Prodrugs of adamts inhibitors, methods of making and medical uses thereof

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 170,371, filed April 2, 2021, pursuant to 35 USC §119(e), the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This 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, such as osteoarthritis and / or rheumatoid arthritis. Background Technology

[0004] Cartilage is a highly specialized connective tissue in articular joints. Its main function is to provide weight-bearing and pressure-resistant capacity for the joint. The main components of cartilage are the extracellular matrix, including proteoglycans and collagen. In diseases such as osteoarthritis, the balance between the production (anabolism) and degradation (catabolism) of proteoglycans and collagen shifts towards catabolism.

[0005] Osteoarthritis is the most common chronic joint disease and a leading cause of pain and disability in developed countries. It is estimated that 250 million people worldwide are currently affected by osteoarthritis, and the prevalence is gradually increasing (Hunter et al., Lancet. 2019, 393:1745–1759). Pain and functional loss are accompanied by an increased risk of other diseases, such as diabetes, cancer, or cardiovascular disease (Valdes AM and Stocks J. Osteoarthritis and ageing. Eur Med J. 2018, 3:116-123). Osteoarthritis is a disease affecting the entire joint: structural changes have been identified, including degradation of articular cartilage, synovitis, and alterations in subchondral bone and other periarticular tissues (Goldring MB and Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011, 23:471-478). The pathogenesis of osteoarthritis is not fully understood, but it involves mechanical injury, inflammation, aging, and metabolic factors. Osteoarthritis is not a passive degenerative disease, but rather an active, dynamic alteration caused by an imbalance between the repair and destruction of joint tissues (Hunter et al., Lancet. 2019, 393:1745–1759). Currently, drug treatments available for osteoarthritis are limited to relieving symptoms of pain and inflammation. There are no disease-relieving drugs that can stop or slow disease progression.

[0006] Progressive loss of articular cartilage is currently considered an early event in osteoarthritis. Aggregatin may play a protective role against collagen loss (Pratta et al., J Biol Chem. 2003, 278:45539-45545). These studies suggest a crucial role for aggregateatin in osteoarthritis and other joint diseases. Aggregatin is a proteoglycan with a core protein consisting of covalently linked sulfated glycosaminoglycan (GAG) chains. Its core protein has three globular domains: N-terminal G1 and G2 domains, and C-terminal G3 domain. A large region between the G2 and G3 domains is heavily modified with GAG keratin sulfate (KS) and chondroitin sulfate (CS). Based on amino acid sequence differences, the CS domain is further divided into two subdomains, CS1 and CS2. The GAG ​​chains provide aggregateatin with a high anionic charge. Multiple proteoglycan monomers bind to hyaluronic acid (HA) via their G1 domains, and are stabilized by linker proteins to form large supramolecular aggregates. These large proteoglycan aggregates absorb water and provide cartilage with elastic properties (Roughley et al., The Journal of Experimental Orthopaedics. 2014, 1:8). Normal cartilage function requires high concentrations of proteoglycans, high sulfation, and the ability to form large aggregates.

[0007] Proteolytic enzymes can cleave the extended structure of aggregated proteoglycans, leading to impaired cartilage function. ADAMTS (de-integrin and metalloproteinases with platelet-reactive protein motifs) belong to the zinc ion-dependent metalloproteinase family. ADAMTS-4 and ADAMTS-5, also known as "aggregatinases," degrade aggregated proteoglycans at several specific sites in the IGD and CS2 domains. ADAMTS-5 deficiency has been shown to prevent aggregated proteoglycan loss and cartilage damage in a surgery-induced mouse model of osteoarthritis (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 loss and the severity of osteoarthritis. Some studies on human cartilage explant culture also suggest that ADAMTS-4, in addition to ADAMTS-5, is also important for human osteoarthritis (Verma et al., Journal of Cellular Biochemistry. 2011, 112:3507-3514). These studies strongly suggest that inhibiting the enzymatic function of ADAMTS-5 and ADAMTS-4 may provide protection against osteoarthritis.

[0008] In summary, the role of ADAMTS-5 and / or ADAMTS-4 in cartilage degradation has been well established. Therefore, inhibitors of ADAMTS-5 and / or ADAMTS-4 may have therapeutic value in the treatment of arthritis. Patent applications for compounds disclosed as inhibitors of ADAMTS-5 and / or ADAMTS-4 include WO2014066151A1, WO2016102347A1, WO2017211667A1, WO2017211666A1, WO2017211668A1, WO2021011720A2, and WO2021011723A1.

[0009] Although various prodrug strategies exist to provide options for drug molecule delivery modulation conditions with a variety of benefits, the identification of prodrugs with desired properties is often difficult and not straightforward. None of the prior art teaches or suggests the specific prodrugs disclosed herein. Summary of the Invention

[0010] On the one hand, this disclosure provides compounds of formula (I):

[0011]

[0012] Or its pharmaceutically acceptable salt.

[0013] in:

[0014] X 1 and X 2 Same or different, and each independently is hydrogen or -LR 0 The condition is X 1 and X 2 Not all of them are hydrogen;

[0015] 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 -;

[0016] 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)OQ4 -OP(=O)(OQ) 4 )2、-OQ 5 -NQ 6 Q 7 -OC(=O)(CQ 1 Q 2 ) t -(Cy) s -OP(=O)(OH)2、-OC(=O)-NQ 6 Q 7 , -OC(=O)CH=CHC(=O)OH, -OC(=O)-O-(CQ 1 Q 2 ) t -OP(=O)(OH)2, -OC(=O)-NH-(CQ 1 Q 2 ) t -OP(=O)(OH)2, hydrogen, heterocyclic groups and heteroaryl groups;

[0017] Cy is aryl or heteroaryl, each optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0018] Q 1 and Q 2 The same or different, and each independently selected from hydrogen, deuterium and alkyl, wherein the alkyl group is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0019] Q 3 The group is selected from hydrogen, alkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally one or more, sometimes preferably one to five, and sometimes more preferably one to three, independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, -NQ. 6 Q 7 Substitution with nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0020] Q 4 and Q 5The same or different, and each independently selected from alkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally one or more, sometimes preferably one to five, and 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 Substitution with cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0021] Q 6 and Q 7 They may be the same or different, and each is independently selected from hydrogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0022] Q 8 Selected from alkyl, haloalkyl, and deuteralkyl groups;

[0023] R 1 The group is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalkyl groups;

[0024] R 2a R 2b R 3a and R 3b Each may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0025] Or R 2a R 2b R 3a and R 3b The two atoms in the group, together with the carbon atoms they are attached to, form cycloalkyl or heterocyclic groups;

[0026] R 4a R 4b R 5a and R 5bEach may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0027] Or R 4a R 4b R 5a and R 5b The two atoms in the group, together with the carbon atoms they are attached to, form cycloalkyl or heterocyclic groups;

[0028] R 6a R 6b R 6c and R 6d They may be the same or different, and each independently selected from hydrogen, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0029] n is 1 or 2;

[0030] m is 1 or 2;

[0031] t is 1 or 2; and

[0032] s is 0 or 1.

[0033] In another aspect, this 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.

[0034] In another aspect, this disclosure also provides a method for preventing and / or treating inflammatory conditions or diseases involving cartilage degradation and / or disruption of cartilage homeostasis, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0035] The diseases or conditions include arthritis, preferably rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis, which are further preferably associated with the activity of ADAMTS-5 and / or ADAMTS-4.

[0036] Other aspects or advantages of this disclosure will be better understood through the following detailed description, embodiments and claims. Detailed Implementation

[0037] On the one hand, this disclosure provides compounds of formula (I):

[0038]

[0039] Or its pharmaceutically acceptable salt.

[0040] in:

[0041] X 1 and X 2 Same or different, and each independently is hydrogen or -LR 0 The condition is X 1 and X 2 Not all of them are hydrogen;

[0042] 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 -;

[0043] 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 -OC(=O)(CQ 1 Q 2 ) t -(Cy) s -OP(=O)(OH)2、-OC(=O)-NQ 6 Q 7 , -OC(=O)CH=CHC(=O)OH, -OC(=O)-O-(CQ 1 Q 2 ) t -OP(=O)(OH)2, -OC(=O)-NH-(CQ 1 Q 2 ) t -OP(=O)(OH)2, hydrogen, heterocyclic groups and heteroaryl groups;

[0044] Cy is aryl or heteroaryl, each optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0045] Q 1 and Q 2 The same or different, and each independently selected from hydrogen, deuterium and alkyl, wherein the alkyl group is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three substituents independently selected from alkoxy, halogen, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0046] Q 3 The group is selected from hydrogen, alkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally one or more, sometimes preferably one to five, and sometimes more preferably one to three, independently selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, -NQ. 6 Q 7 Substitution with nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0047] Q 4 and Q 5 The same or different, and each independently selected from alkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally one or more, sometimes preferably one to five, and 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 Substitution with cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0048] Q 6 and Q 7 They may be the same or different, and each is independently selected from hydrogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0049] Q 8 Selected from alkyl, haloalkyl, and deuteralkyl groups;

[0050] R 1The group is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalkyl groups;

[0051] R 2a R 2b R 3a and R 3b Each may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, cycloalkyl and heterocyclic groups, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more, sometimes preferably one to five, and sometimes more preferably one to three groups selected from halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0052] Or R 2a R 2b R 3a and R 3b The two atoms in the group, together with the carbon atoms they are attached to, form cycloalkyl or heterocyclic groups;

[0053] R 4a R 4b R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0054] Or R 4a R 4b R 5a and R 5b The two atoms in the group, together with the carbon atoms they are attached to, form cycloalkyl or heterocyclic groups;

[0055] R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen, halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by 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, heterocyclic, aryl and heteroaryl;

[0056] n is 1 or 2;

[0057] m is 1 or 2;

[0058] t is 1 or 2; and

[0059] s is 0 or 1.

[0060] In some embodiments of this disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, n is 1; and m is 1.

[0061] In some embodiments of this disclosure, R is a compound of formula (I) or a pharmaceutically acceptable salt thereof. 2a R 2b R 3a R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, hydroxyl groups and C 1-6 Hydroxyalkyl; preferably, R 2a R 2b R 3a R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, halogens, and C. 1-6 alkyl.

