but not limited to, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic airway disease (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g, Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., complications after bypass surgery or chronic endotoxin states contributing to, e.g, chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g, asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly refers to rheumatoid arthritis, and osteoarthritis (OA). Most particularly refers to osteoarthritis (OA).

The “diseases involving degradation of cartilage and/or disruption of cartilage homeostasis” include conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, achondroplasia, Paget's disease, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amylosis, hydarthrosis, periodical disease, rheumatoid spondylitis, endemic forms of arthritis like osteoarthritis deformans endemic, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis; and particularly, refers to osteoarthritis(OA). The pharmaceutical compositions of this disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Thus, the active compounds of this disclosure can be formulated as various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, inhalation or insufflation administration. The compounds of this disclosure can also be formulated as sustained release dosage forms. The dosage of a compound or composition used in this disclosure will be changed with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, active compounds are preferred in unit doses or in that patients can self-administer in a single dose. The expression mode of unit dose of the disclosed compound or composition may be tablet, capsule, flat capsule, bottled liquid, powder, granule, tablet, suppository, regenerated powder or liquid preparation. An appropriate unit dose may be from 0.1 mg to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: filler (diluent), adhesive, wetting agent, disintegrating agent or excipient, etc. Depending on the method of administration, the composition may contain the active compound from 0.1% to 99 % by weight.

Suitable dosage forms include, but are not limited to, a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. Oral compositions can be prepared according to any known method in the art for the preparation of pharmaceutical compositions. Such compositions can contain one or more additives selected from sweeteners, flavoring agents, colorants and preservatives, in order to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, and lubricants. The tablet can be uncoated or coated by means of a known technique to mask the taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period. For example, water soluble taste masking materials can be used.

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

An aqueous suspension contains the active ingredient in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents, dispersants or humectants, and can be naturally occurring phospholipids. The aqueous suspension can also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners. An oil suspension can be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension can contain a thickener. The aforementioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant. The present pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil, or mixture thereof. Suitable emulsifying agents can be naturally occurring phospholipids. Sweeteners can be used. Such formulations can also contain moderators, preservatives, colorants and antioxidants.

The pharmaceutical composition can be in the form of a sterile injectable aqueous solution. The acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-inwater microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be introduced into an individual’s bloodstream by local bolus injection. Alternatively, it can be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compound. In order to maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such a suspension can be formulated with suitable dispersants or wetting agents and suspending agents as described above according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. Moreover, sterile fixed oils can easily be used as a solvent or suspending medium, and fatty acids can also be used to prepare injections. The present compound can be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid in the rectum, thereby melting in the rectum to release the drug.

For buccal administration, the compositions can be formulated as tablets or lozenges by conventional means. For intranasal administration or administration by inhalation, the active compounds of the present disclosure are conveniently delivered in the form of a solution or suspension released from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray released from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules or cartridges (for example, made from gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the present disclosure and a suitable powder base such as lactose or starch.

It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to, the following factors: activity of the specific compound, age, weight, general health, behavior, diet of the patient, administration time, administration route, excretion rate, drug combination and the like. In addition, the best treatment, such as treatment mode, daily dose of the compound or the type of pharmaceutically acceptable salt thereof can be verified by traditional therapeutic regimens.

Definitions

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

“Alkyl” refers to a saturated aliphatic hydrocarbon group including C1-C20 straight chain and branched chain groups. Preferably an alkyl group is an alkyl having 1 to 12 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (namely, Ci-12 alkyl). In some embodiments, sometimes preferably, an alkyl group is an alkyl having 1 to 8 carbon atoms (namely, Ci-₈ alkyl). Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, l-ethyl-2-methylpropyl, 1,1,2- trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2- ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2 -m ethyl-3 - ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. In some embodiments, sometimes more preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms (namely, Ci-₆ alkyl) and sometimes more preferably 1 to 4 carbon atoms (namely, Ci-4 alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2- dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- dimethylbutyl, 2-ethylbutyl, 2-m ethylpentyl, 3 -m ethylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point, preferably the substituent group(s) is one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo group.

“Alkenyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc., preferably C2-20 alkenyl, more preferably C2-12 (for example including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkenyl, and sometimes more preferably C2-6 alkenyl, and sometimes even more preferably C2-4 alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from halogen, alkoxy, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo group.

“Alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C2-20 alkynyl, more preferably C2-12 (for example including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkynyl, and sometimes preferably C2-6 alkynyl, and sometimes even more preferably C2-4 alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from alkenyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

“Alkylene” refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkane. The straight or branched chain group contains 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) carbon atoms, sometimes more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1 -ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1 -propylene (-CH^CThCTb)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylidene (- CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is (are) preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from selected from alkenyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

“Alkenylene” refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C_2-20 alkenylene, more preferably C_2-12 (for example including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) alkenylene, sometimes more preferably C_2-6 alkenylene, and sometimes even more preferably C_2-4 alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH₂-, - CH=CHCH₂CH₂-, and -CH₂CH=CHCH₂-, etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

“Cycloalkyl” refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 (for example including 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon) carbon atoms (namely 3 to 12-membered cycloalkyl), more preferably 3 to 10 carbon atoms, sometimes more preferably 3 to 8 (for example 3, 4, 5, 6, 7 or 8) carbon atoms (namely 3 to 8-membered cycloalkyl), and sometimes even more preferably 3 to 6 carbon atoms (namely 3 to 6-membered cycloalkyl). Representative examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.

“Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings can contain one or more double bonds. Preferably a spiro cycloalkyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 3-membered/5-membered, 3- membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6- membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to, the following groups:

“Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds. Preferably, a fused cycloalkyl group is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon), more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 3-membered/4- membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5- membered, 5-membered/6-membered, 6-membered/3 -membered, 6-membered/4-membered, 6- membered/5-membered or 6-membered/6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following groups:

“Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds. Preferably, a bridged cycloalkyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following groups:

The cycloalkyl may also include the cycloalkyl said above which fused to the ring of an aryl, heteroaryl or heterocyclyl, wherein the ring bound to the parent structure is cycloalkyl. Representative examples include, but are not limited to indanyl, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocyclylthio and oxo group.

“Heterocyclyl” refers to 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 the sulfur can be optionally oxygenated to form S(=0) or S(=0)₂, but does not include -0-0-, -O-S- or -S-S-. Preferably, heterocyclyl is a 3 to 12 membered having 1 to 4 (example 1, 2, 3 or 4) heteroatoms (namely 3 to 12-membered heterocyclyl); more preferably a 3 to 10 (example 3, 4, 5, 6, 7, 8, 9 and 10) membered having 1 to 3 heteroatoms (namely 3 to 10- membered heterocyclyl); more preferably a 6 to 10 membered having 1 to 3 heteroatoms (namely

6 to 10-membered heterocyclyl); most preferably a 5 to 6 membered having 1 to 2 heteroatoms (namely 5 to 6-membered heterocyclyl). Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.

“Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from N, O and S as ring atoms, wherein the sulfur can be optionally oxygenated to form S(=0) or S(=0)₂, but does not include -0-0-, -O-S- or -S-S-, wherein one or more rings can contain one or more double bonds. Preferably a spiro heterocyclyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably

7 to 10 (example 7, 8, 9 and 10) membered. According to the number of common spiro atoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6- membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:

“Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, and wherein said rings have one or more heteroatoms selected from N, O and S as ring atoms, wherein the sulfur can be optionally oxygenated to form S(=0) or S(=0)₂, but does not include -0-0-, -O-S- or -S-S-. Preferably a fused heterocyclyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 3- membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4- membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5- membered/5-membered, 5-membered/6-membered, 6-membered/3 -membered, 6-membered/4- membered, 6-membered/5-membered or 6-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following groups:

“Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, and the rings have one or more heteroatoms selected from N, O and S as ring atoms, wherein the sulfur can be optionally oxygenated to form S(=0) or S(=0)₂, but does not include -0-0-, -O- S- or -S-S-. Preferably a bridged heterocyclyl is 6 to 14 membered (for example including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 (example 7, 8, 9 and 10) membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following groups:

The ring of said heterocyclyl include the heterocyclyl said above which fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following groups:

The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

“Aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group and has a completely conjugated pi-electron system. Preferably aryl is 6 to 10 membered (namely 6 to 10-membered aryl), such as phenyl and naphthyl, most preferably phenyl. The aryls include the aryl said above which fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following groups:

The aryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

“Heteroaryl” refers to an aryl system having 1 to 4 (example 1, 2, 3 and 4)heteroatoms selected from O, S and N as ring atoms wherein the sulfur can be optionally oxygenated to form S(=0) or S(=0)₂, but does not include -0-0-, -0-S- or -S-S-, and having 5 to 14 (for example including 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms) annular atoms (namely 5 to 14-membered heteroaryl). Preferably a heteroaryl is 5- to 10- membered (example 5, 6, 7, 8, 9 and 10) (namely 5 to 10-membered heteroaryl), more preferably 5- or 6- membered (namely 5 to 6-membered heteroaryl), for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, /V-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl include the heteroaryl said above which fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following groups:

The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio. “Alkoxy” refers to both an -O-(alkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy and butoxy, and the like. The alkoxy 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, independently selected from alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocyclyloxy, cycloalkylthio and heterocyclylthio.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups contain one monovalent residue derived from the removal of one hydrogen atom from the parent ring atom, or one divalent residue derived from the removal of two hydrogen atoms from the same or different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclyl", "arylene", and "heteroarylene".

“Bond” refers to a covalent bond using a sign of “ — ”.

“Haloalkyl” refers to an alkyl group substituted by one or more halogen(s), wherein alkyl is as defined above.

“Deuterium alkyl” or “deuterated alkyl” refers to an alkyl group substituted by one or more deuterium atom, wherein alkyl is as defined above.

“Hydroxy alkyl” refers to an alkyl group substituted by one or more hydroxy group, wherein alkyl is as defined above.

“Hydroxy” refers to an -OH group.

“Thiol” refers to a -SH group.

“Alkylthio” refers to an alkyl-S- group, wherein alkyl is as defined above.

“Haloalkylthio” refers to a haloalkyl-S- group, wherein haloalkyl is as defined above.

“Cycloalkoxyl” refers to a cycloalkyl-O-, wherein cycloalkyl is as defined above.

“Heterocyclyloxy” refers to a heterocyclyl-O-, wherein heterocyclyl is as defined above.

“Cycloalkylthio” refers to a cycloalkyl-S-, wherein cycloalkyl is as defined above.

“Heterocyclylthio” refers to a heterocyclyl-S-, wherein heterocyclyl is as defined above.

“Halogen” refers to fluoro, chloro, bromo or iodo atoms.

“Amino” refers to a -MB group.

“Cyano” refers to a -CN group.

“Nitro” refers to a -NO2 group.

“Oxo group” refers to a =0 group.

“Carboxyl” refers to a -C(0)0H group. “Carboxylate” refers to a -C(0)0(alkyl), -C(0)0(cycloalkyl), (alkyl)C(0)0- or (cycloalkyl)C(0)0- group, wherein the alkyl and cycloalkyl are defined as above.

The compounds of the present disclosure may exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, ( D ) - and ( L ) - isomers, tautomers, hindered isomers, conformational isomers and mixtures thereof (such as mixtures of racemates and diastereomers). The substituents in the compounds of the present disclosure may have additional asymmetric atoms. All these stereoisomers and mixtures thereof are included within the scope of the present disclosure. Optically active (-) - and (+) - isomers, ( R ) - and (S) - enantiomers and (/⁾) - and ( L ) - isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure can be prepared by asymmetric synthesis or chiral additives, or when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), form a salt of diastereomer with an appropriate optically active acid or base, and then carry out diastereomer resolution by a conventional method known in the art, Pure isomers were obtained. In addition, the separation of enantiomers and diastereomers is usually completed by chromatography.

In the chemical structure of the compound described in the present disclosure, the bond

” represents an unspecified configuration, that is, if there is a chiral isomer in the chemical structure, the bond can be “

” or “ ^ ” or contain both “

” or “ ^ ” configurations. The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomer form” refers to a structural isomer that exists in equilibrium and is easily transformed from one isomer to another. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of any proportion of a mixture of the tautomers. Non limiting examples include ketone enol, imine enamine, lactam lactimide, etc. An example of the lactam lactimide equilibrium is as follows:

For example pyrazolyl, it 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 present disclosure, and the name of compounds does not exclude any tautomers.

“Optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclic group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.

“Substituted” refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxy group having free hydrogen and carbon atoms having unsaturated bonds (such as olefmic) may be unstable.

A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.

“Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity.

The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable group with a suitable alkaline or acid. Alkalines commonly employed to form pharmaceutically acceptable salts include inorganic alkalines such as sodium, potassium, lithium, calcium, magnesium, or ammonium hydroxide; organic ammonium hydroxide such as tetramethylammonium or tetraethylammonium hydroxide, as well as organic alkalines such as various organic amines, including, but not limited to, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributyl amine, pyridine, N,N- dimethylaniline, A^f-m ethyl pi peri di ne, and A'-methylmorpholine.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids.

