CN117136051A

CN117136051A - Prodrugs of ADAMTS inhibitors, preparation method and medical application thereof

Info

Publication number: CN117136051A
Application number: CN202280026358.4A
Authority: CN
Inventors: 赵鹏; 刘建; 张凤岐; 宋春英
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2021-04-02
Filing date: 2022-03-31
Publication date: 2023-11-28
Also published as: TW202304886A; WO2022212638A1

Abstract

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

Description

Prodrugs of ADAMTS inhibitors, preparation method and medical application thereof

Cross Reference to Related Applications

The present application claims priority from U.S. c. ≡119 (e) to U.S. provisional patent application No. 63/170,371 filed on 2/4/2021, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates to prodrug compounds and methods for inhibiting ADAMTS-5 and/or ADAMTS-4 function and their use in the treatment of diseases involving cartilage degradation or disruption of cartilage homeostasis (e.g., osteoarthritis and/or rheumatoid arthritis).

Background

Cartilage is a highly specialized connective tissue of the joint. Its main function is to provide the bearing and compression resistance to the joint. The major components of cartilage are extracellular matrices, including aggrecan and collagen. In diseases such as osteoarthritis, the balance between aggrecan and collagen production (anabolism) and degradation (catabolism) shifts to catabolism.

Osteoarthritis is the most common chronic joint disease and is the leading cause of pain and disability in developed countries. It is estimated that 2.5 million people worldwide are currently affected by osteoarthritis and the prevalence is increasing (Hunter et al, lancet.2019, 393:1745-1759). Pain and loss of function are accompanied by an increased risk of other diseases such as diabetes, cancer or cardiovascular diseases (Valdes AM and Stocks J. Osteoarthritis and imaging. Eur Med J.2018, 3:116-123). Osteoarthritis is a total joint disease: structural changes have been found to include degradation of articular cartilage, synovitis, and alterations in subchondral bone and other periarticular tissues (Goldring MB and Otero M. Infromation in osseoarthritis. Curr Opin Rheumatoid.2011, 23:471-478). The pathogenesis of osteoarthritis is not well understood, involving mechanical injury, inflammation, aging, and metabolic factors. Osteoarthritis is not a passive degenerative disease, but an active dynamic change caused by an imbalance between repair and destruction of joint tissue (Hunter et al, lancet.2019,393: 1745-1759). Currently, the pharmacological treatments available for osteoarthritis are limited to relief of symptoms of pain and inflammation. There is no disease modifying drug that prevents or slows the progression of the disease.

Progressive loss of articular cartilage is currently considered an early event of osteoarthritis. Aggrecan may have the effect of protecting collagen loss (Pratta et al, J Biol chem.2003, 278:45539-45545). These studies suggest a key role for aggrecan in osteoarthritis and other joint diseases. Aggrecan is a proteoglycan with a core protein having covalently linked sulfated glycosaminoglycan (GAG) chains. The core protein has three globular domains, the N-terminal G1 and G2 domains, and the C-terminal G3 domain. The vast area between the G2 and G3 domains is largely modified by GAG Keratan Sulfate (KS) and Chondroitin Sulfate (CS). Based on the amino acid sequence differences, the CS domain is further divided into two subdomains of CS1 and CS 2. GAG chains provide high anionic charge to aggrecan. A number of aggrecan monomers bind to Hyaluronic Acid (HA) through the G1 domain, which is stabilized by a connexin, forming large supramolecular aggregates. Large aggrecan aggregates absorb water and provide elastic properties to cartilage (Roughley et al The Journal of Experimental orthographics.2014, 1:8). The normal function of cartilage requires high concentrations of aggrecan, high sulfation and the ability to form large aggregates.

Proteolytic enzymes can cleave the extended structure of aggrecan, resulting in impaired normal function of cartilage. ADAMTS (disintegrin and metalloprotease with thrombospondin motif) is a family of zinc ion-dependent metalloproteases. ADAMTS-4 and ADAMTS-5 are also known as "aggrecanases" that degrade aggrecan at several specific locations in the IGD and CS2 domains. ADAMTS-5 has been shown to be deficient in preventing aggrecan and cartilage damage in surgically-induced murine models of osteoarthritis disease (Glasson et al, nature.2005,434:644-648; stanton et al, nature.2005, 434:648-652), suggesting that ADAMTS-5 is involved in driving cartilage and osteoarthritis disease severity. Some studies of human cartilage explant culture also suggest that not only ADAMTS-5, ADAMTS-4 is also important for human osteoarthritis (Verma et al, journal of Cellular biochemistry.2011, 112:3507-3514). These studies strongly suggest that inhibition of ADAMTS-5 and ADAMT-4 enzyme function can provide protection in osteoarthritis.

In summary, the role of ADAMTS-5 and/or ADAMTS-4 in cartilage degradation has been well established. Thus, 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 disclosed as ADAMTS-5 and/or ADAMTS-4 inhibitors include WO2014066151A1, WO2016102347A1, WO2017211667A1, WO2017211666A1, WO2017211668A1, WO2021011720A2 and WO2021011723A1.

Although there are a variety of prodrug strategies to provide selection of drug molecule delivery modulation conditions with various benefits, identification of prodrugs with desirable characteristics is often difficult and not straightforward. None of the prior art teaches or suggests specific prodrugs of the present disclosure.

Disclosure of Invention

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

X ¹ and X ² Identical or different and are each independently hydrogen or-L-R ⁰ Provided that X ¹ And X ² Not all hydrogen;

l is selected from- (CQ) ¹ Q ² ) _t -、-C(＝O)O-、-C(＝O)O(CQ ¹ Q ² ) _t -and-C (=o) S (CQ ¹ Q ² ) _t -；

R ⁰ Selected from-OP (=O) (OH) ₂ 、-OP(＝O)(OH)-OP(＝O)(OH) ₂ 、-OC(＝O)Q ³ 、-NQ ⁶ C(＝O)Q ³ 、-OC(＝O)OQ ⁴ 、-NQ ⁶ C(＝O)OQ ⁴ 、-OP(＝O)(OQ ⁴ ) ₂ 、-OQ ⁵ 、-NQ ⁶ Q ⁷ 、-O-C(＝O)(CQ ¹ Q ² ) _t -(Cy) _s -OP(＝O)(OH) ₂ 、-OC(＝O)-NQ ⁶ Q ⁷ 、-OC(＝O)CH＝CHC(＝O)OH、-O-C(＝O)-O-(CQ ¹ Q ² ) _t -OP(＝O)(OH) ₂ 、-O-C(＝O)-NH-(CQ ¹ Q ² ) _t -OP(＝O)(OH) ₂ Hydrogen, heterocyclyl and heteroaryl;

cy is aryl or heteroaryl, each optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ¹ and Q ² Identical or different and each is independently selected from hydrogen, deuterium and alkyl, wherein said alkyl is optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ³ Selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, groups independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, -NQ ⁶ Q ⁷ Substituents for nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ⁴ and Q ⁵ Identical or different and are each independently selected from alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ ⁶ Q ⁷ 、-OC(＝O)Q ⁸ 、-OC(＝O)OQ ⁸ Substituents for cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ⁶ and Q ⁷ Identical or different, and are each independently selectedFrom hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

Q ⁸ selected from alkyl, haloalkyl and deuterated alkyl;

R ¹ selected from the group consisting of 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, sometimes more preferably one to three groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy, and hydroxyalkyl;

R ^2a 、R ^2b 、R ^3a And R is ^3b Each identical or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R is ^2a 、R ^2b 、R ^3a And R is ^3b Together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group;

R ^4a 、R ^4b 、R ^5a and R is ^5b Each identical or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

or R is ^4a 、R ^4b 、R ^5a And R is ^5b Together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group;

R ^6a 、R ^6b 、R ^6c and R is ^6d Identical or different and are each independently selected from hydrogen, halogen, alkyl, deuterated 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 is also provided with

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 disorder or a disease involving cartilage degradation and/or disruption of cartilage homeostasis comprising 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 disorder includes arthritis, preferably rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and hypertrophic arthritis, which is further preferably associated with ADAMTS-5 and/or ADAMTS-4 activity.

Other aspects or advantages of the disclosure will be better understood from the following detailed description, examples, and claims.

Detailed Description

In one aspect, the present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Q ⁴ And Q ⁵ Identical toOr different and are each independently selected from alkyl, cycloalkyl, and heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ ⁶ Q ⁷ 、-OC(＝O)Q ⁸ 、-OC(＝O)OQ ⁸ Substituents for cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ⁶ and Q ⁷ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;

Q ⁸ selected from alkyl, haloalkyl and deuterated alkyl;

R ^2a 、R ^2b 、R ^3a and R is ^3b Each identical or different and each 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, sometimes more preferably one to three groups selected from halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^4a 、R ^4b 、R ^5a and R is ^5b Each identical or different and each independently selected from hydrogen, deuterium, halogen, alkaneAlkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl;

R ^6a 、R ^6b 、R ^6c and R is ^6d Identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, deuteroalkyl, 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, sometimes more preferably one to three groups selected from the group consisting of 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 is also provided with

s is 0 or 1.