[0062] In some embodiments of this disclosure, R is in a compound of formula (I) or a pharmaceutically acceptable salt thereof. 2a R 2b and R 3a They may be the same or different, and each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, hydroxyl groups and C 1-6 Hydroxyalkyl; preferably, R 2a R 2b and R 3a They may be the same or different, and each is independently selected from hydrogen, halogens, and C. 1-6 Alkyl; more preferably, R 2a R 2b and R 3a It is hydrogen.

[0063] In some embodiments of this disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, halogen, and C.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, hydroxyl groups and C 1-6 Hydroxyalkyl; preferably, R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, halogens, and C. 1-6 Alkyl; more preferably, R 6c and R 6d It is hydrogen.

[0064] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0065]

[0066] in:

[0067] X 1 X 2 R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (I) above.

[0068] In some embodiments of this disclosure, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is the compound of formula (II-1) or a pharmaceutically acceptable salt thereof:

[0069]

[0070] in:

[0071] X 1 X 2 R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (I) above.

[0072] In some embodiments of this disclosure, in compounds of formula (I), (II), or (II-1) or pharmaceutically acceptable salts thereof, R 1 It is a 3- to 6-membered cycloalkyl group; preferably, R 1 It is cyclopropyl.

[0073] In some embodiments of this disclosure, in compounds of formula (I), (II), or (II-1) or pharmaceutically acceptable salts thereof, R 3b Selected from hydrogen, halogens and C 1-6 Alkyl; preferably, R 3b It is hydrogen.

[0074] In some embodiments of this disclosure, a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0075]

[0076] in:

[0077] X 1 R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (I) above.

[0078] In some embodiments of this disclosure, compounds of formula (I), (II), (II-1), or (III), or pharmaceutically acceptable salts thereof, are compounds of formula (III-1) or pharmaceutically acceptable salts thereof:

[0079]

[0080] in:

[0081] X 1 R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (I) above.

[0082] In some embodiments of this disclosure, in compounds of formula (I), (II), or (II-1) or pharmaceutically acceptable salts thereof, X 2 For hydrogen or -LR 0 L is -CQ 1 Q 2 -;R 0 Q 1 and Q 2 As defined in equation (I) above; preferably, X 2 For hydrogen or -LR 0 L is -CQ 1 Q 2 -;R 0Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; Q 1 Q 2 and Q 3 As defined in equation (I) above; more preferably, X 2 For hydrogen or -LR 0 L is -CQ 1 Q 2 -;R 0 For -OP(=O)(OH) 2 And Q 1 and Q 2 As defined in equation (I) above; most preferably, X 2 It is hydrogen.

[0083] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Q 1 and Q 2 As defined in equation (I) above; preferably, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; Q 1 Q 2 and Q 3 As defined in equation (I) above; more preferably, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 =-OP(=O)(OH)2; and Q 1 and Q 2 As defined in equation (I) above.

[0084] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, Q 1 and Q 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl; and / or Q3 C 1-6 Alkyl; preferably, Q 1 and Q 2 It is hydrogen; and Q 3 C 1-6 alkyl.

[0085] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 4a R 4b R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl.

[0086] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 4a and R 4b Each may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl; preferably, R 4a and R 4b Each may be the same or different, and each is independently hydrogen or deuterium; more preferably, R 4a and R 4b It is deuterium.

[0087] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 4a and R 4b It is hydrogen.

[0088] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl; preferably, R 5a and R 5b Each may be the same or different, and each is independently hydrogen or C. 1-6 Alkyl; more preferably, R 5a It is hydrogen and R 5b C 1-6 alkyl.

[0089] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R5a and R 5b It is hydrogen.

[0090] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 4a R 4b R 5a and R 5b It is hydrogen.

[0091] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 4a and R 4b For deuterium; R 5a It is hydrogen and R 5b C 1-6 alkyl.

[0092] In some embodiments of this disclosure, in compounds of formula (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyl, cyano, amino, nitro, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups.

[0093] In some implementation schemes, R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Deuterated alkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0094] In some implementation schemes, R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some preferred embodiments, R 6a and R 6b Each may be the same or different, and each is independently selected from halogens and C. 1-6 Halogenated alkyl; more preferably, R 6a It is a halogen; and R 6b C1-6 Halogenated alkyl; in some more preferred embodiments, R 6a It is -Cl; and R 6b It is -CF3.

[0095] In some embodiments of this disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; Q 1 and Q 2 It is hydrogen; Q 3 C 1-6 Alkyl; R 4a R 4b R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl; R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Deuterated alkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0096] In some embodiments of this disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; Q 1 and Q 2 It is hydrogen; Q 3 C 1-6 Alkyl; R 4a R 4b R 5a and R 5b It is hydrogen; R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0097] In some embodiments of this disclosure, in a compound of formula (III) or a pharmaceutically acceptable salt thereof, X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; Q 1 and Q 2 It is hydrogen; Q 3 C 1-6 Alkyl; R 4a and R 4b For deuterium; R 5a and R 5b Each may be the same or different, and each is independently hydrogen or C. 1-6 Alkyl; R 6a and R 6b Each may be the same or different, and each is independently selected from halogens and C. 1-6 Halogenated alkyl groups.

[0098] Table A. Exemplary compounds of this disclosure include, but are not limited to:

[0099]

[0100]

[0101] Table B. Other compounds that can be prepared based on this disclosure include, but are not limited to:

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] In another aspect, this disclosure provides a compound of formula (IA) or a salt thereof:

[0109]

[0110] in:

[0111] R t It is an alkyl group; preferably, R t C1-6 alkyl;

[0112] X 2 It is hydrogen; and

[0113] L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d , n and m are each defined as in equation (I).

[0114] In another aspect, this disclosure provides a compound of formula (IIA) or a salt thereof:

[0115]

[0116] in:

[0117] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0118] X 2 It is hydrogen; and

[0119] L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II).

[0120] In another aspect, this disclosure provides a compound of formula (II-1A) or a salt thereof:

[0121]

[0122] in:

[0123] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0124] X 2 It is hydrogen; and

[0125] L, R 1 R3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in formula (II-1). In another aspect, this disclosure provides a compound of formula (IIIA) or a salt thereof:

[0126]

[0127] in:

[0128] R t It is an alkyl group; preferably, R t C 1-6 Alkyl; and

[0129] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III).

[0130] In another aspect, this disclosure provides a compound of formula (III-1A) or a salt thereof:

[0131]

[0132] in:

[0133] R t It is an alkyl group; preferably, R t C 1-6 Alkyl; and

[0134] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III-1).

[0135] Exemplary intermediate compounds disclosed herein include, but are not limited to:

[0136]

[0137]

[0138] In another aspect, this disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0139]

[0140] Remove R from compound of formula (IA) or its salt t To obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0141] in:

[0142] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0143] X 2 It is hydrogen;

[0144] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0145] L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d , n and m are each defined as in equation (I).

[0146] In another aspect, this disclosure provides a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0147]

[0148] Remove R from compounds of formula (IIA) or their salts t To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0149] in:

[0150] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0151] X 2 It is hydrogen;

[0152] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0153] L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II).

[0154] In another aspect, this disclosure provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0155]

[0156] Remove R from compound of formula (II-1A) or its salt t To obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0157] in:

[0158] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0159] X 2 It is hydrogen;

[0160] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0161] L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II-1).

[0162] In another aspect, this disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0163]

[0164] Remove R from compounds of formula (IIIA) or their salts t To obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0165] in:

[0166] R tIt is an alkyl group; preferably, R t C 1-6 alkyl;

[0167] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0168] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III).

[0169] In another aspect, this disclosure provides a method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0170]

[0171] Remove R from compound of formula (III-1A) or its salt t To obtain a compound of formula (III-1) or a pharmaceutically acceptable salt thereof,

[0172] in:

[0173] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0174] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0175] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III-1).

[0176] In another aspect, this disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0177]

[0178] Compound of formula (IB) or its salt with R 0 -LR w The compound reacts to yield a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0179] in:

[0180] R w It is a halogen; preferably, R w For Cl;

[0181] X 1 For -LR 0 ;

[0182] X 2 For hydrogen or -LR 0 ;and

[0183] R 0 L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d , n and m are each defined as in equation (I).

[0184] In another aspect, this disclosure provides a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0185]

[0186] Compound of formula (IIB) or its salt with R 0 -LR w The compound reacts to give a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0187] in:

[0188] R w It is a halogen; preferably, R w For Cl;

[0189] X 1 For -LR 0 ;

[0190] X 2 For hydrogen or -LR 0 ;and

[0191] R 0 L, R 1 R 3b R 4a R 4b R5a R 5b R 6a and R 6b Each is as defined in equation (II).

[0192] In another aspect, this disclosure provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0193]

[0194] Compound of formula (II-1B) or its salt with R 0 -LR w The compound reacts to give a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0195] in:

[0196] R w It is a halogen; preferably, R w For Cl;

[0197] X 1 For -LR 0 ;

[0198] X 2 For hydrogen or -LR 0 ;and

[0199] R 0 L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II-1).

[0200] In another aspect, this disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0201]

[0202] Compound of formula (IIIB) or its salt with R 0 -LR w The compound reacts to give a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0203] in:

[0204] R w It is a halogen; preferably, R w For Cl;

[0205] X 1 For -LR 0 ;and

[0206] R 0 L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III).

[0207] In another aspect, this disclosure provides a method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0208]

[0209] Compound of formula (III-1B) or its salt with R 0 -LR w The reaction of the compounds yields a compound of formula (IIII-1) or a pharmaceutically acceptable salt thereof.

[0210] in:

[0211] R w It is a halogen; preferably, R w For Cl;

[0212] X 1 For -LR 0 ;and

[0213] R 0 L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III-1).

[0214] This disclosure also provides a pharmaceutical composition comprising a compound of formula (I), (II), (II-1), (III) or (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and / or other excipients.

[0215] This disclosure also provides a method for inhibiting ADAMTS-5 and / or ADAMTS-4, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), (II), (II-1), (III) or (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound.

[0216] This disclosure also provides a method for preventing or treating inflammatory conditions or diseases involving cartilage degradation and / or disruption of cartilage homeostasis, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), (II), (II-1), (III), or (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound.

[0217] This disclosure also provides a method for preventing or treating arthritis, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I), (II), (II-1), (III) or (III-1), or a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound; preferably, wherein said arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and hypertrophic arthritis.

[0218] In another aspect, this disclosure also relates to the use of compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds in the preparation of medicaments for inhibiting ADAMTS-5 and / or ADAMTS-4.