“Prodrug” refers to compounds that can be transformed in vivo to yield the active parent compound under physiological conditions, such as through hydrolysis in blood.

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

The term “therapeutically effective amount,” as used herein, refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.

The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it.

As used herein, the singular forms “a”, “an”, and “the” include plural reference, and vice versa, unless the context clearly dictates otherwise. The term “subject” or “patient”, as used herein, refers to a human or a mammalian animal, 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 can vary by ±10%, and sometimes more preferably within ±5%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting.

The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (¾), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (D) or carbon-13(¹³C). Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the disclosure may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents.

The compound of the present disclosure, any atom not specifically designated as a specific isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position should be understood as having hydrogen according to its natural abundance isotopic composition. Likewise, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", the position should be understood as deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (that is, at least 45% incorporation of deuterium). Exampled compounds have deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (that is, at least 15% incorporation of deuterium), at least 2000 times greater than the natural abundance of deuterium (that is, at least 30% incorporation of deuterium), at least 3000 times greater than the natural abundance of deuterium (that is, at least 45% incorporation of deuterium), at least 3340 times greater than the natural abundance of deuterium (that is, at least 50.1% incorporation of deuterium), at least 3500 times greater than the natural abundance of deuterium (that is, at least 52.5% incorporation of deuterium), at least 4000 times greater than the natural abundance of deuterium (that is, at least 60% incorporation of deuterium), at least 4500 times greater than the natural abundance of deuterium (that is, at least 67.5% incorporation of deuterium), at least 5000 times greater than the natural abundance of deuterium (that is, at least 75% incorporation of deuterium), at least 5,500 times greater than the natural abundance of deuterium (that is, at least 82.5% incorporation of deuterium), at least 6000 times greater than the natural abundance of deuterium (that is, at least 90% incorporation of deuterium) at least 6333.3 times greater than the natural abundance of deuterium (that is, at least 95% incorporation of deuterium), at least 6466.7 times greater than the natural abundance of deuterium (that is, at least 97% incorporation of deuterium), at least 6600 times greater than the natural abundance of deuterium (that is, at least 99% incorporation of deuterium), at least 6633.3 times greater than the natural abundance of deuterium (that is, at least 99.5% incorporation of deuterium) or a higher abundance of deuterium.

SYNTHESIS METHODS

The compounds disclosed in the present application were, or can be, prepared according to the following synthetic schemes:

Scheme 1

A preparation process of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an acidic condition, removing R^l of the compound of formula (IA) or a salt thereof to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl;

X² is hydrogen;

X¹ is -L-R°, wherein R° is -0P(=0)(0H)₂; and

L, R¹, 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). Scheme 2

A preparation process of a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an acidic condition, removing R¹ of the compound of formula (IIA) or a salt thereof to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

R¹ is alkyl; preferably, R^l is Ci-₆ alkyl;

X² is hydrogen; X¹ is -L-R°, wherein R° is -0P(=0)(0H)₂; and

L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II).

Scheme 3

A preparation process of a compound of formula (II- 1) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an acidic condition, removing R^l of the compound of formula (II- 1 A) or a salt thereof to obtain the compound of formula (II- 1) or a pharmaceutically acceptable salt thereof, wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl; X² is hydrogen;

X¹ is -L-R°, wherein R° is -0P(=0)(0H)₂; and

L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II- 1). Scheme 4

A preparation process of a compound of formula (III) or a pharmaceutically acceptable salt, comprising a step of:

under an acidic condition, removing R^l of the compound of formula (IIIA) or a salt thereof to obtain the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl;

X¹ is -L-R°, wherein R° is -0P(=0)(0H)2; and L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III).

Scheme 5

A preparation process of a compound of formula (IP-l) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an acidic condition, removing R^l of the compound of formula (III-1A) or a salt thereof to obtain the compound of formula (III-l) or a pharmaceutically acceptable salt thereof, wherein:

R^l is alkyl; preferably, R^l is Ci-₆ alkyl;

X¹ is -L-R°, wherein R° is -0P(=0)(0H)₂; and L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (IP-1).

Scheme 6

A process of preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an alkaline condition, reacting a compound of formula (IB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°;

X² is hydrogen or -L-R°; and

R°, L, R¹, 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). Scheme 7

A process of preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an alkaline condition, reacting a compound of formula (IIB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°; X² is hydrogen or -L-R°; and

R°, L, R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (II). Scheme 8

A process of preparing the compound of formula (II-l) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an alkaline condition, reacting a compound of formula (II-1B) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (II- 1) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl; X¹ is -L-R°;

X² is hydrogen or -L-R°; and

Scheme 9

A process of preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an alkaline condition, reacting a compound of formula (MB) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°; and R°, L, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in formula (III).

Scheme 10

A process of preparing the compound of formula (IP-l) or a pharmaceutically acceptable salt thereof, comprising a step of:

under an alkaline condition, reacting a compound of formula (III-1B) or a salt thereof with a compound of R°-L-R^w to obtain the compound of formula (PI-l) or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen; preferably, R^w is Cl;

X¹ is -L-R°; and

The reagents providing acidic conditions in the above synthesis schemes include, but are not limited to, acetic acid, trifluoroacetic acid, /Moluenesulfonic acid, /Moluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid and nitric acid, preferably acetic acid or trifluoroacetic acid.

The reagents providing alkaline conditions in the above synthesis schemes include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, /V, A -di i sopropy 1 ethyl am i ne, //-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butanol or potassium tert-butanol; the inorganic bases include, but are 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 conducted in one or more solvents, which include, but are not limited to, acetic acid, trifluoroacetic acid, methanol, ethanol, butanol, dimethyl ether, acetonitrile, petroleum ether, n-hexane, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4- dioxane, water, A^f,A^f-di methyl form amide, A^f, A^f-di m ethyl acetam i de, 1,2-dibromoethane, and mixtures thereof.

EXAMPLES

The following examples serve to illustrate the invention, but the examples should not be considered as limiting the scope of the invention. If specific conditions for the experimental method are not specified in the examples of the present invention, they are generally in accordance with conventional conditions or recommended conditions of the raw materials and the product manufacturer. The reagents without a specific source indicated are commercially available, conventional reagents.

The structure of each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR chemical shifts (d) were given in 10^'6 (ppm). NMR was determined by Bruker AVANCE-300, AVANCE-400 or AVANCE-500 machine. The solvents were deuterated-dimethyl sulfoxide (DMSO-i¾), deuterated-chloroform (CDCh) and deuterated- methanol (CD₃OD).

