CA3169225A1 - Adamts inhibitors, preparation methods and medicinal uses thereof - Google Patents

Abstract

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

Description

ADAMTS INHIBITORS, PREPARATION METHODS AND
MEDICINAL USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119(e) to United States Provisional Patent Application No. 62/969,992, filed on February 4, 2020; No. 63/046,267, filed on June 30, 2020; No. 63/066,148, filed on August 14, 2020; and No. 63/087,656, filed on October 5, 2020, the disclosures of all of which are incorporated herein by reference in their entireties.
FIELD OF THE DISCLOSURE
The present disclosure relates to compounds and methods in inhibiting the function of ADAMTS-5 and/or ADAMTS-4 and their application in the treatment of diseases involving degradation of cartilage or disruption of cartilage homeostasis, such as osteoarthritis and/or rheumatoid arthritis.
BACKGROUND OF THE DISCLOSURE
Cartilage is the highly specialized connective tissue of diarthrodial joints.
Its principal function is to provide the joints the capability of load bearing and compression resistance.
Chondrocyte is the cellular component of articular cartilage, taking about only 5% of the tissue volume. The main component of cartilage is extracellular matrix comprising aggrecan and collagen. Under physiological conditions, cartilage homeostasis is maintained by a balance between production (anabolism) and degradation (catabolism) of aggrecan and collagen.
However, the balance is shifted to catabolism in diseases such as osteoarthritis.
Osteoarthritis is the most common chronic joint disease and a leading cause of pain and disability in developed countries. It can happen to the joints of the hips, knees, spines, hands and others. It was estimated that worldwide 250 million people are currently being affected by osteoarthritis, and the prevalence is progressively rising (Hunter et al., Lancet. 2019, 393:
1745-1759). Pain and loss of functional capacity are accompanied by an increased risk of additional disease conditions such as diabetes, cancer or cardiovascular disease (Valdes AM
and Stocks J Osteoarthritis and ageing. Eur Med J. 2018, 3:116-123).
Osteoarthritis is a whole joint disease, the structural changes of which are found to be 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 very clear, with mechanical damage, inflammation, aging, and metabolism factors being involved. Osteoarthritis is not a passive degenerative disease, but an active dynamic alteration arising from an imbalance between the repair and destruction of joint tissues (Hunter et al., Lancet. 2019, 393: 1745-1759). Currently, the pharmacological treatments available for osteoarthritis are limited to symptomatic relief of pain and inflammation. Disease-modifying drugs that arrest or slow down disease progression are not available.
Progressive loss of articular cartilage is currently viewed as an early event in osteoarthritis. Aggrecan may have a role protecting loss of collagen (Pratta et al., J Biol Chem.
2003, 278: 45539-45545). These studies suggest the critical role of aggrecan in osteoarthritis and other joint diseases. Aggrecan is a proteoglycan, possessing a core protein with covalently attached sulfated glycosaminoglycan (GAG) chains. Its core protein has three globular domains, G1 and G2 domains in the N-terminus, and G3 in the C-terminus. The extensive region between the G2 and G3 domains is heavily modified by GAG keratan sulfate (KS) and chondroitin sulfate (CS). Based on the difference in the amino acid sequence, the CS
domain is further divided into two subdomains, CS 1 and C52. The GAG chains provide aggrecan with its high anionic charge. Multiple aggrecan monomers bind to hyaluronan (HA) through G1 domains, which is stabilized by a link protein, forming large supramolecular aggregates. The large aggrecan aggregates absorb water and provide the resilient properties for the cartilage (Roughley et al., The Journal of Experimental Orthopaedics. 2014, 1: 8). A
high concentration of aggrecan, a high degree of sulfation and the ability to form large aggregation is required for the normal function of cartilage.
The extended structure of aggrecan can be cleaved by proteolytic enzymes, leading to impaired normal function of cartilage. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a family of zinc ion-dependent metalloproteases.
ADAMTS-4 and -5, also termed "aggrecanases", degrade aggrecan at several specific locations in the IGD and the C52 domain. It was demonstrated that ADAMTS-5 deficiency protects against aggrecan loss and cartilage damage in mouse osteoarthritis disease model induced by surgeries (Glasson et al., Nature. 2005, 434: 644-648; Stanton et al., Nature. 2005, 434:648-652), implicating ADAMTS-5 in driving cartilage loss and osteoarthritis disease severity.
However, some studies in human cartilage explant culture suggested that not only ADAMTS-5, but also are important for human osteoarthritis (Verma et al., Journal of Cellular Biochemistry. 2011, 112: 3507-3514). These studies strongly suggest that inhibiting the enzymatic function of ADAMTS-5 and ADAMT-4 might provide a protecting role in osteoarthritis.

2 In sum, the role of ADAMTS-5 and/or ADAMTS-4 in cartilage degradation has been well-established. Therefore, compounds that can inhibit ADAMTS-5 and/or ADAMTS-4 may be of therapeutic value in the treatement of arthritis.
SUMMARY OF THE DISCLOSURE
The compounds of this disclosure inhibit the function of ADAMTS-5 and/or ADAMTS-4 and accordingly may serve as therapeutic agents for the treatment of diseases involving degradation of cartilage or disruption of cartilage homeostasis, in particular, osteoarthritis and/or rheumatoid arthritis.
The present disclosure, in one aspect, provides a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R2a R2b R4a 0 R4b HN R3b R3a \\G2 0 R5a R5b G4G3 (I) wherein:
G1, G2, G3 and G4 are each independently N or CR6, provided that no more than two of them are N;
R1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl and heteroaryl are each optionally substituted with one or more, preferably one to five, and sometimes more preferably one to three, groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, hydroxyalkyl, SO2R11a, NRilaR1113, C(=0)0R1 la, C(=0)NRilaR1113, NH
c(=o)Riia, NH C(=0)0R11a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2a, R213, R3a and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more, preferably one to five, and sometimes more preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, NR12aR1213,

3 C(=0)0R12a, C(=0)NR12aR1213, NHC(=o)R12a, NHC(=0)0R12a, oR12a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or alternatively, two of R2a, R21), R3a and R31 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
R4a, R4b, R5a and x -.-s5b are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more, preferably one to five, and sometimes more preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or alternatively, two of R4a, R41, R5a and R5b together with the carbon atom they are attached form cycloalkyl or heterocyclyl;
R6 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R13a, SO2NR13aRl3b, NR13aR1313, C(=0)0R13a, C(=0)NR13aR1313, NHC(=0)R13a, NHC(=0)0R13a, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more, preferably one to five, and sometimes more preferably one to three, groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R14a, SO2NR14aRl4b, NR14aRl4b, C(=0)0R14a, C(=0)NR14aR1413, NHC(=o)R14a, NHC(=0)0R14a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each of R1 la, R12a, R13a and K-14a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with halogen, hydroxy, alkoxy, alkyl, aryl and cycloalkyl;
each of Rlib, R121), R131, and R1413 is independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted with halogen, hydroxyl and alkoxy;
n is 1 or 2; and m is 1 or 2.
In another aspect, this disclosure provides a preparation process of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:

4 R4a R2a R2b R4b R2a R2b -pp 4a 0 0 " R4b Ri Ri OH HN
Gi ___________________________________________________________________ Gi HN
R3b R3b R3a R3a R5a R5b G4=G3 0 0 R5a R5b G4 ¨G3 ( IA ) ( IB ) ( I ) reacting a compound of formula (IA) with a compound of formula (IB), or a pharmaceutically acceptable salt thereof, to obtain the compound of formula (I), wherein:
the pharmaceutically acceptable salt of the compound (IB) preferably is hydrochloride;
and Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (I).
In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof thereof, and a pharmaceutically acceptable carrier.In another aspect, the present disclosure provides a method of preventing and/or treating inflammatory conditions, and/or diseases involving degradation of cartilage, and/or disruption of cartilage homeostasis, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or an isomer, pharmaceutically acceptable salt, solvate, or prodrug, or a pharmaceutical composition containing the compound.
In another aspect, the present disclosure also relates to use of a compound of formula (I), or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for treatment of an inflammatory condition, and/or a disease involving degradation of cartilage, and/or disruption of cartilage homeostasis.
The disease or condition includes arthritis, preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis, which are further preferably related to the activity of ADAMTS-5 and/or ADAMTS-4.
Other aspects or advantages of the disclosure will be better appreciated in view of the following detailed description, examples, and claims.
DETAILED DESCRIPTION OF THE DISCLOSURE
In one aspect, the present disclosure provides a compound of formula (I), or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof:

5

6 R2a R2b R4a 0 R4b HN R3b R3a G2 0 R5a R5b G4¨G3 (I) wherein:
G1, G2, G3 and G4 are each identical or different, and each is N or CR6, provided that no more than two of them are N;
IV is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, hydroxyalkyl, SO2R11a, NRi laR1 lb, C(=0)0R1 la, C(=0)NR1 laR1 lb, mic(=o)Rila NHC(=0)0R1la, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2a, R213, R3a and R31 are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more .. groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, NR12aR1213, C(=0)0R12a, C(=0)NR12aR1213, NHC(=o)R12a, NHC(=0)0R12a, oR12a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R2a, R213, R3a and R31 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
R4a, R413, R5a and x -.-s5b are each identical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R4a, R41, R5a and R5b together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;

each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R13a, SO2NR13aR1313, NR13aR1313, C(=0)0R13a, C(=0)NR13aR1313, NHC(=0)R13a, NHC(=0)0R13a, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R14a, SO2NR14aR1413, NR14aR1413, C(=0)0R14a, C(=0)NR14aR1413, NHC(=0)R14a, NHC(=0)0R14a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R11a, R12a, Rt3a, and R14 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, alkyl, aryl and cycloalkyl;
Rub, R1213, R131, R1413 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted with one or more groups selected .. from the group consisting of halogen, hydroxyl and alkoxy;
n is 1 or 2; and m is 1 or 2.
In some embodiments of the disclosure, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, G1, G2, G3 and G4 are each identical or different, and each is N or CR6, provided that no more than two of them are N;
R1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, hydroxyalkyl, SO2R11a, NRi laR1 lb, C(=0)0R1 la, C(=0)NRilaR1113, mic(=o)Rila NHC(=0)0R1 la, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2a, R213, R3a and R31 are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, NR12aR1213, C(=0)0R12a, C(=0)NR12aR1213, NHC(=o)R12a, NHC(=0)0R12a, cycloalkyl, heterocyclyl, aryl and heteroaryl;

7 or two of R2a, R21), R3a and R36 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
R4a, R413, R5a and x -.-s5b are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R4a, R413, R5a and R5b together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R13a, SO2NR13aR1313, NR13aR1313, C(=0)0R13a, C(=0)NR13aR1313, NHC(=0)R13a, NHC(=0)0R13a, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R14a, SO2NR14aR1413, NR14aR1413, C(=0)0R14a, C(=0)NR14aR1413, NHC(=0)R14a, NHC(=0)0R14a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Rua, R12a, Rt3a, and R14 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, alkyl and cycloalkyl;
Rub, R1213, R131, R1413 are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl and alkoxy;
n is 1 or 2; and m is 1 or 2.
In some embodiments of the disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

8 R2a R2b R4a 0 R4b 0 Ri HN R3b \\G2 R3a 0 R5a R5b G4--k_Tr'3 ( II ) wherein Gl, G2, G3, G4, R1, R2a to R5a, R21 to R5b, n and m are each as defined in formula (I).
In some embodiments of the disclosure, in the compound of formula (I) or formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Gl and G2 are each independently N or CR6; G3 and G4 are each CR6; and R6 is as defined in formula (I) .
In some embodiments of the disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula (III) or (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R2a R2b R4a 0 R4b R2a R2b R4a 0 R1 R4b HN eio 6\
R3b ) ) HN , ,6r,NH R3a \
17 R3b (R.1sr,NH
R3a \
0 R5a R5b 0 R5a R5b ( III) ( ) wherein:
S iS 0, I or 2; and R2a to R5a, R21 to R5b, R6, n and m are each as defined in formula (I) above.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Rl is selected from the group consisting of alkyl, cycloalkyl and heteroaryl, wherein the alkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl and alkoxy; preferably Rl is selected from the group consisting of C1-6 alkyl, 3 to 8-member cycloalkyl and 5 to 10-member heteroaryl, wherein the C1_6 alkyl, 3

9 to 8-member cycloalkyl and 5 to 10-member heteroaryl are optionally substituted with one or more, some times preferably one to three, groups independently selected from the group consisting of C1_6 alkyl and C1_6 alkoxy; more preferably, R1 is selected from the group _/
consisting of ¨17< N¨R
, -CH2OCH3, Rlw R1w N,0 N¨R1w N N I I Ns= \
and ;
and Rlw is C1-6 alkyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R1 is alkyl, cycloalkyl or heteroaryl, each optionally substituted by an alkyl or alkoxy;
preferably R1 is cycloalkyl, sometimes more preferably cyclopropyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R1 is cycloalkyl or heteroaryl, each optionally substituted by alkyl; preferably R1 is cycloalkyl, sometimes more preferably cyclopropyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (I), formula (II), formula (III) or formula (Ina), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R1 is heteroaryl, optionally substituted by alkyl; preferably R1 is pyrazolyl, thiazolyl, imidazolyl, pyridyl or pyrimidyl, each optionally substituted by C1_6 alkyl;
more preferably R1 is imidazolyl, optionally substituted by C1_6 alkyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (I), formula (II), formula (III) or formula (Ina), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R2a and R21 are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl and cyano; preferably R2a and R21 are each hydrogen.
In some embodiments of the disclosure, the compound of formula (I) or formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula (IV) or (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
Rt.a R4a 0 R4b 0 R4b HN R5a HN
)r-NH R31' R6 )rNH R3b R6 0 R5b 0 R5a R5b (IV) 1Va ) wherein:
R4a, R5a, R31 to R513, n and m are each as defined in formula (I).
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R3a and R31 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and hydroxyalkyl, wherein the alkyl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, OR12a and alkoxy.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R3a and R31 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and hydroxyalkyl, wherein the alkyl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen and alkoxy.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III) or formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R3a and R31 are identical or different, and each is selected from the group consisting of hydrogen, halogen, C1_6 alkyl, C1_6 alkoxy and C1_6 hydroxyalkyl, wherein the C1_6 alkyl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen and C1_6 alkoxy.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV) or formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R4a, R4b, R5a and R5b are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1_6 alkyl; or R5 and R5b together with the carbon atom to which they are attached form 3 to 8-member cycloalkyl, R4a. and R41 are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1_6 alkyl; or R4a and R41 together with the carbon atom to which they are attached form 3 to 8-member cycloalkyl, R5a and R5b are dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1_6 alkyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV) or formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R4a, R4b, R5a and R5b are each identical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl and cyano; preferably R4a, R41, R5a and R5b are each independently selected from the group consisting of hydrogen, deuterium, halogen and alkyl;
and sometimes more preferably R4a, 1('-µ413, R5" and R5b are each independently selected from the group consisting of hydrogen, halogen and alkyl.
In some embodiments of the disclosure, in the compound of formula (I) or formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a R4a Rab ).1\T
GI

/
' pharmaceutically acceptable salt, solvate or prodrug thereof, R5 R5b G4 ¨G3 is selected from 4_ RR45a b R4b RI
R4b "555'4'N µ \ (R6)s µ (R6) 4 R6a the group consisting of R6Rb4a¨/ , 9 , R4a R4a Raa (R6), :a / __ (/ R 6)s and :a4/3 (R6)s ; sometimes preferably :a N or R4a *(N
(R6)s =
s is 0,1 or 2; and R4a, R413, R5a, R513, R6 and s are as defined in formula (I).
In some embodiments of the disclosure, in the compound of formula (I) or formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a R4a Rab \\G2 pharmaceutically acceptable salt, solvate or prodrug thereof, R5a R5b G4¨G3 is selected from R4a R4a )(N
the group consisting of R5a R5a R4a R4a R4a N (R6)s N
and R5a , and preferably R5a or R4a (R6)s R5a =
s is 0,1 or 2; and K-4a, R5a and R6 are as defined in formula (I) above.
In some embodiments of the disclosure, in the compound of formula (I) or formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a R4a R4b kO
N
at6)s pharmaceutically acceptable salt, solvate or prodrug thereof, R5a R5b is selected Rita R4a N N
(R6)s (R6)s (R6), from the group consisting of R5a R5a and =

S is 0,1 or 2; and ¨4a, R5a and R6 are as defined in formula (I) , above.
In some embodiments of the disclosure, in the compound of formula (I) or formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a ittb ,55s.-1\T

R5a R5b pharmaceutically acceptable salt, solvate or prodrug thereof, R6 is selected R4a R4a .cs!
R6 R6 V**-N R6 R5a R5a from the group consisting of R6 R6 , and R6 ;
s is 0,1 or 2; and K-4a, R5a and R6 are as defined in formula (I) above.
In some embodiments of the disclosure, the compound of formula (I), formula (III), formula (IV), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula (V), (Va) or (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R4a 0 Ri 0 R4a Ri 0 HN
)rNH R3b 40 R6 FIN)r-NH R3b R6 R5a R5a ( V ) ( Va ) R4a HN
R3b R6 II
R5a ( Vb ) wherein:
Rl is selected from the group consisting of cycloalkyl and heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalkyl;
and R31), K-rs4a, R5a and R6 are each as defined in formula ( I) above.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, R6 is identical or different, and at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and C(=0)0R13a; R13a is as defined in formula (I); preferably, R6 is identical or different, and at each occurrence is independently selected from the group consisting of hydrogen, halogen, C1_6 alkyl, C1_6 alkoxy, C16 haloalkyl, C1_6 haloalkoxy, cyano and C(=0)0R13a; and R13 is hydrogen or C1_6 alkyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, R6 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, nitro, C(=0)oR13a, NR14aR1413, haloalkoxy and cyano;
sometimes preferably R6 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, R11a, R12a, R13, and R14a are each independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is optionally substituted with one or more, sometimes preferably one to three, groups independently selected from the group consisting of halogen, hydroxy, alkoxy and aryl.
In some embodiments of the disclosure, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, R 11b, R1213, R131, R14b are each independently selected from the group consisting of hydrogen and alkyl.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV) or formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, n is 1.
In some embodiments of the disclosure, in the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV) or formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, m is 1.
Exemplified compounds of the disclosure include, but are not limited to:
Example Compound structure and name No.
(:) V 0 HN

(S)-5 -c ycloprop yl- 5 -(3 -oxo-3 -(5 -(trifluoromethyl) iso indolin-2 -yl)prop yl) imidazolidine-2 ,4-dione IHNNEd (S)-5 -(3 -(5 -chloroiso indolin-2 - y1)- 3 -oxoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione (S)-2-(3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)propanoyl)isoindoline-5-carbonitrile 0 o HN NH N
4 )T 4 AP

(S)-5 -cyclopropy1-5-(3-oxo-3-(5-(trifluoromethoxy)isoindolin-2-yl)propyflimidazolidine-2,4-dione eNH

(S)-5 -cyclopropy1-5-(3-(7-methoxy-4,5-dihydro-1H-benzo [di azepin-3(2H)-y1)-3-oxopropyflimidazolidine-2,4-dione HN)LT441 (S)-5 -cyclopropy1-5-(3-oxo-3-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)propyl)imidazolidine-2,4-dione )4fr)LN

HN
NH

(S)-5 -cyclopropy1-5-(3-oxo-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(111)-yl)propyflimidazolidine-2,4-dione HN )LT)LN
=

CI
(5 S)- 5 -(3-(8-chloro-l-methy1-4,5-dihydro-1H-benzo [di azepin-3(2H)-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione OL

(S)-5 -cyclopropy1-5-(3-(4,5-dihydro-1H-benzo [d] azepin-3(2H)-y1)-3-oxopropyl)imidazolidine-2,4-dione H N
)NH C H F2 (S)-5 -cyclopropy1-5-(3-(5-(difluoromethoxy)isoindolin-2-y1)-3-oxopropyflimidazolidine-2,4-dione H N

=

(S)-5 -cyclopropy1-5-(3-(isoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione %M
HN11---r NH \

(S)-5 -cycloprop y1-5-(3-oxo-3-(5H-pyrrolo13,4-blpyridin-6(7H)-yl)propyl)imidazolidine-2,4-dione HNI Ng, 13 .NH N
¨/

(S)-5 -cyclopropy1-5-(3-oxo-3-(1H-pyrrolo13,4-clpyridin-2(3 H) -yl)propyl)imidazolidine-2,4-dione f " 14 HN; N
NH