[0219] In another respect, this disclosure also relates to the use of compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds in the preparation of medicaments for the prevention and / or treatment of inflammatory conditions or diseases involving cartilage degradation and / or disruption of cartilage homeostasis.

[0220] In another aspect, this disclosure also relates to the use of compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds in the preparation of a medicament for the prevention and / or treatment of arthritis; preferably, said arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

[0221] This disclosure also relates to compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds, which are used as pharmaceuticals.

[0222] This disclosure also relates to compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds for inhibiting ADAMTS-5 and / or ADAMTS-4.

[0223] This disclosure also relates to compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or combinations of pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds for the prevention and / or treatment of inflammatory conditions or diseases involving cartilage degradation and / or disruption of cartilage homeostasis.

[0224] This disclosure also relates to compounds of formula (I), (II), (II-1), (III) or (III-1), or compounds selected from Table A or Table B, or combinations of pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing said compounds for the prevention and / or treatment of arthritis; preferably, said arthritis is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis and hypertrophic arthritis.

[0225] In this disclosure, inflammatory conditions, diseases involving cartilage degradation and / or disruption of cartilage homeostasis, and arthritis are preferably mediated by ADAMTS-5 and / or ADAMTS-4.

[0226] The phrase "inflammatory conditions" refers to a group of conditions, 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 after bypass surgery, or chronic endotoxin states leading to, for example, chronic heart failure), and cartilage-related diseases (e.g., joint diseases). Specifically, it refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, it refers to rheumatoid arthritis and osteoarthritis (OA). Most specifically, it refers to osteoarthritis (OA).

[0227] "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, algodystrophy, achondroplasia, Paget's disease, Tietze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neurogenic arthritis, arthropathy, sarcoidosis, amyloidosis, joint effusion, periodic diseases, rheumatoid spondylitis, endemic forms of arthritis (such as endemic deforming osteoarthritis, Mseleni's disease, and Handigodu's disease); degradation caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis; and especially osteoarthritis of the fingers (OA).

[0228] The pharmaceutical compositions of this disclosure can be formulated using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), rectal, inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms.

[0229] The dosage of the compounds or compositions used in this disclosure will vary depending on the severity of the disease, the patient's weight, and the relative efficacy of the compound. However, as a general guideline, the active compound is preferably administered in unit doses or can be self-administered by the patient in single doses. The unit doses of the compounds or compositions disclosed herein may be in the form of tablets, capsules, flat capsules, bottled liquids, powders, granules, suppositories, recycled powders, or liquid formulations. Suitable unit doses may range from 0.1 mg to 1000 mg.

[0230] In addition to the active compound, the pharmaceutical compositions disclosed herein may also contain one or more excipients selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrants, or other excipients. Depending on the method of administration, the composition may contain from 0.1% by weight to 99% by weight of the active compound.

[0231] Suitable dosage forms include, but are not limited to, tablets, troche, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Oral compositions can be prepared according to any known methods in the art for preparing pharmaceutical compositions. These compositions may contain one or more additives selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pleasant and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients may be inert excipients, granulating agents, disintegrants, and lubricants. Tablets may be uncoated or coated using known techniques to mask the taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period. For example, water-soluble taste-masking materials may be used.

[0232] Oral formulations can also be provided as soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier.

[0233] Aqueous suspensions contain active ingredients mixed with excipients suitable for manufacturing aqueous suspensions. These excipients are suspending agents, dispersants, or humectants, and may be naturally occurring phospholipids. Aqueous suspensions may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0234] Oily suspensions can be formulated by suspending the active ingredients in vegetable or mineral oil. Oily suspensions may contain thickeners. The aforementioned sweeteners and flavorings can be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0235] The pharmaceutical compositions disclosed herein 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 emulsifiers may be naturally occurring phospholipids. Sweeteners may be used. This formulation may also contain moderators, preservatives, colorants, and antioxidants.

[0236] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may also be a sterile injectable oil-in-water microemulsion, wherein the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be introduced into an individual's bloodstream by local injection. Alternatively, it is advantageous to administer the solution or microemulsion in a manner that maintains a constant circulating concentration of the compound. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0237] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions prepared in non-toxic, parenteral-acceptable diluents or solvents. Furthermore, sterile, non-volatile oils can be readily used as solvents or suspension media, and fatty acids can also be used in the preparation of injectable formulations.

[0238] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, thereby melting in the rectum to release the drug.

[0239] For intrabuccal administration, the composition can be formulated into tablets or lozenges using conventional methods.

[0240] The active compounds of this disclosure are conveniently delivered for intranasal or inhalation administration, either as a solution or suspension released by a pump-operated spray container squeezed or pumped by a patient, or as an aerosol spray released by a pressurized container or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). For pressurized aerosols, the dosage unit may be determined by a valve that provides the measured amount delivered. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules or cartridges (e.g., made of gelatin) may be formulated for inhalers or blowpipes containing the powder mixtures of this disclosure and a suitable powder matrix (such as lactose or starch).

[0241] As is well known to those skilled in the art, drug dosage depends on a variety of factors, including but not limited to: the activity of the specific compound, the patient's age, weight, health status, behavior, diet, timing of administration, route of administration, rate of excretion, and combination of drugs. Furthermore, the optimal treatment approach can be validated through traditional treatment regimens, such as the treatment modality, daily dose of the compound, or the type of pharmaceutically acceptable salt thereof.

[0242] definition

[0243] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0244] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including C1-C64 groups. 20 Straight-chain and branched-chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12 carbon atoms (e.g., including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) (i.e., C12). 1-12Alkyl group). In some embodiments, it is sometimes preferred that the alkyl group is an alkyl group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkyl groups. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl and their branched isomers. In some embodiments, it is sometimes more preferable that the alkyl group is a lower alkyl group having 1 to 6 carbon atoms (i.e., C16). 1-6 Alkyl groups, sometimes more preferably, lower alkyl groups having 1 to 4 carbon atoms (i.e., C14-C ... 1-4 Alkyl groups. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. Preferably, there are one or more substituents, sometimes one to five, and sometimes more preferably one to three, independently selected from halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylsulfonyl groups, alkylamino groups, mercapto groups, hydroxyl groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, cycloalkyloxy groups, heterocyclic oxy groups, cycloalkyl thio groups, heterocyclic thio groups, and oxo groups.

[0245] "Alkenyl" refers to 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, preferably C10. 2-20 Alkenyl, more preferably C 2-12 (e.g., including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) alkenyl groups, sometimes more preferably C 2-6 Alkenyl, sometimes even more preferably C 2-4 Alkenyl. The alkenyl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from halogen, alkoxy, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, heterocyclic alkylthio, and oxo groups.

[0246] "Alkynyl" refers to an alkyl group as defined above that has 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, preferably C10. 2-20 Alkyne group, more preferably C 2-12 (For example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) ynyl group, sometimes preferably C 2-6 Alkyne group, sometimes even more preferably C 2-4 Alkynyl group. The alkynyl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkenyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio.

[0247] "Alkylene" refers to a saturated straight-chain or branched divalent aliphatic hydrocarbon group derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. The straight-chain or branched group contains 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (e.g., including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms), sometimes more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkenyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio.

[0248] "Alkenyl" refers to an alkenyl group as defined above, having at least two carbon atoms and at least one carbon-carbon double bond, preferably C. 2-20 alkenyl, more preferably C 2-12 (e.g., including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbons) alkenyl groups, sometimes more preferably C 2-6 alkenyl, sometimes even more preferably C 2-4 Idemenyl. Non-limiting examples of imenyl groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, and -CH2CH=CHCH2-. The imenyl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio groups.

[0249] "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), and 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, cyclohepttrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include cycloalkyl groups having spirocyclic, fused, or bridged rings.

[0250] "Spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which a ring is linked by a shared carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds. Preferably, the spirocycloalkyl group is 6 to 14 members (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, and 14 carbons), more preferably 7 to 10 members (e.g., 7, 8, 9, and 10). Based on the number of shared spiro atoms, spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or dispirocycloalkyl, more preferably 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Representative examples of spirocycloalkyl groups include, but are not limited to, the following groups:

[0251]

[0252] "Fused cycloalkyl" refers to a 5- to 20-membered polycyclic hydrocarbon group, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring, and one or more rings may contain one or more double bonds. Preferably, the fused cycloalkyl is 6 to 14 members (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, and 14 carbons), more preferably 7 to 10 members (e.g., 7, 8, 9, and 10). Based on the number of member rings, fused cycloalkyl is classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic fused cycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, or 6 / 6 bicyclic fused cycloalkyl. Representative examples of fused cycloalkyl include, but are not limited to, the following groups:

[0253]

[0254] "Bridged cycloalkyl" refers to a 5- to 20-membered polycyclic hydrocarbon group, wherein each pair of rings in the system shares two unconnected carbon atoms. The rings may have one or more double bonds. Preferably, the bridged cycloalkyl is 6 to 14 members (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, and 14 carbons), more preferably 7 to 10 members (e.g., 7, 8, 9, and 10). Bridged cycloalkyl is classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl based on the number of member rings, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyl include, but are not limited to, the following groups:

[0255]

[0256] The cycloalkyl group may also include the aforementioned cycloalkyl group fused to a ring of an aryl, heteroaryl, or heterocyclic group, wherein the ring connected to the parent structure is a cycloalkyl group. Representative examples include, but are not limited to, indanyl, tetrahydronaphthalene, benzocycloheptyl, etc. The cycloalkyl group may optionally be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl sulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, heterocyclic alkylthio, and oxo groups.

[0257] "Heterocyclic group" refers to a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic group having one or more heteroatoms selected from N, O, and S as ring atoms, wherein sulfur may optionally be oxidized to form S(=O) or S(=O)2, but excluding -OO-, -OS-, or -SS-. Preferably, the heterocyclic group is a 3- to 12-membered heterocyclic group having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms, more preferably a 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms (e.g., 3, 4, 5, 6, 7, 8, 9, and 10) heteroatoms (i.e., a 3- to 10-membered heterocyclic group), even more preferably a 6- to 10-membered heterocyclic group having 1 to 3 heteroatoms, and most preferably a 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms (i.e., a 5- to 6-membered heterocyclic group). Representative examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include heterocyclic groups having spirocyclic, fused, or bridged rings.