High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 150x4.6 mm chromatographic column), a Waters 2695-2996 high pressure liquid chromatography spectrometer (Gimini C18 150x4.6 mm chromatographic column), or Shimadzu UFLC equipped with an Xbridge C18 (5um 150x4.6mm) column.

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

MS was determined by a SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020), Waters UPLC-QDa equipped with an ACQUITY UPLC ® BEH (2.1*50mm 1.7pm) column, or Agilent Agilent6120 equipped with a Xbridge C18 (5um 50x4.6mm) column.

The thin-layer silica gel plates used in thin-layer chromatography were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The dimension of the plates used in TLC was 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.

Column chromatography generally used Yantai Huanghai 200 to 300 mesh silica gel as carrier. The known starting material of the invention can be prepared by the conventional synthesis method 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 reactions were placed under argon atmosphere or nitrogen atmosphere.

The term “argon atmosphere” or “nitrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of argon or nitrogen.

Unless otherwise stated in the examples, the solution used in following reactions refers to an aqueous solution.

Unless otherwise stated in the examples, the reaction temperature in the following reactions was room temperature.

Unless otherwise stated, the reaction temperature in the reactions refers to room temperature, and the range of the room temperature was 20°C to 30°C.

The reaction process was monitored by LC-MS or thin layer chromatography (TLC), and the developing solvent system includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds. The elution system for purification of the compounds by column chromatography, thin layer chromatography and CombiFlash flash rapid preparation instrument 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 compounds, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as acetic acid can be added.

Final compounds were purified by Shimadzu (LC-20AD, SPD20A) Preparative HPLC (Phenomenex Gemini-NX 5 mM C1821.2x100mm column), Waters 2767 equipped with a Sunfire Pre C18 (10 pm 19x250mm) column, or Waters 2767-QDa equipped with an Xbridge Pre C18 (10 pm 19x250mm) column instrument, with water/MeOH or water/ CH3CN elution systems with optional additives, such as HCOOH, TFA, NH4HCO3.

CombiFlash was performed on systems from Teledyne ISCO or Agela Technologies.

The following abbreviations are used in this application:

DIPEA is N, A^f-Di i sopropy 1 ethyl am i ne, HATU is l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

DCM is dichloromathene,

DMF is A^f,A-di methyl form amide, DMSO is dimethyl sulfoxide,

EtOAc is ethyl acetate,

TBAI is tetrabutylammonium iodide,

TFA is trifluoroacetic acid,

Prep HPLC is Preparative High Performance Liquid Chromatography, NMR is proton nuclear magnetic resonance,

MS is mass spectroscopy with (+) referring to the positive mode which generally gives a M+l (or M+H) absorption where M = the molecular mass.

Experimental Procedures Intermediate 1 (Int-1)

(A)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl (propanoic acid Intermediate 1 (Int-1)

Step 1 Tert-butyl 4-cyclopropyl-4-oxobutanoate 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 before the solution of cyclopropyl methyl ketone Int-1-1 (10 g, 118.88 mmol) in THF (10 mL) was added dropwise. The resulting solution was warmed to 20˚C and stirred for 30 min. The reaction mixture was then re-cooled 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 at room temperature overnight. After the reaction completed, the reaction was quenched with saturated NH₄Cl (50 mL, aq.), the mixture was extracted with EtOAc (50 mL × 3), the organic phase was washed with brine (100 mL), dried over Na₂SO₄ and concentrated to give the crude tittle compound Int-1-2 (22 g, 110.97 mmol, 93.34% yield). 1H NMR (400 MHz, CDCl₃): 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 (±)-Tert-butyl 3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoate 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 heated to 80˚C for 18h. The reaction mixture was cooled and poured into a mixture of EtOAc (100 mL) and water (100 mL), the layers were separated, and the aq. layer was extracted with EtOAc (100 mL× 3). The organic solution was 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 tittle compound Int-1-3 (5.7 g, 21.24 mmol, 51.36% yield). 1H 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). Steps 3 and 4 (S)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid Int-1 A solution of Int-1-3 (7.2 g, 26.83 mmol) in HCl/Dioxane (4M, 50 mL) was stirred at room temperature for 4h and concentrated. The resulting solid was triturated in MeCN (30mL) for 1h and filtrated to give pure racemic target Int-1-4 as a white solid. The solid was chiral separated by SFC (using a chiral column CHIRALPAK AD-H 10μm 2.5*25 cm; Flow Rate/detection: 70 g/min; Detector Wavelength: 214 nm; Mobile phase A: Supercritical CO_2; Mobile phase B: methanol) to give the tittle compound Int-1 (2 g, 9.42 mmol, 35.12% yield). 1H 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)isoindolin-2-yl)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 1

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 hours, the resulting mixture was poured into ice water (20 mL) and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over Na₂SO₄(s) and filtered. The filtrate was concentrated to afford 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 lb (1 g, 3.52 mmol) in MeOH (10 mL) was added H₂SO₄ (18 M, 0.7 mL) dropwise. After the mixture was stirred at 75 °C overnight, the mixture was cooled down to room temperature and poured into ice water (20 mL), the mixture was extracted with EtOAc (50 mL). The organic fraction was dried over Na₂S0₄(s) and filtered. The filtrate was concentrated to afford crude lc (1 g, 3.36 mmol, 95.29% yield).

NMR (400 MHz, DMSO -d₆): d 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 Id To a solution of lc (1 g, 3.36 mmol) in DMF (10 mL) was added Pd(PPli3)4 (430 mg, 372.11 umol), K3PO4 (2.2 g, 10.36 mmol) and methyl boronic acid (1 g, 16.71 mmol). After the mixture was stirred at 130 °C under N2 atmosphere overnight, the mixture was cooled down to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography column to afford Id (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 le Concentrated HC1 (2 mL) was added to a solution of Id (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 -5-0 °C, a solution of NaNCh (600 mg, 8.70 mmol) in H2O (2.5 mL) was added dropwise, and the mixture was stirred at an ambient temperature for 30 min. CuCl (849.11 mg, 8.58 mmol) was added portion-wise at 0 °C, and the mixture was stirred at room temperature for 2h. After completion of the reaction, the mixture was poured into IN HC1 (50 mL) and the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford le (1.3g, 5.15 mmol, 60.00% yield).

Step 5

Methyl 2-bromo-5-chloro-4-(trifluoromethyl)benzoate If To a solution of le (1.3 g, 5.15 mmol) in CCL (20 mL) was added NBS (1.10 g, 6.18 mmol) and AGBN (25.35 mg, 154.38pmol), the mixture was heated to 70 °C and stirred overnight. The mixture was cooled to room temperature and filtered, the cake was washed with CCL, the filtrate was concentrated in vacuo to give crude If (1.9 g, 5.73 mmol, 111.37% yield). Step 6

6-chloro-5-(trifluoromethyl)isoindolin-l-one lg

To a solution of If (1.9 g, 5.73 mmol) in MeOH (10 mL) was added ME/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=l:l) to afford lg (920 mg, 3.91 mmol, 68.14% yield).