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

In some embodiments of the present disclosure, in a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ^2a 、R ^2b 、R ^3a 、R ^6c And R is ^6d Identical or different and are each 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 A hydroxyalkyl group; preferably, R ^2a 、R ^2b 、R ^3a 、R ^6c And R is ^6d Identical or different and are each independently selected from hydrogen, halogen and C _1-6 An alkyl group.

In some embodiments of the present disclosure, in a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ^2a 、R ^2b And R is ^3a Identical or different, and eachSelected 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 A hydroxyalkyl group; preferably, R ^2a 、R ^2b And R is ^3a Identical or different and are each independently selected from hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^2a 、R ^2b And R is ^3a Is hydrogen.

In some embodiments of the present disclosure, in a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ^6c And R is ^6d The same or different and are each 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 A hydroxyalkyl group; preferably, R ^6c And R is ^6d Identical or different and are each independently selected from hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^6c And R is ^6d Is hydrogen.

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

wherein:

X ¹ 、X ² 、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a and R is ^6b Each as defined in formula (I) above.

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

In some embodiments of the present disclosure, in a compound of formula (I), (II) or (II-1), or a pharmaceutically acceptable salt thereof, R ^3b Selected from hydrogen, halogen and C _1-6 An alkyl group; preferably, R ^3b Is hydrogen.

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

wherein:

X ¹ 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a and R is ^6b Each as defined in formula (I) above.

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

Wherein:

In some embodiments of the present disclosure, in a compound of formula (I), (II) or (II-1), or a pharmaceutically acceptable salt thereof, X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ 、Q ¹ And Q ² As defined in formula (I) above; preferably X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ ；Q ¹ 、Q ² And Q ³ As defined in formula (I) above; more preferably X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ is-OP (=O) (OH) ² The method comprises the steps of carrying out a first treatment on the surface of the And Q is ¹ And Q ² As defined in formula (I) above; most preferably, X ² Is hydrogen.

In some embodiments of the present disclosure, a compound of formula (I), (II-1), (III), or (III-1), or a pharmaceutically acceptable salt thereof, X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ 、Q ¹ And Q ² As defined in formula (I) above; preferably X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ ；Q ¹ 、Q ² And Q ³ As defined in formula (I) above; more preferably X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ is-OP (=O) (OH) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And Q is ¹ And Q ² As defined in formula (I) above.

In some embodiments of the present disclosure, in a compound of formula (I), (II-1), (III) or (III-1), or a pharmaceutically acceptable salt thereof, Q ¹ And Q ² Identical or different and are each independently selected from hydrogen, deuterium and C _1-6 An alkyl group; and/or Q ³ Is C _1-6 An alkyl group; preferably Q ¹ And Q ² Is hydrogen; and Q is ³ Is C _1-6 An alkyl group.

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

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

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

In some embodiments of the present disclosure, in a compound of formula (I), (II-1), (III) or (III-1), or a pharmaceutically acceptable salt thereof, R ^5a And R is ^5b Each identical or different and each independently selected from hydrogen, deuterium and C _1-6 An alkyl group; preferably, R ^5a And R is ^5b Each identical or different and each independently hydrogen or C _1-6 An alkyl group; more preferably, R ^5a Is hydrogen and R ^5b Is C _1-6 An alkyl group.

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

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

In some embodiments of the present disclosure, in a compound of formula (I), (II-1), (III) or (III-1), or a pharmaceutically acceptable salt thereof, R ^4a And R is ^4b Deuterium; r is R ^5a Is hydrogen and R ^5b Is C _1-6 An alkyl group.

In some embodiments of the present disclosure, in a compound of formula (I), (II-1), (III) or (III-1), or a pharmaceutically acceptable salt thereof, R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, nitro, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl.

In some embodiments, R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Deuterated alkyl, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments, R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; in some preferred embodiments, R ^6a And R is ^6b Each identical or different and each independently selected from halogen and C _1-6 A haloalkyl group; further preferably, R ^6a Is halogen; and R is ^6b Is C _1-6 A haloalkyl group; in some more preferred embodiments, R ^6a is-Cl; and R is ^6b is-CF ₃ 。

In some embodiments of the present disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ ；Q ¹ And Q ² Is hydrogen; q (Q) ³ Is C _1-6 An alkyl group; r is R ^4a 、R ^4b 、R ^5a And R is ^5b Each identical or different and each independently selected from hydrogen, deuterium and C _1-6 An alkyl group; r is R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Deuterated alkyl, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ ；Q ¹ And Q ² Is hydrogen; q (Q) ³ Is C _1-6 An alkyl group; r is R ^4a 、R ^4b 、R ^5a And R is ^5b Is hydrogen; r is R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ ；Q ¹ And Q ² Is hydrogen; q (Q) ³ Is C _1-6 An alkyl group; r is R ^4a And R is ^4b Deuterium; r is R ^5a And R is ^5b Each identical or different and each independently hydrogen or C _1-6 An alkyl group; r is R ^6a And R is ^6b Each identical or different and each independently selected from halogen and C _1-6 A haloalkyl group.

Exemplary compounds of the present disclosure include, but are not limited to:

other compounds that may be prepared based on the present disclosure include, but are not limited to:

/>

in another aspect, the present disclosure provides a compound of formula (IA):

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen; and is also provided with

L、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a 、R ^6b 、R ^6c 、R ^6d Each of n and m is as defined in formula (I).

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

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen; and is also provided with

L、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (II).

In another aspect, the present disclosure provides a compound of formula (II-1A) or a salt thereof:

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen; and is also provided with

L、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (II-1). In another aspect, the present disclosure provides a compound of formula (IIIA) or salt thereof:

Wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group; and is also provided with

L、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (III).

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

wherein:

L、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (III-1).

Exemplary intermediate compounds of the present disclosure include, but are not limited to:

/>

in another aspect, the present disclosure provides a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of a compound of formula (IA) or a salt thereof ^t To obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

X ¹ is-L-R ⁰ Wherein R is ⁰ is-OP (=O) (OH) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

In another aspect, the present disclosure provides a method of preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of the compound of formula (IIA) or a salt thereof ^t To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

In another aspect, the present disclosure provides a method of preparing a compound of formula (II-1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of the compound of formula (II-1A) or a salt thereof ^t To obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

L、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (II-1).

In another aspect, the present disclosure provides a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of the compound of formula (IIIA) or a salt thereof ^t Obtaining a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

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

removing R of the compound of formula (III-1A) or a salt thereof ^t To obtain a compound of formula (III-1) or a pharmaceutically acceptable salt thereof,

Wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

a compound of formula (IB) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

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

X ¹ is-L-R ⁰ ；

X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ⁰ 、L、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a 、R ^6b 、R ^6c 、R ^6d Each of n and m is as defined in formula (I).

a compound of formula (IIB) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

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

X ¹ is-L-R ⁰ ；

R ⁰ 、L、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (II).

a compound of formula (II-1B) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

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

X ¹ is-L-R ⁰ ；

R ⁰ 、L、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (II-1).

a compound of formula (IIIB) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

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

X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ⁰ 、L、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (III).

a compound of formula (III-1B) or a salt thereof and R ⁰ -L-R ^w Reacting the compounds to obtain a compound of formula (IIII-1) or a pharmaceutically acceptable salt thereof,

wherein:

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

R ⁰ 、L、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a And R is ^6b Each as defined in formula (III-1).

The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I), (II-1), (III), or (III-1), or a compound selected from table a or table B, or a pharmaceutically acceptable salt thereof, and 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-1), (III), or (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

The present disclosure also provides a method of preventing or treating an inflammatory disorder or a disease involving cartilage degradation 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-1), (III) or (III-1), or a compound selected from table a or table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound.

The present 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-1), (III) or (III-1), or a compound selected from table a or table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound; preferably, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

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

In another aspect, the present disclosure also relates to the use of a compound of formula (I), (II-1), (III) or (III-1), or a compound selected from table a or table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound, in the manufacture of a medicament for the prevention and/or treatment of an inflammatory disorder or a disease involving cartilage degradation and/or disruption of cartilage homeostasis.

In another aspect, the present disclosure also relates to the use of a compound of formula (I), (II-1), (III) or (III-1), or a compound selected from table a or table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound, in the manufacture of a medicament for the prevention and/or treatment of arthritis; preferably, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

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

The present disclosure also relates to compounds of formula (I), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compounds, for use in inhibiting ADAMTS-5 and/or ADAMTS-4.

The present disclosure also relates to compounds of formula (I), (II-1), (III) or (III-1), or a compound selected from table a or table B, or a combination of pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds, for use in the prevention and/or treatment of inflammatory disorders or diseases involving cartilage degradation and/or disruption of cartilage homeostasis.

The present disclosure also relates to a compound of formula (I), (II-1), (III) or (III-1), or a compound selected from table a or table B, or a combination of pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing said compound, for use in the prevention and/or treatment of arthritis; preferably, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

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

The phrase "inflammatory disorder" refers to a group of disorders including, but not limited to, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic airway diseases (e.g., asthma, rhinitis), chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease (e.g., crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., complications following bypass surgery, or chronic endotoxin states leading to e.g., chronic heart failure), and cartilage-related diseases (e.g., joint diseases). In particular rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease. More particularly rheumatoid arthritis and Osteoarthritis (OA). Most particularly phalangeal arthritis (OA).