[0258] "Spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group with rings linked by a shared carbon atom (called a spiro atom), wherein the ring has 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 excluding -OO-, -OS-, or -SS-, and wherein one or more rings may contain one or more double bonds. Preferably, the spiroheterocyclic group is 6 to 14-membered (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms), more preferably 7 to 10-membered (e.g., 7, 8, 9, and 10). Based on the number of shared spiro atoms, spiroheterocyclic groups are classified into monospirocyclic, dispirocyclic, or polyspirocyclic groups, preferably monospirocyclic or dispirocyclic, more preferably 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic groups. Representative examples of spiroheterocyclic groups include, but are not limited to, the following groups:

[0259]

[0260] "Fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring in the system shares a pair of adjacent carbon atoms with other rings, wherein one or more rings may contain one or more double bonds, wherein the rings have 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 excluding -OO-, -OS-, or -SS-. Preferably, the fused heterocyclic group is 6 to 14 members (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms), more preferably 7 to 10 members (e.g., 7, 8, 9, and 10). Based on the number of member rings, fused heterocyclic groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, or 6-membered / 6-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocyclic groups include, but are not limited to, the following groups:

[0261]

[0262] "Bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group, wherein each pair of rings in the system shares two unconnected atoms, the rings may have one or more double bonds, and the rings have 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 excluding -OO-, -OS-, or -SS-. Preferably, the bridged heterocyclic group is 6 to 14-membered (e.g., including 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms), more preferably 7 to 10-membered (e.g., 7, 8, 9, and 10). Based on the number of member rings, bridged heterocyclic groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Representative examples of bridged heterocyclic groups include, but are not limited to, the following groups:

[0263]

[0264] The ring of the heterocyclic group includes the aforementioned heterocyclic group fused with the ring of an aryl, heteroaryl, or cycloalkyl group, wherein the ring connected to the parent structure is a heterocyclic group. Representative examples include, but are not limited to, the following groups:

[0265]

[0266] wait.

[0267] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio.

[0268] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system is one in which each ring shares an adjacent pair of carbon atoms with another ring in the system) group, and has a fully conjugated π-electron system. Preferably, the aryl group is 6- to 10-membered (i.e., 6- to 10-membered aryl), such as phenyl and naphthyl, with phenyl being the most preferred. Aryl groups include those described above fused with a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl group. Representative examples include, but are not limited to, the following groups:

[0269]

[0270] The aryl group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio.

[0271] "Heteroaryl" refers to 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 may be optionally oxidized to form S(=O) or S(=O)2, but excluding -OO-, -OS- or -SS-, and having 5 to 14 (e.g., including 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms) ring atoms (i.e. 5 to 14 membered heteroaryls). Preferably, the heteroaryl group is 5 to 10 quintiles (e.g., 5, 6, 7, 8, 9, and 10 quintiles) (i.e., 5 to 10 quintile heteroaryl groups), more preferably 5 or 6 quintiles (i.e., 5 to 6 quintile heteroaryl groups), such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group includes the above-mentioned heteroaryl groups fused to a ring of an aryl, heterocyclic, or cycloalkyl group, wherein the ring connected to the parent structure is a heteroaryl group. Representative examples include, but are not limited to, the following groups:

[0272]

[0273] The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclic oxy, cycloalkylthio, and heterocyclic alkylthio. "Alkoxy" refers to an -O-(alkyl) group, wherein the alkyl group is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. The alkoxy group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclicoxy, cycloalkylthio, and heterocyclic alkylthio.

[0274] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include a monovalent residue derived from removing one hydrogen atom from a parent ring atom, or a divalent residue derived from removing two hydrogen atoms from the same or different ring atoms on the parent ring, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", and "heteroarylene".

[0275] A "bond" refers to a covalent bond marked with "—".

[0276] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0277] “Deuterium alkyl” or “deuterated alkyl” refers to an alkyl group that has been replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0278] "Hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0279] "Hydroxy group" refers to the -OH group.

[0280] "Thiol group" refers to the -SH group.

[0281] "alkylthio" refers to an alkyl-S-group, where the alkyl group is as defined above.

[0282] "Halogenated alkyl thioyl" refers to a halogenated alkyl-S-group, wherein the halogenated alkyl group is as defined above.

[0283] "Cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

[0284] "Heterocyclic oxygen group" refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0285] "Cycloalkylthio" refers to cycloalkyl-S-, where cycloalkyl is as defined above.

[0286] "Heterocyclic thio-" refers to the heterocyclic group -S-, where the heterocyclic group is as defined above.

[0287] "Halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0288] "Amino" refers to the -NH2 group.

[0289] "Cyano" refers to the -CN group.

[0290] "Nitro" refers to the -NO2 group.

[0291] "Oxide group" refers to the =O group.

[0292] "Carboxyl group" refers to the -C(=O)OH group.

[0293] "Carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0294] The compounds disclosed herein can exist in specific stereoisomer 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, transisomers, conformational isomers, and mixtures thereof (e.g., racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may have additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Isomers of the disclosed compounds can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Alternatively, the separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0295] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if a chiral isomer exists in the chemical structure, then the bond... It can be or both Configuration. The compounds of this disclosure may exist in different tautomeric forms, and all such forms are included within the scope of this disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and readily transforms 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 proportion. Non-limiting examples include keto-enol, imine-enamine, lactam-lactamimide, etc. An example of a lactam-lactamimide equilibrium is as follows:

[0296]

[0297] For example, the pyrazolyl group should be understood to include any one or a mixture of two of the following structures:

[0298]

[0299] All tautomers are within the scope of this disclosure, and the names of compounds do not exclude any tautomers.

[0300] "Optional" or "optionally" means that the event or situation described below may occur but is not required to occur, and the description includes instances in which the event or situation may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may be present but is not required to be present, and the description includes cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted.

[0301] "Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by the corresponding number of substituents. Those skilled in the art can determine whether substitution is possible or not through experimentation or theory without much effort. For example, a combination of an amino or hydroxyl group with free hydrogen and a carbon atom with an unsaturated bond (such as an alkene) may be unstable.

[0302] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this disclosure or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components (such as physiologically / pharmaceutically acceptable carriers and excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism, which aids in the absorption of the active ingredient and thus exhibits biological activity.

[0303] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that is safe and effective when used in mammals and has the corresponding biological activity.

[0304] Salts can be prepared during the final separation and purification of compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, or ammonium hydroxide; organic ammonium hydroxides such as tetramethylammonium 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,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

[0305] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and hydrogen disulfide) and organic acids (such as 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, and acetic acid) and related inorganic and organic acids.

[0306] "Prodrugs" are compounds that can be converted in the body to produce active parent compounds under physiological conditions, such as through hydrolysis in the blood.

[0307] As used herein, the term “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that are suitable for contact with a patient’s tissues within reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications with a reasonable benefit / risk ratio, and are effective for their intended use.

[0308] As used herein, the term "therapeutic effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit (e.g., a 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 amount of active ingredients (whether administered in combination, sequentially, or simultaneously) that produce a therapeutic effect.

[0309] The terms “treat,” “treating,” “treatment,” etc., refer to: (i) suppressing a disease, symptom, or condition, i.e., preventing its development; and (ii) alleviating a disease, symptom, or condition, i.e. causing the remission of the disease, symptom, and / or condition. Furthermore, the compounds disclosed herein can be used for their preventive effect to prevent the occurrence of a disease, symptom, or condition in subjects who may be susceptible to the disease, symptom, and / or condition but have not yet been diagnosed with it.

[0310] As used herein, the singular forms “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly specifies otherwise.

[0311] As used herein, the terms “subject” or “patient” refer to a human or mammal, including but not limited to dogs, cats, horses, cattle, monkeys, etc.

[0312] When the term "about" is applied to parameters (such as pH, concentration, temperature, etc.), it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, numerical values ​​are usually given for illustrative purposes only, not as limitations.

[0313] The compounds disclosed herein may also contain non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. Non-natural proportions of isotopes can be defined as amounts ranging from those found in nature to those consisting of 100% of the relevant atoms. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 (14 C), or non-radioactive isotopes, such as deuterium (D) or carbon-13 (C). 13 C). Such isotopic variations can provide additional utility for those described elsewhere in this application. For example, isotopic variants of the compounds disclosed herein may be found to have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents.

[0314] In the compounds disclosed herein, any atom not specifically designated as a particular isotope refers to any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position should be understood to have hydrogen according to its native abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as “D” or “deuterium”, that position should be understood to have a deuterium abundance at least 3000 times greater than the native abundance of deuterium (i.e., 0.015%), i.e., at least 45% deuterium doping. The exemplary compounds have a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium doping), at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium doping), at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium doping), at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium doping), and at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium doping). 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 90% deuterium incorporation), at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation), or greater deuterium abundance.

[0315] Synthesis method

[0316] The compounds disclosed in this application are, or can be prepared according to, the following synthetic methods:

[0317] Option 1

[0318] A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0319]

[0320] Under acidic conditions, remove R from the compound of formula (IA) or its salt. t To obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0321] in:

[0322] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0323] X 2 It is hydrogen;

[0324] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0325] L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d , n and m are each defined as in equation (I).

[0326] Option 2

[0327] A method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0328]

[0329] Under acidic conditions, remove R from compounds of formula (IIA) or their salts. t To obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0330] in:

[0331] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0332] X 2 It is hydrogen;

[0333] X 1 For -LR 0 , where R 0It is -OP(=O)(OH)2; and

[0334] L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II).

[0335] Option 3

[0336] A method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0337]

[0338] Under acidic conditions, remove R from compound (II-1A) or its salt. t To obtain a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0339] in:

[0340] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0341] X 2 It is hydrogen;

[0342] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0343] L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II-1).

[0344] Option 4

[0345] A method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0346]

[0347] Under acidic conditions, remove R from compounds of formula (IIIA) or their salts. tTo obtain a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0348] in:

[0349] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0350] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0351] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III).

[0352] Option 5

[0353] A method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0354]

[0355] Under acidic conditions, remove R from compound (III-1A) or its salt. t To obtain a compound of formula (IIII-1) or a pharmaceutically acceptable salt thereof,

[0356] in:

[0357] R t It is an alkyl group; preferably, R t C 1-6 alkyl;

[0358] X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and

[0359] L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III-1).

[0360] Option 6

[0361] A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0362]

[0363] Under alkaline conditions, the compound of formula (IB) or its salt reacts with R. 0 -LR w The compound reacts to yield a compound or drug of formula (I) or its acceptable salt.