(S)-5 -cyclopropy1-5 -(3 -((R)- 1-methylisoindolin-2 -y1)-3 -oxopropyl)imidazolidine-2,4-dione 15 y NH

(S)-5 -cycloprop y1-5 -(3 -((S)- 1-methylisoindolin-2 -y1)-3 -oxopropyflimidazolidine-2,4-dione =)7,-= NH

(S)-5 -cycloprop y1-5 -(3 -(4-fluoroisoindolin-2-y1)-3 -oxopropyflimidazolidine-2,4-dione O V
HNN
= )r-NH F

(S)-5 -cycloprop y1-5 -(3 -(5 -fluoroisoindolin-2-y1)-3 -oxopropyflimidazolidine-2,4-dione HN),r-NH

(5S)-5-cyclopropy1-5 -(3 -oxo-3 -(1,2,3,4 -tetrahydro-1,4 -epiminonaphthalen-9-yl)propyl)imidazolidine-2 ,4-dione O V
HN()LN
)r, NH F

(S)-5 -cyclopropy1-5 -(3-(5 ,6-difluoroisoindolin-2-y1)-3 -oxopropyflimidazolidine-2,4-dione HNC"--21"

CI
(S)-5 -cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione (:) V
H NH
CI

(S)-5 -(3-((R)-8-chloro-1-methy1-4,5-dihydro-1H-benzokllazepin-3(2H)-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione )r-NH

(5 S)-5 -cyclopropy1-5-(3-(8-fluoro-l-methy1-4,5-dihydro-1H-benzo [d] azepin-3(2H)-y1)-3-oxopropyl)imidazolidine-2,4-dione (Mixture of two diastereomers) CI
)r-(S)-5 -(3-(7-chloro-4,5-dihydro-1H-benzokllazepin-3(2H)-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione (:) VHN

OMe (S)-5 -cyclopropy1-5-(3-(5-methoxyisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione OMe 25 HN)rNH

(S)-5 -cycloprop y1-5 -(3 -(6-methoxy-4,5 -dihydro-1H-benzo [d] azepin-3 (211)-y1)-3 -o xoprop yflimidazolidine-2 ,4 -dione HHN

(S)-5 -c ycloprop y1-5 -(3 -(1,1 -dimethy1-4 ,5 -dihydro- 1H-benzoldlazepin-3 (211)-y1)-3 -o xoprop yflimidazolidine-2 ,4 -dione HN)r-NH

(S)-5-c ycloprop y1-5 -(3 -((R)-8-fluoro- 1 -methyl-1,2,4,5 -tetrahydro-3 H-benzo [di azepin-3 - y1)-3 -o xoprop yflimidazolidine-2 ,4 -dione HN"
)r-NH

(S)-5-c ycloprop y1-5 -(3 -((S)-8 -fluoro-1 -methyl-1,2 ,4,5 -tetrahydro-3 H-benzo [di azepin-3 - y1)-3 -o xoprop yflimidazolidine-2 ,4 -dione 29 )(NH C F3 (5S)-5 -c ycloprop y1-5 -(2-methyl-3-oxo-3-(5 -(trifluoromethyl)isoindolin-2-yl)propyllimidazolidine-2,4-dione o HNI \NH

(S)-5 -cyclopropy1-54(S)-2-methyl-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-y1)propyl)imidazolidine-2,4-dione N
HNNH
29-2 Nz CF

(S)-5 -cycloprop y1-5 -((R)-2-methyl-3 -oxo-3 -(5-(trifluoromethyl)isoindolin-yl)propyl)imidazolidine-2 ,4-dione HNOn)CL) )i-NH =CF3 (5 R)-5-cyclopropy1-5-(2-methy1-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione z N
HN rNH

(R)-5 -cyclopropy1-5 -((R)-2-methyl-3 -oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2 ,4-dione 0) HN yNH

(R)-5-cyclopropy1-54(S)-2-methyl-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione HN)i-NHri CF3 5-cyclopropy1-5-(2-(5-(trifluoromethyflisoindoline-2-carbonyl)butyl)imidazolidine-2,4-dione Or*L) HN)(NH = cF3 (5R)-5 -cyclopropy1-5-(2-(5-(trifluoromethyl)isoindoline-2-carbonyl)butyl)imidazolidine-2,4-dione V
HN
yeNH cF3 (5 S)-5-cyclopropy1-5-(2-(5-(trifluoromethyl)isoindoline-2-carbonyl)butyl)imidazolidine-2,4-dione )r-NH

(S)-5-cyclopropy1-54(S)-2-(5-(trifluoromethyl)isoindoline-2-carbonyl)butyl)imidazolidine-2,4-dione 0 VH~I 0 NH 110, (S)-5-cyclopropy1-54(R)-2-(5-(trifluoromethyflisoindoline-2-carbonyl)butyl)imidazolidine-2,4-dione OH L
HN)rNH = CI

CI
5-cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-2-methyl-3-oxopropyl)imidazolidine-2,4-dione (R) HN),rNH
CI

(5R)-5 -cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-2-methyl-3-oxopropyl)imidazolidine-2,4-dione HNs) yNH
CI

(SS)-5 -cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-2-methyl-3-oxopropyl)imidazolidine-2,4-dione )r-NH CI

(SS)-5 -cyclopropy1-5-((S)-(3-(5,6-dichloroisoindolin-2-y1)-2-methy1-3-oxopropy1))imidazolidine-2,4-dione H N

(SS)-5 -cyclopropy1-5-((R)-(3-(5,6-dichloroisoindolin-2-y1)-2-methy1-3-oxopropy1))imidazolidine-2,4-dione CI elHrTs) NH OMe (S)-5-(3-(5-chloro-6-methoxyisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione 0,W
yNH OMe CI
-(3 -(5-chloro-6-methoxyisoindolin-2- y1)-2-methy1-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione si r CI \)(N
(s) HN)i-NH OM e (5 S)-5 -(3 -(5-chloro-6-methoxyisoindolin-2- y1)-2-methy1-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione HN)7,-NH CI

(S)-5 -c ycloprop y1-5 -(3 -(7,8-dichloro-1 -methyl-1,2,4,5 -tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop yl)imidazolidine-2 ,4-dione HN)r-NH CI

(S)-5 -cycloprop y1-5 -(3 -((S)-7,8-dichloro-1 -methyl- 1,2 ,4,5 -tetrahydro-3 H -benzo [di azepin-3 - y1)-3 -o xoprop yl)imidazolidine-2 ,4-dione (\2N
HN CI

(S)-5 -c ycloprop y1-5 -(3 -((R)-7,8 -dichloro-l-methyl-1,2,4,5 -tetrahydro-3 H-benzo [di azepin-3 - y1)-3 -o xoprop yl)imidazolidine-2 ,4-dione CI

(S)-5 -c ycloprop y1-5 -(3 -(8,9-dichloro-1 -methyl-1,2,4,5 -tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop yflimidazolidine-2 ,4-dione CI
HNNH CI

(S)-5 -cycloprop y1-5 -(3 -((S)-8,9-dichloro-1 -methyl- 1,2 ,4,5 -tetrahydro-3 H -benzo [di azepin-3 - y1)-3 -o xoprop yflimidazolidine-2 ,4-dione HN),i-NH CI

(S)-5 -c ycloprop y1-5 -(3 -((R)-8,9-dichloro-l-methy1-1,2,4,5 -tetrahydro-3 H-benzo [di azepin-3 - y1)-3 -o xoprop yflimidazolidine-2 ,4-dione (:) V
HN)r-NH

(S)-5 -c ycloprop y1-5 -(3 -(5-fluoro-6-(trifluoromethyflisoindolin-2- y1)-3 -oxoprop yl)imidazolidine-2,4-dione HN)r-NH CF3 CI
(S)-5 -(3 -(5 -chloro-6-(trifluoromethyflisoindolin-2-y1)-3 -oxoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione r)Lo (:) CI
(SS)-5 -(3 -(5 -chloro-l-methy1-6-(trifluoromethyflisoindolin-2- y1)-3 -o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione V
HN
CI

(S)-5 -(3 - ((S)- 5 -chloro-1 -methyl-6-(trifluoromethyl)isoindolin-2- y1)-3 -o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione V
HN
y NH CI

(S)-5 -(3 -((R)-5 -chloro-1 -methyl-6-(trifluoromethyl)isoindolin-2- y1)-3 -o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione HN' 4.el\JH
OH CI

-cycloprop y1-5 -(3 -(5 ,6-dichloroisoindolin-2- y1)-2-(hydroxymethyl)-3 -oxopropyl)imidazolidine-2,4-dione HN
0 /s N

5 -(3 -o xo-3-(5 -(trifluoromethyl)isoindolin-2- yl)prop y1)-5 -(thiazol-2 -yl)imidazolidine-2,4-dione HNLN

(S)-5 -cyclopropy1-5-(3-(7-fluoro-4,5-dihydro-1H-benzo [di azepin-3(2H)-y1)-3-oxopropyl)imidazolidine-2,4-dione NH

(S)-5 -cyclopropy1-5-(3-oxo-3-(7-(trifluoromethyl)-4,5-dihydro-1 H-benzokllazepin-3(2H)-yl)propyl)imidazolidine-2,4-dione D D
HNIThs) N CI
?r-NH

(S)-5-(3-(5-chloro-6-(trifluoromethypisoindolin-2-y1-1,1,3,3-d4)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione N CI

(S)-5-cyclopropy1-5-(3-(5',6'-dichlorospiro1cyclopropane-1,1'-isoindolin1-2'-y1)-3-oxopropyl)imidazolidine-2,4-dione JN

HNNH CI

5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyridin-3-yl)imidazolidine-2,4-dione 49 HNLN )r-NH CF3 5-cyclopropy1-5-(3-methy1-2-(5-(trifluoromethyflisoindoline-2-carbonyflbutyflimidazolidine-2,4-dione yNH CF3 (5R)-5-cyclopropy1-5-(3-methyl-2-(5-(trifluoromethyflisoindoline-2-carbonyflbutyflimidazolidine-2,4-dione HN(33L
yNH CF3 (5S)-5-cyclopropy1-5-(3-methy1-2-(5-(trifluoromethyflisoindoline-2-carbonyflbutyflimidazolidine-2,4-dione HN NH =
= CF
49-2a 0 49-2a (5S)-5-cyclopropy1-5-R2R)-3-methy1-2-[5-(trifluoromethyl)-1, 3, 3a, 7a-tetrahydroisoindole-2-carbonyl] butyl] imidazolidine-2, 4-dione o, 7 HN NXH

49-2b 49-2b (5R)-5-cyclopropy1-5-R2S)-3-methy1-2-[5-(trifluoromethyl)-1, 3, 3a, 7a-tetrahydroisoindole-2-carbonyl] butyl] imidazolidine-2, 4-dione (s) 50 HN)r_NH 40 50 NO2 CI

(S)-5-(3-(5-chloro-6-nitroisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione V

)r-N51 (5 S)- 5 -cyclopropy1-5-(3-(5-(1-hydroxyethyDisoindolin-2-y1)-3-oxopropyflimidazolidine-2,4-dione (:) V
HN
)r-NH cHF2 (S)-5-cyclopropy1-5-(3-(5-(difluoromethyflisoindolin-2-y1)-3-oxopropyflimidazolidine-2,4-dione HNyNH 41 I

(S)-5-(3 -(5-chloro-6-iodoisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione HNnP) NH CI

(S)-5-(3-(5-amino-6-chloroisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione JV
0\\
HNRs) y NH = NH

(S)-N-(6-chloro-2-(3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)propanoyl)isoindolin-5-yl)acetamide y. N OH

(S)-2-(3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)propanoyl)isoindoline-5-carboxylic acid HN L(s) 1010I
)r NH CH3 (S)-5 -(3-(5-chloro-6-methylisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione )(NH CI

(SS)-5 -cyclopropy1-5-(3-(5,6-dichloro-1-ethylisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione )r, NH

Br (S)-5 -(3-(5-bromo-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione L.,E3 5-(3-oxo-3-(5-(trifluoromethyflisoindolin-2-yflpropy1)-5-(pyridin-2-y1)imidazolidine-2,4-dione o HNy NH
CI

CI
-(3 -(5 ,6-dichloroisoindolin-2- y1)-3 -o xoprop y1)-5 -(pyridin-2-yl)imidazolidine-2,4-dione HN'ANH 0 N
-5 -(1-methyl- 1H-imidazol-2- y1)-5-(3 -oxo-3 -(5-(trifluoromethyflisoindolin-2 -yflpropyflimidazolidine-2,4-dione HN-1(0 0.1 \NI
N

(S)-5 -(1 -methyl- 1H-imidazol-2- y1)-5 -(3-o xo-3 -(5 -(trifluoromethyl)isoindolin-2 - yl)prop yl)imidazolidine-2 ,4-dione HN-1( 0 0 .4 N%\
62-2 __Ls2 ¨

(R)-5-(1 -methyl- 1H-imidazol-2 - y1)-5 -(3 -o xo-3-(5 -(trifluoromethyl)isoindolin-2 - yl)prop yl)imidazolidine-2 ,4-dione HN 's 63 yNH CF3 -(methoxymethyl)-5 -(3 -oxo-3 -(5 - (triflu oromethyl)iso indolin-2 -yl)propyl)imidazolidine-2 ,4-dione H
63-1 N)rNH afr CF

(S)-5 -(methoxymethyl)-5 -(3 -oxo-3 -(5 -(trifluoromethyl) isoindolin-2-yl)prop yl) imidazolidine-2 ,4-dione C) 0 0 HN)r. NH afr C F3 (R)-5 - (metho xymethyl)-5 -(3 -oxo-3 -(5- (trifluoromethyl) isoindo lin-2-yl)prop yl) imidazolidine-2 ,4-dione jCL
H Ny NH CF3 5 -(1 -methylc yc loprop y1)-5 -(3 -oxo-3 - (5- (trifluoromethyl) isoindolin-2-yl)prop yl) imidazolidine-2 ,4-dione Od%
HN/
y NH = 64-1 0 C F3 (R)-5-(1-methylcycloprop y1)-5 - (3-o xo -3 -(5 -(triflu oro methyl) isoindo lin-2-yl)prop yl) imidazolidine-2 ,4-dione HN

64-2 'NH0 (S)-5-(1-methylcyclopropy1)-5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione OZ)Ct HNIN ' 141 )r 441 0 CF3 5-(2-((benzyloxy)methyl)-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propy1)-5-cyclopropylimidazolidine-2,4-dione O
HNLN
),r NH CI

(SS)-5 -cyclopropy1-5-(3-(5,6-dichloro-1-methylisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione O V
HNL
yNH CI

(S)-5 -cyclopropy1-5-(3 - ((S) -5 ,6 - dichlo ro -1-methylisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione O V
CI

(S)-5 -cyclopropy1-5-(3 - ((R) -5 ,6- dichlo r o-l-methylisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione N
CI

(5S)-5 -(3 -(8-chloro-9-fluoro-1 -methyl- 1 ,2,4,5-tetrahydro-3H-benzo kflazepin-3 - y1)-3 -oxoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione =s- F
HN),rNH CI
67-i 67-1 (S)-5-(3 -((R)-8-chloro-9-fluoro-1 -methyl- 1 ,2,4,5 -tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione O V
HNH") CI
yNH

(S)-5 -(3 -((S)-8-chloro-9-fluoro-1 -methyl- 1 ,2,4,5-tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione HN)r_NH CI

(5S)-5 -(3 -(8-chloro-7 -fluoro-1 -methyl- 1 ,2,4,5-tetrahydro-3H-benzoldlazepin-3 - y1)-3 -oxoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione O

HNHHLN
CI
y-N0 68-1 (S)-5 -(3 -((S)-8-chloro-7 -fluoro-1 -methyl- 1 ,2,4,5-tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione O V

CI
y-N

(S)-5-(3 -((R)-8-chloro-7-fluoro-1-methy1-1 ,2,4,5 -tetrahydro-3H-benzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -c ycloprop ylimidazolidine-2 ,4-dione ci HN (s) N
CI
D D

(5S)-5 -cycloprop y1-5 -(3 -(5,6-dichloro-l-methylisoindolin-2-y1-3 ,3 -d2)-3-oxoprop yflimidazolidine-2,4-dione HN (s) N
)i-NH

CI

(S)-5 -cycloprop y1-5 -(3 -((S)-5 ,6-dichloro-1 -methylisoindolin-2- y1-3 ,3 -d2)-3 -oxoprop yflimidazolidine-2,4-dione D D
(s) HNy-NH
(R) CI

CI

(S)-5 -c ycloprop y1-5 -(3 -((R)-5 ,6-dichloro-l-methylisoindolin-2- y1-3 ,3 -d2)-3 -oxoprop yflimidazolidine-2,4-dione HN's---r# )L
),rNH CI

(5S)-5 -cycloprop y1-5 -(3 -(5 ,6-dichloro-l-methylisoindolin-2- y1)-2-methy1-oxoprop yl)imidazolidine-2,4-dione cF3 (s) N
HN),r-NH CI
D D

(SS)-5 -(3 -(5 -chloro-l-methy1-6-(trifluoromethyflisoindolin-2- y1-3 ,3 -d2)-o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione HN/
irNH CI

(S)-5-(3 -((R)-5-chloro-l-methy1-6-(trifluoromethyflisoindolin-2- y1-3 ,3-d2)-o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione )LV
HN/
NH H3C" CI

(S)-5 -(3 -((S)-5 -chloro-l-methy1-6-(trifluoromethypisoindolin-2- y1-3 ,3-d2)-o xoprop y1)-5 -cycloprop ylimidazolidine-2,4-dione HN()L

(S)-5 -cycloprop y1-5 -(3 -o xo-3-(5 -(2,2,2-trifluoroethyl)isoindolin-2-yl)prop yl)imidazolidine-2 ,4-dione /=\

HN)rNH CF3 -(3 -(5-chloro-6-(trifluoromethyl)isoindolin-2- y1)-3 -oxoprop y1)-5 -(1-methyl-1H-imidazol-2- yflimidazolidine-2 ,4-dione 0 N, HN),r-NH CF3 (S)-5 -(3 -(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3 -oxoprop y1)-5 -(1-methy1-1H-imidazol-2- yflimidazolidine-2,4-dione /=\
1\1 0 H
73-2 N)7,-NH CF3 (R)-5 -(3 -(5 -chloro-6-(trifluoromethyl)isoindolin-2- y1)-3 -o xoprop y1)-5 -(1-methy1-1H-imidazol-2- yl)imidazolidine-2,4-dione (:) V
HNrjL
)(NH CHF2 (S)-5 -cycloprop y1-5 -(3 -(5 -(difluoromethyl)-6-fluoroisoindolin-2- y1)-3 -oxoprop yl)imidazolidine-2,4-dione tr) /
,N 0 HN),rNH
75 ci 5 -(3 -(5 -chloro-6-(trifluoromethyl)isoindolin-2- y1)-3 -oxoprop y1)-5 -(5 -methyliso xazol-3 - yl)imidazolidine-2,4-dione HN)r NH

(S)-5-c ycloprop y1-5 -(3 -(5 -(methylamino)-6-(trifluoromethyl)isoindolin-2-y1)-3 -o xoprop yl)imidazolidine-2,4-dione HN
NH

5 -(3 -(5-chloro-6-(trifluoromethyl)isoindolin-2- y1)-3 -oxoprop y1)-5 -(1-methyl-1H-p yrazol-3 - yl)imidazolidine-2 ,4-dione Hd 0 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(5-methyl-1H-pyrazol-3-yl)imidazolidine-2,4-dione N 1\1 0 HN)r-NH CF3 5-(3-(5-chloro-6-(trifluoromethypisoindolin-2-y1)-3-oxopropy1)-5-(pyrimidin-2-yflimidazolidine-2,4-dione HNyNH

CI

(S)-5-cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1-1,1,3,3-d4)-3-oxopropyl)imidazolidine-2,4-dione II
HNyNH CF3 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(2-methyloxazol-4-yflimidazolidine-2,4-dione CI

5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(1-ethyl-1H-imidazol-2-yl)imidazolidine-2,4-dione 1-1Ny NH CF3 CI
5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(thiazol-2-yl)imidazolidine-2,4-dione 0,1,µõ), N
HN)r_ NH CF3 (S)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(thiazol-2-yl)imidazolidine-2,4-dione 0 Nr R
HN)r_ NH CF3 (R)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(thiazol-2-yl)imidazolidine-2,4-dione HN
84 )7,-NH CF