"diseases involving cartilage degradation and/or disruption of cartilage homeostasis" include conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, suppurative or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, bone pain degeneration (algodydrophy), achondroplasia, paget's disease, tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amyloidosis (amyosis), joint water, periodic diseases, rheumatoid spondylitis, endemic forms of arthritis (such as endemic malformation osteoarthritis, msseleni disease and handicodu disease); degradation caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis; in particular phalangeal arthritis (OA).

The pharmaceutical compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present disclosure may be formulated in various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), rectal, inhaled, or insufflation administration. The compounds of the present disclosure may also be formulated as sustained release dosage forms.

The dosage of the compounds or compositions used in the present disclosure will vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compounds. However, as a general guideline, the active compounds are preferably administered in unit doses or the patient may self-administer a single dose. The unit dosage form of the compounds or compositions of the present disclosure may be in the form of a tablet, capsule, caplet, bottled liquid, powder, granule, tablet, suppository, reconstituted powder, or liquid formulation. Suitable unit doses may be from 0.1mg to 1000mg.

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

Suitable dosage forms include, but are not limited to, tablets, troches (troche), lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. The oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions. These compositions may contain one or more additives selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasant and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, and lubricating agents. The tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption of the drug in the gastrointestinal tract and thereby provide a sustained release over an extended period. For example, water-soluble taste masking materials may be used.

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

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

Oily suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. The foregoing sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phosphatides. Sweeteners may be used. Such formulations may also contain a demulcent (modulator), a preservative, a colorant and an antioxidant.

The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion may be introduced into the blood stream of the individual by topical bolus injection. Alternatively, it is advantageous to apply the solution or microemulsion in such a way that a constant circulating concentration of the present compound is maintained. To maintain this constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS. TM.5400 intravenous injection pump.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated according to known techniques with suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. In addition, sterile, fixed oils can be readily employed as a solvent or suspending medium, and fatty acids can be employed in the preparation of injectables.

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

For buccal administration, the compositions may 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 delivered by a pump spray container that is squeezed or pumped by the patient, or in the form of an aerosol spray delivered by a pressurized container or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). For a pressurized aerosol, the dosage unit may be determined by a valve that provides delivery of a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules or cartridges (e.g., made of gelatin) for use in an inhaler or insufflator may 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: the activity of a particular compound, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt thereof, can be validated by conventional treatment regimens.

Definition of the definition

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

"alkyl" refers to a saturated aliphatic hydrocarbon group including C ₁ -C ₂₀ Linear and branched groups. Preferably, alkyl is an alkyl (i.e., C) having 1 to 12 carbon atoms (e.g., including 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) _1-12 Alkyl). In some embodiments, it is sometimes preferred that the alkyl group is an alkyl group having 1 to 8 carbon atoms (i.e., C _1-8 Alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2, 2-diethylhexyl and branched isomers thereof. In some embodiments, and sometimes more preferably, the alkyl is a lower alkyl having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl), sometimes more preferably, lower alkyl having 1 to 4 carbon atoms (i.e., C _1-4 Alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-diMethylbutyl, 1, 2-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3 groups independently selected from halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

"alkenyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl, and the like, preferably C _2-20 Alkenyl groups, more preferably C _2-12 (e.g., comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) alkenyl groups, sometimes more preferably C _2-6 Alkenyl groups, sometimes even more preferably C _2-4 Alkenyl groups. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from halogen, alkoxy, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylalkylthio and oxo.

"alkynyl" means an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl, and the like, preferably C _2-20 Alkynyl, more preferably C _2-12 (e.g., including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) alkynyl groups, sometimes preferably C _2-6 Alkynyl, sometimes even more preferably C _2-4 Alkynyl groups. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more,sometimes 1 to 5, sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

"alkylene" refers to a saturated straight or branched divalent aliphatic hydrocarbon radical derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. The linear or branched groups contain from 1 to 20 carbon atoms, preferably from 1 to 12 (e.g., including 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms), and sometimes more preferably from 1 to 6 carbon atoms, and sometimes more preferably from 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ (-), 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-) and 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

"alkenylene" means an alkenyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, preferably C _2-20 Alkenylene, more preferably C _2-12 (e.g., comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) alkenylene, sometimes more preferably C _2-6 Alkenylene radicals, sometimes even more preferably C _2-4 Alkenylene radicals. Non-limiting examples of alkenylenes include, but are not limited to, -ch=ch-, -ch=chch ₂ -、-CH＝CHCH ₂ CH ₂ -and-CH ₂ CH＝CHCH ₂ -and the like. Alkenylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

"cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 (e.g., including 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms) (i.e., 3 to 20 membered cycloalkyl), more preferably 3 to 10 carbon atoms, sometimes more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), sometimes even more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include cycloalkyl groups having spiro, fused or bridged rings.

"spirocycloalkyl" refers to a 5-to 20-membered polycyclic group in which the rings are attached via a shared carbon atom, known as a spiro atom, wherein one or more of the rings may contain one or more double bonds. Preferably, the spirocycloalkyl groups are 6 to 14 membered (e.g., comprising 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), more preferably 7 to 10 membered (e.g., 7, 8, 9 and 10). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of shared spiro atoms, preferably a single spirocycloalkyl group or a double spirocycloalkyl group, more preferably a 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 single spirocycloalkyl group. Representative examples of spirocycloalkyl groups include, but are not limited to, the following groups:

"fused ring alkyl" refers to 5-to 20-membered polycyclic hydrocarbon groups wherein each ring in the system shares a pair of adjacent carbon atoms with the other ring, wherein one or more of the rings may contain one or more double bonds. Preferably, the fused ring alkyl groups are 6 to 14 membered (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, and 14 carbons), more preferably 7 to 10 membered (e.g., 7, 8, 9, and 10). The condensed ring alkyl group is classified into a double-, triple-, tetra-or polycyclic condensed ring alkyl group, preferably a double-or tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/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 double-cyclic condensed ring alkyl group, depending on the number of member rings. Representative examples of fused ring alkyl groups include, but are not limited to, the following groups:

"bridged cycloalkyl" means a 5 to 20 membered polycyclic hydrocarbon group wherein every two rings in the system share two unconnected carbon atoms. The ring may have one or more double bonds. Preferably, bridged cycloalkyl groups are 6 to 14 membered (e.g., comprising 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), more preferably 7 to 10 membered (e.g., 7, 8, 9 and 10). Bridged cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups, according to the number of member rings. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following groups:

cycloalkyl groups may also include those described above which are fused to a ring of aryl, heteroaryl or heterocyclyl groups, wherein the ring attached to the parent structure is cycloalkyl. Representative examples include, but are not limited to, indanyl, tetrahydronaphtalene, benzocycloheptyl, and the like. Cycloalkyl groups are optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylalkylthio and oxo.

"heterocyclyl" means a 3 to 20 membered saturated and/or partially unsaturated mono-or polycyclic group having one or more heteroatoms selected from N, O and S as ring atoms, wherein sulfur may optionally be oxidized to form S (=o) or S (=o) ₂ But does not include-O- -O-S-or-S-S-. Preferably, the heterocyclyl is 3 to 12 membered (i.e., 3 to 12 membered heterocyclyl) having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms, more preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, and 10) membered (i.e., 3 to 10 membered heterocyclyl) having 1 to 3 heteroatoms, more preferably 6 to 10 membered (i.e., 6 to 10 membered heterocyclyl) having 1 to 3 heteroatoms, and most preferably 5 to 6 membered (i.e., 5 to 6 membered heterocyclyl) having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include heterocyclic groups having spiro, fused or bridged rings.

"spiroheterocyclyl" means a 5-to 20-membered polycyclic heterocyclic group in which the rings are connected via a shared carbon atom (referred to as the spiro atom), wherein the rings have one or more heteroatoms selected from N, O and S as ring atoms, wherein sulfur can optionally be oxidized to form S (=o) or S (=o) ₂ But does not include-O- -O-S-or-S-S-, wherein one or more of the rings may contain one or more double bonds. Preferably, the spiroheterocyclyl is 6 to 14 membered (e.g., comprising 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), more preferably 7 to 10 (e.g., 7, 8, 9 and 10) membered. The spiro heterocyclic group is classified into a mono-, di-or multi-spiro heterocyclic group according to the number of shared spiro atoms, preferably a mono-or di-spiro heterocyclic group, more preferably a 3-or 5-membered, 3-or 6-membered, 4-or 4-membered, 4-or 5-membered, 4-or 6-membered, 5-or 6-membered mono-spiro heterocyclic group. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:

"fused heterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclyl wherein each ring in the system shares a pair of adjacent carbon atoms with the other rings, wherein one or more of the rings may contain one or more double bonds, wherein the ring has one or more heteroatoms selected from N, O and S as ring atoms, wherein sulfur may optionally oxidize to form S (=o) or S (=o) ₂ But does not include-O- -O-S-or-S-S-. Preferably, the fused heterocyclyl is 6 to 14 membered (e.g., comprising 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), more preferably 7 to 10 (e.g., 7, 8, 9 and 10) membered. The fused heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group according to the number of member rings, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/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 bicyclic fused heterocyclic group. Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups:

"bridged heterocyclyl" means a 5-to 14-membered polycyclic heterocyclyl wherein every two rings in the system share two unconnected atoms, a ring may have one or more double bonds, a ring having as ring atoms one or more heteroatoms selected from N, O and S, wherein sulfur may optionally oxidize to form S (=o) or S (=o) ₂ But does not include-O- -O-S-or-S-S-. Preferably, the bridged heterocyclyl is 6 to 14 membered (e.g., comprising 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), more preferably 7 to 10 (e.g., 7, 8, 9 and 10) membered. The bridged heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group according to the number of member rings, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

the heterocyclic ring includes the above heterocyclic ring fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic ring. Representative examples include, but are not limited to, the following groups:

etc.