[0364] in:

[0365] R w It is a halogen; preferably, R w For Cl;

[0366] X 1 For -LR 0 ;

[0367] X 2 For hydrogen or -LR 0 ;and

[0368] R 0 L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d , n and m are each defined as in equation (I).

[0369] Option 7

[0370] A method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0371]

[0372] Under alkaline conditions, the compound of formula (IIB) or its salt reacts with R 0 -LR w The compound reacts to yield a compound or drug of formula (II) or its acceptable salt.

[0373] in:

[0374] R w It is a halogen; preferably, R w For Cl;

[0375] X 1 For -LR 0 ;

[0376] X 2 For hydrogen or -LR 0 ;and

[0377] R 0 L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II).

[0378] Option 8

[0379] A method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0380]

[0381] Under alkaline conditions, the compound of formula (II-1B) or its salt reacts with R 0 -LR w The compound reacts to give a compound of formula (II-1) or a pharmaceutically acceptable salt thereof.

[0382] in:

[0383] R w It is a halogen; preferably, R w For Cl;

[0384] X 1 For -LR 0 ;

[0385] X 2 For hydrogen or -LR 0 ;and

[0386] R 0 L, R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (II-1).

[0387] Option 9

[0388] A method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0389]

[0390] Under alkaline conditions, the compound of formula (IIIB) or its salt reacts with R 0 -LR w The compound reacts to give a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0391] in:

[0392] R w It is a halogen; preferably, R w For Cl;

[0393] X 1 For -LR 0 ;and

[0394] R 0 L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III).

[0395] Option 10

[0396] A method for preparing a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0397]

[0398] Under alkaline conditions, the compound of formula (III-1B) or its salt reacts with R 0 -LR w The reaction of the compounds yields a compound of formula (III-1) or a pharmaceutically acceptable salt thereof.

[0399] in:

[0400] R w It is a halogen; preferably, R w For Cl;

[0401] X 1 For -LR 0 ;and

[0402] R 0 L, R 4a R 4b R 5a R 5b R 6a and R 6b Each is as defined in equation (III-1).

[0403] The reagents providing acidic conditions in the above synthesis scheme include, but are not limited to, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, and nitric acid, with acetic acid or trifluoroacetic acid being preferred.

[0404] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, 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.

[0405] The reaction is preferably carried out in one or more solvents, including but not limited to acetic acid, trifluoroacetic acid, methanol, ethanol, butanol, dimethyl ether, acetonitrile, petroleum ether, n-hexane, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.

[0406] Example

[0407] The following examples are used to illustrate the present invention, but they should not be considered as limiting the scope of the invention. Unless otherwise specified, the experimental conditions in the examples generally follow the conventional or recommended conditions of the raw material and product manufacturers. Reagents not specifically sourced are all commercially available conventional reagents.

[0408] The structure of each compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) were determined at 10⁻⁶. -6 (ppm) values ​​are given. NMR was determined using a Bruker AVANCE-300, AVANCE-400, or AVANCE-500 instrument. Solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD).

[0409] High-performance liquid chromatography (HPLC) determination was performed using an Agilent 1200DAD HPLC system (Sunfire C18 150×4.6mm column), a Waters 2695-2996 HPLC system (Gimini C18 150×4.6mm column), or a Shimadzu UFLC system equipped with an Xbridge C18 (5µm 150×4.6mm) column.

[0410] Chiral high-performance liquid chromatography (HPLC) was performed on an LC-10A vp (Shimadzu), SFC-analytical (Berger Instruments Inc.), or Waters-UPC2 instrument.

[0411] MS was performed using a SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020), equipped with ACQUITY. Determination was performed using a Waters UPLC-QDa with a BEH (2.1*50mm 1.7μm) column, or an Agilent 6120 with an Xbridge C18 (5um 50×4.6mm) column.

[0412] The thin-layer silica gel plates used in the thin-layer chromatography (TLC) are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The plate size used in TLC is 0.15 mm to 0.2 mm, while the plate size used in TLC for product purification is 0.4 mm to 0.5 mm.

[0413] Column chromatography typically uses 200-300 mesh silica gel from Yantai Huanghai as the carrier.

[0414] The known starting materials of this invention can be prepared according to conventional synthesis methods in the prior art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Technology Co., Ltd., Darui Chemical, Fisher Scientific or Shanghai Yubo Biotechnology Co., Ltd., etc.

[0415] Unless otherwise stated, all reactions in the examples are performed under an argon or nitrogen atmosphere.

[0416] The terms "argon atmosphere" or "nitrogen atmosphere" refer to a reaction flask equipped with a 1L balloon of argon or nitrogen.

[0417] Unless otherwise stated, all solutions used in the following reactions are aqueous solutions.

[0418] Unless otherwise stated, all reaction temperatures in the examples are at room temperature.

[0419] Unless otherwise stated, the reaction temperature in the context refers to room temperature, which ranges from 20°C to 30°C.

[0420] The reaction process is monitored by LC-MS or thin-layer chromatography (TLC). The developing solvent system includes: 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 used for purifying the compound by column chromatography, thin-layer chromatography, and the CombiFlashflash rapid preparation instrument includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvent can be adjusted according to the polarity of the compound, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as acetic acid can be added.

[0421] The final compounds were purified by a Shimadzu (LC-20AD, SPD20A) preparative HPLC instrument (Phenomenex Gemini-NX 5μM C18 21.2×100mm column) equipped with a Sunfire Pre C18 (10μm 19×250mm) column in a Waters 2767 or equipped with an Xbridge Pre C18 (10μm 19×250mm) column in a Waters 2767-QDa instrument, using a water / MeOH or water / CH3CN elution system and optional additives such as HCOOH, TFA, and NH4HCO3.

[0422] CombiFlash is performed on Teledyne ISCO or Agela Technologies systems.

[0423] The following abbreviations are used in this application:

[0424] DIPEA is N,N-diisopropylethylamine.

[0425] HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0426] DCM stands for dichloromethane.

[0427] DMF is N,N-dimethylformamide.

[0428] DMSO stands for dimethyl sulfoxide.

[0429] EtOAc is ethyl acetate.

[0430] TBAI stands for tetrabutylammonium iodide.

[0431] TFA stands for trifluoroacetic acid.

[0432] Prep HPLC is a preparative high-performance liquid chromatography method.

[0433] NMR stands for proton nuclear magnetic resonance.

[0434] MS stands for mass spectrometry, where (+) indicates positive mode. It usually gives the M+1 (or M+H) absorption, where M = molecular mass.

[0435] Experimental steps

[0436] Intermediate 1 (Int-1)

[0437] (S)-3-(4-cyclopropyl-2,5-dioxoimidazoline-4-yl)propionic acid intermediate 1 (Int-1)

[0438]

[0439] Step 14 - Cyclopropyl-4-oxobutyrate tert-butyl ester Int-1-2

[0440] A solution of LDA (15.28 g, 142.66 mmol, 71.43 mL) in THF (50 mL) was cooled to -78 °C, and then a solution of cyclopropyl methyl ketone Int-1-1 (10 g, 118.88 mmol) in THF (10 mL) was added dropwise. The resulting solution was heated to 20 °C and stirred for 30 minutes. The reaction mixture was then cooled back to -78 °C, 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 overnight at room temperature. After the reaction was complete, the reaction was quenched with saturated NH4Cl (50 mL, aqueous solution), the mixture was extracted with EtOAc (50 mL × 3), the organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated to give the crude title compound Int-1-2 (22 g, 110.97 mmol, 93.34% yield).

[0441] 1 H NMR (400MHz, CDCl3): 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).

[0442] Step 2

[0443] (±)-3-(4-Cyclopropyl-2,5-Dioxoimidazoline-4-yl)tert-butyl propionate Int-1-3

[0444] A mixture of Int-1-2 (8.2 g, 41.36 mmol), ammonium carbonate (33.78 g, 351.56 mmol), sodium cyanide (5.07 g, 103.40 mmol), EtOH (50 mL), and water (50 mL) was sealed and heated to 80 °C for 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, washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography (EtOAc / hexane = 1 / 2) to give the title compound Int-1-3 (5.7 g, 21.24 mmol, 51.36% yield).

[0445] 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).

[0446] Steps 3 and 4

[0447] (S)-3-(4-Cyclopropyl-2,5-dioxoimidazolin-4-yl)propionic acid Int-1

[0448] A solution of Int-1-3 (7.2 g, 26.83 mmol) in HCl / dioxane (4 M, 50 mL) was stirred at room temperature for 4 hours and concentrated. The resulting solid was milled in MeCN (30 mL) for 1 hour and filtered to give the pure racemic target product Int-1-4 as a white solid. The solid was chirally separated by SFC (using a chiral column CHIRALPAK AD-H 10 μm 2.5*25 cm; flow rate / detection: 70 g / min; detector wavelength: 214 nm; mobile phase A: supercritical CO2; mobile phase B: methanol) to give the title compound Int-1 (2 g, 9.42 mmol, 35.12% yield).

[0449] 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).

[0450] Chiral HPLC: 98.04% ee, Rt: 2.918 min.

[0451] LCMS: MS m / z (ESI): 213.1 [M+1].

[0452] Example 1

[0453] (S)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[0454]

[0455] Step 15 - Amino-2-bromo-4-(trifluoromethyl)benzoic acid 1b

[0456] NBS (870 mg, 4.89 mmol) was added to a solution of 3-amino-4-(trifluoromethyl)benzoic acid 1a (1 g, 4.87 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 2 hours, and the resulting mixture was poured into ice water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give crude product 1b (1 g, 3.52 mmol, 72.22% yield).

[0457] Step 25 - Methyl 2-amino-2-bromo-4-(trifluoromethyl)benzoate 1c

[0458] H₂SO₄ (18M, 0.7mL) was added dropwise to a solution of 1b (1g, 3.52mmol) in MeOH (10mL). The mixture was stirred overnight at 75°C, then cooled to room temperature and poured into ice water (20mL). The mixture was extracted with EtOAc (50mL). The organic fraction was dried over Na₂SO₄ and filtered. The filtrate was concentrated to give crude product 1c (1g, 3.36mmol, 95.29% yield).

[0459] 1 H NMR (400MHz, DMSO-d6): δ7.57(s,1H),7.21(s,1H),6.11(brs,2H),3.85(s,3H).