LCMS: MS m/z (ESI): 236.0 [M+H]⁺.

Step 7

5-chloro-6-(trifluoromethyl)isoindoline lh

To a solution of lg (570 mg, 2.42 mmol) in THF (5 mL) was added BLL/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 HC1. Then the mixture was heated to 45 °C and stirred for 30 min. After cooled to rt, the mixture was adjusted to pH 7-8 with 1M NaOH. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous NaiSCL, filtered and concentrated in vacuo. The residue was purified prep-TLC (DCM: MeOH=10:l) to give lh (10 mg, 45.13pmol, 1.87% yield).

¾NMR (400 MHz, DMSO -d6): d 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)i soindolin-2-yl)-3 -oxopropyl)-5 - cyclopropylimidazolidine-2,4-dione 1

To a solution of lh (10 mg, 45.12 umol) in DMF (2 mL) was added TEA (50 uL), Int-1 (10 mg, 47, 12pmol), and HATU (17.16 mg, 45.12pmol). The reaction mixture was stirred at room temperature for 3h. Water was added, the mixture extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude was purified by prep-HPLC to give compound 1 (5 mg, 12.03 mihoΐ, 26.65% yield).

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). ¹⁹F NMR (376.5 MHz, DMSO-i/e): d -60 86 LCMS: MS m/z (ESI): 416.4 [M+H]⁺.

Example 2 (5,S)-5-(3-(5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-i/₂)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 2 (mixture of diastereomers)

Methyl 5-amino-4-(trifluoromethyl)-2-vinyl-benzoate 2b To a solution of lc (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)Cl2 (1.34 g, 1.83 mmol) and K2CO3 (6.35 g, 45.71 mmol). The resulting mixture was evacuated and refilled with N2 for 3 times. The resulting mixture was stirred at 80 °C for 16 h. The mixture was diluted with EtOAc (100 mL), the combined organic phase was washed with brine (100 mL), dried over Na₂SC>₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the tittle 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, 285.48μL, 10% purity). The resulting mixture was evacuated and refilled with ¾. The resulting mixture was stirred at room temperature for 16 h and the LCMS indicated the reaction was finished. The mixture was filtered, and the cake was washed with MeOH, the filtrate was concentrated under reduced pressure to afford the tittle 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 HC1 (3.36 mL). The resulting mixture was stirred at room temperature for 20 min. After the mixture was cooled to 0 °C, a solution of NaN0₂ (1.88 g, 27.18 mmol) in water (5 mL) was added. Then CuCl (1.48 g, 14.95 mmol) was added in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was poured into 1M HC1 (60 mL), the aqueous phase was extracted with EtOAc (100 mL x 3), the combined organic phases were washed with brine (100 mL), dried over NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with hexane / EtOAc=50/l) to afford the title compound 2d (2.23 g, 8.36 mmol, 61.53% yield).

Ή NMR (400 MHz, DMSO-i/e): d 7.99 (s, 1H), 7.87 (s, 1H), 3.88 (s, 3H), 2.92 (q, 2H), 1.17 (t, 3H).

Step 4

(±)-Methyl 2-(l-bromoethyl)-5-chloro-4-(trifluoromethyl) benzoate 2e To a solution of 2d (2.23 g, 8.36 mmol) in CCL (35 mL) was added AGBN (412.00 mg, 2.51 mmol) and NBS (1.64 g, 9.20 mmol). The resulting mixture was stirred at 80 °C for 16 h. The mixture was filtered. The solid was washed with DCM and the filtrate was concentrated in vacuo to afford the crude tittle compound 2e (2.5 g, 7.24 mmol, 86.51% yield).

Ή NMR (400 MHz, DMSO-i/e): d 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-l-one 2f To a solution of 2e (2.5 g, 7.24 mmol) in MeOH (10 mL) was added ML/MeOH (7 M, 30 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was purified by prep-HPLC to afford the tittle compound 2f (1.18 g, 4.73 mmol, 65.34% yield).

NMR (400 MHz, DMSO-i/e): d 9.11 (brs, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 4.71 (q, 1H), 1.42 (d, 3H).

¹⁹F NMR (376.5 MHz, DMSO -d₆): d -60 99 LCMS: MS m/z (ESI): 250.0 [M+H]⁺.

Step 6

(±)-5-chloro-l-methyl-6-(trifluoromethyl)isoindoline-3,3-ifc 2g To a solution 6-chloro-3-methyl-5-(trifluoromethyl)isoindolin-l-one 2f (800 mg, 3.20 mmol) in THF (10 ml) was added BD3 (1M in THF, 64 ml, 64 mmol). After addition, the reaction was stirred at 60 °C (in a sealed tube) for 10 hours. It was quenched with MeOH (10 ml), followed by HC1 (6 M, 20 mL). It then was stirred at 80 °C for 8 hours. 2 N NaOH was added to adjust pH to 7 and extracted with EtOAc, the combined organic phases were washed with brine (50 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5 % MeOH in DCM, to get the desired product 2g which is used for next step.

LCMS: MS m/z (ESI): 238.1 [M+H]⁺.

Step 7

(5ri)-5-(3-(5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-i/₂)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 2 (mixture of diastereomers)

To a solution of fV)-3-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)propanoic acid Int-1 (680 mg, 3.2 mmol) in DMF (10 mL) was added EDCI (920 mg, 4.8 mmol) and HATU (1.83 g, 4.8 mmol). After stirring for 10 minutes, the isoindoline 2g collected from the previous step was added. The reaction was stirred at ambient temperature for 3 hours. LCMS showed that the reaction was completed. It was directly purified on a reverse phase HPLC to get the desired product 2 (1.10 g, 79.6 % yield over two steps). ^JH NMR (400 MHz, CD₃OD,): 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, 2 H), 1.56-1.50 (m, 3 H), 1.28-1.21 (m, 1 H), 0.62-0.58 (m, 1 H), 0.49-0.41 (m, 3 H).

LCMS: MS m/z (ESI): 432 [M+H]⁺.

Examples 2-1 and 2-2

(_<S)-5-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ifc)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 2-1

(S)-5-(3-((,S)-5-chloro-l-methyl-6-(trifluorc>methyl)isoindolin-2-yl-3,3-<i₂)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 2-2

2 (1.10 g) was separated by SFC to give two diastereomers 2-1 (325mg, yield 29.5%) and 2-2 (415mg, yield 37.7%).