The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

"aryl" refers to a 6 to 14 membered all-carbon monocyclic or multicyclic fused ring ("fused" ring system refers to each ring in the system sharing an adjacent pair of carbon atoms with the other ring in the system) group, and having a fully conjugated pi-electron system. Preferably, aryl is 6 to 10 membered (i.e., 6 to 10 membered aryl), such as phenyl and naphthyl, most preferably phenyl. Aryl includes the above aryl groups fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is aryl. Representative examples include, but are not limited to, the following groups:

aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

"heteroaryl" means an aryl system having 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from O, S and N as ring atoms, wherein sulfur can optionally be oxidized to form S (=o) or S (=o) ₂ But does not include-O-, -O-S-, or-S-, and has 5 to 14 (e.g., including 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms) ring atoms (i.e., a 5 to 14 membered heteroaryl). Preferably, the heteroaryl group is 5 to 10 membered (e.g., 5, 6, 7, 8, 9, and 10 membered) (i.e., 5 to 10 membered heteroaryl group), more preferably 5 or 6 membered (i.e., 5 to 6 membered heteroaryl group), such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl includes the aforementioned heteroaryl fused to a ring of aryl, heterocyclyl or cycloalkyl, wherein the ring attached to the parent structure is heteroaryl. Representative examples include, but are not limited to, the following groups:

heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio. "alkoxy" refers to an-O- (alkyl) group wherein alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio and heterocyclylalkylthio.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above include a monovalent residue derived by removing one hydrogen atom from a parent ring atom, or a divalent residue derived by removing two hydrogen atoms from the same or different ring atoms on a parent ring, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

"bond" refers to a covalent bond using the label "-".

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

"deuteroalkyl" or "deuteroalkyl" refers to an alkyl substituted with one or more deuterium atoms, where alkyl is as defined above.

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

"hydroxy" refers to an-OH group.

"mercapto" refers to the-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.

"Cycloalkyloxy" means a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

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

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

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

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

"amino" means-NH ₂ A group.

"cyano" refers to a-CN group.

"nitro" means-NO ₂ A group.

"oxo" refers to an =o group.

"carboxyl" refers to a-C (=o) OH group.

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

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to isomers having the same structure but different atomic spatial arrangements. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., mixtures of racemates and diastereomers). Substituents in compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral syntheses, chiral reagents or other conventional techniques. Isomers of the compounds of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when the molecule contains a basic functionality (e.g., amino) or an acidic functionality (e.g., carboxyl), form diastereomeric salts with an appropriate optically active acid or base, and then undergo diastereoisomeric resolution by conventional methods known in the art to give the pure isomer. In addition, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondRepresenting an unspecified configurationI.e. bond +.if chiral isomers are present in the chemical structure>Can be +.>Or at the same time contain-> Configuration. The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomer to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of tautomers in any proportions. Non-limiting examples include keto-enols, imine-enamines, lactam-lactams, and the like. The lactam-lactam balance is exemplified below:

for example pyrazolyl, is understood to include either of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the name of the compound does not exclude any tautomer.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclyl" means that an alkyl group may be present but is not required to be present, and the description includes the case where the heterocyclyl group is substituted with an alkyl group and the heterocyclyl group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. Those skilled in the art can determine whether a substitution is possible or not through experimentation or theory without undue effort. For example, an amino group or hydroxyl group having free hydrogen in combination with a carbon atom having an unsaturated bond (e.g., olefinic) may be unstable.

"pharmaceutical composition" refers to a mixture of one or more compounds described in this disclosure, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components (e.g., physiologically/pharmaceutically acceptable carriers and excipients). The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism, which aids in the absorption of the active ingredient and thus shows biological activity.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective when used in a mammal, and which has a corresponding biological activity.

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

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen disulfide) and organic acids (e.g., p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartrate, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid) and related inorganic and organic acids.

"prodrug" refers to a compound that can be converted in vivo under physiological conditions, for example by hydrolysis in blood, to yield the active parent compound.

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 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 ingredient sufficient to exhibit a meaningful patient benefit (e.g., sustained reduction in viral load). When applied to a single active ingredient administered alone, the term refers to the individual ingredient. When applied to a combination, the term refers to the combined amounts of the active ingredients (whether administered in combination, serially or simultaneously) that bring about a therapeutic effect.

The terms "treatment", "treatment" and the like refer to: (i) Inhibiting the disease, disorder or condition, i.e., arresting its development; and (ii) alleviating the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. Furthermore, the compounds of the present disclosure may be used for their prophylactic effect to prevent the occurrence of a disease, disorder, or condition in a subject who may be susceptible to the disease, disorder, and/or condition but who has not yet been diagnosed with the disease, disorder, and/or condition.

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

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

When the term "about" is applied to a parameter (e.g., pH, concentration, temperature, etc.), it means that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As one skilled in the art will appreciate, where parameters are not critical, values are generally given for illustration purposes only and are not 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. The unnatural proportion of isotopes can be defined as the amount found in nature to an amount consisting of 100% of the relevant atoms. For example, the compounds may incorporate radioactive isotopes, such as tritium @, for example ³ H) 125% of iodine ¹²⁵ I) Or carbon 14% ¹⁴ C) Or non-radioactive isotopes, such as deuterium (D) or carbon 13 #, for example ¹³ C) A. The application relates to a method for producing a fibre-reinforced plastic composite Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present disclosure can find additional uses, including, but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radioactive toxic therapeutic agents.

In the compounds of the present disclosure, any atom not specifically designated as a particular isotope refers to any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen according to its natural abundance isotopic composition. Also, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," that position is understood to mean that the abundance of deuterium is at least 3000 times greater than the natural abundance of deuterium (i.e., 0.015%), i.e., at least 45% deuterium incorporation. Exemplary compounds have a deuterium abundance that is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater than the natural abundance of deuterium (i.e., at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 66% deuterium incorporation), at least 6600% greater than the natural abundance of deuterium (i.e., at least 66% deuterium incorporation).

Synthesis method

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

scheme 1

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

removing R of a compound of formula (IA) or a salt thereof under acidic conditions ^t To obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

Scheme 2

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

removing R of a compound of formula (IIA) or a salt thereof under acidic conditions ^t To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

Scheme 3

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

removing R of the compound of formula (II-1A) or a salt thereof under acidic conditions ^t To obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

Wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

X ² is hydrogen;

Scheme 4

A process for the preparation of a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of the compound of formula (IIIA) or a salt thereof under acidic conditions ^t Obtaining a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

Scheme 5

A process for the preparation of a compound of formula (III-1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing R of a compound of formula (III-1A) or a salt thereof under acidic conditions ^t To obtain a compound of formula (IIII-1) or a pharmaceutically acceptable salt thereof,

wherein:

R ^t is alkyl; preferably, R ^t Is C _1-6 An alkyl group;

Scheme 6

under basic conditions, a compound of formula (IB) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Wherein:

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

X ¹ is-L-R ⁰ ；

Scheme 7

under basic conditions, a compound of formula (IIB) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

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

X ¹ is-L-R ⁰ ；

Scheme 8

/>

under alkaline conditions, a compound of formula (II-1B) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

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

X ¹ is-L-R ⁰ ；

Scheme 9

a compound of formula (IIIB) or a salt thereof and R under basic conditions ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof,

Wherein:

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

Scheme 10

under basic conditions, a compound of formula (III-1B) or a salt thereof and R ⁰ -L-R ^w Reacting the compound to obtain a compound of formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

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

Reagents that provide acidic conditions in the above synthetic schemes include, but are not limited to, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, and nitric acid, with acetic acid or trifluoroacetic acid being preferred.

Reagents that provide basic conditions in the above synthetic schemes include organic bases and inorganic bases. The organic base includes, but is not limited to, triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide or potassium tert-butoxide; 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; sodium hydroxide is preferred.

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

Examples

The following examples are illustrative of the invention but should not be construed as limiting the scope of the invention. In the embodiment of the invention, unless specific conditions of an experimental method are noted, the experimental method is generally performed according to conventional conditions or recommended conditions of raw materials and product manufacturers. Reagents not specifically identified are commercially available conventional reagents.

The structure of each compound was identified by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR chemical shift (delta) of 10 ^-6 (ppm) is given. NMR was measured by Bruker AVANCE-300, AVANCE-400 or AVANCE-500 instruments. The solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) ₃ ) And deuterated methanol (CD) ₃ OD)。

High Performance Liquid Chromatography (HPLC) was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18×4.6mm column), waters 2695-2996 high pressure liquid chromatograph (Gimini C18×4.6mm column), or Shimadzu UFLC equipped with Xbridge C18 (5 um 150×4.6 mm) column.