[0460] Step 35: Methyl 5-amino-2-methyl-4-(trifluoromethyl)benzoate 1d

[0461] To a solution of 1c (1 g, 3.36 mmol) in DMF (10 mL), Pd(PPh3)4 (430 mg, 372.11 μmol), K3PO4 (2.2 g, 10.36 mmol), and methylboric acid (1 g, 16.71 mmol) were added. The mixture was stirred overnight at 130 °C under a nitrogen atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 1d (500 mg, 2.14 mmol, 63.91% yield).

[0462] LCMS: MS m / z(ESI): 234.1[M+H] + .

[0463] Step 45 - methyl 4-chloro-2-methyl-4-(trifluoromethyl)benzoate 1e

[0464] Concentrated HCl (2 mL) was added to a solution of 1d (2.0 g, 8.58 mmol) in acetone (20 mL), and the mixture was stirred at room temperature for 20 minutes. The mixture was cooled to -5 to 0 °C, and a solution of NaNO2 (600 mg, 8.70 mmol) in H2O (2.5 mL) was added dropwise, and the mixture was stirred at ambient temperature for 30 minutes. CuCl (849.11 mg, 8.58 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into 1N HCl (50 mL) and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to give 1e (1.3 g, 5.15 mmol, 60.00% yield).

[0465] Step 52-Bromo-5-chloro-4-(trifluoromethyl)benzoate methyl ester 1f

[0466] To a solution of 1e (1.3 g, 5.15 mmol) in CCl4 (20 mL), NBS (1.10 g, 6.18 mmol) and AIBN (25.35 mg, 154.38 μmol) were added. The mixture was heated to 70 °C and stirred overnight. The mixture was cooled to room temperature and filtered. The filter cake was washed with CCl4, and the filtrate was concentrated under vacuum to give crude product 1f (1.9 g, 5.73 mmol, 111.37% yield).

[0467] Step 66 - Chloro-5-(trifluoromethyl)isoindoline-1-one 1g

[0468] To a solution of 1f (1.9 g, 5.73 mmol) in MeOH (10 mL), NH3 / MeOH (20 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (hexane:EtOAc = 1:1) to give 1 g (920 mg, 3.91 mmol, 68.14% yield).

[0469] LCMS: MS m / z(ESI): 236.0[M+H] + .

[0470] Step 75 - Chloro-6-(trifluoromethyl)isoindoline 1h

[0471] Add 1 g (570 mg, 2.42 mmol) of BH3 / THF (167.36 mg, 12.10 mmol, 15 mL) to a solution of 1 g (570 mg, 2.42 mmol) in THF (5 mL) and stir the mixture overnight at 60 °C. Cool the reaction to room temperature and quench with methanol. Adjust the pH of the mixture to 1–2 with 1 M HCl. Then heat the mixture to 45 °C and stir for 30 min. After cooling to room temperature, adjust the pH of the mixture to 7–8 with 1 M NaOH. Add water and extract the mixture with EtOAc. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by preparative TLC (DCM:MeOH = 10:1) to 1 h (10 mg, 45.13 μmol, 1.87% yield).

[0472] 1 HNMR (400MHz, DMSO-d6): δ7.78(s,1H),7.65(s,1H),4.16(br,2H),4.14(br,2H).

[0473] LCMS: MS m / z(ESI): 222.1[M+H] + .

[0474] Step 8

[0475] (S)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione

[0476] TEA (50 μL), Int-1 (10 mg, 45.12 μmol), and HATU (17.16 mg, 45.12 μmol) were added to a solution of 1 h (10 mg, 45.12 μmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 3 h. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to give compound 1 (5 mg, 12.03 μmol, 26.65% yield).

[0477] 1 H NMR (400MHz, DMSO-d6): 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).

[0478] 19 F NMR (376.5MHz, DMSO-d6): δ-60.86.

[0479] LCMS: MS m / z(ESI): 416.4[M+H] + .

[0480] Example 2

[0481] (5S)-5-(3-(5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3-d2)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione 2 (diastereomeric mixture)

[0482]

[0483]

[0484] Step 15 - Methyl amino-4-(trifluoromethyl)-2-vinylbenzoate 2b

[0485] 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), Pd(dppf)Cl2 (1.34 g, 1.83 mmol) and K2CO3 (6.35 g, 45.71 mmol) were added. The resulting mixture was evacuated and refilled three times with N2. The mixture was stirred at 80 °C for 16 hours. The mixture was diluted with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give title compound 2b (3.56 g, 14.52 mmol, 79.40% yield).

[0486] LCMS: MS m / z(ESI): 246.1[M+H] + .

[0487] Step 25 - Methyl 2-amino-2-ethyl-4-(trifluoromethyl)benzoate 2c

[0488] Pd / C (1.55 g, 1.45 mmol, 285.48 μL, 10% purity) was added to a solution of 2b (3.56 g, 14.52 mmol) in MeOH (20 mL). The resulting mixture was evacuated and refilled with H2. The mixture was stirred at room temperature for 16 hours, and LC-MS indicated that the reaction was complete. The mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to give the title compound 2c (3.45 g, 13.96 mmol, 96.12% yield).

[0489] LCMS: MS m / z(ESI): 248.1[M+H] + .

[0490] Step 35 - methyl 2-chloro-2-ethyl-4-(trifluoromethyl)benzoate 2d

[0491] HCl (3.36 mL) was added to a solution of 2c (3.36 g, 13.59 mmol) in acetone (34 mL). The resulting mixture was stirred at room temperature for 20 minutes. After cooling the mixture to 0 °C, a solution of NaNO2 (1.88 g, 27.18 mmol) in water (5 mL) was added. Then, CuCl (1.48 g, 14.95 mmol) was added in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into 1 M HCl (60 mL), and the aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, 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, 8.36 mmol, 61.53% yield).

[0492] 1 H NMR (400MHz, DMSO-d6): δ7.99(s,1H),7.87(s,1H),3.88(s,3H),2.92(q,2H),1.17(t,3H).

[0493] Step 4

[0494] (±)-2-(1-bromoethyl)-5-chloro-4-(trifluoromethyl)benzoate methyl ester 2e

[0495] AIBN (412.00 mg, 2.51 mmol) and NBS (1.64 g, 9.20 mmol) were added to a solution of 2d (2.23 g, 8.36 mmol) in CCl4 (35 mL). The resulting mixture was stirred at 80 °C for 16 hours. The mixture was filtered. The solid was washed with DCM, and the filtrate was concentrated under vacuum to give the crude title compound 2e (2.5 g, 7.24 mmol, 86.51% yield).

[0496] 1 H NMR (400MHz, DMSO-d6): δ8.17(s,1H),8.04(s,1H),6.08(q,1H),3.92(s,3H),2.05(d,3H).

[0497] Step 5

[0498] (±)-6-chloro-3-methyl-5-(trifluoromethyl)isoindolin-1-one 2f

[0499] NH3 / MeOH (7M, 30mL) was added to a solution of 2e (2.5g, 7.24mmol) in MeOH (10mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound 2f (1.18g, 4.73mmol, 65.34% yield).

[0500] 1 H NMR (400MHz, DMSO-d6): δ9.11(brs,1H),8.20(s,1H),7.91(s,1H),4.71(q,1H),1.42(d,3H).

[0501] 19 F NMR (376.5MHz, DMSO-d6): δ-60.99.

[0502] LCMS: MS m / z(ESI): 250.0[M+H] + .

[0503] Step 6

[0504] (±)-5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-3,3-d2 2g

[0505] To a solution of 2f (800 mg, 3.20 mmol) of 6-chloro-3-methyl-5-(trifluoromethyl)isoindolin-1-one in 10 mL of THF, BD3 (1 M THF solution, 64 mL, 64 mmol) was added. After addition, the reaction was stirred at 60 °C (in a sealed tube) for 10 h. It was quenched with MeOH (10 mL), followed by HCl (6 M, 20 mL). The mixture was then stirred at 80 °C for 8 h. 2N NaOH was added to adjust the pH to 7, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% MeOH in DCM solution to give 2 g of the desired product for the next step.

[0506] LCMS: MS m / z(ESI): 238.1[M+H] + .

[0507] Step 7

[0508] (5S)-5-(3-(5-chloro-1-methyl-6-(trifluoromethyl)isoindoline-2-yl-3,3-d2)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione 2 (diastereomeric mixture)

[0509] To (S)-3-(4-cyclopropyl-2,5-dioxoimidazoline-4-yl)propionic acid Int-1 (680 mg, 3.2 mmol), EDCI (920 mg, 4.8 mmol) and HATU (1.83 g, 4.8 mmol) were added to a 10 mL DMF solution. After stirring for 10 minutes, 2 g of isoindoline collected from the previous step was added. The reaction was stirred at ambient temperature for 3 hours. LCMS showed that the reaction was complete. It was then purified directly by reversed-phase HPLC to give the desired product 2 (1.10 g, two-step yield 76.9%).

[0510] 1 H NMR(400MHz,CD3OD,):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).

[0511] LCMS:MS m / z(ESI):432[M+H] + .

[0512] Examples 2-1 and 2-2

[0513] (S)-5-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindololin-2-yl-3,3-d2)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione 2-1

[0514] (S)-5-(3-((S)-5-chloro-1-methyl-6-(trifluoromethyl)isoindololin-2-yl-3,3-d2)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione 2-2

[0515]

[0516] Two diastereomers, 2-1 (325 mg, 29.5% yield) and 2-2 (415 mg, 37.7% yield), were obtained by separation of 2 (1.10 g) using SFC.

[0517] Compound 2-1:

[0518] 1H NMR(500MHz,DMSO-d6)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).

[0519] LCMS: MS m / z(ESI): 432.3[M+H] + .

[0520] Chiral HPLC (1% DEA in ethanol / hexane solution 60 / 40, 1.0 mL / min, 35 °C, CHIRALPAK IG, 150*4.6 mm, 5 μm): Rt: 4.594 min, de: 100%.

[0521] Compound 2-2:

[0522] 1 H NMR(500MHz,DMSO-d6)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).

[0523] LCMS: MS m / z(ESI): 432.3[M+H] + .

[0524] Chiral HPLC (1% DEA in ethanol / hexane solution 60 / 40, 1.0 mL / min, 35℃, CHIRALPAK IG, 150*4.6 mm, 5 μm): Rt: 10.931 min, de: 100%.

[0525] Example 3

[0526] (S)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylpentanoate 3

[0527]

[0528] At 0 °C, 0.3 mL of 1 N NaOH aqueous solution was added to a solution of (S)-5-(3-(5-chloro-6-(trifluoromethyl)isoindoline-2-yl)-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione 1 in DMF (5 mL). After stirring at this temperature for 10 min, methyl tert-pentanoate (48 mg, 0.32 mmol) was added. The reaction was slowly heated to ambient temperature and stirred for 12 h. The reaction was then directly applied to a reversed-phase preparative HPLC system using 10–60% CH3CN / H2O as eluent to give the desired product 3 (75 mg, 88.6% yield).