Compound 2-1:

NMR (500 MHz, DMSO -d₆) d 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, 5um): Rt: 4.594 min, de:100%.

Compound 2-2:

NMR (500 MHz, DMSO -d₆) d 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, 5um): Rt: 10.931 min, de:100%.

Example 3 fV)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5- dioxoimidazolidin-l-yl)methyl pivalate 3

To a solution of (ri)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-5- cyclopropylimidazolidine-2,4-dione 1 (66 mg, 0.16 mmol) in DMF (5 mL) was added IN aqueous NaOH (0.3 mL) at 0 °C. After stirring at this temperature for 10 minutes, chloromethyl pivalate (48 mg, 0.32 mmol) was added. The reaction was slowly warmed up to ambient temperature and stirred for 12 hours. It was directly applied onto a reverse phase prepHPLC using 10-60% CTLCN / ThO as eluent to afford the desired product 3 (75 mg, 88.6 % yield).

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

((ri)-4-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ifc)-3-oxopropyl)-4- cyclopropyl-2, 5-dioxoimidazolidin-l-yl)methyl pivalate 4

To a solution of the compound 2-1 (120 mg, 0.28 mmol) in DMF (10 mL) was added IN 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 up to ambient temperature and stirred for 12 hours. It was purified on a reverse phase prep-HPLC using 10-60% CTLCN and ThO as eluent to result the desired product 4 (40 mg, 26.2 % yield).

Ή NMR (400MHz, CDCb): d 7.76 (s, 1H), 7.60 (s, 1H), 5.50 (m, 2H), 5.32 (m, 1H), 2.48- (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

(S)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5- dioxoimidazolidin-l-yl)methyl dihydrogen phosphate 5

Step 1 fV)-di-tert-butyl ((4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4- cyclopropyl-2,5-dioxoimidazolidin-l-yl)methyl) phosphate 5a To a suspension solution of 1 (166 mg, 0.40mmol) in THF (1 mL), 0.2N aqueous NaOH solution (2.0 mL) was added. The reaction mixture got clear and was stirred at room temperature for 10 min. The solvent was removed under vacuum. Then DMF (2 mL) and K2CO3 (94 mg, 0.68 mmol) were added followed by the addition of 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 -70% conversion. EtOAc (100 mL) was added, and the organic phase washed by brine (40 mL). The organic solvent was dried over anhydrous NaiSCL and purified by silica gel chromatography eluting with hexane/EtOAc to result crude product 5a which was used for next step directly. LCMS: m/z (ESI): 638.2 [M+H]⁺.

Step 2 fV)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5- dioxoimidazolidin-l-yl)methyl dihydrogen phosphate 5 To the crude compound 5a (0.40 mmol from the previous step), a mixture of ACOH/H2O (0.60 / 0.15 mL) was added. The mixture was heated at 60 °C for 1.5 hr. Then the reaction mixture was neutralized carefully to pH = 7.0 at 0 °C by 2N aqueous Na₂CC>₃ solution. The resulted mixture was purified by prepHPLC using 10-30% CH3CN and H2O with 0.5% NH4HCO3 as eluent to obtain the desired product 5 after lyophilization (53 mg, 25.2% yield over 2 steps).

³H NMR (400 MHz, Methanol-A): d 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).

³¹P NMR (400 MHz, CD₃OD): d -0 50 1⁹F NMR (376.5 MHz, CD3OD): d -63 6 LCMS: m/z (ESI): 526.1 [M+H]⁺.

Example 6

((,S)-4-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ifc)-3-oxopropyl)- 4-cyclopropyl-2,5-dioxoimidazolidin-l-yl)methyl dihydrogen phosphate 6

(_<S')-5-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ifc)-3-oxopropyl)-5- cyclopropyl -3-((methylthio)methyl)imidazolidine-2,4-dione 6a To a solution of the 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 addition, it was warmed to ambient temperature and stirred for 30 minutes. Then (chloromethyl)(methyl)sulfane (394 mg, 4.08 mmol) was added. The reaction was stirred at ambient temperature for one hour and worked up with water and ethyl acetate (40 + 120 mL). The organic layer was collected and purified by silica gel chromatography eluting with 75 % EtOAc in CH2CI2, to get desired product 6a (250 mg, 71.0 % yield).

LCMS: m/z (ESI): 492.1 [M+H]⁺.

Step 2

(_<S)-5-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ifc)-3-oxopropyl)-3- (chloromethyl)-5-cyclopropylimidazolidine-2,4-dione 6b

To a solution of 6a (250 mg, 0.51 mmol) in CH2CI2 (20 mL) was added triethylamine hydrochloride (210 mg, 1.53 mmol), followed by sulfuryl chloride (IN in CH2CI2, 0.77 mL, 0.77 mmol). After addition, the reaction was stirred at ambient temperature for 2 hours. LC-MS showed the reaction is completed. The solvent was removed under vacuum and the resulted crude mixture 6b was used for next step directly.

LCMS: m/z (ESI): 480.1 [M+H]⁺.

Step 3 di-tert-butyl ((fV)-4-(3-((//)-5-chloro- l -methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-_<7₂)-3- oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolidin-l-yl)methyl) phosphate 6c To a solution of 6b (0.51mmol from the previous step) in acetonitrile (20 mL) was added potassium di-t-butylphosphate (228 mg, 0.92 mmol), followed by NaHCCb (10 mg, 0.1 mmol). After addition, the reaction was stirred at 75 °C for 12 hours. LC-MS showed that the reaction was complete. It was concentrated under vacuum and purified by silica gel chromatography, eluting with 90 % EtOAc in CH2CI2, to get desired product 6c (301 mg, 90 % over 2 steps).

³H NMR (400MHz, CD3OD): d 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

((ri)-4-(3-((i?)-5-chloro-l-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-ife)-3-oxopropyl)-4- cyclopropyl-2, 5-dioxoimidazolidin-l-yl)methyl dihydrogen phosphate 6

A solution of 6c (255 mg, 0.41 mmol) in a mixture of CH₃CN/water/TFA=2/2/l (50 mL) was stirred at ambient temperature for 16 hours. LC-MS showed that the reaction was completed. It was directly applied onto a reverse phase prepHPLC using 10-30% CH3CN and H2O with 0.5% NH4HCO3 as eluent to get desired product 6 after lyophilization (221 mg, 99.5 % yield).

³H NMR (400MHz, CD3OD): d 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).

³¹P NMR (400MHz, CD3OD): d -1 5

¹⁹F NMR (376.5 MHz, CD3OD): d -63 6

LCMS: m/z (ESI): 542.1 [M+H]⁺.