5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione I
4N o o HN)rNH = CF3 (R)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione HN>rNH cF, (S)-5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yflimidazolidine-2,4-dione H
85 N),[-NH 40 a cF, 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyrazin-2-yl)imidazolidine-2,4-dione ==µµ\)N
HN)(NH =CI

85-1 cF, (R)-5-(3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-3-oxopropy1)-5-(pyrazin-2-yl)imidazolidine-2,4-dione HNN
y-NH

(S)-5-(3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-3-oxopropy1)-5-(pyrazin-2-yl)imidazolidine-2,4-dione %._\/
HNI-T N
NH ClOH

86-1 cF, (S)-54(S)-3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione N
NH
OH CI

(S)-5-((R)-3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione HN = y NH
OH CI

(R)-54(S)-3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione s )r¨NH N
OH CI

(R)-5 -((R)-3 -(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione HN)i_NH CF3 5-cyclopropy1-5-(2-methy1-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione HN)r¨NH
OMe CF3 5-cyclopropy1-5-(2-(methoxymethyl)-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione o HNN
)r¨NH CF3 (5 S)-5 -cyclopropy1-5-(3-(1-methyl-8-(trifluoromethyl)-4,5-dihydro-1H-benzoldlazepin-3(2H)-y1)-3-oxopropyflimidazolidine-2,4-dione H N
)r_ NH

(5S)-5 -cyclopropy1-5-(3-(1-fluoro-4,5-dihydro-1H-benzoldlazepin-3(2H)-y1)-3-oxopropyflimidazolidine-2,4-dione HN)rNH

(S)-5 -cyclopropy1-5-(3-(6-fluoro-4,5-dihydro-1H-benzoldlazepin-3(2H)-y1)-3-oxopropyflimidazolidine-2,4-dione V o HN)r-NH CHF2 CI
(S)-5 -(3-(5-chloro-6-(difluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione N-N

HN)r NH CF3 CI
5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(1-methyl-1H-pyrazol-4-yl)imidazolidine-2,4-dione In another aspect, this disclosure provides a process for preparation of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:

R4a R2a R2b R4b R2a R2b 0 0 R4a 0 Ri 0 Ri R4b OH HN
+
R3b G2 R3b / %2 )r..-NH R3a )r--NH 3a n / n R3a R5b G4=G3 /
0 0 R3a R5b G4¨G3 ( IA ) ( IB ) ( I ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB), or a salt thereof, to obtain the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
the salt of the compound (IB) preferably is hydrochloride; and Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (I).
In another aspect, this disclosure provides a process for preparation of a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R2a R2b R2a R2b D 4a 0 R4h 0 -1' R4b 0 R1 0 Ri HN
+
R3b )r,NH 3a G2 R5a R5b G4G3 /
0 0 R5a R5b G4G3 ( IIA ) ( IB ) ( II ) reacting a compound of formula (IIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IB), or a salt thereof, to obtain the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IB) preferably is hydrochloride; and Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (II).
In another aspect, this disclosure provides a process for preparation of a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R2a R2b R4a R4a R4b R2a R2 b 0b R1 HN
OH +
R3b 0 R5a R5a R5b R5b ( IA ) ( IIIB ) ( III ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IIIB), or a salt thereof, to obtain the compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IIIB) preferably is hydrochloride; and Rl, R2a to R5a, R21 to R5b, R6, n, m and s are each as defined in formula (III).
In another aspect, this disclosure provides a process for preparation of a compound of formula (Ma), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R2a R
R4a 4b 2a R2b R4a R2b R
0 R4b 0 Ri Ri OH HN
6s (R
HN
R3b R3b R3a R3a p 5a 0 R5b 0 R5a R5b ( IIA ) ( IIIB ) ( ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IIIB), or a salt thereof, to obtain the compound of formula (Ma) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IIIB) preferably is hydrochloride; and Rl, R2a to R5a, R21 to R5b, R6, n, m and s are each as defined in formula (Ma).

In another aspect, this disclosure provides a process for preparation of a compound of formula (IV), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a 0 R4a R4b R4b 0 HN
OH
HN
HN R3b )rNH R3b D 5a 0 n 5a 0 R5b R5b ( WA ) ( IVB ) ( W) reacting a compound of formula (IVA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IVB), or a salt thereof, to obtain the compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IV) preferably is hydrochloride; and R4a, R5a. R31 to R5b K-rs n and m are each as defined in formula (IV).
In another aspect, this disclosure provides a process for preparation of a compound of formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R4a R4b R4b HN
OH H R3b HN
HN R3b ) R6 R6 r,N
n 5a n 5a R5b R5b ( IVaA ) ( IVB ) ( IVa ) reacting a compound of formula (IVaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (IVB), or a salt thereof, to obtain the compound of formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IVB) preferably is hydrochloride; and R4a, R5a, R31 to R5b, K n and m are each as defined in formula (IVa).
In another aspect, this disclosure provides a process for preparation of a compound of formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a 0 R4a 0 Ri FIN
OH
HN
HN )r¨NH R3b )r,NH R3b R5a 0 R5a ( VA ) ( VB ) (V) reacting a compound of formula (VA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (VB), or a salt thereof, to obtain the compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (VB) preferably is hydrochloride; and R4a, R5a, R31, 1 K and R6 are each as defined in formula (V).
In another aspect, this disclosure provides a process for preparation of a compound of formula (Va) or (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R4a Ri Ri HN
OH +
HN
HN ) R6 )r¨NH R3b R6 R6 r,NH
R3b R5a 0 R5a ( VaA ) ( VB ) ( Va ) R4a R4a Ri _________________________________________ . HN
HN R3b R3b R6 R6 R5a 0 R5a ( VbA ) ( VB ) ( Vb ) reacting a compound of formula (VaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (VB), or a salt thereof, to obtain the compound of formula (Va) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
reacting a compound of formula (VbA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (VB), or a salt thereof, to obtain the compound of formula (Vb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (VB) preferably is hydrochloride; and R4a, R5a, R31 , tc and R6 are each as defined in formula (V).
In another aspect, the present disclosure also provides a pharmaceutical composition, comprising a compound of formula (I), formula (II), formula (III), formula (Ma), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents and/or other excipients.
In another aspect, the present disclosure provides a method of inhibiting and/or ADAMTS-4, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound.
In another aspect, the present disclosure provides a method of preventing and/or treating inflammatory conditions, and/or diseases involving degradation of cartilage, and/or disruption of cartilage homeostasis, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound.

In another aspect, the present disclosure provides a method of preventing and/or treating arthritis, comprising a step of administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound; preferably, wherein arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.
In another aspect, the present disclosure also relates to use of a compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for the inhibition of ADAMTS-5 and/or ADAMTS-4.
In another aspect, the present disclosure also relates to use of a compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for preventing and/or treating inflammatory conditions, and/or diseases involving degradation of cartilage, and/or disruption of cartilage homeostasis.
In another aspect, the present disclosure also relates to use of a compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, in the manufacture of a medicament for preventing and/or treating arthritis; preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.
The present disclosure further relates to the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the same, for use as a medicament.

The present disclosure also relates to the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition .. containing the compound, for use in inhibiting ADAMTS-5 and/or ADAMTS-4 .
The present disclosure also relates to the combination of the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, for use in preventing and/or treating inflammatory conditions, and/or diseases involving degradation of cartilage, and/or disruption of cartilage homeostasis.
The present disclosure also relates to the combination of the compound of formula (I), formula (II), formula (III), formula (Ina), formula (IV), formula (IVa), formula (V), formula (Va) or formula (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, for use in preventing and/or treating arthritis;
preferably, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.
Further, the present disclosure encompasses all compounds that can exist based on any chemically plausible combinations of the embodiments disclosed or substituents on the exemplified compounds, as would be understood by a person of skill in the art.
The term "inflammatory conditions" refers to the group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), endotwdn-driven disease states (e.g.complications after bypass surgery or chronic endotwdn states contributing to e.g.
chronic cardiacfailure), and related diseases involving cartilage, such as that of the joints.
Particularly refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases.
More particularly refers to rheumatoid arthritis, and osteoarthritis (OA). Most particularly refers to osteoarthritis (OA).
The term "diseases involving degradation of cartilage and/or disruption of cartilage homeostasis" includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, achondroplasia, Paget's disease, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amylosis, hydarthrosis, periodical disease, rheumatoid spondylitis, endemic forms of arthritis like osteoarthritis deformans endemic, Mseleni disease and Handigodu disease;
degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis; and particularly, refers to osteoarthritis (OA).
The compositions of this disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Thus, the active compounds of this disclosure can be formulated as various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, inhalation or insufflation administration. The compounds of this disclosure can also be formulated as sustained release dosage forms.
Suitable dosage forms include, but are not limited to, a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. Oral compositions can be prepared according to any known method in the art for the preparation of pharmaceutical compositions. Such compositions can contain one or more additives selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, in order to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, and lubricants. The tablet can be uncoated or coated by means of a known technique to mask the taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period. For example, water soluble taste masking materials can be used.
Oral formulations can also be provided as soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or the active ingredient is mixed with a water soluble carrier.
An aqueous suspension contains the active ingredient in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents, dispersants or humectants, and can be naturally occurring phospholipids. The aqueous suspension can also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.
An oil suspension can be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension can contain a thickener. The aforementioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant.
The present pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil, or mixture thereof. Suitable emulsifying agents can be naturally occurring phospholipids. Sweeteners can be used. Such formulations can also contain moderators, preservatives, colorants and antioxidants.
The pharmaceutical composition can be in the form of a sterile injectable aqueous solution. The acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be introduced into an individual's bloodstream by local bolus injection. Alternatively, it can be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compound. In order to maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is Deltec CADD-PLUS . TM. 5400 intravenous injection pump.
The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such a suspension can be formulated with suitable dispersants or wetting agents and suspending agents as described above according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. Moreover, sterile fixed oils can easily be used as a solvent or suspending medium, and fatty acids can also be used to prepare injections.
The present compound can be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid in the rectum, thereby melting in the rectum to release the drug.
For buccal administration, the compositions can be formulated as tablets or lozenges by conventional means.
For intranasal administration or administration by inhalation, the active compounds of the present disclosure are conveniently delivered in the form of a solution or suspension released from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray released from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer can contain a solution or suspension of the active compound.
Capsules or cartridges (for example, made from gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the present disclosure and a suitable powder base such as lactose or starch.
It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to, the following factors: activity of the specific compound, age, weight, general health, behavior, diet of the patient, administration time, administration route, excretion rate, drug combination and the like. In addition, the best treatment, such as treatment mode, daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt thereof can be verified by traditional therapeutic regimens.
Unless otherwise stated, the terms used in the specification and claims take ordinary meanings as understood by those in the ordinary skill in the relevant art.
Certain terms have the meanings described below.
"Alkyl" refers to a saturated aliphatic hydrocarbon group including C1-C12 (for example, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) straight chain and branched chain groups. Preferably an alkyl group is an alkyl having 1 to 8 carbon atoms, sometimes more preferably 1 to 6 carbon atoms, and sometime more preferably 1 to 4 carbon atoms.
Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, 1-ethy1-2-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 the isomers of branched chain thereof. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point, preferably the substituent group(s) is one or more, preferably one to five, and more preferably one to three, groups independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
"Alkenyl" refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. preferably C2_12 (for example, including 2, 3, 4, 5, 6, 7, 8, 9,

10, 11 and 12 carbons) alkenyl, more preferably C2_8 alkenyl, sometimes more preferably C2_6 alkenyl, and sometimes more preferable C2_4 alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, preferably one to five, and more preferably one to three, group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
"Alkynyl" refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C2-12 (for example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) alkynyl, more preferably C2_6 alkynyl, some times more preferably C2_6 alkynyl, and sometimes more preferable C2_4 alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, preferably one to five, and more preferably one to three, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Alkylene" refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. The straight or branched chain group containing 1 to 12 (for example, including 1,2, 3,4, 5, 6,7, 8, 9, 10, 11 and 12 carbons) carbon atoms, preferably has 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1 ,4-butylidene (-CH2CH2CH2CH2-) etc. The alkylene group can be substituted or unsubstituted.
When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Alkenylene" refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C2-12 (for example, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) alkenylene, more preferably C2_8 alkenylene, sometimes more preferably C2_6 alkenylene, and sometimes even more prefereably C2_4 alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic .. alkylthio.
"Cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 (for example, including 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbons) carbon atoms, more preferably 3 to 10 carbon atoms, sometimes more preferably 3 to 8 carbon atoms, and sometimes even more .. preferably 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
"Spiro Cycloalkyl" refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings can contain one or more double bonds. Preferably a spiro cycloalkyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), and more preferably 7 to 10 membered.
According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5 -membered/5 -membered, or 5 -membered/6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to the following groups:

g414 Era7nd .
"Fused Cycloalkyl" refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds. Preferably, a fused cycloalkyl group is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), more preferably 7 to 10 membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following groups:
and ' "Bridged Cycloalkyl" refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds. Preferably, a bridged cycloalkyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons), and more preferably 7 to 10 membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following groups:
and 1;1.-- =
The cycloalkyl includes the cycloalkyl said above fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl.

Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
"Heterocycly1" refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, 0, S, S(0) and S(0)2 as ring atoms, but excluding -0-0-, -0-S- or -S-S- in the ring, the remaining ring atoms being C. Preferably, heterocyclyl is a 3 to 12 membered having 1 to 4 heteroatoms(for example, including 1, 2, 3 or 4 heteroatoms.); more preferably a 3 to 10 membered (for example, including 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms) having 1 to 3 heteroatoms (for example, including 1, 2 or 3 heteroatoms.);
most preferably a 5 to 6 membered having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.
"Spiro heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, 0, S, 5(0) and S(0)2 as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds. Preferably a spiro heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 membered. According to the number of common spiro atoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, membered/5 -membered, 4-membered/6-membered, 5 -membered/5 -membered, or 5-membered/6-membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:

-LA
N
¨07-7 x o 0 Q 0_ _________ and N
"Fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, and wherein said rings have one or more heteroatoms selected from the group consisting of N, 0, S, S(0) and S(0)2 as ring atoms, the remaining ring atoms being C. Preferably a fused heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms), and more preferably 7 to membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or 10 tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following groups:
c 1) 7 ,The N
CINTt Nst.õ 0j ak) cD, and "Bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, and the rings have one or more heteroatoms selected from the group consisting of N, 0, S, S(0) and S(0)2 as ring atoms, the remaining ring atoms being C.
Preferably a bridged heterocyclyl is 6 to 14 membered (for example, including 6, 7, 8, 9, 10,

11, 12, 13 or 14 ring atoms), and more preferably 7 to 10 membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following groups:

kNA ___________________________ N
-AA
and1N-----) The ring of said heterocyclyl include the heterocyclyl said above which fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following groups:
AT N . $'-xj a . s . , N) ' - $N
/
_ -/
H H H

1.I lel : N 110 0 00 and s , etc.
The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Aryl" refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl include the aryl said above which fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl.
Representative examples include, but are not limited to, the following groups:
IL N

N
wi 0 / 0 0 0 0 0 (00 H H H
N s N N N
N' \ . 1 0 /
N S e N 0 0 and .

The aryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Heteroaryl" refers to an aryl system having 1 to 4 heteroatoms (for example, including 1, 2, 3 or 4 heteroatoms) selected from the group consisting of 0, S and N as ring atoms and having 5 to 14 annular atoms (for example, including 5, 6,7, 8, 9, 10, 11, 12, 13 or 14 annular atoms). Preferably a heteroaryl is 5- to 10- membered, more preferably 5- or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl include the heteroaryl said above which fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl.
Representative examples include, but are not limited to, the following groups:
N-N N N-N
N
efT N I
.rNH NH HN z HN V N 0 N
N
5C0 0 and The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more , sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Alkoxy" refers to an -0-(alkyl) group, wherein the alkyl is defined as above.
Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxyl can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, groups independently selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
"Bond" refers to a covalent bond using a sign of "¨".
"Hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxy group(s), wherein alkyl is as defined above.
"Hydroxy" refers to an -OH group.
"Halogen" refers to fluoro, chloro, bromo or iodo atoms.
"Amino" refers to a -NH2 group.
"Cyano" refers to a -CN group.
"Nitro" refers to a -NO2 group.
"Oxo group" refers to a =0 group.
"Carboxyl" refers to a -C(=0)0H group.
"Alkoxycarbonyl" refers to a -C(=0)0(alkyl) or -C(=0)0 (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
"Optional" or "optionally" means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, "the heterocyclic group optionally substituted by an alkyl" means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
A "pharmaceutical composition" refers to a mixture of one or more of the compounds described in the present disclosure or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.
"Pharmaceutically acceptable salts" refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide as well as organic acids, such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid acid, and related inorganic and organic acids.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.
As a person skilled in the art would understand, the compounds of formula (I) or pharmaceutically acceptable salts thereof disclosed herein may exist in prodrug or solvate forms, which are all encompassed by the present disclosure.
The term "solvate," as used herein, means a physical association of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
"Prodrug" refers to compounds that can be transformed in vivo to yield the active parent compound under physiological conditions, such as through hydrolysis in blood.
Common .. examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Amides and esters of the compounds of the present disclosure may be prepared according to conventional methods. In particular, in the present disclosure, a prodrug may also be formed by acylation of an amino group or a nitrogen atom in a heterocyclyl ring structure, which acyl group can be hydrolyzed in vivo.
Such acyl group includes, but is not limited to, a Ci-C6 acyl, preferably Ci-C4 acyl, and more preferably Ci-C2 (formyl or acetyl) group, or benzoyl.
The term "pharmaceutically acceptable," as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The term "therapeutically effective amount," as used herein, refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
The term "treat", "treating", "treatment", or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it.
As used herein, the singular forms "a", "an", and "the" include plural reference, and vice versa, unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter, such as pH, concentration, temperature, or the like, it indicates that the parameter can vary by 10%, and some times more preferably within 5%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting.
The compound of the present disclosure, any atom not specifically designated as a specific isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position should be understood as having hydrogen according to its natural abundance isotopic composition. Likewise, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", the position should be understood as deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (That is, at least 45% of deuterium is incorporated).