[0529] 1 H NMR (400MHz, CDCl3): 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).

[0530] LCMS:m / z(ESI):530.1[M+H] + .

[0531] Example 4

[0532] ((S)-4-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-d2)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylpentanoate 4

[0533]

[0534] To a solution of compound 2-1 (120 mg, 0.28 mmol) in 10 mL of DMF, 0.6 mL of 1 N NaOH aqueous solution was added at 0 °C. After stirring for 10 min, methyl tert-pivalate (168 mg, 1.12 mmol) was added. The reaction was slowly heated to ambient temperature and stirred for 12 h. The product was purified by reversed-phase preparative HPLC using 10-60% CH3CN and H2O as eluents to give the desired product 4 (40 mg, 26.2% yield).

[0535] 1H NMR (400MHz, CDCl3): 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).

[0536] LCMS:m / z(ESI):546.1[M+H] + .

[0537] Example 5

[0538] (S)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylphosphodihydrogen ester 5

[0539]

[0540] Step 1

[0541] (S)-Di-tert-butyl((4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazoline)-1-yl)methyl)phosphate 5a

[0542] To a suspension of 1 (166 mg, 0.40 mmol) in THF (1 mL), 2.0 mL of 0.2 N NaOH aqueous solution was added. The reaction mixture became clear and was stirred at room temperature for 10 min. The solvent was removed under vacuum. Then, 2 mL of DMF and 94 mg, 0.68 mmol of K₂CO₃ were added, followed by di-tert-butyl (chloromethyl)phosphate (0.14 mL, 0.54 mmol). The reaction mixture was stirred at 45 °C for 16 h. LC-MS showed a conversion of approximately 70%. EtOAc (100 mL) was added, and the organic phase was washed with brine (40 mL). The organic solvent was dried over anhydrous Na₂SO₄ and purified by silica gel chromatography, eluting with hexane / EtOAc, to give crude product 5a, which was used directly in the next step.

[0543] LCMS:m / z(ESI):638.2[M+H] + .

[0544] Step 2

[0545] (S)-(4-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-yl)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylphosphodihydrogen ester 5

[0546] A mixture of AcOH / H2O (0.60 / 0.15 mL) was added to crude compound 5a (0.40 mmol, from the previous step). The mixture was heated at 60 °C for 1.5 h. The reaction mixture was then carefully neutralized to pH 7.0 at 0 °C with an aqueous solution of 2N Na2CO3. The resulting mixture was purified by preparative HPLC using 10–30% CH3CN and H2O with 0.5% NH4HCO3 as eluent, and lyophilized to give product 5 (53 mg, 25.2% two-step yield).

[0547] 1 H NMR (400MHz, Methanol-d4): δ7.70(d,1H),7.54(d,1H),5.18(d,1H),5.11(t,1H),4.83(d,2H),4.6 8(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).

[0548] 31 P NMR (400MHz, CD3OD): δ-0.50.

[0549] 19 F NMR (376.5MHz, CD3OD): δ-63.6.

[0550] LCMS:m / z(ESI):526.1[M+H] + .

[0551] Example 6

[0552] ((S)-4-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-d2)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylphosphodihydrogen ester 6

[0553]

[0554] Step 1

[0555] (S)-5-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-d2)-3-oxopropyl)-5-cyclopropyl

[0556] -3-((methylthio)methyl)imidazoline-2,4-dione 6a

[0557] To a solution of compound 2-1 (500 mg, 1.02 mmol) in DMF (12 mL), NaOH (82 mg, 2.04 mmol) and TBAI (754 mg, 2.04 mmol) were added at 0 °C. After addition, the mixture was heated to ambient temperature and stirred for 30 min. Then, (chloromethyl)(methyl)thione (394 mg, 4.08 mmol) was added. The reaction was stirred at ambient temperature for 1 h and post-treated with water and ethyl acetate (40 + 120 mL). The organic layer was collected and purified by silica gel chromatography, eluting with 75% EtOAc / CH2Cl2 to give the desired product 6a (250 mg, 71.0% yield).

[0558] LCMS:m / z(ESI):492.1[M+H] + .

[0559] Step 2

[0560] (S)-5-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindololin-2-yl-3,3-d2)-3-oxopropyl)-3-(chloromethyl)-5-cyclopropylimidazoline-2,4-dione 6b

[0561] Triethylamine hydrochloride (210 mg, 1.53 mmol) was added to a solution of 6a (250 mg, 0.51 mmol) in CH₂Cl₂ (20 mL), followed by sulfonyl chloride (1 N CH₂Cl₂ solution, 0.77 mL, 0.77 mmol). After addition, the reaction mixture was stirred at ambient temperature for 2 hours. LC-MS showed that the reaction was complete. The solvent was removed under vacuum, and the resulting crude mixture 6b was used directly for the next step.

[0562] LCMS:m / z(ESI):480.1[M+H] + .

[0563] Step 3

[0564] Di-tert-butyl(((S)-4-(3-(((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-d2)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methyl)phosphate 6c

[0565] To a solution of 6b (0.51 mmol, from the previous step) in acetonitrile (20 mL), potassium di-tert-butyl phosphate (228 mg, 0.92 mmol) was added, followed by the addition of NaHCO3 (10 mg, 0.1 mmol). After addition, the reaction was stirred at 75 °C for 12 hours. LC-MS showed the reaction was complete. The solution was concentrated under vacuum and purified by silica gel chromatography, eluting with 90% EtOAc / CH2Cl2 to give the desired product 6c (301 mg, 90% from both steps).

[0566] 1 H NMR (400MHz, CD3OD): 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).

[0567] LCMS:m / z(ESI):654.1[M+H] + .

[0568] Step 4

[0569] ((S)-4-(3-((R)-5-chloro-1-methyl-6-(trifluoromethyl)isoindolin-2-yl-3,3-d2)-3-oxopropyl)-4-cyclopropyl-2,5-dioxoimidazolin-1-yl)methylphosphodihydrogen ester 6

[0570] The solution of 6c (255 mg, 0.41 mmol) in a CH3CN / water / TFA = 2 / 2 / 1 (50 mL) mixture was stirred at ambient temperature for 16 hours. LC-MS showed that the reaction was complete. The solution was then directly applied to a reversed-phase preparative HPLC, using 10-30% CH3CN and H2O with 0.5% NH4HCO3 as eluents, and lyophilized to give the desired product 6 (221 mg, 99.5% yield).

[0571] 1 H NMR (400MHz, CD3OD): 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).

[0572] 31 P NMR (400MHz, CD3OD): δ-1.5.

[0573] 19 F NMR (376.5MHz, CD3OD): δ-63.6.

[0574] LCMS:m / z(ESI):542.1[M+H] + .

[0575] Biological tests

[0576] This disclosure will be further described in conjunction with the following test examples, but these examples should not be considered as limiting the scope of this disclosure.

[0577] Test Example 1. In vitro fluorescence assay of ADAMTS-4 or ADAMTS-5 activity

[0578] The fluorescence resonance energy transfer (FRET) peptide was cleaved into two separate fragments by recombinant ADAMTS-4 or ADAMTS-5 protein, resulting in a quantifiable increase in fluorescence signal. The peptide, 5-FAM-TEGEARGSVILLK(5-TAMRA)K-NH2, was custom-made from ANASPEC. Recombinant ADAMTS-4 protein (catalog number 4307-AD) and recombinant ADAMTS-5 protein (catalog number 2198-AD) were purchased from R&D Systems.

[0579] An assay buffer containing 50 mM HEPES (pH 7.5), 100 mM NaCl, 5 mM CaCl2, 0.1% CHAPS, and 5% glycerol was prepared. 2.5 μL of the compound in the assay buffer was aliquoted into 384-well plates, and 2.5 μL of ADAMTS-4 or ADAMTS-5 protein (final concentration in the reaction was 10 nM) was added. The compound and protein were pre-incubated at room temperature for 15 min. Then, 5 μL of substrate was added to each well. The final substrate concentrations for ADAMTS-4 and ADAMTS-5 were 15 μM and 8 μM, respectively. After incubation at 37 °C for 3 hours, the fluorescence signal in each well was measured using a TECAN plate reader (excitation, 490 nm; emission, 520 nm).

[0580] Data Analysis:

[0581] Input the data into GraphPad Prism and use the function "log(inhibitor) vs. response -- Variable slope (four parameters)" to calculate the IC. 50Values. (See Table 1)

[0582] Table 1. IC50 of example compounds in FRET-peptidase assay 50 value

[0583]

[0584] Conclusion: The parent compounds 1 and 2-1 disclosed herein exhibit significant inhibitory effects on the enzymatic activities of ADAMTS-4 and ADAMTS-5. Their prodrug molecules 3, 4, 5, and 6 show no enzymatic activity against ADAMTS-4 and ADAMTS-5.

[0585] Example 2. In vitro ELISA (enzyme-linked immunosorbent assay) for ADAMTS-5 activity.

[0586] In this assay, the enzyme activity of recombinant ADAMTS-5 protein (catalog number 2198-AD, R&D Systems) was measured using a protein substrate (aggregatin IGD protein). Aggregatin IGD protein is a polypeptide linked to human aggregatin globular domains 1 and 2 (T331-G458) expressed in E. coli with a C-terminal His tag (catalog number 30411000, BIOTEZ). The enzymatic product ARGSVIL-peptide was detected using an ELISA kit from BioTEZ (catalog number 30510111).

[0587] Prepare an assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM CaCl2, 0.1% CHAPS, and 5% glycerol. Dilute recombinant ADAMTS-5 protein to 0.3 nM in the assay buffer. Transfer 10 μL of the buffer and 10 μL of the compound solution to each well of a 96-well plate and incubate at room temperature for 15 min. Dilute the substrate agglutinin-IGD to 100 nM with the assay buffer and add 20 μL to each well. Incubate the plate at 37 °C for 45 min. After incubation, measure the newly generated epitope ARGSVIL-peptide using the Aggrecanase Activity ELISA Assay Kit according to the manufacturer's instructions. Then, add 100 μL of stop solution and read the absorbance of each well at 450 nM on a TECAN plate reader, using 620 nM as a reference.