Chiral High Performance Liquid Chromatography (HPLC) was performed on LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.) or Waters-UPC2 instruments.

MS was equipped with ACQUITY by SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: shimadzu, type: LC-20AD, LCMS-2020)The Waters UPLC-QDa of BEH (2.1 x 50mm 1.7 μm) column, or the Agilent Agilent6120 assay of Xbridge C18 (5 um 50 x 4.6 mm) column.

The thin-layer silica gel plate used in the thin-layer chromatography is a tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. The plate size used in TLC was 0.15mm to 0.2mm and the plate size used in thin layer chromatography for product purification was 0.4mm to 0.5mm.

Column chromatography generally adopts 200-300 mesh silica gel of yellow sea as carrier.

The starting materials known in the invention can be prepared according to a conventional synthesis method in the prior art, and can also be purchased from ABCR GmbH & Co.KG, acros Organics, aldrich chemical company, shaoshima far technology Co., ltd, darui chemical, fisher Scientific or Shanghai Jabo biotechnology Co., ltd.

In the examples, unless otherwise indicated, the following reactions were placed under an argon atmosphere or a nitrogen atmosphere.

The term "argon atmosphere" or "nitrogen atmosphere" means that the reaction flask is equipped with 1L of argon or nitrogen balloon.

In the examples, unless otherwise indicated, the solutions used in the following reactions all refer to aqueous solutions.

In the examples, unless otherwise indicated, the reaction temperatures in the following reactions were all room temperature.

Unless otherwise indicated, the reaction temperature in the reaction refers to room temperature, which ranges from 20 ℃ to 30 ℃.

The reaction process was monitored by LC-MS or Thin Layer Chromatography (TLC), and developing the solvent system included: a: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound. The elution system for purifying compounds by column chromatography, thin layer chromatography and combiflastflash rapid prep comprises: a: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvent may be adjusted according to the polarity of the compound, and a small amount of an alkaline agent such as ammonia or an acidic agent such as acetic acid may be added in some cases.

The final compounds were purified by Shimadzu (LC-20 AD, SPD 20A) preparative HPLC (Phenomenex Gemini-NX 5. Mu. M C18.21.2X100 mm column), waters2767 equipped with Sunfire Pre C18 (10. Mu.m19mm) column or Waters2767-QDa instrument equipped with Xbridge Pre C18 (10. Mu.m19mm) column, using water/MeOH or water/CH ₃ CN elution systems and optional additives, e.g. HCOOH, TFA, NH ₄ HCO ₃ 。

CombiFlash is performed on a Teledyne ISCO or Agela Technologies system.

The following abbreviations are used in the present application:

DIPEA is N, N-diisopropylethylamine,

HATU was 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate,

the DCM was taken to be dichloromethane,

DMF is N, N-dimethylformamide,

the DMSO is dimethyl sulfoxide (DMSO),

the EtOAc was ethyl acetate and the water was added to the solution,

the TBAI is tetrabutylammonium iodide and the TBAI is a tetrabutylammonium iodide,

the TFA is a trifluoroacetic acid and,

prep HPLC is preparative high performance liquid chromatography,

the NMR is proton nuclear magnetic resonance,

MS is mass spectrometry, where (+) refers to the positive mode, typically giving m+1 (or m+h) absorption, where m=molecular mass.

Experimental procedure

Intermediate 1 (Int-1)

(S) -3- (4-cyclopropyl-2, 5-dioxo-imidazolin-4-yl) propionic acid intermediate 1 (Int-1)

Step 14-cyclopropyl-4-oxobutanoic acid tert-butyl ester Int-1-2

A solution of LDA (15.28 g,142.66mmol,71.43 mL) in THF (50 mL) was cooled to-78deg.C and then a solution of cyclopropylmethylketone Int-1-1 (10 g,118.88 mmol) in THF (10 mL) was added dropwise. The resulting solution was warmed to 20 ℃ and stirred for 30 minutes. The reaction mixture was then re-cooled to-78 ℃ and a solution of tert-butyl 2-bromoacetate (23.19 g,118.88 mmol) in THF (10 mL) was slowly added. The reaction was stirred at room temperature overnight. After completion of the reaction, saturated NH was used ₄ The reaction was quenched with Cl (50 mL, aq), the mixture extracted with EtOAc (50 mL. Times.3), the organic phase washed with brine (100 mL) and dried over Na ₂ SO ₄ Drying and concentration gave the crude title compound Int-1-2 (22 g,110.97mmol,93.34% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ2.83(t,2H),2.50(t,2H),1.97-1.92(m,1H),1.45(s,9H),1.06-1.01(m,2H),0.91-0.86(m,2H)。

Step 2

(±) -3- (4-cyclopropyl-2, 5-dioxoimidazolin-4-yl) propionic acid tert-butyl ester Int-1-3

A mixture of Int-1-2 (8.2 g,41.36 mmol), ammonium carbonate (33.78 g,351.56 mmol), sodium cyanide (5.07 g,103.40 mmol), etOH (50 mL) and water (50 mL) was sealed and heated to 80℃for 18 hours. The reaction mixture was cooled and poured into a mixture of EtOAc (100 mL) and water (100 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (100 ml×3). The organic solutions were combined and washed with brine, over Na ₂ SO ₄ Drying and concentrating. The residue was purified by silica gel chromatography (EtOAc/hexane=1/2) to give the title compound Int-1-3 (5.7 g,21.24mmol,51.36% yield).

¹ H NMR(400MHz,DMSO-d6):δ10.61(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-dioxo-imidazolin-4-yl) propionic 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 4 hours and concentrated. The resulting solid was triturated in MeCN (30 mL) for 1 hour and filtered to give the pure racemic target product Int-1-4 as a white solid. SFC (using chiral column CHIRALPAK AD-H10 μm2.5 x 25cm; flow rate/detection: 70 g/min; detector wavelength: 214nm; mobile phase A: supercritical CO) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Mobile phase B: methanol) to give the title compound Int-1 (2 g,9.42mmol,35.12% yield).

¹ H NMR(400MHz,DMSO-d6):δ12.20(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 minutes.

LCMS：MS m/z(ESI)：213.1[M+1]。

Example 1

(S) -5- (3- (5-chloro-6- (trifluoromethyl) isoindolin-2-yl) -3-oxopropyl) -5-cyclopropylimidazoline-2, 4-dione 1

Step 15-amino-2-bromo-4- (trifluoromethyl) benzoic acid 1b

To a solution of 3-amino-4- (trifluoromethyl) benzoic acid 1a (1 g,4.87 mmol) in DMF (20 mL) was added NBS (87mg, 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 phases were washed with water (20 mL), brine (20 mL), and dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated to give crude 1b (1 g,3.52mmol,72.22% yield).

Step 25-amino-2-bromo-4- (trifluoromethyl) benzoic acid methyl ester 1c

To a solution of 1b (1 g,3.52 mmol) in MeOH (10 mL) was added dropwise H ₂ SO ₄ (18M, 0.7 mL). After stirring the mixture at 75 ℃ overnight, the mixture was cooled to room temperature and poured into ice water (20 mL) and the mixture was extracted with EtOAc (50 mL). The organic fraction was treated with Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated to give crude 1c (1 g,3.36mmol,95.29% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.57(s,1H),7.21(s,1H),6.11(brs,2H),3.85(s,3H)。

Step 35-amino-2-methyl-4- (trifluoromethyl) benzoic acid methyl ester 1d

To a solution of 1c (1 g,3.36 mmol) in DMF (10 mL) was added Pd (PPh) ₃ ) ₄ (430mg,372.11umol)、K ₃ PO ₄ (2.2 g,10.36 mmol) and methylboronic acid (1 g,16.71 mmol). The mixture is put under N ₂ After stirring overnight at 130 ℃ under an atmosphere, the mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography to give 1d (500 mg,2.14mmol,63.91% yield).

LCMS：MS m/z(ESI)：234.1[M+H] ⁺ 。

Step 45-chloro-2-methyl-4- (trifluoromethyl) benzoic acid methyl ester 1e

Concentrated HCl (2 mL) was added to 1d (2.0 g,8.58 mmol) in acetone (20 mL)In solution, and the mixture was stirred at room temperature for 20 minutes. Cooling the mixture to-5-0deg.C, and dripping NaNO ₂ (600 mg,8.70 mmol) in H ₂ A solution in O (2.5 mL) and the mixture was stirred at ambient temperature for 30 min. CuCl (849.11 mg,8.58 mmol) was added in portions at 0deg.C and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into 1N HCl (50 mL) and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 1e (1.3 g,5.15mmol,60.00% yield).

Step 52-bromo-5-chloro-4- (trifluoromethyl) benzoic acid methyl ester 1f

To 1e (1.3 g,5.15 mmol) in CCl ₄ To a solution in (20 mL) was added NBS (1.10 g,6.18 mmol) and AIBN (25.35 mg, 154.38. Mu. Mol), and the mixture was heated to 70℃and stirred overnight. The mixture was cooled to room temperature and filtered, and CCl was used ₄ The filter cake was washed and the filtrate concentrated in vacuo to give crude 1f (1.9 g,5.73mmol,111.37% yield).

Step 66-chloro-5- (trifluoromethyl) isoindolin-1-one 1g

To a solution of 1f (1.9 g,5.73 mmol) in MeOH (10 mL) was added NH ₃ MeOH (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (hexane: etoac=1:1) to give 1g (920 mg,3.91mmol,68.14% yield).