SYNTHESIS METHODS
In order to complete the purpose of the disclosure, the present disclosure applies, but is not limited to, the following technical solution:
Scheme 1 A preparation process of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R2a R2b R4b R2a R2b R4a 0 0 R4b 0 Ri 0 Ri OH FIN
+ Gi N 1 FIN / \\G2 FIN G
R3b R3b / \\G2 )r.,-NH R3a )r,NH R3a n / n R5a R5b GziG3 /
0 0 R3a R5b G4 G3 ( IA ) ( IB ) ( I ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IB) preferably is hydrochloride salt; and Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (I).
Scheme 2 A preparation process of a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R4a R2a R2b R4b R2a R2b pp 4a 0 Ri 0 Ri ¨ R4b FIN / \\G2 FIN
R3b )r 3 R3b / \\G2 ¨NH Ra )r-NH R3a n / n /
R5a R5b G4 G3 R5a R5b G4 ¨G3 ( ILA ) ( IB ) ( II ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IB) preferably is hydrochloride salt; and Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (II).
Scheme 3 A preparation process of a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R2a R2b R4a R4a 0 R2a R2b R4b 0 Ri R4b 0 Ri OH
FIN
(R6), \ 7 (R6), R3b D 5a 0 R5a R5b 0 R5b ( IA ) (IIIB ) ( III ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IIIB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IIIB) preferably is hydrochloride salt; and Rl, R2a to R5a, R26 to R5b, R6, n, m and s are each as defined in formula (III).
Scheme 4 A preparation process of a compound of formula (Ina), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
Ra R2b R4a R2a R2b 4a R4b R2 0 R4b 0 Ri OH FIN
(R6) (R6), FIN ><, s FIN
R3b R3a R3 n 5a 0 1\- R5b ____________ 0 R5a R5b ( IIA ) ( IIIB ) ( IIIa ) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IIIB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (Ma) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IIIB) preferably is hydrochloride salt; and Rl, R2a to R5a, R21 to R5b, R6, n, m and s are each as defined in formula (Ma).
Scheme 5 A preparation process of a compound of formula (IV), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R4a R4b R4b HN
OH
HN
HN R3b ).rNH R3b p 5a 5a R5b R R5b ( IVA ) ( IVB ) ( IV) reacting a compound of formula (IVA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IVB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IVB) preferably is hydrochloride salt; and R4a, R5a, R31 to R5b, K n and m are each as defined in formula (IV).
Scheme 6 A preparation process of a compound of formula (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R4a R4b R4b -7;
OH HN
HN
HN )r )r,NH R3b R6 R6 ¨NH
R3b D 5a D 5a R5b R5b ( IVaA ) ( IVB ) ( IVa ) reacting a compound of formula (IVaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IVB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (IVa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (IVB) preferably is hydrochloride salt; and R4a, R5a, R31 to R5b, K n and m are each as defined in formula (IVa).
Scheme 7 A preparation process of a compound of formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R4a R4a 0 Ri 0 HN
OH
HN
HN R3b )rNH R3b R5a 0 R5a ( VA ) ( VB ) R6 (V) R6 reacting a compound of formula (VA) or a tautomer, mesomer, racemate, enantiomer, .. diastereomer, or mixture thereof, or a salt thereof with a compound of formula (VB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (VB) preferably is hydrochloride salt; and R4a, R5a, R3b, K and R6 are each as defined in formula (V).
Scheme 8 A preparation process of a compound of formula (Va) or (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:

R4a o R4a o R1 o R1 0 HN N
OH HN
-1.-HN + R6 )r,NH R3b R5a 0 R5a ( VaA ) ( VB ) R ( Va ) R6 R4a 0 R4a OH + HN N
HN _,,.
)R3b R5a )r..-NH R3b R6 R6 r,NH 0 R5a ( VbA ) ( VB ) R6 ( Vb ) R6 reacting a compound of formula (VaA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (VB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (Va) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
reacting a compound of formula (VbA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (VB) or a salt thereof under alkaline conditions and in the presence of a condensing agent to obtain the compound of formula (Vb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
the salt of the compound (VB) preferably is hydrochloride salt; and R4a, R5a, R313, R1 and R6 are each as defined in formula (V).
Scheme 9 A preparation process of a compound of formula (II) or (Ilb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
2R a R2b 0 R4a 2R a R2b 0 R4a R2a R2b 0 R4a 0 RI R4b 0 RI R4b 0 RI R4b N N
+
HN
n n 0 R3a R5b 04-03 0 R3a R5b 04-03 0 R3a R5b 04-03 ( I ) ( II ) ( IIb ) Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, was chiral separated to give Formula (II) and (Ilb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (II).
Scheme 10 A preparation process of a compound of formula (Ma) or (11Th), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
R2a R2b R2a R2b R46 R26 R2b 0 R46 R4b 0 R4b \& );IL R46 R4b N N 3a) \'R3b N
)7,----N1-1 R36 R3b )7,----NH R36 R3b a 1 R
0 R56 R5b 0 R56 R5b 0 R56 R5b (III) ( Ma ) ( Mb ) Formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, was chiral separated to give Formula (Ma) and (IIIb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
IV, R2a to R5a, R21 to R5b, R6, s, n and m are each as defined in formula (III).
Scheme 11 A preparation process of a compound of formula (IVa) or (IVb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
0 R4a < 0 R4a Rab 0 R4a R4b HN HN
R6 HN)r,NH R3b ( , R6 )r...NH R3b , R6 , 0 R5a R5b 0 R56 R5b 0 R56 R5b (W) (IVa) (IVb) Formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, was chiral separated to give Formula (IVa) and (IVb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
R' to R5a, R36 to R5b, R6, n and m are each as defined in formula (IV).

Scheme 12 A preparation process of a compound of formula (Va) or (Vb), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, the preparation process comprising the steps of:
0 R4a 0 R4a HN 0 R4a 0 Ri 0 Ri 0 R HN
R3bR3b 1 R6 )r-NH R3b R6 0 R" 0 R5a 0 R5a (Va) (Vb) Formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, was chiral separated to give Formula (Va) and (Vb) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
Rl, R4a to R5a, R36, and R6 are each as defined in formula (V).
Scheme 13 A preparation process of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R2a R2b R Rza R2b 4a R4a 0 0 R4b R4b Ri 0 R1 Gi Gi R3b R3b \\G2 R'aG2)r,NH R3 a R5a R5b G3 0 R5a R5b G4 G3 ( IC ) ( I ) reacting a compound of formula (IC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with ammonium carbonate (or ammonium bicarbonate) and sodium cyanide (or potassium cyanide) to obtain the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
Gl, G2, G3, G4, Rl, R2a to R5a, R21 to R5b, n and m are each as defined in formula (I).

Scheme 14 A preparation process of a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R2a R2 2b R2a R2b R4a 0 R4b 0 R4b Ri 0 R1 0 (R6) \(R6)s R3b HN R3b R3a R3a R5a R5b 0 R5a R5b ( IIIC ) ( III ) reacting a compound of formula (IIIC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with ammonium carbonate (or ammonium bicarbonate) and sodium cyanide (or potassium cyanide) to obtain the compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
Rl, R2a to R5a, R21 to R5b, R6, n, m and s are each as defined in formula (III).
Scheme 15 A preparation process of a compound of formula (IV), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R4a R4a R4b 0 0 R4b FIN
R3b R3b a a R5a R5b 0 R5a R5b ( WC) (1V) reacting a compound of formula (IVC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with ammonium carbonate (or ammonium bicarbonate) and sodium cyanide (or potassium cyanide) to obtain the compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:

R4a, R5a, R31 to R5b, n and m are each as defined in formula (IV).
Scheme 16 A preparation process of a compound of formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R4a R4a R1 0 0 Ri 0 Ok>CN HN
R3b R3b R5a 0 R5a (VC) (V) reacting a compound of formula (VC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with ammonium carbonate (or ammonium bicarbonate) and sodium cyanide (or potassium cyanide) to obtain the compound of formula (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
R4a, R5a, R31 , tc and R6 are each as defined in formula (V).
The agent which provides the alkaline condition includes organic bases and inorganic bases, wherein the organic base includes, but is not limited to, triethylamine, N,N-disopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butwdde and potassium tert-butoxide, and wherein the inorganic base includes, but is not limited to, magnesium chloride, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate and N-(3 -Dimethylaminoprop y1)-N'-ethylcarbodiimide hydrochloride (EDCI).
The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxyb enzo triazole, 1 -hydro xy-7 - azobenzo triazo le, 0-benzo triazo le-N,N,N',N'-tetramethyluronium hexafluoro phosphate, 2 - (7-o xobenzo triazo le)-N,N,N',N'-tetramethyluroniu m hexafluorophosphate, 2 -(7- azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol- 1 -ylo xytri s(dimethylamino)pho sphonium hexafluorophosphate and benzo triazol- 1 -yl-oxytripyrrolidinylphosphonium phosphate.

The reaction is preferably conducted in a solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethylsulfoxide, 1,4-dioxane, water, N, N-dimethylformamide, and the mixtures thereof.
The following examples serve to illustrate the disclosure, but the examples should not be considered as limiting the scope of the disclosure. If specific conditions for the experimental method are not specified in the examples of the present disclosure, they are generally in accordance with conventional conditions or recommended conditions of the raw materials and the product manufacturer. The reagents without a specific source indicated are commercially available, conventional reagents.
The structures of the compounds were identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR was determined by a Bruker AVANCE II (or III)-400MHz. The solvents are deuterated-dimethyl sulfoxide (DMSO-d6), deuterated-chloroform (CDC13) and deuterated-methanol (CD30D) with tetramethylsilane (TMS) as an internal standard. NMR chemical shifts (5) are given in 10-6 (ppm).
LC/MS (ESI) analyses were performed on a Shimadzu LCMS2020 equipped with a Sunfire C18 (Sum 50x4.6mm) column, Waters UPLC-QDa equipped with an ACQUITY
UPLC 0 BEH (2.1*50mm 1.7um) column, Agilent Agilent6120 equipped with a Xbridge C18 (Sum 50x4.6mm) column.
HPLC analyses were performed on an Agilent 1200DAD equipped with a Sunfire C18 (Sum 150x4.6mm) column and Shimadzu UFLC equipped with an Xbridge C18 (Sum 150x4.6mm) column.
Chiral HPLC analyses were performed on a Waters-UPC2 instrument.
The known raw materials of the present disclosure were prepared by the conventional synthesis methods in the art, or purchased from Aldrich Chemical Company, Fisher Scientific or Combi-Blocks, etc.
Unless otherwise stated, the reactions were carried out under nitrogen atmosphere.
Unless otherwise stated, the reaction temperature in the reactions refers to room temperature, and the range of the temperature was 20 C to 30 C.
The reaction process was monitored by LC-MS or thin layer chromatography (TLC), and the developing solvent system includes: A: dichloromethane and methanol, B:
hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds. The elution system for purification of the compounds by column chromatography, thin layer chromatography and CombiF/ash flash rapid preparation instrument includes: A:

dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as acetic acid was added.
Prep-HPLC was performed on Shimadzu (LC-20AD, SPD20A) Preparative HPLC
(Phenomenex Gemini-NX 5uM C18 21.2x100mm column), Waters 2767 equipped with a Sunfire Pre C18 (10um 19x250mm) column and Waters 2767-QDa equipped with an Xbridge Pre C18 (10um 19x250mm) column instrument.
Pre-SFC was performed on a Waters-SFC80 equipped with Daciel AD/OD/al/IC/IA/ID

(10um 20x250mm) column instrument.
CombiFlash was performed on systems from Teledyne ISCO or Agela Technologies.
The following abbreviations are used:
AIBN is 2,2 -Azobis(2-methylpropionitrile), DAST is (Diethylamino)sulfur trifluoride, DIPEA (or DIEA) is N,N-diisopropylethylamine, EDCI is N-(3-Dimethylaminopropy1)-N' -ethylcarbodiimide hydrochloride, HOBt is 1-Hydroxybenzotriazole hydrate, HATU is 0-(7-Azabenzotriazol-1-y1)-N,N,N',N'-te-tramethyluronium hexafluorophosphate, HBTU is 0-(Benzotriazol-1-y1)-N,N,N ,N -tetramethyluronium hexafluorophosphate, HC1 is hydrogen chloride, LDA is Lithium diisopropylamide, LiHMDS is Lithium bis(trimethylsilyl)amide, n-BuLi is n-Butyllithium, NBS is N-Bromosuccinimide, NCS is N-Chlorosuccinimide, Pd(dppf)C12 is 111,1 -Bis(diphenylphosphino)ferrocene[dichloropalladium(II), TEA is triethylamine, DCE is 1,2-dichloroethane, DCM is dichloromathane, DMF is N,N-dimethylformamide, Et0Ac (or EA) is ethyl acetate, Et0H is ethanol, MeCN or ACN is acetonitrile, Me0H is methanol, n-BuOH is n-Butanol, PE is petroleum ether, THF is Tetrahydrofuran, NMR is nuclear magnetic resonance, MS is mass spectroscopy with (+) referring to the positive mode which generally gives a M+1 (or M+H) absorption where M = the molecular mass.
Prep HPLC is Prepative High performance liquid chromatography.
SFC is Supercritical fluid chromatography.
Intermediate 1 (Int-1) (S)-3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)propanoic acid Intermediate 1 (Int-1) HN (S) OH
y-NH
It-1 I-1 r\._vNI-j( 0 Step 1 Step 2 Step 3 ___________________________________ ,v)Hr0 ___ v7L0 0 It-1-1 It-1-2 It-1-3 H N 0 Step 4 H N "AN0 0V\).... 0 H 0 0 H
It-1-4 It-1 Step 1 Tert-butyl 4-cyclopropy1-4-oxobutanoate Int-1-2 The solution of LDA (15.28 g, 142.66 mmol, 71.43 mL) in THF (50 mL) was cooled to -78 C before the solution of cyclopropyl methyl ketone Int-1-1 (10 g, 118.88 mmol) in THF
(10 mL) was added dropwise. The resulting solution was warmed to 20 C and stirred for 30 min. The reaction mixture was then re-cooled to -78 C and tert-butyl 2-bromoacetate (23.19 g, 118.88 mmol) in THF (10 mL) was added slowly. The reaction was stirred at room temperature overnight. After the reaction completed, the reaction was quenched with saturated NH4C1 (50 mL, aq.), the mixture was extracted with Et0Ac (50 mL X 3), the organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated to give the crude tittle compound Int-1-2 (22 g, 110.97 mmol, 93.34% yield).
1H NMR (400 MHz, CDC13): 6 2.83 (t, 2H), 2.50 (t, 2H), 1.97-1.92 (m, 1H), 1.45 (s, 9H), 1.06-1.01 (m, 2H), 0.91-0.86 (m, 2H).
Step 2 Tert-butyl 3 -(4 -cyc loprop y1-2,5 -dio xo imidazolidin-4- yl)prop ano ate Int-1-3 The 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), Et0H (50 mL) and water (50 mL) was sealed and heated to 80 C for 18h. The reaction mixture was cooled and poured into a mixture of Et0Ac (100 mL) and water (100 mL), the layers were separated, and the aq.
layer was extracted with Et0Ac (100 mL X 3). The organic solution was combined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatagraphy (Et0Ac/hexane =1/2) to give the tittle compound Int-1-3 (5.7 g, 21.24 mmol, 51.36% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.61 (s, 1H), 7.66 (s, 1H), 2.29-2.08 (m, 2H), 1.93-1.88 (m, 2H), 1.29 (s, 9H), 1.09-1.02 (m, 1H), 0.47-0.26 (m, 3H), 0.11-0.04 (m, 1H).
Steps 3 and 4 (S)-3 -(4-c yc loprop y1-2,5 -dioxoimid azolidin-4- yl)prop anoic acid It-1 The solution of Int-1-3 (7.2 g, 26.83 mmol) in HO/Dioxane (4M, 50 mL) was stirred at room temperature for 4h and concentrated. The resulting solid was triturated in MeCN
(30mL) for lh and filtrated to give pure racemic target as a white solid. The solid was chiral separated by SFC (using a chiral column CHIRALPAK AD-H 10um 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 tittle compound It-1 (2 g, 9.42 mmol, 35.12% yield).
1H NMR (400 MHz, DMSO-d6): 6 12.20 (s, 1H), 10.63 (s, 1H), 7.71 (s, 1H), 2.32-2.09 (m, 2H), 1.99-1.87 (m, 2H), 1.11-1.03 (m, 1H), 0.48-0.27 (m, 3H), 0.12-0.05 (m, 1H).
Chiral HPLC: 98.04% cc, Rt: 2.918 mm.
LCMS: MS m/z (ES!): 213.1 1M+11 Intermediate 2 (Int-2) 3 -(4-c ycloprop y1-2 ,5 -dioxoimidazo lidin-4 - y1)-2-methylprop ano ic acid Int-2 OH
HN NH
Int-2 Step 1 0 Step 2 0<

Int-2-1 Int-2-2 Int-2-3 O
Step 3 0_Y(*-Lo Step 4 OH
HN NH HN NH

Int-2-4 Int-2 Step 1 1-(tert-butyl) 4-ethyl 3-(cyclopropanecarbony1)-2-methylsuccinate Int-2-2 To a mixture of ethyl 3-cyclopropy1-3-oxopropanoate Int-2-1 (32 g, 204.89 mmol) in butan-2-one (400 mL) was added tert-butyl 2-bromopropanoate (44.54 g, 213.04 mmol), K2CO3 (57 g, 409.79 mmol) and NaI (3.07 g, 20.49 mmol). The reaction mixture was heated at 100 C for 16h and cooled to RT. Water was added and the reaction mixture acidified to pH
8. The the mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatagraphy (hexane) to give Int-2-2 (11.7 g, 41.15 mmol, 20.08%
yield).
11INMR (400 MHz, CDC13): 6 4.25-4.21 (m, 2H), 3.92 (dd, 1H), 3.19-3.09 (m, 1H), 2.17-2.07 (m, 1H), 1.43 (d, 9H), 1.30-1.24 (m, 3H), 1.19-1.13 (m, 3H), 1.11-1.06 (m, 2H), 0.98-0.91 (m, 2H).
Step 2 tert-butyl 4-cyclopropy1-2-methyl-4-oxo-butanoate Int-2-3 To a solution of the Int-2-2 (4 g, 14.07 mmol) in THF (50 mL) was added LiOH
(1.68 g, 70.34 mmol) and H20 (50 mL). The reaction mixture was stirred at room temperature overnight. To the mixture was added aq. Citric acid solution to adjust to pH<5 and then stirred at 40-50 C for 10 min. After the reaction was completed, water was added and the reaction mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatagraphy to give Int-2-3 (1.81 g, 8.55 mmol, 60.74% yield).
11INMR (400 MHz, CDC13): 6 2.97 (dd, 1H), 2.89-2.79 (m, 1H), 2.56 (dd, 1H), 1.96-1.88 (m, 1H), 1.43 (s, 9H), 1.15 (d, 3H), 1.05-1.00 (m, 2H), 0.90-0.84 (m, 2H).
Step 3 Tert-butyl 3- 4 -cyc loprop y1-2 ,5 -dio xo -imidazolidin-4- y11-2-methyl-prop ano ate Int-2-4 To a solution of the Int-2-3 (1.89 g, 8.91 mmol) in Et0H (60 mL) was added (NH4)2CO3 (6.86 g, 71.36 mmol), H20 (60 mL) and NaCN (1.09 g, 22.30 mmol). The reaction mixture was stirred at 80 C in a seal tube overnight and cooled to rt. Water was added and reaction mixture extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with Et0Ac/hexane (1/5), filtered and dried to give Int-2-4 (1.23 g, 4.34 mmol, 48.71% yield).
11INMR (400 MHz, DMSO-d6): 6 10.54 (brs, 0.5H) 10.52(brs, 0.5H), 7.64 (brs, 0.5H), 7.52 (brs, 0.5H), 2.41-2.06 (m, 2H), 1.70 (dd, 0.5H), 1.56 (dd, 0.5H), 1.37 (d, 9H), 1.07 (d, 1.5H), 1.08-1.01 (m, 1H), 1.02 (d, 1.5H), 0.48-0.29 (m, 3H), 0.14-0.05 (m, 1H).
Step 4 3 -(4-c ycloprop y1-2 ,5 -dioxoimidazo lidin-4 - y1)-2-methylprop ano ic acid Int-2 The solution of Int-2-4 (100 mg, 354.19 umol) in HC1/Dioxane (2N, 4 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuum to give Int-2 (100 mg). The product was used directly in the next step without further purification.
Intermediate 2A (Int-2A) and Intermediate 2B (Int-2B) 3 -((S)-4-c yc loprop y1-2,5-dioxoimid azo lidin-4 -y1)-2 -methylprop ano ic acid Int-2A
3 -((R)-4-c ycloprop y1-2,5 -dioxoimidazolidin-4- y1)-2-methylprop anoic acid Int-2B

OH OH
HN 1,(NH HN NH
0 Int-2A I nt-2B

Int-2-4 (1.22g) was separated by silica gel chromagraphy (hexane:Et0Ac=20:1) to give diastereoisomers 1 (360 mg) and diastereoisomers 2 (350 mg). Diastereoisomers 1 were converted to Int-2A using similar procdure as Step 4 for Int-2.
Diastereoisomers 2 were converted to Int-2B using similar procdure as Step 4 for Int-2.
Int-2A

11INMR (400 MHz, DMSO-d6): 6 12.15 (brs, 1H), 10.62 (s, 1H), 7.64 (s, 1H), 2.33-2.27 (m, 1H), 2.19-2.13 (m, 1H), 1.77-1.71 (m, 1H), 1.05 (d, 4H), 0.45-0.26 (m, 3H), 0.09-0.04 (m, 1H).
LCMS: MS nth (ES!): 227.2 1M+Hr.
Int-2B
1HNMR (400 MHz, DMSO-d6): 6 12.16 (brs, 1H), 10.57 (s, 1H), 7.68 (s, 1H), 2.40-2.35 (m, 1H), 2.30-2.24 (m, 1H), 1.60 (dd, 1H), 1.12- 1.05(m, 1H), 1.11 (d, 3H), 0.43-0.30 (m, 3H), 0.13-0.07 (m, 1H).
LCMS: MS nth (ES!): 227.2 1M+Hr.
EXAMPLES
Example 1 (S)-5 -c ycloprop y1-5 -(3 -o xo -3-(5 -(triflu oromethyl) iso indolin-2 -yl)prop yl) imidazo lidine-2 ,4-dione 1 HNN
)r-NH 1 CF3 HN
OH
CF HN.niNH oA HN)r.NH