BIOLOGICAL ASSAYS

The present disclosure will be further described with reference to the following test examples, but the examples should not be considered as limiting the scope of the disclosure.

Test Example 1. In vitro fluorescence assay of ADAMTS-4 or ADAMTS-5 activity

A FRET (fluorescence resonance energy transfer) peptide was cleaved by recombinant ADAMTS-4 or ADAMTS-5 proteins into two separate fragments resulting in an increase of fluorescence signal which was quantified. The peptide was 5-FAM-TEGEARGSVILLK(5- TAMRA)K-NH2, customized from ANASPEC. ADAMTS-4 recombinant protein (catalog 4307- AD) and ADAMTS-5 recombinant protein (catalog 2198-AD) were purchased from R&D Systems.

An assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM CaCh, 0.1% CHAPS and 5 % Glycerol was prepared. A volume of 2.5 μL of compound in the assay buffer was dispensed to a 384-well plate, and 2.5 μL of ADAMTS-4 or ADAMTS-5 protein (final concentration in the reaction was 10 nM) was added. The compounds and proteins were preincubated at room temperature for 15 minutes. Then, 5 μL of substrate was added to each well. The final substrate concentrations for ADAMTS-4 and ADAMTS-5 were 15 pM and 8 pM, respectively. The fluorescence signal in each well was determined, after incubation at 37°C for 3 hours, on a TECAN plate reader (Excitation, 490 nm; Emission, 520 nm).

Data Analysis:

The data was inputted into GraphPad Prism, and the IC₅₀ values were calculated using function “log (inhibitor) vs. response — Variable slope (four parameters)”. (See Table 1).

Table 1. The IC₅₀ values of the exemplified compounds in FRET -peptide enzymatic assays

Conclusion: The parent compounds 1 and 2-1 in the present disclosure have a significant inhibition effect on the enzymatic activity of ADAMTS-4 and ADAMTS-5. Their prodrug molecules 3, 4, 5 and 6 do not have any enzymatic activity on 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 recombinant ADAMTS-5 protein (catalog 2198-AD, R&D Systems) was assayed with a protein substrate, the aggrecan IGD protein. The aggrecan IGD protein is a polypeptide connecting human aggrecan globular domains 1 and 2 (T331 - G458) expressed in E. Coli with a C-terminal His-tag (catalog 30411000, BIOTEZ). The enzymatic product ARGSVIL-peptide was detected using an ELISA kit from BioTEZ (catalog 30510111).

An assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM CaCE, 0.1% CHAPS and 5 % Glycerol was prepared. Recombinant ADAMTS-5 protein was diluted to 0.3 nM in the assay buffer. 10 μL of buffer and 10 μL of compound solution was transferred to each well of a 96-well plate and incubated at room temperature for 15 minutes. Substrate aggrecan-IGD was diluted to 100 nM with the assay buffer and 20 μL was added to each well. The plate was incubated at 37°C for 45 minutes. After incubation, the newly generated epitope ARGSVIL-peptides were measured using the Aggrecanase Activity ELISA Assay Kit following the manufacturer’s instructions. Then, 100 μL of stop solution was added and the absorbance of each well was read at 450 nM, using 620 nM as reference on a TECAN plate reader.

Data Analysis:

A standard curve of the ELISA assay was generated in GraphPad Prism using Sigmoidal 4PL function and the corresponding peptide concentrations were calculated based on the standard curve. The IC50 values were calculated using function “log (inhibitor) vs. response — Variable slope (four parameters)”. (See Table 2).

Table 2. The IC50 values of the exemplified compounds from the Aggrecan-IGD enzymatic assay

Conclusion: The parent compounds 1 and 2-1 of the present disclosure have a significant inhibition effect on the enzymatic activity of ADAMTS-5.

Test Example 3. Fassif solubility test of the compound in present disclosure

3.1 Preparation of reference solution Weight appropriate amount of compound to be tested and dissolve it into DMSO to result a 10 mM stock solution. Precisely measure 10 μL stock solution and 990 μL organic solvent (a mixture of DMSO: acetonitrile: ethanol = 1:1:1 (v/v/v)) into a 2 mL vial and mix well. This clear 100 pM sample solution was used as the reference solution. 3.2 Preparation of test compound Fassif solution

Dissolve 1 mg of the test sample into 900 μL FaSSIF solution and mix vigorously. Two such solutions were prepared in parallel and shook in a 37°C water bath for 24 hours. Then the solution was centrifuged at 4000 rpm for 30 min and the supernatant was transferred to HPLC for analysis. 3.3. Data Processing Solubility (pM) = sample peak area/reference peak area * reference concentration (pM) * sample solution dilution factor. Take the average of two measurements as the final solubility. (See Table 3).

Table 3. Solubility assay of the compounds in present disclosure

Conclusion: When compared to their parent compounds 1 and 2-1, prodrug molecules 3, 4, 5 and 6 have improved Fassif solubility separately.

Test Example 4. Pharmacokinetics assay Instruments

API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra high-performance liquid chromatography system, Shimadzu, Japan.

Chromatographic condition :

Column: Welch Xtimate C18 1.8pm 30x2. lmm

Mobile phase A: 0.5% formic acid, 5 mM ammonium acetate in water (gradient elution)

Mobile phase B: 0.5% formic acid 5mM ammonium acetate in 95% acetonitrile / water solution (gradient elution)

Column temperature: 35 °C

Preparation of the test samples

25 μL of plasma samples was mixed with 50 μLof Internal Standard solution (100 ng / mL) and 200 μL of CH₃CN precipitant, the solution was vortexed for 5 min then centrifuged for 10 min (4000 rpm). 8 μL of supernatant was sampled for LC/MS/MS analysis.

Process

In Sprague Dawley rat PK study, each group of animals (N = 4, 2 male & 2 female) are fasting overnight. Intragastric administration (ig) group receives drug by oral gavage. Serial blood samples (0.2 mL) are collected from the orbit into di-potassium ethylenediaminetetraacetic acid (K2 EDTA) blood collection tube at time point 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours then centrifuged at 4 ⁰ C (10,000 rpm) for 1 min to obtain plasma. For Intravenous administration (iv) group, serial blood samples (0.2 mL) are collected from the orbit into di-potassium ethylenediaminetetraacetic acid (K2 EDTA) blood collection tube at time point -5min, 5 min, 15 min, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, 24.0 h. The plasma sample was separated within 1 h and store at -20 °C until analysis by Liquid chromatography-tandem mass spectrometry (LC/MS/MS). The whole procedure from blood collection to centrifugation was performed under ice condition. 2 hours after administration, the rats were fed with food.