LCMS：MS m/z(ESI)：236.0[M+H] ⁺ 。

Step 75-chloro-6- (trifluoromethyl) isoindoline 1h

To a solution of 1g (570 mg,2.42 mmol) in THF (5 mL) was added BH ₃ THF (167.36 mg,12.10mmol,15 mL) and the mixture was stirred overnight at 60 ℃. The reaction was cooled to room temperature and quenched with methanol. The mixture was adjusted to pH 1-2 with 1M HCl. The mixture was then heated to 45 ℃ and stirred for 30 minutes. After cooling to room temperature, the mixture was adjusted to pH 7-8 with 1M NaOH. Water was added and the mixture extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. Residue (C)Purification of the residue by preparative TLC (DCM: meoh=10:1) gave 1h (10 mg,45.13 μmol,1.87% yield).

¹ HNMR(400MHz,DMSO-d6):δ7.78(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

To a solution of 1h (10 mg, 45.12. Mu. Mol) in DMF (2 mL) were added TEA (50 uL), int-1 (10 mg, 47.12. Mu. Mol) and HATU (17.16 mg, 45.12. Mu. Mol). The reaction mixture was stirred at room temperature for 3 hours. Water was added and the mixture extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 1 (5 mg,12.03 μmol,26.65% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.63(s,1H),7.90(s,1H),7.76(s,1H),7.75(s,1H),4.85(d,2H),4.67(d,2H),2.46-2.22(m,2H),2.03-1.98(m,2H),1.15-1.08(m,1H),0.49-0.31(m,3H),0.15-0.08(m,1H)。

¹⁹ F NMR(376.5MHz,DMSO-d ₆ ):δ-60.86。

LCMS：MS m/z(ESI)：416.4[M+H] ⁺ 。

Example 2

(5S) -5- (3- (5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -5-cyclopropylimidazoline-2, 4-dione 2 (diastereomeric mixture)

/>

Step 15-amino-4- (trifluoromethyl) -2-vinylbenzoic acid methyl ester 2b

To a solution of 1c (5.45 g,18.29 mmol) and potassium vinyltrifluoroborate (2.45 g,18.29 mmol) in dioxane (50 mL) and water (10 mL) was added Pd (dppf) Cl ₂ (1.34 g,1.83 mmol) and K ₂ CO ₃ (6.35 g,45.71 mmol). The resulting mixture was evacuated and N was used ₂ Refilling 3 times. The resulting mixture was stirred at 80℃for 16 hours. The mixture was diluted with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound 2b (3.56 g,14.52mmol,79.40% yield).

LCMS：MS m/z(ESI)：246.1[M+H] ⁺ 。

Step 25-amino-2-ethyl-4- (trifluoromethyl) benzoic acid methyl ester 2c

To a solution of 2b (3.56 g,14.52 mmol) in MeOH (20 mL) was added Pd/C (1.55 g,1.45mmol, 285.48. Mu.L, 10% purity). The resulting mixture was evacuated and H was used ₂ And (5) refilling. The resulting mixture was stirred at room temperature for 16 hours and LCMS indicated the reaction was complete. The mixture was filtered, the filter cake washed with MeOH and the filtrate concentrated under reduced pressure to give the title compound 2c (3.45 g,13.96mmol,96.12% yield).

LCMS：MS m/z(ESI)：248.1[M+H] ⁺ 。

Step 35-chloro-2-ethyl-4- (trifluoromethyl) benzoic acid methyl ester 2d

To a solution of 2c (3.36 g,13.59 mmol) in acetone (34 mL) was added HCl (3.36 mL). The resulting mixture was stirred at room temperature for 20 minutes. After cooling the mixture to 0deg.C, naNO was added ₂ (1.88 g,27.18 mmol) in water (5 mL). CuCl (1.48 g,14.95 mmol) was then added in small portions at 0deg.C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into 1M HCl (60 mL), the aqueous phase was extracted with EtOAc (100 mL. Times.3), the combined organic phases were washed with brine (100 mL) and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with hexane/etoac=50/1) to give the title compound 2d (2.23 g,8.36mmol,61.53% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.99(s,1H),7.87(s,1H),3.88(s,3H),2.92(q,2H),1.17(t,3H)。

Step 4

(±) -2- (1-bromoethyl) -5-chloro-4- (trifluoromethyl) benzoic acid methyl ester 2e

To 2d (2.23 g,8.36 mmol) at CCl ₄ AIBN (412.00 mg,2.51 mmol) and NBS (1.64 g,9.20 mmol) were added to the solution in (35 mL). The resulting mixture was stirred at 80℃for 16 hours. The mixture was filtered. The solid was washed with DCM and the filtrate concentrated in vacuo to give the crude title compound 2e (2.5 g,7.24mmol,86.51% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.17(s,1H),8.04(s,1H),6.08(q,1H),3.92(s,3H),2.05(d,3H)。

Step 5

(±) -6-chloro-3-methyl-5- (trifluoromethyl) isoindolin-1-one 2f

To a solution of 2e (2.5 g,7.24 mmol) in MeOH (10 mL) was added NH ₃ MeOH (7M, 30 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound 2f (1.18 g,4.73mmol,65.34% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.11(brs,1H),8.20(s,1H),7.91(s,1H),4.71(q,1H),1.42(d,3H)。

¹⁹ F NMR(376.5MHz,DMSO-d ₆ ):δ-60.99。

LCMS：MS m/z(ESI)：250.0[M+H] ⁺ 。

Step 6

(±) -5-chloro-1-methyl-6- (trifluoromethyl) isoindoline-3, 3-d ₂ 2g

BD was added to a solution of 6-chloro-3-methyl-5- (trifluoromethyl) isoindolin-1-one 2f (800 mg,3.20 mmol) in THF (10 ml) ₃ (1M in THF, 64ml,64 mmol). After addition, the reaction was stirred at 60 ℃ (in a sealed tube) for 10 hours. It was quenched with MeOH (10 ml) followed by HCl (6M, 20 mL). Then it was stirred at 80℃for 8 hours. 2N NaOH was added to adjust pH to 7 and extracted with EtOAc, and the combined organic phases were washed with brine (50 mL) over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography eluting with 5% MeOH in DCM to give 2g of the desired product, which was used in the next step.

LCMS：MS m/z(ESI)：238.1[M+H] ⁺ 。

Step 7

To a solution of (S) -3- (4-cyclopropyl-2, 5-dioxo-imidazolin-4-yl) propionic 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, 2g of isoindoline collected from the previous step was added. The reaction was stirred at ambient temperature for 3 hours. LCMS showed the reaction was complete. This was purified directly on reverse phase HPLC to give the desired product 2 (1.10 g, 76.9% yield in two steps).

¹ H NMR(400MHz,CD ₃ OD,):7.76(s,1H),7.63-7.60(m,1H),5.57-5.53(m,1H),2.59-2.40(m,2H),2.28-2.19(m,2H),1.56-1.50(m,3H),1.28-1.21(m,1H),0.62-0.58(m,1H),0.49-0.41(m,3H)。

LCMS:MS m/z(ESI):432[M+H] ⁺ 。

Examples 2-1 and 2-2

(S) -5- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -5-cyclopropylimidazoline-2, 4-dione 2-1

(S) -5- (3- ((S) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -5-cyclopropylimidazoline-2, 4-dione 2-2

Separation of 2 (1.10 g) by SFC gave two diastereomers, 2-1 (325 mg,29.5% yield) and 2-2 (418 mg,37.7% yield).

Compound 2-1:

¹ H NMR(500MHz,DMSO-d ₆ )δ10.63(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 ethanol/hexane 60/40,1.0mL/min,35 ℃, CHIRALPAK IG,150 x 4.6mm,5 um) Rt:4.594 minutes, de:100%.

Compound 2-2:

¹ H NMR(500MHz,DMSO-d ₆ )δ10.53(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 ethanol/hexane 60/40,1.0mL/min,35 ℃, CHIRALPAK IG,150 x 4.6mm,5 um) Rt:10.931 minutes, de:100%.