1-1 It-1 1 To a mixture of 5-(trifluoromethyl)isoindoline 1-1 (150 mg, 801.45 umol) in DMF (10 mL) was added triethylamine (324 mg, 3.21 mmol), Int-1 (170mg, 801.45 umol) and HATU
(365 mg, 961.74 umol). The reaction was stirred at r.t for 18h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with Prep-HPLC to give title compound example 1 (80 mg, 209.78 umol, 26.18% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.77-7.74 (m, 2H), 7.66 (d, 1H), 7.58 (d, 1H), 4.89-4.69 (m, 4H), 2.48-2.38 (m, 1H), 2.33-2.24 (m, 1H), 2.04-1.99 (m, 2H), 1.16-1.08 (m, 1H), 0.50-0.46 (m, 1H), 0.43-0.29 (m, 2H), 0.15-0.08 (m, 1H).
LCMS: MS nth (ES!): 382.1 1M+Hr.
Example 2 (S)-5 -(3 -(5 -chloro isoindolin-2- y1)-3 -oxoprop y1)-5 -cyc loprop ylimidazo lidine-2,4-dione 2 0oN
HN NH
)T

NH HCI 0)L
OH
HN),r-NH
CI HN/I\IH
11 .410. ci 2-1 It-1 2 To a solution of 5-chloroisoindoline hydrochloride 2-1 (100 mg, 526.12 umol) in DMF
(3 mL) was added TEA (0.22 mL), It-1 (134 mg, 631.35 umol) and HATU (240 mg, 631.35 umol). The mixture was stirred at room temperature overnight. LCMS showed starting material was completely reacted. Water (20 mL) was added and the mixture extracted with Et0Ac (15 mL X 2). The combined organic layers are washed with water (30 mL) and brine (30 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude was purified by prep-HPLC to give title compound 2 (70 mg, 38.03%).
11INMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.73 (s, 1H), 7.45(s, 1H), 7.39-7.33 (m, 2H), 4.77(d, 2H), 4.61 (d, 2H), 2.43-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.00 (t, 2H), 1.15-1.07 (m, 1H), 0.49-0.45 (m, 1H), 0.40-0.29 (m, 2H), 0.13-0.08 (m, 1H).
LCMS: MS nth (ES!): 348.1 1M+Hr.
Example 3 (S)-2-(3 - (4-cycloprop y1-2,5 -dioxoimidazolidin-4- yl)prop ano yl) isoindo line-5 -carbonitrile 3 0 \7 0 V NH + 0 V 0 0( OH ___ (s) 10 hilpTANH HN
NC NH
= ON

3-1 It-1 3 To a mixture of isoindoline-5-carbonitrile 3-1 (50 mg, 346.81 umol) in DMF (10 mL) was added Triethylamine (140 mg, 1.39 mmol), It-1 (88 mg, 416.17 umol) and HATU (158 mg, 416.17 umol). The reaction was stirred at r.t for 18h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 3 (25 mg, 73.89 umol, 21.30% yield).
111 NMR (400 MHz, CDC13): 6 7.97-7.92 (m, 1H), 7.65-7.57 (m, 2H), 7.45-7.38 (m, 1H), 6.15 (brs, 1H), 4.84 (brs, 4H), 2.58-2.30 (m, 4H), 1.25-1.18 (m, 1H), 0.64-0.57 (m, 1H), 0.50-0.44 (m, 1H), 0.42-0.32 (m, 2H).
LCMS: MS raiz (ES!): 339.1 [M+Hr.
Example 4 (S)-5 -c yc loprop y1-5 -(3 -oxo-3 -(5 -(trifluorometho xy)isoindo lin-2-yl)propyl)imidazolidine-2,4-dione 4 HN)rNH

0)-N= 11 step 1 ,=-"\AOH

.NH 0 V
Int-1 o N HN ,* 0 F
________________ HN )7-NH
step 2 step 3 0 Step 1 tert-butyl 5 - (((methylthio)c arbonothio yl)o xy) isoindoline-2-c arboxyl ate To a solution of tert-butyl 5-hydroxyisoindoline-2-carboxylate 4-1 (1.5 g, 6.38 mmol) in DMF (20 ml) was added sodium hydride (0.4 g, 9.57 mmol), at 0 C. After stirring for 30 minutes, carbon disulfide (0.5 ml) was added. It was stirred for one hour, and methyl iodide (0.6 ml, 8.30 mmol) was added. The reaction mixture was stirred at ambient temperature for 14 hours. It was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to get 4-2 as a pale solid (1.95 g, 93.8 % yield).

1H NMR (400 MHz, CDC13): 7.24 (d, 1 H), 7.18 (s, 1 H), 6.95 9d, 1 H), 4.61 (dd, 4 H), 2.60 (s, 3 H), 1.44 (s, 9 H).
LCMS: MS mh (ES!): 326 [M+Hr.
Step 2 5 -(trifluorometho xy) isoindoline 4-3 To a solution of 4-2 in pyridine-hydrogen fluoride complex (15 ml) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (5.5 g, 19.2 mmol), at 0 C. The reaction mixture was stirred at ambient temperature for 14 hours. It was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated.
.. The residue was purified on a silica gel column, eluting with ethyl acetate in hexanes, to get 4-3, as a white solid (910 mg).
LCMS: MS mh (ES!): 204 [M+Hr.
Step 3 (S )-5-c yc loprop y1-5 -(3 -oxo-3 - (5- (trifluorometho xy) isoindo lin-2-yl)prop yl) imid azolidine-2,4-dione 4 A solution of Int-1 (10 mg. 0.047 mmol), EDCI (14 mg, 0.071 mmol) and HATU (27 mg, 0.071 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 minutes, before 4-3 (10 mg, 0.047 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. It was directly loaded onto and purified on a reverse phase HPLC.
The appropriate fraction was lyophilized to afford example 4.
1H NMR (400 MHz, CD30D): 8.00-7.78 (m, 3 H) 4.87 (m, 2 H), 4.68 (m, 2 H), 3.70 (m, 1 H), 3.10 (m, 1 H), 2.26 (m, 2 H), 1.14 (m, 1 H), 0.49 (m, 1 H), 0.32 (m, 2 H), 0.25 (m, 1 H).
LCMS: MS mh (ES!): 398 [M+Hr.
Example 5 (S)-5 -c yc loprop y1-5 - (3 -(7-methoxy-4,5-dihydro-1H-benzo [d] azep in-3 (2H)- y1)-3 -oxoprop yllimidazolidine-2 ,4-dione 5 HN)4fr)L
e NH 400 5 0/

HN (:) 0 HN)H)LN
HCI )1.- NH 41 01 5-1 It-1 5 A solution of It-1 (10 mg. 0.047 mmol), EDCI (14 mg, 0.071 mmol) and HATU (27 mg, 0.071 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 minutes, before 7 -metho xy-2 ,3,4,5-tetrahydro-1H-benzo kllazepine hydrochloride 5-1 (10 mg, 0.047 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. It was directly loaded onto and purified on a reverse phase HPLC. The appropriate fraction was lyophilized to afford 5.
1H NMR (400 MHz, CD30D): 7.06 (dd, 1 H), 6.74 (m, 1 H), 6.70 (dt, 1 H), 3.77 (d, 3 H), 3.72-3.59 (m, 4 H), 2.96-2.84 (m, 4 H), 2.54 (m, 1 H), 2.42 (m, 1 H), 2.11 (m, 2 H), 1.21 (m, 1 H), 0.56 (m, 1 H), 0.44-0.30 (m, 3 H).
LCMS: MS rniz (ES!): 372 [M+Hr.
Example 6 (S)-5 -c ycloprop y1-5 -(3 -oxo-3 - (6-(triflu oromethyl)- 3 ,4-dihydroiso qu ino lin-2 (1 H)-yl)propyl)imidazolidine-2,4-dione 6 NH

0 t>, 1101 HN = HN"..:,,&\..4 e NH
CF3 + HN N CF

6-1 It-1 6 A solution of It-1 (10 mg. 0.047 mmol), EDCI (14mg, 0.071 mmol) and HATU (27 mg, 0.071 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 minutes, before 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 6-1 (10 mg, 0.047 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. It was directly loaded onto and purified on a reverse phase HPLC. The appropriate fraction was lyophilized to afford 6.
1H NMR (400 MHz, CD30D): 8.15-7.50 (m, 3 H), 4.10 (m, 1 H), 3.55-3.85 (m, 4 H), 3.00 (m, 2 H), 2.50-2.10 (m, 3 H), 1.21 (m, 1 H), 0.60 (m, 1 H), 0.49-0.30 (m, 3 H).
LCMS: MS rniz (ES!): 396 [M+Hr.

Example 7 (S)-5 -c ycloprop y1-5 -(3 -oxo-3 - (7 -(triflu oromethyl)- 3 ,4-dihydroiso qu ino lin-2 (1 H)-yl)pr op yl)imid azolidine -2 ,4 -dione 7 ) HN )LN

NH

0 N, HN cF3 HN CF
eNH

7-1 It-1 7 A solution of It-1 (10 mg. 0.047 mmol), EDCI (14 mg, 0.071 mmol) and HATU (27 mg, 0.071 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 minutes, before 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline 7-1 (10 mg, 0.047 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. It was directly loaded onto and purified on a reverse phase HPLC. The appropriate fraction was lyophilized to afford 7, as a white solid.
11-1 NMR (400 MHz, CD30D): 8.10-7.60 (m, 3 H), 4.12 (m, 1 H), 3.55-3.85 (m, 4 H), 3.00 (m, 2 H), 2.50-2.10 (m, 3 H), 1.21 (m, 1 H), 0.60 (m, 1 H), 0.49-0.30 (m, 3 H).
LCMS: MS mh (ES!): 396 [M+Hr.
Example 8 (5 S)-5 -(3 -(8-chloro-1-methy1-4,5-dihydro-1H-benzo [di azep in-3 (2H)- y1)-3 -oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 8 0 o HN N
eNH

CI

ip 01 0 NH =HN
o."-N1H 0 OH
CI
8-1 It-1 8 A solution of It-1 (10 mg. 0.047 mmol), EDCI (14 mg, 0.071 mmol) and HATU (27 mg, 0.071 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 minutes, before 8-chloro-1-methy1-2,3,4,5-tetrahydro-1H-benzoldlazepine 8-1 (12 mg, 0.047 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. It was directly loaded onto and purified on a reverse phase HPLC. The appropriate fraction was lyophilized to afford 8 (mixture of two diastereomers).
LCMS: MS nth (ES!): 390 [M+Hr.
Example 9 (S)- 5 -c yc loprop y1-5 - (3 - (4,5 -dihydro -1H-benzo [d] azep in-3 (21/)-y1)-3 -oxoprop yl)imidazolidine-2 ,4-dione 9 V
O
HN NH

HN HN
(s) + (s) OH ________ HN zNH
9-1 Int-1 0 9 To a solution of 2,3,4,5-tetrahydro-1H-benzoldlazepine 9-1 (100 mg, 679.27 umol) in DMF (4 mL) was added Triethylamine (275 mg, 2.72 mmol, 377.67 uL), It-1 (173 mg, 815.13 umol) and HATU (310 mg, 815.13 umol). The mixture was stirred at room temperature overnight. LCMS showed starting material was completely reacted. Water (25 mL) was added and the reaction mixture extracted with Et0Ac (20 mL X2). The combined organic layers are washed with water (40 mL) and brine (40 mL X 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude was purified by prep-HPLC to give title compound 9 (11 mg, 4.74%).
1H NMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.72 (s, 1H), 7.15-7.13 (m, 4H), 3.58-3.51 (m, 4H), 2.91-2.90 (m, 2H), 2.82-2.81 (m, 2H), 2.45-2.35 (m, 1H), 2.30-2.25 (m, 1H), M.94 (m, 2H), 1.12-1.08 (m, 1H), 0.48-0.46 (m, 1H), 0.40-0.29 (m, 2H), 0.10-0.08 (m, 1H).
LCMS: MS nth (ES!): 342.2 1M+Hr.

Example 20 (S)-5 -c ycloprop y1-5 - (3- (5 ,6-dichloroiso indo lin-2 -y1)-3 -o xoprop yl) imidazolidine-2 ,4-dione (:) V 0 H 1\1 y NH CI

Step 1 Step 2 CI Int-1 0 NH ___________ NH Ste HNN
CI CI CI )r-NH CI
p 3 20a 20b 20c 5 ci Step 1 5,6 -dichloro isoindoline- 1 ,3 -dione 20b The mixture of 5,6-dichloroisobenzofuran-1,3-dione 20a (5 g, 23.04 mmol) in formamide (1.04 g, 23.04 mmol) was stirred at 200 C for 2 h. The mixture was poured into ice water 10 (100 mL), the mixture was filtered and the solid was dried to afford the tittle compound 20b (4.5 g, 20.83 mmol, 90.41% yield).
111 NMR (400 MHz, DMSO-d6): 6 11.62 (s, 1H), 8.12 (s, 2H).
Step 2 5 ,6-dichloroisoindoline 20c 15 To a solution of 20b (1 g, 4.63 mmol) in THF (5 mL) was added BH3 (1 M
in THF, 46.29 mL).
The resulting mixture was stirred at 80 C for 16 h. Con. HC1 (10 mL) was added to quench the reaction. Then aq NaOH was added to adjust the mixture to pH-13, the aqueous phase was extracted with Et0Ac (80 mL X 3), the combined organic phases were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was 20 purified by silica gel chromatography (eluting with DCM/Me0H=10/1) to afford the tittle compound 20c (150 mg, 797.64 umol, 17.23% yield).
111 NMR (400 MHz, DMSO-d6): 6 7.55 (s, 2H), 4.06 (s, 4H).
Step 3 (S)-5-cycloprop y1-5 - (3 -(5 ,6 -dichloro isoindo lin-2- y1)-3 -o xoprop yl) imid azolidine-2 ,4 -dio ne 20 To a solution of It-1 (140 mg, 659.75 umol) in DMF (7 mL) was added DIEA (111 mg, 857.67 umol). The resulting mixture was followed by the addition of 20c (149 mg, 791.70 umol) and EDCI (116 mg, 857.67 umol). The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by prep-HPLC to afford the tittle compound 20 (109 mg, 283.66 umol, 43.00% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.74 (s, 1H), 7.67 (s, 2H), 4.77 (brs, 2H), 4.60 (brs, 2H), 2.50-2.37 (m, 1H), 2.29-2.24 (m, 1H), 2.02-1.97 (m, 2H), 1.12-1.10 (m, 1H), 0.46-0.33 (m, 3H), 0.13-0.11 (m, 1H).
LCMS: MS miz (ES!): 382.011M+Hr.
Examples 29 and 30 (SS)-5 -cycloprop y1-5 -(2-methyl-3 - o xo -3- (5 -(trifluoro methyl) isoindo lin-2-yl)propyl)imidazolidine-2 ,4-dione 29 (5R)-5 -c ycloprop y1-5 -(2-methyl-3 - o xo-3 -(5 - (triflu oro methyl) isoindo lin-2-yl)prop yl) imidazolidine-2 ,4-dione 30 HN CF3 HN),T,NH

To a solution of 5-(trifluoromethyl)isoindoline 1-1 (1.0 g, 4.47 mmol, HC1 salt) in DMF (30 mL) was added TEA (3.5 mL), Int-2 (1.21 g, 5.37 mmol) and HATU (2.04 g, 5.37 mmol). The mixture was stirred at room temperature overnight. LCMS monitoring, the starting material was completely reacted. Water was added and the mixture was extracted with Et0Ac. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give two sets of diastereomers 29 (960 mg, 2.43 mmol, 56.56% yield) and 30 (300 mg, 0.76 mmol, 17.68%
yield).
Examples 29-1 and 29-2 (S)-5 -c ycloprop y1-5 -((S)-2-methyl-3 -oxo-3 -(5 - (trifluoromethyl) isoindo lin-2-yl)propyl)imidazolidine-2,4-dione 29-1 (S)-5 -cycloprop y1-5 -((R)-2-methyl-3 -oxo-3 -(5 - (trifluoromethyl) iso indolin-2-yl)propyl)imidazolidine-2,4-dione 29-2 HNIN:NH
CF3 HN1rNH E

29 (200 mg) was separated by SFC (Daicel CHIRALPAK AS) to give two single enantiomers (67 mg and 75 mg).
Enantiomer (shorter retention time):
1HNMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.75 (d, 1H), 7.69-7.65 (m, 2H), 7.58 (t, 1H), 4.92 (d, 2H), 4.75-4.64 (m, 2H), 2.66 (br, 1H), 2.39-2.32 (m, 1H), 1.74-1.70 (m, 1H), 1.06 (d, 3H), 1.06-1.00 (m, 1H), 0.43-0.38 (m, 1H), 0.31-0.21 (m, 2H), 0.03-0.01 (m, 1H).
LCMS: MS m/z (ES!): 396.1 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 5%-40% 1.5m1/min AS,3um,3*100(Daicel)): cc: 100%, Rt:
1.370 min.
Enantiomer (longer retention time):
11INMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.75 (d, 1H), 7.69-7.66 (m, 2H), 7.59 (t, 1H), 4.93 (d, 2H), 4.75-4.64 (m, 2H), 2.65 (br, 1H), 2.39-2.32 (m, 1H), 1.74-1.70 (m, 1H), 1.07 (d, 3H), 1.07-1.05 (m, 1H), 0.38 (br, 1H), 0.29-0.25 (m, 2H), 0.03-0.00 (m, 1H).
LCMS: MS m/z (ES!): 396.1 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 5%-40% 1.5m1/min AS,3um,3*100(Daicel)): cc: 96.62%, Rt: 1.972 min.
Examples 30-1 and 30-2 (R)-5 -cyclopropy1-5-((R)-2-methy1-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione 30-1 (R)-5 -cyclopropy1-54(S)-2-methyl-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione 30-2 iõ),0 : N j N
HNNzNH HNN,NH
C F3 n cF3 30 (300 mg) was separated by SFC (Daicel CHIRALPAK IA) to give two single enantiomers (70.6 mg and 71.6 mg).

Enantiomer (shorter retention time):
11INMR (400 MHz, DMSO-d6): 6 10.50 (s, 1H), 7.75 (d, 1H), 7.70-7.65 (m, 2H), 7.59 (t, 1H), 4.98-4.86 (m, 2H), 4.72-4.59 (m, 2H), 2.81 (br, 1H), 2.41-2.34 (m, 1H), 1.69-1.64 (m, 1H), 1.11 (d, 3H), 1.11-1.06 (m, 1H), 0.46-0.40 (m, 1H), 0.35-0.26 (m, 2H), 0.11-0.06 (m, 1H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.72 LCMS: MS miz (ES!): 396.0 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): ee:
99.48%, Rt: 3.580 min.
Enantiomer (longer retention time):
11INMR (400 MHz, DMSO-d6): 6 10.50 (s, 1H), 7.75 (d, 1H), 7.70-7.65 (m, 2H), 7.60-7.56 (m, 1H), 4.98-4.86 (m, 2H), 4.72-4.59 (m, 2H), 2.84-2.78 (m, 1H), 2.41-2.34 (m, 1H), 1.69-1.64 (m, 1H), 1.11 (d, 3H), 1.11-1.04 (m, 1H), 0.45-0.40 (m, 1H), 0.36-0.27 (m, 2H), 0.12-0.09 (m, 1H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.57 LCMS: MS m/z (ES!): 396.1 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): ee:
96.26%, Rt: 4.368 min.
Examples 31-1 and 31-2 (5R)-5 -c ycloprop y1-5 -(2 -(5-(trifluoromethyl) iso indoline-2-c arbo nyl)bu tyl)imidazolidine-2 ,4-dione 31-1 (5S)-5 -c ycloprop y1-5 -(2-(5 -(triflu oro methyl) i so indoline-2-c arbo nyl)b utyl)imidazolidine-2 ,4 -dione 31-2 OL(:) N _________ N =HN2rNH = 0F3 0F3 Step 1 A Step 2 cy< Step 3 '11 Int-2-1 31b 31c t=-0.< Step 4 "LOH Step 5 N H N
HN)./..- NH HN)./..- NH HN)r, NH ____ 110 CF3 31d 31e 31-1 31-2 Step 1 1-(tert-butyl) 4-ethyl 3-(cyclopropanecarbony1)-2-ethylsuccinate 31b To a mixture of Int-2-1 (30 g, 192.09 mmol) and tert-butyl 2-bromobutanoate (45.00 g, 201.69 mmol) in 2-butanone (400 mL) was added potassium carbonate (53.10 g, 384.18 mmol) and Sodium iodide (2.88 g, 19.21 mmol). The reaction was stirred at 100 C for 72h.
The mixture was filtered and the filtrate was diluted with water (500 mL); the mixture was extracted with Et0Ac (200 mL x 3), the combined organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give 31b (55.6 g, 186.34 mmol, 97.01% yield).
Step 2 Tert-butyl 4-cyclopropy1-2-ethyl-4-oxobutanoate 31c To a mixture of 31b (7.5 g, 25.14 mmol) in THF (80 mL) was added a solution of Li0H.H20 (3.17 g, 75.41 mmol) in water (80 mL). The reaction was stirred at r.t for 18h. The reaction mixture was diluted with Citric acid to pH =6 and then stirred at 50 C for 10min. The mixture was diluted with water (100 mL) and the mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexane:Et0Ac=20:1) to give 31c (5.1 g, 22.54 mmol, 89.65% yield).
Step 3 Tert-butyl 2-((4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)methyl)butanoate 31d To a mixture of 31c (5.1 g, 22.54 mmol) in Et0H (80 mL) was added to a solution of ammonium carbonate (17.32 g, 180.28 mmol) in water (80 mL). Then sodium cyanide (2.76 g, 56.34 mmol) was added. The reaction was stirred at 80 C for 18h in the sealed tube. The reaction was cooled to r.t and the mixture was poured into a mixture of water and Et0Ac, the obtained mixture was extracted with Et0Ac (100 mL x 2). The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was triturated with hexane (50 mL) for lh and filtered; the solid was dried to give 31d (mixture, 1.5 g, 5.06 mmol, 22.46%
yield).
Step 4 24(4 -cyc loprop y1-2,5 -dioxoimidazolidin-4-y0methyl)butanoic acid 31e The solution of 31d (1.5 g, 5.06 mmol) in HCl/Dioxane (4N, 20 mL) was stirred at r.t for 18h.
The mixture was concentrated, the residue was triturated with hexane (50 mL) and filtered, the solid was dried to give 31e (1.4 g, 5.06 mmol, 99.96% yield).