Data analysis

The pharmacokinetic parameters were obtained by non-compartmental analysis of plasma concentration (determined by LC/MS/MS) vs. time data. The peak concentration (Cmax) and time for C_max was recorded directly from experimental observations. The area under curve (AUCo-_t) from time zero to the last sampling time was calculated using a combination of linear and log trapezoidal summations. Results

The rat ig PK results were shown in Table 4.

Table 4. Rat PK results of Example 2-1 and prodrug Example 6

Conclusion: Prodrug molecule 6 can be almost fully converted into its parent compound 2-1 by oral dosing in rat. Much higher parent drug exposure was observed with Example 6 in the study of rat ig 100 mpk PK when compared to Example 2-1 at the same dose.

Abbreviations:

C_max: maximum serum concentration; PEG400: polyethylene glycol 400;

HPMC K100LV: hydroxypropyl methylcellulose (HPMC) K100LV;

TPGS: D-a-Tocopherol polyethylene glycol 1000 succinate.

The foregoing embodiments and examples are provided for illustration only and are not intended to limit the scope of the disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on the present disclosure, and such changes and modifications may be made without departure from the spirit and scope of the present disclosure. All literature cited are incorporated herein by reference in their entireties without admission of them as prior art.

Claims

CLAIMS What is claimed is: 1. A compound of formula (I): or a pharmaceutic

wherein: X¹ and X² are identical or different, and each is independently hydrogen or -L-R⁰, provided that X¹ and X² are not both hydrogen; L is selected from -(CQ¹Q²)_t-, -C(=O)O-, -C(=O)O(CQ¹Q²)_t- and -C(=O)S(CQ¹Q²)_t-; R⁰ is selected from -OP(=O)(OH)₂, -OP(=O)(OH)-OP(=O)(OH)₂, -OC(=O)Q³, - NQ⁶C(=O)Q³, -OC(=O)OQ⁴, -NQ⁶C(=O)OQ⁴, -OP(=O)(OQ⁴)₂, -OQ⁵, -NQ⁶Q⁷, -O- C(=O)(CQ¹Q²)_t-(Cy)_s-OP(=O)(OH)₂, -OC(=O)-NQ⁶Q⁷, -OC(=O)CH=CHC(=O)OH, -O-C(=O)- O-(CQ¹Q²)_t-OP(=O)(OH)₂, -O-C(=O)-NH-(CQ¹Q²)_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 alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q¹ and Q² are identical or different, and each is independently selected from hydrogen, deuterium and alkyl, wherein the alkyl is optionally substituted by one or more substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q³ is selected from hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, - NQ⁶Q⁷, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; Q⁴ and Q⁵ are identical or different, and each is independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ⁶Q⁷, -0C(=0)Q⁸, - 0C(=0)0Q⁸, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q⁸ is selected from alkyl, haloalkyl and deuterium alkyl;

R¹ is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalky;

R^2a, R^2b, R^3a and R^3b are each identical or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxy, hydroxy, 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 atom(s) to which they are attached form cycloalkyl or heterocyclyl;

R^4a, R^4b, R^5a and R^5b are each identical or different, and each is 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(s) to which they are attached form cycloalkyl or heterocyclyl; p^6c _an(j p^6d _are id_enti_{cai or} different, and each is independently selected from hydrogen, halogen, alkyl, deuterium alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxy, hydroxy, 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.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1; and m is 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^2a, R^2b, R^3a, R^6c and R^6d are identical or different, and each is independently selected from hydrogen, halogen and C_1-6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, being a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

X¹, X², R¹, R^3b, R^4a, R^4b, R^5a, R^5b, R^6a and R^6b are each as defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, being a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, wherein:

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R¹ is 3 to 6-membered cycloalkyl.

7. The compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, being a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: X¹, R^4a, R^4b, R^5a, R

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X² is hydrogen or -L-R⁰; L is -CQ¹Q²-; and R⁰, Q¹ and Q² are as defined in claim 1; preferably, X² is hydrogen or -L-R⁰; L is -CQ¹Q²-; R⁰ is selected from - OP(=O)(OH)₂, -OC(=O)Q³ and -OP(=O)(OH)-OP(=O)(OH)₂; and Q¹, Q² and Q³ are as defined in claim 1.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X¹ is -L-R⁰; L is-CQ¹Q²-; and R⁰, Q¹ and Q² are as defined in claim 1; preferably, X¹ is -L-R⁰; L is-CQ¹Q²-; R⁰ is selected from -OP(=O)(OH)₂, -OC(=O)Q³ and - OP(=O)(OH)-OP(=O)(OH)₂; and Q¹, Q² and Q³ are as defined in claim 1.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Q¹ and Q² are identical or different, and each is independently selected from hydrogen, deuterium and C_1-6 alkyl; and/or Q³ is C_1-6 alkyl.

11. 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 identical or different, and each is independently selected from hydrogen, deuterium and C_1-6 alkyl.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, C_1-6 alkyl, C_1-6 deuterium alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, hydroxy, C_1-6 hydroxyalkyl, cyano, amino, nitro, 3 to 6- membered cycloalkyl and 3 to 6-membered heterocyclyl; preferably, R^6a and R^6b are each identical or different, and each is independently selected from hydrogen, halogen, C_1-6 deuterium alkyl, C_1-6 alkyl and C_1-6 haloalkyl.

13. A compound selected from: C^l 3

pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, or a pharmaceutically acceptable salt, wherein r Vci

CF₃ the compound is selected from:

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

wherein:

R¹ is alkyl, preferably Ci-₆ alkyl;

X² is hydrogen; and

L, R¹, 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.

16. The compound according to claim 15, or a salt thereof, wherein the compound is selected from:

and

17. A method of preparing the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, comprising a step of:

removing R¹ of the compound of formula (IA), or a salt thereof, to obtain the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R¹ is alkyl, preferably Ci-₆ alkyl;

X² is hydrogen;

X¹ is -L-R°, wherein R° is -0P(=0)(0H)₂; and

L, R¹, 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.

18. A method of preparing the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (IB), or a salt thereof, with a compound of R°-L-R^w to obtain the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R^w is halogen, preferably Cl;

X¹ is -L-R°;

X² is hydrogen or -L-R°; and

R°, L, R¹, 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.

19. A pharmaceutical composition comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of inhibiting ADAMTS-5 and/or ADAMTS-4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19.

21. A method of preventing or treating an inflammatory condition or disease involving degradation of cartilage and/or involving disruption of cartilage homeostasis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19.

22. A method of preventing or treating arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19; preferably, wherein the arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertrophic arthritis.