[0588] Data Analysis:

[0589] A standard curve for ELISA assays was generated in GraphPad Prism using the Sigmoidal 4PL function, and the corresponding peptide concentrations were calculated based on the standard curve. The IC50 was calculated using the function "log(inhibitor) vs. effect - variable slope (four parameters)". 50 Values. (See Table 2).

[0590] Table 2. IC50 of example compounds in proteoglycan-IGD enzyme assay 50 value

[0591] Example number <![CDATA[ADAMTS-5(IC 50 ,nM)]]> 1 92 2-1 13

[0592] Conclusion: The parent compounds 1 and 2-1 disclosed herein have a significant inhibitory effect on the enzyme activity of ADAMTS-5.

[0593] Test Example 3. Fassif Solubility Test of the Compounds of this Disclosure

[0594] 3.1 Preparation of the reference solution

[0595] Weigh an appropriate amount of the analyte and dissolve it in DMSO to obtain a 10 mM stock solution. Accurately measure 10 μL of the stock solution and 990 μL of organic solvent (a mixture of DMSO:acetonitrile:ethanol = 1:1:1 (v / v / v)) into a 2 mL vial and mix thoroughly. This clear 100 μM sample solution is used as a reference solution.

[0596] 3.2 Preparation of the Fassif solution for the test compound

[0597] Dissolve 1 mg of the test sample in 900 μL of FaSSIF solution and mix vigorously. Prepare two parallel solutions and shake in a 37°C water bath for 24 hours. Then centrifuge the solutions at 4000 rpm for 30 minutes and transfer the supernatant to HPLC for analysis.

[0598] 3.3. Data Processing

[0599] Solubility (μM) = Sample peak area / Reference peak area * Reference concentration (μM) * Sample solution dilution factor. The average of the two measurements is taken as the final solubility (see Table 3).

[0600] Table 3. Solubility test of the compounds disclosed herein

[0601]

[0602] Conclusion: Prodrug molecules 3, 4, 5 and 6 exhibit improved Fassif solubility compared to their parent compounds 1 and 2-1.

[0603] Test Example 4. Pharmacokinetic Determination

[0604] instrument

[0605] API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA;

[0606] Shimadzu LC-30AD Ultra-High Performance Liquid Chromatography System, Shimadzu, Japan.

[0607] Chromatographic conditions:

[0608] Column: Welch Xtimate C18 1.8μm 30x2.1mm

[0609] Mobile phase A: 0.5% formic acid, 5mM ammonium acetate aqueous solution (gradient elution)

[0610] Mobile phase B: 0.5% formic acid in 5mM ammonium acetate in 95% acetonitrile / aqueous solution (gradient elution)

[0611] Column temperature: 35℃

[0612] Preparation of test samples

[0613] Mix 25 μL of plasma sample with 50 μL of internal standard solution (100 ng / mL) and 200 μL of CH3CN precipitant. Vortex the solution for 5 minutes, then centrifuge for 10 minutes (4000 rpm). Take 8 μL of the supernatant for LC / MS / MS analysis.

[0614] process

[0615] In the Sprague Dawley rat PK study, animals in each group (N=4, 2 males and 2 females) were fasted overnight. The gavage (ig) group received the drug via oral force-feeding. Serial blood samples (0.2 mL) were collected from the orbital cavity at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours and deposited into dipotassium ethylenediaminetetraacetate (K2 EDTA) blood collection tubes, followed by centrifugation at 4°C (10,000 rpm) for 1 minute to obtain plasma. For the intravenous (iv) group, serial blood samples (0.2 mL) were collected from the orbital cavity at time points of -5 minutes, 5 minutes, 15 minutes, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours and deposited into dipotassium ethylenediaminetetraacetate (K2 EDTA) blood collection tubes. Plasma samples were isolated within 1 hour and stored at -20°C until analysis by liquid chromatography-tandem mass spectrometry (LC / MS / MS). The entire process from blood collection to centrifugation was performed on ice. Rats were fed 2 hours after drug administration.

[0616] Data Analysis

[0617] Pharmacokinetic parameters were obtained through non-compartmental analysis of plasma concentrations (measured by LC / MS / MS) versus time data. Peak concentrations (C0.05) were recorded directly from experimental observations. max ) and C max The area under the curve (AUC) from time zero to the last sampling time is calculated using a combination of linear and logarithmic trapezoidal summations. 0-t ).

[0618] result

[0619] The results of rat ig PK are shown in Table 4.

[0620] Table 4. Rats pharmacokinetic results of Examples 2-1 and Example 6 (prodrug).

[0621]

[0622] Conclusion: Upon oral administration to rats, prodrug molecule 6 was almost completely converted to its parent compound 2-1. Significantly higher parent drug exposure was observed in Example 6 in a rat ig 100mpk PK study compared to the same dose of Example 2-1.

[0623] abbreviation:

[0624] C max Maximum serum concentration;

[0625] PEG400: Polyethylene glycol 400;

[0626] HPMC K100LV: Hydroxypropyl methylcellulose (HPMC) K100LV;

[0627] TPGS: D-α-Tocopherol Polyethylene Glycol 1000 Succinate.

[0628] The foregoing embodiments and examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on this disclosure, and such changes and modifications can be made without departing from the spirit and scope of this disclosure. All cited documents are incorporated herein by reference in their entirety, but are not acknowledged as prior art.

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt. in: X 1 and X 2 Same or different, and each independently is hydrogen or -LR 0 The condition is X 1 and X 2 Not all of them are 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 and hydrogen; Cy is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, each optionally selected independently from C10 by one or more groups. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Substitution with hydroxyalkyl, cyano, amino, nitro, 3- to 8-membered cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups; Q 1 and Q 2 They may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally selected independently from C10. 1-6 Substituents of alkoxy, halogen, hydroxyl, cyano, amino, nitro, 3 to 8-membered cycloalkyl, 3 to 10-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Q 3 Selected from hydrogen, C 1-6 Alkyl, 3- to 8-membered cycloalkyl and 3- to 10-membered heterocyclic groups, wherein the C 1-6 Alkyl, 3- to 8-membered cycloalkyl, or 3- to 10-membered heterocyclic groups may be selected independently of one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, -NQ 6 Q 7 Substitution with nitro, 3 to 8-membered cycloalkyl, 3 to 10-heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl groups; Q 4 and Q 5 Same or different, and each independently selected from C 1-6 Alkyl, 3- to 8-membered cycloalkyl and 3- to 10-membered heterocyclic groups, wherein the C 1-6 Alkyl, 3- to 8-membered cycloalkyl, or 3- to 10-membered heterocyclic groups may be selected independently of one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, -NQ 6 Q 7 -OC(=O)Q 8 -OC(=O)OQ 8 Substituents of 3- to 8-membered cycloalkyl, 3- to 10-heterocyclic, 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups; Q 6 and Q 7 They may be the same or different, and each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl and 3- to 10-heterocyclic groups; Q 8 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl groups; R 1 Selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl and 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, 3- to 6-membered cycloalkyl, or 5- to 6-membered heteroaryl groups may be selected independently from C10. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Hydroxyl group substitution; R 2a R 2b R 3a and R 3b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally substituted with one or more independent C24 groups. 1-6 Alkoxy and C 1-6 Hydroxyl group substitution; R 4a R 4b R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or R 4a R 4b R 5a and R 5b The two atoms in the group, together with the carbon atoms they are attached to, form 3- to 4-membered cycloalkyl groups or 5- to 6-membered heterocyclic groups; R 6a R 6b R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyl, cyano, and nitro groups; n is 1 or 2; m is 1 or 2; t is 1 or 2; and s is 0 or 1.

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

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 3a R 6c and R 6d They may be the same or different, and each is independently selected from hydrogen, halogens, and C. 1-6 alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is a compound of formula (II) or a pharmaceutically acceptable salt thereof. in: X 1 X 2 R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each as defined in claim 1.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof. in: X 1 X 2 R 1 R 3b R 4a R 4b R 5a R 5b R 6a and R 6b Each as defined in claim 1.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a 3- to 6-membered cycloalkyl group.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is a compound of formula (III) or a pharmaceutically acceptable salt thereof. in: X 1 R 4a R 4b R 5a R 5b R 6a and R 6b Each as defined in claim 1.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 2 For hydrogen or -LR 0 L is -CQ 1 Q 2 -;R 0 Q 1 and Q 2 As defined in claim 1.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein, X 2 For hydrogen or -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; and Q 1 Q 2 and Q 3 As defined in claim 1.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Q 1 and Q 2 As defined in claim 1.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein X 1 For -LR 0 L is -CQ 1 Q 2 -;R 0 Selected from -OP(=O)(OH)2, -OC(=O)Q 3 and -OP(=O)(OH)-OP(=O)(OH)2; and Q 1 Q 2 and Q 3 As defined in claim 1.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 1 and Q 2 They are the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl; and / or Q 3 C 1-6 alkyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4a R 4b R 5a and R 5b Each may be the same or different, and each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, hydroxyl groups and C 1-6 Hydroxyalkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b Each may be the same or different, and each is independently selected from hydrogen, halogen, and carbon. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

16. Selected from the following compounds: and Or its pharmaceutically acceptable salt.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , and .

18. Compounds of formula (IA) or their salts: in: R t C 1-6 alkyl; X 2 It is hydrogen; and L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d n and m are each as defined in claim 1.

19. The compound of claim 18 or a salt thereof, wherein the compound is selected from: and .

20. A method for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Remove R from compound of formula (IA) or its salt t To obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof, in: R t C 1-6 alkyl; X 2 It is hydrogen; X 1 For -LR 0 , where R 0 It is -OP(=O)(OH)2; and L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d m and n are each as defined in claim 1.

21. A method for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Compound of formula (IB) or its salt with R 0 -LR w The compound reacts to yield a compound of formula (I) or a pharmaceutically acceptable salt thereof. in: R w It is a halogen; X 1 For -LR 0 ; X 2 For hydrogen or -LR 0 ;and R 0 L, R 1 R 2a R 2b R 3a R 3b R 4a R 4b R 5a R 5b R 6a R 6b R 6c R 6d m and n are each as defined in claim 1.

22. The method for preparing the compound of formula (I) according to claim 21 or a pharmaceutically acceptable salt thereof, wherein, R w It is Cl.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 23, in the preparation of a medicament for the prevention or treatment of arthritis.

25. The use according to claim 24, wherein, The arthritis referred to is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and hypertrophic arthritis.

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