11INMR (400 MHz, DMSO-d6): 6 12.13 (brs, 1H), 10.58, 10.53 (s, 1H), 7.64, 7.60 (s, 1H), 2.27-2.06 (m, 2H), 1.81-1.77 (m, 1H), 1.64-1.36 (m, 2H), 1.21-1.00 (m, 1H), 0.84-0.79 (m, 3H), 0.47-0.25 (m, 3H), 0.14-0.02 (m, 1H).
Step 5 (SR)-5 -cyc loprop y1-5 -(2-(5 -(triflu oro methyl)isoindo line-2 -carbonyl)b utyl)imid azolidine-2,4 -dione (diastereoisomers 1, Rt: 6.567 min) 31-1 (SS)-5 -cyc loprop y1-5 -(245 -(trifluoromethyl) isoindo line-2 -carbonyl)b utyflimid azolidine-2,4-dione (diastereoisomers 2, Rt: 7.063 min) 31-2 To a solution of 31e (400 mg, 1.66 mmol) in DMF (15 mL) was added 5-(trifluoromethyl)isoindoline 1-1 (372.31 mg, 1.66 mmol, HC1 salt) and Triethylamine (673.88 mg, 6.66 mmol), then HATU (696.35 mg, 1.83 mmol) was added. The reaction was stirred at r.t for 4h. Water (100 mL) was added and the mixture was extracted with Et0Ac (50 mL x 2), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give 31-1 (12.5 mg) and 31-2 (55 mg).
31-1:
11INMR (400 MHz, DMSO-d6): 6 10.48 (s, 1H), 7.78-7.56 (m, 4H), 4.93-4.90 (m, 1H), 4.81-4.50 (m, 3H), 2.69-2.67 (m, 1H), 2.40-2.32 (m, 1H), 1.78-1.65 (m, 1H), 1.59-1.39 (m, 3H), 1.08-1.02 (m, 1H), 0.89-0.79 (m, 3H), 0.49-0.25 (m, 3H), 0.12-0.05 (m, 1H).
HPLC (SunFire C18 Sum 4.6*150mm 1.0ml/min 16min, 0.03% CH3CN/H20): Rt: 6.567 min.
LCMS: MS miz (ES!): 410.2 [M+Hr.
31-2:
11INMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.78-7.55(m, 4H), 4.92-4.90 (m, 1H), 4.78-4.53 (m, 3H), 2.48-2.42 (m, 1H), 2.33-2.24 (m, 1H), 1.84-1.76 (m, 1H), 1.58-1.37 (m, 2H), 1.08-1.00 (m, 1H), 0.89-0.83 (m, 3H), 0.45-0.22 (m, 3H), 0.05-0.00 (m, 1H).
HPLC (SunFire C18 Sum 4.6*150mm 1.0ml/min 16min, 0.03% CH3CN/H20): Rt: 7.063 min.
LCMS: MS miz (ES!): 410.1 [M+Hr.
Examples 32 and 33 (S)-5 -c ycloprop y1-5 -((S)-2 -(5-(trifluoromethyl) isoindoline-2-c arbonyebutyflimid azo lidine-2,4-dione 32 (S)-5 -cyc loprop y1-5 -((R)-2-(5 -(trifluoro methyl) isoindo line-2 -carbonyflb utyflimid azolidine-2,4-dione 33 _ = HN'N
)i-NH
CF3 yNNH N

31-2 (350 mg) was separated by SFC (Daicel CHIRALPAK IG, 250*25mm 10p,m) to give single enantiomers (120 mg and 100 mg).
Enantiomer (shorter retention time):
1HNMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.75 (d, 1H), 7.68 (d, 1H), 7.63-7.55 (m, 2H), 4.96-4.85 (m, 2H), 4.79-4.66 (m, 2H), 2.48-2.43 (m, 1H), 2.32-2.25 (m, 1H), 1.83-1.78 (m, 1H), 1.56-1.37 (m, 2H), 1.08-1.00 (m, 1H), 0.86 (t, 3H), 0.44-0.40 (m, 1H), 0.32-0.22 (m, 2H), 0.03-0.00 (m, 1H).
LCMS: MS m/z (ES!): 410.1 [1\4+Hr Chiral HPLC (CO2/Et0H/DEA 5%-40% 1.5ml/min IG,3um,3*100(Daicel)): cc: 100%, Rt:
3.222 min.
Enantiomer (longer retention time):
11INMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.75 (d, 1H), 7.68 (d, 1H), 7.63-7.55 (m, 2H), 4.96-4.85 (m, 2H), 4.79-4.66 (m, 2H), 2.48-2.43 (m, 1H), 2.33-2.25 (m, 1H), 1.84-1.78 (m, 1H), 1.57-1.38 (m, 2H), 1.08-1.00 (m, 1H), 0.86 (t, 3H), 0.44-0.39 (m, 1H), 0.29-0.22 (m, 1H), 0.04-0.00 (m, 1H).
LCMS: MS m/z (ES!): 410.1 [1\4+Hr Chiral HPLC (CO2/Et0H/DEA 5%-40% 1.5ml/min IG,3um,3*100(Daicel)): cc: 99.40%, Rt:
3.854 min.
Example 34-1 (5 R)-5 -c ycloprop y1-5 -(3 -(5 ,6-dichloroiso indolin-2 -y1)-2 -methy1-3 -oxoprop yl) imidazolidine-2,4 -dio ne o JL
(R) HNrNH
CI

HN HN AR) OH 10 NH
(R) C I
It-2B
HN)(NH

CI

CI
CI
20c 34-1 To a mixture of 5,6-dichloroisoindoline 20c (9 mg, 0.047 mmol) in DMF (2 mL) was added Triethylamine (17.22 mg, 0.132 mmol), Int-2B (10 mg, 0.044 mmol) and HATU
(21.8 mg, 0.0574 mmol). The reaction was stirred at r.t for 18h. Water (3 mL) added and the mixture was extracted with Et0Ac (20 mL X 2). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 34-1 (5 mg, 0.0125 mmol, 26 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.53 (d, 2H), 4.70 (d, 4H), 2.58 (dd, 1H), 1.86 (dd, 2H), 1.25-1.14 (m, 3H), 0.62-0.50 (m, 1H), 0.48-0.36 (m, 2H), 0.40-0.25 (m, 2H).
LCMS: MS nth (ES!): 397 1M+H1 .
Example 34-2 (5S)-5 -c ycloprop y1-5 - (3 - (5 ,6-dichloroiso indolin-2 - y1)-2-methy1-3 -o xoprop yl) imidazolidine-2,4 -dione (:)V icj HN (s) N
= CI

HN HN).(NH
104 CI 0 Int-2A
CI

CI
20c 34-2 CI
To a mixture of 5,6-dichloroisoindoline 20c (72 mg, 0.38 mmol) in DMF (4 mL) was added Triethylamine (144 mg, 1.11 mmol), Int-2A (80 mg, 0.37mmo1) and HATU (171.8 mg, 0.45 mmol). The reaction was stirred at r.t for 18h. Water (5 mL) was added and the mixture was extracted with Et0Ac (40 mL X 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 34-2 (55 mg, 0.138 mmol, 37 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.53 (d, 2H), 4.73 (s, 4H), 2.72 (m, 1H), 2.08-1.94 (m, 2H), 1.31-1.16 (m, 3H), 0.53 (td, 1H), 0.49-0.34 (m, 2H), 0.34-0.24 (m, 2H).
LCMS: MS m/z (ES!): 396 [M+Hr.
Example 34-2-A and Example 34-2-B
(SS)-5 -cyclopropy1-5-((S)-(3-(5,6-dichloroisoindolin-2-y0-2-methyl-3-oxopropy1))imidazolidine-2,4-dione 34-2-A
(SS)-5 -cyclopropy1-54(R)-(3-(5,6-dichloroisoindolin-2-y0-2-methyl-3-oxopropy0)imidazolidine-2,4-dione 34-2-B
HN HNLN
yNH = CI ),r-NH z CI

34-2 (27 mg) was separated by chiral HPLC (column: CHIRALPAK IG-3) to give title compounds (9 mg and 10 mg).
Enantiomer (shorter retention time):
Chiral HPLC: (CHERALPAK IG-3, 100% Me0H): Rt= 4.119 mm.
LCMS: m/z (ES!): 394.2 [M-H1-.
Enantiomer (longer retention time):
Chiral HPLC: (CHERALPAK IG-3, 100% Me0H): Rt= 5.239 mm.
LCMS: m/z (ES!): 394.1 [M-H1-.
Example 35 (S)-5 -(3-(5-chloro-6-methoxyisoindolin-2-y1)-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione N is CI
HNyNH OMe jtV
Me0JOJ Me0 Int-1 CI
NH i"Fsr"--N
Step 1 101 NH _____ CI CI step 2 HNr)7.¨NH OMe 35a 35b Step 1 5 -chloro -6-metho xyisoindoline 35b To a solution of 5-chloro-6-methoxyisoindolin- 1-one 35a (1 g, 5 mmol) in THF
(10 mL) was 5 added borane¨tetrahydrofuran (1M, 30 mL) dropwise under N2. The resulting mixture was stirred at 60 C for 24h. The reaction mixture was cooled to ambient temperature and quenched with Me0H (5 mL) until the bubbling ceased. Then 4N HC1 in water (5 mL) was added and the mixture was heated at 80 C for 3 h. After cooled down to RT, 5N KOH was added to adjust pH to 7. The mixture was concentrated under reduced pressure and the residue was purified by 10 silica-gel column (DCM: Me0H(2%NH4OH) = 10: 1) to afford 5-chloro-6-methoxyisoindoline 35b (300 mg, 60% yield).
Step 2 (S)-5-(3 - (5-chloro -6-metho xyisoindo lin-2- y1)-3 -o xoprop y1)-5 -c ycloprop ylimid azolidine-2 ,4-dione 35 15 To a mixture of 5-chloro-6-methoxyisoindoline 35b (10 mg, 0.0514 mmol) in DMF (2 mL) was added triethylamine (18 mg, 0.141 mmol), It-1 (10 mg, 0.047 mmol) and HATU
(22 mg, 0.0567 mmol). The reaction was stirred at r.t for 18h. Water (4 mL) added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title 20 compound 35 (5 mg, 132.2 umol, 28 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.52 (s, 2H), 4.66 (t, 4H), 3.69 (d, 3H), 1.25 (m, 4H), 0.60 (m, 1H), 0.46 (m, 2H), 0.42-0.30 (m, 2H).
LCMS: MS nth (ES!): 378 [M+Hr.
25 Example 36-1 (5S)-5 -(3 - (5-chloro -6-metho xyisoindo lin-2- y1)-2-methy1-3 -o xoprop y1)-c ycloprop ylimidazolidine-2 ,4-dione ci HN)r-NH OMe To a mixture of 5-chloro-6-methoxyisoindoline 35b (10 mg, 546.44umo1) in DMF
(2 mL) was added triethylamine (18 mg, 0.141 mmol), Int-2A (10 mg, 442.4 umol) and HATU
(21 mg, 564 umol). The reaction was stirred at r.t for 18h. Water (4 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give the title compound 36-1 (5 mg, 127 umol, 28 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.52 (s, 2H), 4.66 (t, 4H), 3.69 (d, 3H), 2.25 (m, 1H), 1.95 (m, 2H), 1.25 (m, 1H), 0.60 (m, 4H), 0.46 (m, 2H), 0.42-0.30 (m, 2H).
LCMS: MS nth (ES!): 392 [M+Hr.
Example 37 (S)-5 -cyc loprop y1-5 -(3 -(7,8 -dichloro -1 -methyl- 1 ,2,4,5 -tetrahydro-3H-benzo [di azep in-3 - y1)-3 -o xoprop yl) imid azolidine-2,4-dione 37 H CI
N

ci CI Step 1 CI CF3 Step 2 CI CF3 8-1 37b 37c1 37c2 CI CF3 Step 3 CI Step 4 (s) N¨µ NH
Int-1 HN
)i-NH CI

37c1 37d 37 CI
Step 1 1 -(8-chloro-1 -methyl- 1,2,4 ,5 -tetrahydro-3H-benzo [di azepin-3 -y1)-2 ,2,2-trifluoroethan- 1 -o ne 37b The solution of 8-chloro-l-methyl-2,3,4,5-tetrahydro-1H-benzo [di azep ine 8-1 (5 g, 21.54 mmol, HC1 salt) in DCM (100 mL) was cooled to 0 C before pyridine (3.41 g, 43.08 mmol) was added, then trifluoroacetic anhydride (5.43 g, 25.85 mmol) was added. The reaction was stirred at r.t for lh. The reaction solution was washed with HC1 (2N, aq.
150 mL), NaHCO3 (aq., 150 mL) and brine, dried over Na2SO4 and concentrated to give crude 37b (6.2 g, 21.25 mmol, 98.69% yield).

11INMR (400 MHz, CDC13): 6 7.18-7.12 (m, 2H), 7.08-7.02 (m, 1H), 4.09-3.39 (m, 2H), 3.70-3.25 (m, 2H), 3.20-2.89 (m, 3H), 1.38-1.31 (m, 3H).
Step 2 1-(7 ,8-dichloro-l-methy1-1 ,2 ,4,5 -tetrahydro -3H-b enzo ldl azep in-3 - y1)-2,2,2 -triflu oro ethan-1 -one 37c1 1 -(8,9-dichloro-1 -methyl-1 ,2 ,4,5 -tetrahydro -3H-b enzo ldl azep in-3 -y1)-2,2,2 -triflu oro ethan-1 -one 37c2 To a solution of 37b (1 g, 3.43 mmol) in DCE (20 mL) was added NCS (595.10 mg, 4.46 mmol) and trifluoromethanesulfonic Acid (5.15 g, 34.28 mmol). The reaction was stirred at 90 C
for 72h. Then the mixture was diluted with DCM (100 mL) and washed with brine, the organic solution was dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC
to give 37c1 (270 mg) and 37c2 (210 mg).
37c1 11INMR (400 MHz, DMSO-d6): 6 7.48-7.42 (m, 2H), 3.81-3.74 (m, 2H), 3.59-3.41 (m, 2H), 3.33-3.30 (m, 1H), 3.12-3.01 (m, 2H), 1.27-1.20 (m, 3H).
37c2 11INMR (400 MHz, DMSO-d6): 6 7.46 (d, 1H), 7.22-7.19 (m, 1H), 4.05-3.47 (m, 5H), 3.30-3.21 (m, 1H), 3.03-2.95 (m, 1H), 1.21-1.17 (m, 3H).
Step 3 7,8 -dichloro-1 -methyl-2 ,3 ,4,5 -tetrahydro -1H-benzo [di azep ine 37d To a solution of 37c1 (100.00 mg, 306.62 umol) in Me0H (5 mL) was added a solution of NaOH (61.32 mg, 1.53 mmol) in water (5 mL). The reaction was stirred at r.t for 2h. Water (20 mL) was added and the mixture was extracted with EA (20 mL X 3), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 37d (70 mg, 304.17 umol, 99.20% yield).
LCMS: MS m/z (ES!): 230.1 [M+Hr.
Step 4 (S)-5 -cyc loprop y1-5 -(3 -(7,8 -dichloro -1 -methyl-1 ,2,4,5 -tetrahydro-3H-benzo [di azep in-3 - y1)-3 -o xoprop yl) imid azolidine-2,4-dione 37 To a solution of 37d (70.00 mg, 304.17 umol) and It-1 (71.00 mg, 334.59 umol) in DMF (10 mL) was added triethylamine (92.34 mg, 912.52 umol) and HATU (127.22 mg, 334.59 umol).
The reaction was stirred at r.t for 2h. The reaction mixture was diluted with water (50 mL) and the mixture was extracted with EA (50 mL X 2). The combined layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give 37 (40 mg, 94.27 umol, 30.99% yield).
11INMR (400 MHz, DMSO-d6): 6 10.62, 10.61 (s, 1H), 7.76-7.70 (m, 1H), 7.46-7.39 (m, 2H), 3.66-3.32 (m, 4H), 3.24-2.81 (m, 3H), 2.45-2.19 (m, 2H), 1.91-1.76 (m, 2H), 1.24-1.15 (m, 3H), 1.09-1.01 (m, 1H), 0.46-0.27 (m, 3H), 0.13-0.05 (m, 1H).
LCMS: MS m/z (ES!): 424.1 [M+Hr.
Examples 37-1 and 37-2 (S)-5 -cycloprop y1-5 -(3-((S)-7 ,8-dichloro-1 -methyl- 1,2,4,5 -tetrahydro-3H-benzo [d] azep in-3 -y1)-3-oxopropyl)imidazolidine-2,4-dione 37-1 (S)-5 -cyc loprop y1-5 -(3-((R)-7,8 -dichloro -1 -methyl- 1,2,4,5 -tetrahydro-3H-benzo [d] azep in-3 -y1)-3-oxopropyl)imidazolidine-2,4-dione 37-2 H
CI HNH CI
y N y 37 (55 mg) was chiral separated by SFC to give title compounds (15mg and 17mg).
Enantiomer (shorter retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.60 (s, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 3.65-3.38 (m, 4H), 3.23-2.81 (m, 3H), 2.41-2.21 (m, 2H), 1.93-1.77 (m, 2H), 1.20 (dd, 3H), 1.10-1.01 (m, 1H), 0.47-0.26 (m, 3H), 0.13-0.04 (m, 1H).
LCMS: m/z (ES!): 424.1 [M+Hr.
ChirHPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:1.446 min, ee:100%.
Enantiomer (longer retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.61 (br, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 3.66-3.36 (m, 4H), 3.26-2.80 (m, 3H), 2.44-2.17 (m, 2H), 1.93-1.77 (m, 2H), 1.19 (dd, 3H), 1.09-1.02 (m, 1H), 0.48-0.27 (m, 3H), 0.12-0.05 (m, 1H).
LCMS: m/z (ES!): 424.1 [M+Hr ChirHPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:2.547 min, ee:99.38%.
Example 38 (S)-5 -cyc loprop y1-5 -(3 -(8,9 -dichloro -1-methy1-1 ,2,4,5 -tetrahydro-3H-benzo [di azep in-3 - y1)-3-oxopropyl)imidazolidine-2,4-dione 38 CI
HN)r...NH CI

CI
CF3 Step 1 CI Step 2 CI
(s) _____________________________________________________ HN CI