Example 3

(S) - (4- (3- (5-chloro-6- (trifluoromethyl) isoindolin-2-yl) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxo-imidazolin-1-yl) methyl pivalate 3

To a solution of (S) -5- (3- (5-chloro-6- (trifluoromethyl) isoindolin-2-yl) -3-oxopropyl) -5-cyclopropylimidazoline-2, 4-dione 1 in DMF (5 mL) was added 1N aqueous NaOH (0.3 mL) at 0deg.C. After stirring at this temperature for 10 minutes, chloromethyl pivalate (48 mg,0.32 mmol) was added. The reaction was slowly warmed to ambient temperature and stirred for 12 hours. It was applied directly to reverse phase prep HPLC using 10-60% CH ₃ CN/H ₂ O was used as eluent to give the desired product 3 (75 mg,88.6% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ7.78(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

((S) -4- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxoimidazolin-1-yl) methyl pivalate 4

To a solution of compound 2-1 (120 mg,0.28 mmol) in DMF (10 mL) was added 1N aqueous NaOH (0.6 mL) at 0deg.C. After stirring for 10 minutes, chloromethyl pivalate (168 mg,1.12 mmol) was added. The reaction was slowly warmed to ambient temperature and stirred for 12 hours. Purification on reverse phase prep HPLC using 10-60% CH ₃ CN and H ₂ O was used as eluent to give the desired product 4 (40 mg,26.2% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ7.76(s,1H),7.60(s,1H),5.50(m,2H),5.32(m,1H),2.48-2.13(m,4H),1.55(s,3H),1.21(s,9H),1.30(m,1H),0.62(m,1H),0.42(m,2H),0.32(m,1H)。

LCMS:m/z(ESI):546.1[M+H] ⁺ 。

Example 5

(S) - (4- (3- (5-chloro-6- (trifluoromethyl) isoindolin-2-yl) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxo-imidazolin-1-yl) methylphosphonic acid dihydro ester 5

Step 1

(S) -di-tert-butyl ((4- (3- (5-chloro-6- (trifluoromethyl) isoindolin-2-yl) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxoimidazolin) -1-yl) methyl) phosphate 5a

To a suspension of 1 (166 mg,0.40 mmol) in THF (1 mL) was added 0.2N aqueous NaOH (2.0 mL). The reaction mixture became clear and stirred at room temperature for 10 minutes. Vacuum removal of solvent. DMF (2 mL) and K were then added ₂ CO ₃ (94 mg,0.68 mmol) followed by di-tert-butyl (chloromethyl) phosphate (0.14 mL,0.54 mmol). The reaction mixture was stirred at 45 ℃ for 16 hours. LC-MS showed a conversion of about 70%. EtOAc (100 mL) was added and the organic phase was washed with brine (40 mL). The organic solvent is treated by anhydrous Na ₂ SO ₄ Drying and purification by silica gel chromatography eluting with hexane/EtOAc afforded crude product 5a, which was used directly in the next step.

LCMS:m/z(ESI):638.2[M+H] ⁺ 。

Step 2

To crude compound 5a (0.40 mmol, from the previous step) was added AcOH/H ₂ Mixtures of O (0.60/0.15 mL). The mixture was heated at 60℃for 1.5 hours. Then at 0deg.C with 2N Na ₂ CO ₃ The reaction mixture was carefully neutralized to ph=7.0 with aqueous solution. The resulting mixture was purified by preparative HPLC using 10-30% CH ₃ CN and H ₂ O and 0.5% NH ₄ HCO ₃ As an eluent, the desired product 5 (53 mg,25.2% two-step yield) was obtained after lyophilization.

¹ H NMR(400MHz,Methanol-d ₄ ):δ7.70(d,1H),7.54(d,1H),5.18(d,1H),5.11(t,1H),4.83(d,2H),4.68(d,2H),2.45–2.32(m,2H),2.28–2.04(m,2H),1.24–1.12(m,1H),0.48(dt,1H),0.39–0.16(m,3H)。

³¹ P NMR(400MHz,CD ₃ OD):δ-0.50。

¹⁹ F NMR(376.5MHz,CD ₃ OD):δ-63.6。

LCMS:m/z(ESI):526.1[M+H] ⁺ 。

Example 6

((S) -4- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxoimidazolin-1-yl) methylphosphonic acid dihydro ester 6

Step 1

(S) -5- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -5-cyclopropyl

-3- ((methylthio) methyl) imidazoline-2, 4-dione 6a

To a solution of compound 2-1 (500 mg,1.02 mmol) in DMF (12 mL) was added NaOH (82 mg,2.04 mmol) and TBAI (754 mg,2.04 mmol) at 0deg.C. After addition, it was warmed to ambient temperature and stirred for 30 minutes. (chloromethyl) (methyl) sulfane (390 mg,4.08 mmol) was then added. The reaction was stirred at ambient temperature for 1 hour and worked up with water and ethyl acetate (40+120 mL). The organic layer was collected and purified by silica gel chromatography with 75% EtOAc/CH ₂ Cl ₂ Elution gave the desired product 6a (250 mg,71.0% yield).

LCMS:m/z(ESI):492.1[M+H] ⁺ 。

Step 2

(S) -5- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -3- (chloromethyl) -5-cyclopropylimidazoline-2, 4-dione 6b

6a (250 mg,0.51 mmol) in CH ₂ Cl ₂ To a solution in (20 mL) was added triethylamine hydrochloride (210 mg,1.53 mmol) followed by sulfonyl chloride (1N CH) ₂ Cl ₂ Solution, 0.77ml,0.77 mmol). After addition, the reaction mixture was stirred at ambient temperature for 2 hours. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the resulting crude mixture 6b was used directly in the next step.

LCMS:m/z(ESI):480.1[M+H] ⁺ 。

Step 3

Di-tert-butyl (((S) -4- (3- ((R) -5-chloro-1-methyl-6- (trifluoromethyl) isoindolin-2-yl-3, 3-d) ₂ ) -3-oxopropyl) -4-cyclopropyl-2, 5-dioxoimidazolin-1-yl) methyl phosphate 6c

To a solution of 6b (0.51 mmol, from the previous step) in acetonitrile (20 mL) was added the potassium di-tert-butyl phosphate salt (228 mg,0.92 mmol), followed by the addition ofNaHCO ₃ (10 mg,0.1 mmol). After addition, the reaction was stirred at 75 ℃ for 12 hours. LC-MS showed the reaction was complete. It was concentrated in vacuo and purified by silica gel chromatography with 90% EtOAc/CH ₂ Cl ₂ Elution gave the desired product 6c (301 mg,90% two steps).

¹ H NMR(400MHz,CD ₃ OD):δ7.75(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

6c (255 mg,0.41 mmol) in CH ₃ The solution in the CN/water/tfa=2/2/1 (50 mL) mixture was stirred at ambient temperature for 16 hours. LC-MS showed the reaction was complete. It was applied directly to reverse phase prep HPLC using 10-30% CH ₃ CN and H ₂ O and 0.5% NH ₄ HCO ₃ As eluent, lyophilization afforded the desired product 6 (221 mg,99.5% yield).

¹ H NMR(400MHz,CD ₃ OD):δ7.72(s,1H),7.69(s,1H),5.32-5.28(m,2H),5.24-5.20(m,1H),2.56-2.43(m,2H),2.28-2.24(m,2H),1.53(s,3H),1.30-1.27(m,1H),0.58-0.55(m,1H),0.46-0.36(m,3H)。

³¹ P NMR(400MHz,CD ₃ OD):δ-1.5。

¹⁹ F NMR(376.5MHz,CD ₃ OD):δ-63.6。

LCMS:m/z(ESI):542.1[M+H] ⁺ 。

Biological testing

The present disclosure will be further described in connection with the following test examples, which should not be construed as limiting the scope of the present disclosure.

Test example 1 in vitro fluorescence of ADAMTS-4 or ADAMTS-5 ActivityLight testing

Fluorescence Resonance Energy Transfer (FRET) peptides are cleaved by recombinant ADAMTS-4 or ADAMTS-5 proteins into two separate fragments, resulting in an increase in quantifiable fluorescence signal. The peptide was 5-FAM-TEGEARGSVILLK (5-TAMRA) K-NH2, custom made from ANASPEC. ADAMTS-4 recombinant proteins (catalog number 4307-AD) and ADAMTS-5 recombinant proteins (catalog number 2198-AD) were purchased from R & D Systems.

Preparation of a solution containing 50mM HEPES pH 7.5, 100mM NaCl, 5mM CaCl ₂ Assay buffer of 0.1% CHAPS and 5% glycerol. A volume of 2.5. Mu.L of the compound in the assay buffer was dispensed into 384-well plates, and 2.5. Mu.L of ADAMTS-4 or ADAMTS-5 protein (final concentration in the reaction: 10 nM) was added. The compounds and proteins were pre-incubated for 15 minutes at room temperature. Then, 5. Mu.L of substrate was added to each well. The final substrate concentrations for ADAMTS-4 and ADAMTS-5 were 15. Mu.M and 8. Mu.M, respectively. After incubation for 3 hours at 37℃the fluorescent signal in each well was determined on a TECAN reader (excitation, 490nm; emission, 520 nm).

Data analysis:

data were input into GraphPad Prism and IC was calculated using the function "log (inhibitor) versus effect-Variable slope (four parameters) (log (inhibitor) vs. response-Variable slope (four parameters))" ₅₀ Values. (see Table 1)

TABLE 1 IC of exemplary Compounds in FRET-peptidase assays ₅₀ Value of

Conclusion: the parent compounds 1 and 2-1 of the present disclosure have significant inhibitory effects on the enzymatic activities of ADAMTS-4 and ADAMTS-5. Their prodrug molecules 3, 4, 5 and 6 do not have any enzymatic activity towards ADAMTS-4 and ADAMTS-5.

Test example 2 in vitro ELISA (enzyme Linked immunosorbent assay) for ADAMTS-5 Activity

In this assay, the enzymatic activity of recombinant ADAMTS-5 protein (catalog number 2198-AD, R & D Systems) was measured with a protein substrate (aggrecan IGD protein). An aggrecan IGD protein is a polypeptide that links human aggrecan globular domains 1 and 2 (T331-G458) expressed in e.coli (e.coli) to the C-terminal His tag (catalogue number 3011000, biotez). The enzymatic product ARGSVIL-peptide was detected using ELISA kit (catalog number 30510111) from BioTEZ.