3702 38b 38 Step 1 8,9 -dichloro-1 -methyl-2 ,3 ,4,5 -tetrahydro -1H-benzo [di azep ine 38b To a solution of 37c2 (100 mg, 306.62 umol) in Me0H (5 mL) was added a solution of NaOH
(61.32 mg, 1.53 mmol) in water (5 mL). The reaction was stirred at r.t for 2h.
Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 3), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 38b (70 mg, 304.17 umol, 99.20% yield).
LCMS: MS in/z (ES!): 230.1 [M+Hr.
Step 2 (S)-5 -cyc loprop y1-5 -(3 -(8,9 -dichloro -1-methy1-1 ,2,4,5 -tetrahydro-3H-benzo [di azep in-3 - y1)-3-oxopropyl)imidazolidine-2,4-dione 38 To a solution of 38b (70 mg, 304.17 umol) and It-1 (71.00 mg, 334.59 umol) in DMF (10 mL) was added triethylamine (92.34 mg, 912.52 umol) and HATU (127.22 mg, 334.59 umol).
The reaction was stirred at r.t for 2h. The reaction was diluted with water (50 mL) and the mixture was extracted with Et0Ac (50 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give 38 (35 mg, 82.48 umol, 27.12% yield).
11INMR (400 MHz, DMSO-d6): 6 10.61, 10.58 (s, 1H), 7.74, 7.65 (s, 1H), 7.42 (d, 1H), 7.16 (t, 1H), 3.90-3.35 (m, 5H), 3.25-3.10 (m, 1H), 2.92-2.81 (m, 1H), 2.45-2.07 (m, 2H), 1.85-1.68 (m, 2H), 1.19-1.13 (m, 3H), 1.07-0.95 (m, 1H), 0.45-0.25 (m, 3H), 0.11-0.02 (m, 1H).
LCMS: MS nth (ES!): 424.1 [M+Hr.
Examples 38-1 and 38-2 (S)-5 -cycloprop y1-5 -(3 -((S)-8,9-dichloro-1 -methyl- 1,2 ,4,5 -tetrahydro-3H-b enzo [di azepin-3 -y1)-3-oxopropyflimidazolidine-2,4-dione 38-1 (S)-5 -cyc loprop y1-5 -(3-((R)-8,9 -dichloro -1 -methyl- 1,2,4,5 -tetrahydro-3H-benzo lcll azep in-3 -y1)-3-oxopropyl)imidazolidine-2,4-dione 38-2 0 =ss C
CI
N

HN)r-NH CI )r-NH CI

38 (53 mg) was chiral separated by SFC to give title compounds (14mg and 13mg).
Enantiomer (shorter retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.59 (d, 1H), 7.68 (d, 1H), 7.41 (d, 1H),7.17 (t, 1H), 3.90-3.47 (m, 5H), 3.30-3.10 (m, 1H), 2.92-2.81 (m, 1H), 2.38-2.09 (m, 2H), 1.91-1.66 (m, 2H), 1.16 (dd, 3H), 1.09-0.95 (m, 1H), 0.45-0.24 (m, 3H), 0.11-0.03 (m, 1H).
LCMS: m/z (ES!): 424.1 [M+Hr.
ChirHPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:1.076 mm, ee:100%.
Enantiomer (longer retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.58 (brs, 1H), 7.68 (d, 1H), 7.41 (d, 1H),7.16 (t, 1H), 3.90-3.37 (m, 5H), 3.27-3.10 (m, 1H), 2.91-2.80 (m, 1H), 2.42-2.07 (m, 2H), 1.99-1.69 (m, 2H), 1.19-1.13 (dd, 3H), 1.09-0.98 (m, 1H), 0.46-0.24 (m, 3H), 0.12-0.02 (m, 1H).
LCMS: m/z (ES!): 424.1 [M+Hr.
ChirHPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:2.237 mm, ee:99.70%.
Examlpe 40 (S)-5 -(3-(5 -chloro -6-(trifluoromethyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 40 N
HNL
)r-NH 4100 CF3 CI

H2N Step 1 H2N Step 2 H2N Step 3 OH __________________________________ OH __________________ c) ______ CF3 CF3 Br CF3 Br 40a 40b 40c H2N Step 4 CI Step 5 CI Step 6 0 __________________________________ 0 __________________ 0 _______ Br 40d 40e 40f CI
CI Step 7 Step 8 NH _____________________________________________________ HN'-"-Ted 40g 40h 40 CI
Step 1 5-amino-2-bromo-4-(trifluoromethyl)benzoic acid 40b To a solution of 3-amino-4-(trifluoromethyl)benzoic acid 40a (1 g, 4.87 mmol) in DMF (20 mL) was added NBS (870 mg, 4.89 mmol). The mixture was stirred at room temperature for 2 hours, the resulting mixture was poured into ice water (20 mL) and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated to afford crude 40b (1 g, 3.52 mmol, 72.22% yield).
Step 2 Methyl 5-amino-2-bromo-4-(trifluoromethyl)benzoate 40c To a solution of 40b (1 g, 3.52 mmol) in Me0H (10 mL) was added H2504 (18 M, 0.7 mL) dropwise. After the mixture was stirred at 75 C overnight, the mixture was cooled down to room temperature and poured into ice water (20 mL), the mixture was extracted with Et0Ac (50 mL). The organic fraction was dried over Na2SO4(s) and filtered. The filtrate was concentrated to afford crude 40c (1 g, 3.36 mmol, 95.29% yield).
111 NMR (400 MHz, DMSO-d6): 6 7.57 (s, 1H), 7.21 (s, 1H), 6.11 (brs, 2H), 3.85 (s, 3H).
Step 3 Methyl 5 - amino -2-methy1-4- (trifluoromethyl)b enzo ate 40d To a solution of 40c (1 g, 3.36 mmol) in DMF (10 mL) was added Pd(PPh3)4 (430 mg, 372.11 umol), K3PO4 (2.2 g, 10.36 mmol) and methylboronic acid (1 g, 16.71 mmol).
After the mixture was stirred at 130 C under N2 atmosphere overnight, the mixture was cooled down to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography column to afford 40d (500 mg, 2.14 mmol, 63.91%
yield).
LCMS: MS m/z (ES!): 234.1 [M+Hr.
Step 4 Methyl 5 -chloro-2-methy1-4-(trifluoromethyl)benzo ate 40e Concentrated HC1 (2 mL) was added to a solution of 40d (2.0 g, 8.58 mmol) in acetone (20 mL), and the mixture was stirred at room temperature for 20 min. The mixture was cooled to -5-0 C, a solution of NaNO2 (600 mg, 8.70 mmol) in H20 (2.5 mL) was added dropwise, and the mixture was stirred at an ambient temperature for 30 min. CuCl (849.11 mg, 8.58 mmol) was added portion-wise at 0 C, and the mixture was stirred at room temperature for 2h. After completion of the reaction, the mixture was poured into 1N HC1 (50 mL) and the mixture was extracted with Et0Ac. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 40e (1.3g, 5.15 mmol, 60.00% yield).
Step 5 Methyl 2-bromo-5-chloro-4-(trifluoromethyl)benzoate 40f To a solution of 40e (1.3 g, 5.15 mmol) in CC14 (20 mL) was added NBS (1.10 g, 6.18 mmol) and AIBN (25.35 mg, 154.38 umol), the mixture was heated to 70 C and stirred overnight. The mixture was coldecl to room temperature and filtered, the cake was washed with CC14, the filtrate was concentrated in vacuo to give crude 40f (1.9 g, 5.73 mmol, 111.37% yield).
Step 6 6-chloro-5 -(trifluoro methyl) isoindo lin- 1 -o ne 40g To a solution of 40f (1.9 g, 5.73 mmol) in Me0H (10 mL) was added NH3/Me0H (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (hexane:
Et0Ac=1:1) to afford 40g (920 mg, 3.91 mmol, 68.14% yield).
LCMS: MS m/z (ES!): 236.0 [M+Hr.
Step 7 5 -chloro-6 -(triflu oro methyl) isoindo line 40h To a solution of 40g (570 mg, 2.42 mmol) in THF (5 mL) was added BH3/THF
(167.36 mg,

12.10 mmol, 15 mL) and the mixture was stirred at 60 C overnight. The reaction was colded to room temperature and quenched with methanol. The mixture was adjusted to pH1-2 with 1M HC1. Then the mixture was heated to 45 C and stirred for 30 min. After cooled to rt, the mixture was adjusted to pH 7-8 with 1M NaOH. Water was added and the mixture was extracted with Et0Ac. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified prep-TLC (DCM: Me0H=10:1) to give 40h (10 mg, 45.13 umol, 1.87% yield).
1HNMR (400 MHz, DMSO-d6): 6 7.78 (s, 1H), 7.65 (s, 1H), 4.16 (br, 2H), 4.14 (br, 2H).
LCMS: MS nth (ES!): 222.1 1M+H1 .
Step 8 (S)-5 -(3 -(5 -chloro-6-(triflu oro methyl)isoindo lin-2 -y1)-3 -o xoprop y1)-cyclopropylimidazolidine-2 ,4-dione 40 To a solution of 40h (10 mg, 45.12 umol) in DMF (2 mL) was added TEA (50 uL), It-1 (10 mg, 47.12 umol), and HATU (17.16 mg, 45.12 umol). The reaction mixture was stirred at room temperature for 3h. Water was added, the mixture extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified by prep-HPLC to give 40 (5 mg, 12.03 umol, .. 26.65% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 4.85 (d, 2H), 4.67 (d, 2H), 2.46-2.22 (m, 2H), 2.03-1.98 (m, 2H), 1.15-1.08 (m, 1H), 0.49-0.31 (m, 3H), 0.15-0.08 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.86.
LCMS: MS nth (ES!): 416.4 1M+H1 .
Example 41 (SS)-5 -(3 -(5-chloro-1 -methyl-6-(trifluoromethyl) is oindo lin-2- y1)-3 -o xoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4-dio ne 41 HN>r-NH

CI

Step 1 H2N Step 2 H2N Step 3 CI
CF Br CF3 CF3 CF3 40c 41b 41c 41d CI is Step 4 CI
C NH _____ Step 5 CI Step 6 Step 7 NH _____________________________________________________________________ Br CF3 Int-1 41e 41f 41g HN)r-NH = CF3 CI
Step 1 Methyl 5 - amino-4 -(triflu oro methyl)-2 - vinyl-benzo ate 41b To a solution of 40c (5.45 g, 18.29 mmol) and potassium vinyltrifluoroborate (2.45 g, 18.29 mmol) in dioxane (50 mL) and water (10 mL) was added Pd(dppf)C12 (1.34 g, 1.83 mmol) and K2CO3 (6.35 g, 45.71 mmol). The resulting mixture was evacuated and refilled with N2 for 3 times. The resulting mixture was stirred at 80 C for 16 h. The mixture was diluted with Et0Ac (100 mL), the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the tittle compound 41b (3.56 g, 14.52 mmol, 79.40%
yield).
LCMS: MS m/z (ES!): 246.1 [M+Hr.
Step 2 Methyl 5-amino-2-ethy1-4-(trifluoromethyl) benzoate 41c To a solution of 41b (3.56 g, 14.52 mmol) in Me0H (20 mL) was added Pd/C (1.55 g, 1.45 mmol, 285.48 uL, 10% purity). The resulting mixture was evacuated and refilled with H2. The resulting mixture was stirred at room temperature for 16 h and the LCMS
indicated the reaction was finished. The mixture was filtered and the cake was washed with Me0H, the filtrate was concentrated under reduced pressure to afford the tittle compound 41c (3.45 g,

13.96 mmol, 96.12% yield).
LCMS: MS m/z (ES!): 248.1 [M+Hr.
Step 3 Methyl 5-chloro-2-ethy1-4-(trifluoromethyl) benzoate 41d To a solution of 41c (3.36 g, 13.59 mmol) in acetone (34 mL) was added HC1 (3.36 mL). The resulting mixture was stirred at room temperature for 20 min. After the mixture was cooled to 0 C, a solution of 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 h. The mixture was poured into 1M HC1 (60 mL), the aqueous phase was extracted with Et0Ac (100 mL X 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 /
Et0Ac=50/1) to afford the title compound 41d (2.23 g, 8.36 mmol, 61.53% yield).
111 NMR (400 MHz, DMSO-d6): 6 7.99 (s, 1H), 7.87 (s, 1H), 3.88 (s, 3H), 2.92 (q, 2H), 1.17 (t, 3H).
Step 4 Methyl 2-(1-bromoethyl)-5-chloro-4-(trifluoromethyl) benzoate 41e To a solution of 41d (2.23 g, 8.36 mmol) in CC14 (35 mL) was added AIBN
(412.00 mg, 2.51 .. mmol) and NBS (1.64 g, 9.20 mmol). The resulting mixture was stirred at 80 C for 16 h. The mixture was filtered. The solid was washed with DCM and the filtrate was concentrated in vacuo to afford the crude tittle compound 41e (2.5 g, 7.24 mmol, 86.51%
yield).
1H NMR (400 MHz, DMSO-d6): 6 8.17 (s, 1H), 8.04 (s, 1H), 6.08 (q, 1H), 3.92 (s, 3H), 2.05 (d, 3H).
Step 5 6 -chloro-3 -methyl-5 - (triflu oro methyl) isoindo lin- 1 -o ne 41f To a solution of 41e (2.5 g, 7.24 mmol) in Me0H (10 mL) was added NH3/Me0H (7 M, 30 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was purified by prep-HPLC to afford the tittle compound 41f (1.18 g, 4.73 mmol, 65.34%
yield).
1H NMR (400 MHz, DMSO-d6): 6 9.11 (brs, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 4.71 (q, 1H), 1.42 (d, 3H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.99.
LCMS: MS m/z (ES!): 250.0 [M+Hr.
Step 6 5 -chloro-1 -methyl-6 - (triflu oro methyl) isoindo line 41g To a solution of 41f (730 mg, 2.92 mmol) in THF (5 mL) was added BH3/THF (2 M, 30.93 mL). The resulting mixture was stirred at 60 C for 16 h. The mixture was quenched with Me0H
(5 mL) and HC1 (4 M, 5 mL), the mixture was stirred at 60 C for 3 h. The mixture was basified with aq. NaOH and extracted with Et0Ac (50 mL X 3), the combined organic phase was 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 DCM/Me0H=20/1) to afford the tittle compound 41g (300 mg, 1.27 mmol, 43.53%
yield).
LCMS: MS rn/z (ES!): 236.1 [M+Hr.
Step 7 (SS)-5 -(3 - (5-chloro-1 -methyl-6- (trifluoromethyl) is oindo lin-2- y1)-3 -o xoprop y1)-5 -cyclopropylimidazolidine-2 ,4-dione 41 To a solution of It-1 (54.03 mg, 254.63 umol) in DMF (4 mL) was added TEA
(53.68 mg, 530.49 umol), and then 41g (50 mg, 212.19 umol) and HATU (96.82 mg, 254.63 umol). The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by prep-HPLC to afford the tittle compound 41 (25 mg, 57.89 umol, 27.28% yield).
111 NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.88 (s, 1H), 7.79-7.70 (m, 2H), 5.22-5.18 (m, 1H), 4.91-4.49 (m, 2H), 2.44-2.19 (m, 2H), 2.02-1.97 (m, 2H), 1.42 (d, 3H), 1.14-1.08 (m, 1H), 0.46-0.31 (m, 3H), 0.14-0.08 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.74.
LCMS: MS rn/z (ES!): 430.0 [M+Hr.
Examples 41 -1 and 41-2 (S)-5 -(3 -((S)-5 -chloro-l-methy1-6-(trifluoromethyl)isoindolin-2- y1)-3 -oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 41-1 (S)-5 -(3 -((R)-5 -chloro -1 -methyl-6- (triflu oromethyl)iso indolin-2 - y1)-3 -oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 41-2 HNN
HNN
N H sõ,= CI )7,-NH CI

The two enantiomers of 41 (60mg) was separated by chiral SFC (DAICELCHIRALCEL
IG, 250*25 mm 10 pm) to give title compound as single enantiomers (20mg and 18 mg).
Enantiomer (shorter retentsion time):

11INMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.92-7.88 (m, 1H), 7.80-7.71 (m, 2H), 5.25-5.18 (m, 1H), 4.90-4.54 (m, 2H), 2.37-2.28 (m, 2H), 2.04-1.97 (m, 2H), 1.44 (dd, 3H), 1.15-1.08 (m, 1H), 0.46-0.32 (m, 3H), 0.14-0.09 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.75.
LCMS: MS m/z (ES!): 430.1 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): Rt:
1.171 min, ee: 100%.
Enantiomer (longer retentsion time):
11INMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.92-7.88 (m, 1H), 7.80-7.73 (m, 2H), 5.21-5.19 (m, 1H), 4.89-4.80 (m, 2H), 2.46-2.24 (m, 2H), 2.01-1.97 (m, 2H), 1.44 (dd, 3H), 1.13-1.08 (m, 1H), 0.45-0.32 (m, 3H), 0.13-0.11 (m, 1H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.74.
LCMS: MS m/z (ES!): 430.1 1M+Hr.
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): Rt:
1.982 min, ee: 100%.
Example 42 5-cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropyl)imidazolidine-2,4-dione 42 HN)r-- NH
OH CI

0 7) Br OBn Step 1 0 Ly 0 Step 2 0 Step 3 42a 42b 42c OBn Step 4 Step 5 A
v)wo 0 OH

OBn 0 41 CI

42d 42e 42f Step 6 y N =

Step 7 NH 0 40 CI _____________________________ HN)rNH

CI
42g 42 Step 1 Diethyl (2-cyclopropy1-2-oxoethyl)phosphonate 42b To a mixture of triethyl phosphite (5 g, 30.09 mmol) in acetonitrile (150 mL) was 5 added sodium iodide (460 mg, 3.07 mmol). Then 2-bromo-1-cyclopropylethanone 42a (25 g, 153.36 mmol) was added. The reaction was atirred at r.t for 18h. Water (100 mL) was added and the mixture was extracted with Et0Ac (100mL X 2), the organic solution was washed with brine, dried over Na2SO4 and concentrted. The residue was purified with silica gel chromatography (hexane: Et0Ac=1:1) to give 42b (5.4 g, 79.95% yield).
10 iHNIMR (400 MHz, CDC13): 6 4.18-4.13 (m, 4H), 3.24 (s, 1H), 3.18 (s, 1H), 2.23-2.16 (m, 1H), 1.34 (t, 6H), 1.13-1.10 (m, 2H), 0.99-0.96 (m, 2H).
Step 2 (E)-4 -(benzylo xy)-1 -cyc loprop ylb ut-2-en-1 -one 42c To a mixture of 42b (5.4 g, 24.52 mmol) in acetonitrile (90 mL) was added LiC1 (987.55 mg, 23.30 mmol). Then 2-benzyloxyacetaldehyde (3.13 g, 20.84 mmol) was added. The reaction was atirred at r.t for 18h. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL X 2), the organic solution was washed with brine, dried over Na2S 04 and concentrted.
The residue was purified with silica gel chromatography (hexane:Et0Ac =1:1) to give 42c (3.4 g, 64.11% yield).
iHNIMR (400 MHz, CDC13): 6 7.37-7.28 (m, 5H), 6.92-6.86 (dt, 1H), 6.53-6.48 (dt, 1H), 4.58 (s, 2H), 4.22 (dd, 2H), 2.17-2.10 (m, 1H), 1.12-1.07 (m, 2H), 0.95-0.90 (m, 2H).
Step 3 4 -(benzylo xy)-1 -cyc loprop y1-3 -(5 -methylfuran-2-yl)butan-1 -one 42d To a solution of 42c (3.4 g, 15.72 mmol) in Me0H (75 mL) was added 2-methylfuran (2.58 g, 31.44 mmol) and palladium chloride (279 mg, 1.57 mmol). The reaction was stirred at r.t for 18h. The solution was filtered, the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane: Et0Ac=10:1) to give 42d (2.6 g, 55.43% yield).