Preparation of a solution containing 50mM HEPES pH 7.5, 100mM NaCl, 5mM CaCl ₂ Assay buffer of 0.1% CHAPS and 5% glycerol. Recombinant ADAMTS-5 proteins were diluted to 0.3nM in assay buffer. mu.L of buffer and 10. Mu.L of compound solution were transferred to each well of a 96-well plate and incubated for 15 minutes at room temperature. The substrate aggrecan-IGD was diluted to 100nM with assay buffer and 20. Mu.L was added to each well. Plates were incubated at 37℃for 45 min. After incubation, the newly generated epitope ARGSVIL-peptide was measured using an aggrecanase activity ELISA detection kit (Aggrecanase Activity ELISAAssay Kit) according to the manufacturer's instructions. Then, 100 μl of stop solution was added, and the absorbance of each well was read at 450nM on a TECAN reader, using 620nM as a reference.

Data analysis:

standard curves for ELISA assays were generated in GraphPad Prism using Sigmoidal 4PL function, and the corresponding peptide concentrations were calculated based on the standard curves. Calculation of IC using the function "log (inhibitor) versus effect-variable slope (four parameters)" ₅₀ Values. (see Table 2).

TABLE 2 IC of exemplary Compounds in the aggrecan-IGD enzyme assay ₅₀ Value of

Examples numbering	ADAMTS-5(IC ₅₀ ，nM)
		1	92
2-1	13

Conclusion: the parent compounds 1 and 2-1 of the present disclosure have significant inhibitory effects on the enzymatic activity of ADAMTS-5.

Test example 3 Fassif solubility test of the Compounds of the present disclosure

3.1 preparation of reference solution

An appropriate amount of the test compound was weighed and dissolved in DMSO to obtain a 10mM stock solution. 10. Mu.L of stock solution and 990. Mu.L of organic solvent (DMSO: acetonitrile: ethanol=1:1:1 (v/v/v) mixture) were precisely measured into 2mL vials and thoroughly mixed. The clarified 100. Mu.M sample solution was used as a reference solution.

3.2 preparation of test Compound Fassif solution

1mg of the test sample was dissolved in 900. Mu.L of FaSSIF solution and mixed vigorously. Two such solutions were prepared in parallel and shaken in a 37 ℃ water bath for 24 hours. The solution was then centrifuged at 4000rpm for 30 minutes and the supernatant was transferred to HPLC for analysis.

3.3. Data processing

Solubility (μm) =sample peak area/reference peak area reference concentration (μm) sample solution dilution. The average of the two measurements was taken as the final solubility (see table 3).

TABLE 3 solubility test of compounds of the present disclosure

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

Test example 4 pharmacokinetic assay

Instrument for measuring and controlling the intensity of light

API4000 triple quadrupole tandem mass spectrometer, applied Biosystems, usa;

shimadzu LC-30AD ultra high performance liquid chromatography system, shimadzu, japan.

Chromatographic conditions:

chromatographic column: welch Xtime C18.8 μm 30×2.1mm

Mobile phase a:0.5% formic acid, 5mM ammonium acetate aqueous solution (gradient elution)

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

Column temperature: 35 DEG C

Preparation of test samples

mu.L of plasma sample was combined with 50. Mu.L of internal standard solution (100 ng/mL) and 200. Mu.L of CH ₃ CN precipitants were mixed, the solution was vortexed for 5 minutes, then centrifuged for 10 minutes (4000 rpm). 8 μl of the supernatant was sampled for LC/MS/MS analysis.

Procedure

In the Sprague Dawley rat PK study, each group of animals (n=4, 2 males and 2 females) was fasted overnight. The group administered by gavage (ig) received the drug by oral gavage. Serial blood samples (0.2 mL) were collected from the orbit at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours into disodium ethylenediamine tetraacetate (K2 EDTA) blood collection tubes, and then centrifuged (10,000 rpm) at 4 ℃ for 1 minute to obtain plasma. For the intravenous administration (iv) group, serial blood samples (0.2 mL) were collected from the orbit into disodium ethylenediamine tetraacetate (K2 EDTA) blood collection tubes at time points-5 min, 15 min, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, 24.0 hours. Plasma samples were separated over 1 hour and stored at-20 ℃ until analysis by liquid chromatography-tandem mass spectrometry (LC/MS). The whole process from blood sampling to centrifugation is carried out under ice conditions. Rats were fed 2 hours after dosing.

Data analysis

Pharmacokinetic parameters were obtained by non-atrioventricular analysis of plasma concentrations (determined by LC/MS) vs. time data. Peak concentration was recorded directly from experimental observations (C _max ) And C _max Is a time of (a) to be used. Calculating the area under the curve from time zero to the last sampling time using a combination of linear and logarithmic trapezoidal summations(AUC _0-t )。

Results

Rat ig PK results are shown in table 4.

TABLE 4 rat PK results for example 2-1 and prodrug example 6

Conclusion: by oral administration to rats, prodrug molecule 6 can be almost completely converted to its parent compound 2-1. Significantly higher parent drug exposure of example 6 was observed in the rat ig 100mpk PK study when compared to the same dose of example 2-1.

Abbreviations:

C _max maximum serum concentration;

PEG400: polyethylene glycol 400;

HPMC K100LV: hydroxypropyl methylcellulose (HPMC) K100LV;

TPGS: d-alpha-tocopheryl polyethylene glycol 1000 succinate.

The foregoing embodiments and examples are provided for illustrative purposes only and are not intended to limit the scope of the present 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 departing from the spirit and scope of the present disclosure. All cited documents are incorporated by reference in their entirety, but are not admitted to be prior art.

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

X ¹ and X ² Identical or different, and each independentlyIs hydrogen or-L-R ⁰ Provided that X ¹ And X ² Not all hydrogen;

cy is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ¹ and Q ² Identical or different and each is independently selected from hydrogen, deuterium and alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ³ selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more groups independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, -NQ ⁶ Q ⁷ Substituents for nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ⁴ and Q ⁵ Identical or different and are each independently selected from alkyl, cycloalkyl and hetero A cyclic group wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more groups independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -NQ ⁶ Q ⁷ 、-OC(＝O)Q ⁸ 、-OC(＝O)OQ ⁸ Substituents for cycloalkyl, heterocyclyl, aryl and heteroaryl;

Q ⁸ selected from alkyl, haloalkyl and deuterated alkyl;

R ¹ selected from the group consisting of 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 hydroxyalkyl;

R ^2a 、R ^2b 、R ^3a and R is ^3b Each identical or different and each 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 R is ^4a 、R ^4b 、R ^5a And R is ^5b Two of which together with the carbon atoms to which they are attached form a ringAlkyl or heterocyclyl;

R ^6a 、R ^6b 、R ^6c and R is ^6d The same or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, deuteroalkyl, 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 the group consisting of 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 is also provided with

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 is ^6d Identical or different and are each independently selected from hydrogen, halogen and C _1-6 An alkyl group.

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

wherein:

X ¹ 、X ² 、R ¹ 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a and R is ^6b Each as defined in claim 1.

5. The compound according to any one of claim 1 to 4, which is 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 R ¹ Is a 3-to 6-membered cycloalkyl group.

7. The compound according to any one of claim 1 to 4 or 6, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

X ¹ 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a and R is ^6b Each as defined in claim 1.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ 、Q ¹ And Q ² As defined in claim 1; preferably X ² Is hydrogen or-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And Q is ¹ 、Q ² And Q ³ As defined in claim 1.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ 、Q ¹ And Q ² As defined in claim 1; preferably X ¹ is-L-R ⁰ The method comprises the steps of carrying out a first treatment on the surface of the L is-CQ ¹ Q ² -；R ⁰ Selected from-OP (=O) (OH) ₂ 、-OC(＝O)Q ³ and-OP (=o) (OH) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And Q is ¹ 、Q ² And Q ³ As defined in claim 1.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Q ¹ And Q ² Identical or different and are each independently selected from hydrogen, deuterium and C _1-6 An alkyl group; and/or Q ³ Is C _1-6 An alkyl group.

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 is ^5b Each identical or different and each independently selected from hydrogen, deuterium and C _1-6 An alkyl group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Alkyl, C _1-6 Deuterated alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino, nitro, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; preferably, R ^6a And R is ^6b Each identical or different and each independently selected from hydrogen, halogen, C _1-6 Deuterated alkyl, C _1-6 Alkyl and C _1-6 A haloalkyl group.

13. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

15. a compound of formula (IA):

wherein:

R ^t is alkyl, preferably C _1-6 An alkyl group;

X ² is hydrogen; and is also provided with

L、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a 、R ^6b 、R ^6c 、R ^6d Each of n and m is as defined in claim 1.

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

17. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:

wherein:

R ^t is alkyl, preferably C _1-6 An alkyl group;

X ² is hydrogen;

L、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a 、R ^6b 、R ^6c 、R ^6d Each of m and n is as defined in claim 1.

18. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:

Wherein:

R ^w halogen, preferably Cl;

X ¹ is-L-R ⁰ ；

R ⁰ 、L、R ¹ 、R ^2a 、R ^2b 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^6a 、R ^6b 、R ^6c 、R ^6d Each of m and n is as defined in claim 1.

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

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

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