11INMR (400 MHz, CDC13): 6 7.33-7.25 (m, 5H), 5.93 (d, 1H), 5.85-5.83 (m, 1H), 4.49 (s, 2H), 3.69-3.55 (m, 3H), 3.02-2.85 (m, 2H), 2.23 (d, 3H), 1.94-1.87 (m 1H), 1.00-0.95 (m, 2H), 0.84-0.79 (m, 2H).
Step 4 2-((b enzylo xy)methyl)-4-c yc loprop y1-4-o xobu tanoic acid 42e To a solution of 42d (1 g, 3.35 mmol) in hexane (6 mL), ethyl acetate (18 mL) and water (24 mL) was added, followed by sodium periodate (5.02 g, 23.46 mmol). The reaction was stirred at room temperature for 10 min, ruthenium(III) chloride (695 mg, 3.35 mmol) was added. The reaction was stirred at room temperature for lh. The mixture was filtered, the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM:Me0H=20:1) to give 42e (810 mg, 92.14% yield).
LCMS: m/z (ES!): 261.1 1M-11-.
Step 5 2-((b enzylo xy)methyl)-4-c yc loprop yl- 1-(5 ,6-dichloroiso indo lin-2 -yl)bu tane- 1,4-dione 42f To a solution of 42e (200 mg, 762.48 umol), 20c (174 mg, 914.98 umol) and HATU
(435 mg, 1.14 mmol) in DMF (3 mL) was added DIEA (295 mg, 2.29 mmol), the mixture was stirred at room temperature for 2h. The mixture was diluted with water and extracted with Et0Ac, the organic solution was concentrated and the residue was purified by silica gel chromatagraphy (hexane:Et0Ac=1:1) to give the target 42f (180 mg, 414.41 umol, 54.35% yield).
LCMS: MS m/z (ES!): 432.4 1M+H1 .
Step 6 5 -(2-((b enz ylo xy)methyl)-3 -(5,6-dichloroiso indolin-2 - y1)-3 -oxoprop y1)-5 -cycloprop ylimidazolidine-2 ,4-dione 42g The mixture of 42f (120 mg, 276.27 umol), (NH4)2CO3 (27 mg, 276.27 umol) and NaCN (15 mg, 276.27 umol) in Me0H (5 mL) and H20 (1 mL) was sealed and stirred at 90 C
under Ar for 16h. The mixture was concentrated and the residue was purified by prep-HPLC to give the target 42g (20 mg, 39.65 umol, 14.35% yield).
111 NMR (400 MHz, Methanol-d4): 6 7.51 (s, 1H), 7.44 (s, 1H), 7.20 (brs, 5H), 5.00-4.96 (m, 1H), 4.82-4.73 (m, 2H), 4.64-4.59 (m, 1H), 4.50-4.42 (m, 2H), 3.65-3.59 (m, 2H), 3.30-3.20 (m, 1H), 2.47 (dd, 1H), 1.83 (dd, 1H), 1.18-1.14 (m, 1H), 0.54-0.51 (m, 1H), 0.42-0.38 (m, 1H), 0.33-0.29 (m, 2H).

LCMS: MS m/z (ES!): 502.5 1M+H1 .
Step 7 5-cyclopropy1-5-(3-(5,6-dichloroisoindolin-2-y1)-2-(hydroxymethyl)-3-oxopropyl)imidazolidine-2,4-dione 42 To a solution of 42g (15 mg, 29.74 umol) in Et0Ac (3 mL) was added Pd/C (2 mg, 11.30 umol), then the mixture was stirred at room temperature for 15 mm under H2. The mixture was filtered, and the filtrate was concentrated, the residue was purified by prep-HPLC to give the target 42 (8.0 mg, 19.31 umol, 64.94% yield).
111 NMR (400 MHz, Methanol-d4): 6 7.51 (s, 1H), 7.48 (s, 1H), 5.04-4.99 (m, 1H), 4.86-4.71 (m, 2H), 4.67-4.57 (m, 1H), 3.67-3.57 (m, 2H), 2.87-2.83 (m, 1H), 2.30 (dd, 1H), 2.03-1.97 (m, 1H), 1.19-1.16 (m, 1H), 0.52-0.50 (m, 1H), 0.42-0.35 (m, 2H), 0.29-0.26 (m, 1H).
LCMS: MS m/z (ES!): 412.0 1M+H1 .
Example 43 5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propy1)-5-(thiazol-2-y1)imidazolidine-2,4-dione 43 )LNH 0 HN
0 )2"--5 N

=

Step 1 m Step 2 Step 3 S I N

N S
43a 43b 43c 0 HN

II

411 CF3HN)LNH
HNANH
co 1-1 y N
N S 01-I Step 4 43d 43 CF3 Step 1 Tert-butyl 4-oxo-4-(thiazol-2-yl)butanoate 43b To a solution of 1-(thiazol-2-yl)ethanone 43a (21.88 g, 172.06 mmol) in THF
(175 mL) was added LiHMDS (34.55 g, 206.48 mmol) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (44 mL) at -78 C, then tert-butyl 2-bromoacetate (40.27 g, 206.47 mmol) was added at -78 C.
The resulting mixture was stirred at-78 C for 16 h, and then the mixture was diluted with Et0Ac (200 mL) and H20 (100 mL), the organic phase was washed with water (100 mL X 2), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 43b (16 g, 66.31 mmol, 38.54% yield).
LCMS: MS rah (ES!): 242.1 1M+H1 .
Step 2 tert-butyl 3 -(2,5 -dioxo-4 - (thiazol-2 - yl)imidazolidin-4- yl)prop ano ate 43c A mixture of 43b (5.0 g, 20.72 mmol), (NH4)2CO3 (16.91 g, 176.12 mmol), NaCN
(2.75 g, 51.80 mmol), Et0H (25 mL) and H20 (25 mL) was heated in an autoclave at 85 C
for 18 hours.
The resulting mixture was diluted with water (60 mL), and extracted with Et0Ac (200 mL X
5).The organic layers were combined, washed with brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford 43c (650 mg, 2.09 mmol, 10.08% yield).
LCMS: MS rah (ES!): 312.11M+Hr.
Step 3 3-(2,5-dioxo-4-(thiazol-2-y0imidazolidin-4-y0propanoic acid 43d To a solution of 43c (650 mg, 2.09 mmol) in DCM (5 mL) was added HC1/dioxane (10 mL) drop-wise. The reaction mixture was stirred at room temperature for 18 hours.
Then the reaction mixture was concentrated under reduced pressure to afford crude 43d (600 mg, 2.35 mmol, 112.60% yield).
LCMS: MS rah (ES!): 256.01M+Hr.
Step 4 5 -(3 -o xo -3- (5 -(triflu oro methyl) isoindo lin-2- yl)prop y1)-5 -(thiazol-2 - yl)imid azo lidine-2 ,4-dione 43 A mixture of 43d (100 mg, 391.77 umol), 1-1 hydrochloride (87.61 mg, 391.77 umol), Et3N
(118.71 mg, 1.18 mmol), HATU (148.96 mg, 391.77 umol) and DMF (10 mL) was stirred at room temperature for 18 hours. Then the reaction mixture was purified by prep-HPLC to afford 43 (20 mg, 47.13 umol, 12.03% yield).
1H NMR (400 MHz, DMSO-d6): 6 11.10 (br, 1H), 8.47-8.44 (m, 1H), 7.82 (d, 1H), 7.76-7.73 (m, 2H), 7.66 (d, 1H), 7.59-7.55 (m, 1H), 4.83 (d, 1H), 4.69 (brs, 2H), 2.46-2.38 (m, 4H).
LCMS: MS nth (ES!): 425.2 1M+Hr.
Example 44 (S)-5 -cyc loprop y1-5 -(3 -(7-flu oro -1,2,4 ,5-tetrahydro -3H-b enzo [di azepin-3 - y1)-3 -oxoprop yl)imidazo lidine-2,4-dione N
HN),i-NH

_________________________________________________ HN
+ HN
HN HATU TEA

0 44a 44 It-1 To a mixture of 7-fluoro-2,3,4,5-tetrahydro-1H-benzoldlazepine 44a (23 mg, 0.139 mmol, purchased from Acme Bioscience) in DMF (5 mL) was added Triethylamine (70 mg, 0.51 mmol), It-1 (30 mg, 0.141 mmol) and HATU (57 mg, 0.151 mmol). The reaction was stirred at room temperature for 18h. Water (3 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 44 (25 mg, 69.5 umol, 48 % yield).
1H NMR (400 MHz, Methanol-d4): 6 7.16 (dt, 1H), 6.98-6.81 (m, 2H), 3.80 - 3.55 (m, 4H), 3.37 (s, 1H), 3.03-2.90 (m, 4H), 2.19-2.03 (m, 4H), 1.22 (m, 1H), 0.59 (m, 1H), 0.40 (m, 3H).
LCMS: MS nth (ES!): 360 1M+Hr.
Example 45 (S)-5 -cyc loprop y1-5 -(3 -o xo-3 -(7-(triflu oromethyl)- 1,2,4,5 -tetrahydro-3H-b enzoldl azepin-3 -yl)propyl)imidazolidine-2,4-dione HN Y---teL(s) CF3 OH

HATU/ TEA
+ HN CF3 DMF HN)r-NH CF3 HNy-NH

It-1 To a mixture of 7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzoldlazepine (23 mg, 0.139 mmol) in DMF (5 mL) was added Triethylamine (70 mg, 0.51 mmol), It-1 (30 mg, 0.141 5 mmol) and HATU (57 mg, 0.151 mmol). The reaction was stirred at r.t for 18h. Water (3 mL) added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give the title compound (18 mg, 31 % yield).
111 NMR (400 MHz, CDC13): 6 7.31 (q, 2H), 7.15 (t, 1H), 3.65 (m, 2H), 3.59 ¨
3.45 (m, 2H), 10 2.94 ¨2.79 (m, 4H), 2.45 (hept, 2H), 2.23 (dt, 1H), 2.14 (dt, 7.4 Hz, 1H), 1.12 (td, 1H), 0.40 ¨
0.26 (m, 4H).
LCMS: MS nth (ES!): 410 [M+Hr.
Example 48 15 5 -(3 -(5 -chloro-6- (triflu oro methyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 - (p yridin-3-yl)imidazolidine-2,4-dione 48 N

Step 1 Step 2 Oro __________________________________________ HN)r.- NH
C)<

48a 48b 48c Step 3 Step 4 OH ______________________________________ H N H HN)r-NH 41 CI

48d Step 1 Tert-butyl 4-oxo-4-(pyridin-3-yl)butanoate 48b To a solution of 1-(pyridin-3-y0ethan-1-one 48a (4.97 g, 41.01 mmol) in THF
(50 mL) was added NaHMDS (7.52 g, 41.01 mmol) dropwise at -70 C. The resulting mxiture was stirred at this temperature for 30 min before tert-butyl 2-bromoacetate (8.0 g, 41.01 mmol) was added dropwsie. After addition, the reaction mixture was stirred at -20 C for 1.0 hour, then warmed to room temperature and stirred for 18 hours. The resulting mixture was cooled to 0 C, quenched with aq. NaHCO3 (20 mL). The whole solution was extracted with Et0Ac (30 mL
X 4). The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Et0Ac/hexane= 1/20 to 1/4) to afford 48b (800 mg, 3.40 mmol, 8.29% yield).
LCMS: MS rah (ES!): 236.1 [M+Hr.
Step 2 Tert-butyl 3 -(2,5 -dio xo -4-(p yridin-3- yl)imidazolidin-4- yl)prop ano ate 48c To the solution of 48b (500 mg, 2.13 mmol) in H20 (8 mL) and Et0H (10 mL) was added NaCN (282 mg, 5.31 mmol), (NH4)2CO3 (1.63 g, 17.00 mmol). The reaction was stirred at 85 C
overnight. LCMS showed product produced. Then the reaction mixture was diluted with water and extracted with Et0Ac (10 mL X 2). The organic solution was concentrated, and the residue was purified by silica gel chromatography (Et0Ac/hexane= 1/2 to 1/1) to give 48c (250 mg, 818.79 umol, 38.53% yield).

111 NMR (400 MHz, DMSO-d6): 6 11.21 (s, 1H), 9.07 (s, 1H), 8.92 (s, 1H), 8.90 (s, 1H), 8.45 (d, 1H), 7.90 (s, 1H), 2.57-2.30 (m, 3H), 2.19-2.15 (m, 1H), 1.41 (s, 9H).
LCMS: MS m/z (ES!): 306.1 1M+H1 .
Step 3 3 -(2,5 -dio xo -4-(p yridin-3 - yl)imidazolidin-4- yl)prop ano ic acid 48d The mixture of 48c (250 mg, 818.79 umol) in HC1/1,4-dioxane (2 mL, 2N) was stirred at room temperature for lh. LCMS showed that the product produced. The mixture was concentrated to give 48d (220 mg, 882.75 umol, 107.81% yield).
LCMS: MS m/z (ES!): 250.1 1M+H1 .
Step 4 5 -(3 -(5 -chloro-6-(triflu oro methyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 -(p yridin-3 -yl)imidazolidine-2,4-dione 48 To the solution of 48d (100 mg, 401 umol) in THF (5 mL) was added HATU (232 mg, 609.19 umol), DIEA (63 mg, 487.35 umol) and 40h (90 mg, 406.13 umol). The reaction was stirred at room temperature overnight. LCMS showed that the product produced. The mixture was purified by prep-HPLC to give title compound 48 (5.55 mg, 12.26 umol, 3.02%
yield).
111 NMR (400 MHz, DMSO-d6): 6 11.01 (brs, 1H), 8.87 (d, 1.6 Hz, 1H), 8.72 (d, 1H), 8.56 (dd, 1H), 7.94-7.88 (m, 2H), 7.55 (d, 1H), 7.46 (dd, 1H), 4.81-4.77 (m, 2H), 4.67-4.63 (m, 2H), 2.42-2.23 (m, 4H).
LCMS: MS m/z (ES!): 453.4 1M+H1 .
Examples 49-1 and 49-2 (SR)-5 -cyc loprop y1-5 -(3 -methy1-2 -(5-(trifluoromethyl) isoindo line-2 -carbonyl)butyl)imidazolidine-2,4-dione 49-1 (SS)-5 -c ycloprop y1-5 -(3 -methyl-2-(5 -(triflu oro methyfliso indoline-2-carbonyflbutyflimidazolidine-2,4-dione 49-2 H>X y HN
NH yNhl V') Step1 C) Step 2 Int2-1 49a 49b 49c 0 0 y 0 N
Step 3 Step 4 ________________________________ HN)r-NH
CF3 CF3 HN)T-NH CF3 49d 49-1 49-2 Step 1 Diethyl 2- (c yc loprop anec arbony1)-3 -isopropyl-bu tanedio ate 49b To a solution of Int2-1 (3.59 g, 22.99 mmol) and ethyl 2-bromo-3-methylbutanoate 49a (5 g, 23.91 mmol) in methyl ethyl ketone (60 mL) were added K2CO3 (6.36 g, 45.99 mmol) and NaI
(3.45 g, 22.99 mmol). The resulting mixture was stirred at 110 C for 48 h. The mixture was poured into water (100 mL), the aqueous phase was extracted with Et0Ac (80 mL
X 3), the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the tittle compound 49b (4.29 g, 15.09 mmol, 65.61%
yield).
Step 2 4-cyclopropy1-2-isopropyl-4-oxo-butanoic acid 49c To a solution of 49b (2.29 g, 8.05 mmol) in THF (8 mL) and water (8 mL) was added LiOH
(482.21 mg, 20.13 mmol). The resulting mixture was stirred at room temperature for 16 h. To the mixture was added HC1 (1N, 10 mL), the resulting mixture was stirred at 60 C for 2h. Then the mixture was adjusted to pH=13 with the addition of NaOH (aq) and the layers were separated. The combined aq. phase was adjusted to pH-7 with 1 M HC1 (10 mL), the mixture was then extracted with DCM (50 mL X 3), the organic solution was dried over Na2S0), filtered and concentrated under reduced pressure to afford the crude tittle compound 49c (300 mg, 1.63 mmol, 20.22% yield).
Step 3 4-c ycloprop y1-2 -isoprop y1-1- [5- (trifluoromethyl)- 1, 3, 3a, 7 a-tetrahydroisoindo1-2- yll butane-1, 4-dione 49d To a solution of 49c (270 mg, 1.52 mmol) in DMF (8 mL) was added TEA (753.42 mg, 7.45 mmol), 5-(trifluoromethyl)isoindoline 1-1 (333 mg, 1.49 mmol) and HATU (679.45 mg, 1.79 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water (80 mL), the aqueous phase was extracted with Et0Ac (80 mL X 3), the combined organic phase was 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/Et0Ac=3/1) to afford the tittle compound 49d (340 mg, 956.68 umol, 64.25%
yield).
LCMS: MS nilz (ES!): 354.1 [M+Hr.
Step 4 (51?)-5 -c yc loprop y1-5 -(3 -methyl-2-(5 -(trifluoromethyl)iso indoline-2-carbo nyl)b utyl) imidazolidine-2 ,4 -dio ne 49-1 (5S)-5 -c ycloprop y1-5 -(3 -methyl-2-(5 -(triflu oro methyl)iso indoline-2-carbo nyl)b utyl) imidazolidine-2 ,4 -dio ne 49-2 To a solution of 49d (340 mg, 956.69 umol) in Me0H (5 mL) was added (NH4)2CO3 (735.39 mg, 7.65 mmol), water (5 mL) and NaCN (126.86 mg, 2.39 mmol). The resulting mixture was stirred at 80 C for 16 h. The reaction mixture was poured into water (100 mL), the mixture was extracted with Et0Ac (80 mL X 3), the combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was .. purified with prep-HPLC to afford the tittle compound 49-1 (40 mg, 94.02 umol, 9.83% yield) and 49-2 (250 mg, 587.62 umol, 61.42% yield).
49-1:
111 NMR (400 MHz, DMSO-d6): 6 10.46 (s, 1H), 7.77-7.72 (m, 2H), 7.66 (d, 1H), 7.60-7.56 (m, 1H), 4.91-4.88 (m, 2H), 4.72-4.69 (m, 1H), 4.63-4.58 (m, 1H), 2.58-2.50 (m, 1H), 2.42-2.35 (m, 1H), 1.78-1.73 (m, 2H), 1.07-1.03 (m, 1H), 0.92 (dd, 6H), 0.41-0.27 (m, 3H), 0.10-0.07 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.57.
HPLC: SunFire C18 Sum 4.6*150mm, 0.03%TFA CH3CN/H20, Rt 7.478 min.
LCMS: MS nilz (ES!): 424.1 [M+Hr.
49-2:
111 NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.74 (d, 1H), 7.68-7.65 (m, 1H), 7.60-7.54 (m, 2H), 4.90-4.85 (m, 2H), 4.74-4.71 (m, 2H), 2.33-2.28 (m, 2H), 1.88-1.75 (m, 2H), 1.07-1.03 (m, 1H), 0.92-0.89 (m, 6H), 0.42-0.39 (s, 1H), 0.29-0.25 (m, 2H), 0.01-0.00 (m, 1H).

19F NMR (376.5 MHz, DMSO-d6): 6 -60.57.
HPLC: SunFire C18 Sum 4.6*150mm, 0.03%TFA CH3CN/H20, Rt 8.141 min.
LCMS: MS m/z (ES!): 424.3 [M+Hr.
Examples 49-2a and 49-2b (5S)-5 -c ycloprop y1-5 - [(2R)-3-methy1-2- [5-(trifluoromethyl)- 1, 3, 3a, 7 a-tetrahydro isoindo le-2-carbonyl] butyl] imidazolidine-2, 4-dione 49-2a (51?)-5 -c yc loprop y1-5 - [(2S)-3-methy1-2- [5-(trifluoromethyl)- 1, 3, 3a, 7 a-tetrahydro isoindo le-2-carbonyl] butyl] imidazolidine-2, 4-dione 49-2b f, V 0 0 o _=
\- X1(N
HN NH
HN NH =
itS CF3 CF3 49-2a 49-2b 49-2 (140 mg) was seperated by chiral SFC to afford the title compounds (50 mg and 50mg).
Enantiomer (shorter retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.74 (d, 1H), 7.68-7.65 (m, 1H), 7.61-7.54 (m, 2H), 4.90-4.86 (m, 2H), 4.74-4.71 (m, 2H), 2.33-2.28 (m, 2H), 1.87-1.75 (m, 2H), 1.05-1.03 (m, 1H), 0.92-0.89 (m, 6H), 0.40-0.38 (m, 1H), 0.28-0.25 (m, 2H), 0.01-0.00 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.57.
LCMS: MS m/z (ES!): 424.5 [M+Hr.
Chiral HPLC (CO2/Et0H/DEA 5%-40% 1.5ml/min IG,3um,3*100(Daicel)): Rt:3.003 min, cc: 100%.
Enantiomer (longer retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.75 (d, 1H), 7.68-7.65 (m, 1H), 7.60-7.54 (m, 2H), 4.90-4.86 (m, 2H), 4.73-4.69 (m, 2H), 2.32-2.28 (m, 2H), 1.88-1.74 (m, 2H), 1.05-1.02 (m, 1H), 0.92-0.86 (m, 6H), 0.42-0.40 (m, 1H), 0.28-0.25 (m, 2H), 0.01-0.00 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.57.
LCMS: MS m/z (ES!): 424.2 [M+Hr.
Chiral HPLC (CO2/Et0H/DEA 5%-40% 1.5ml/min IG,3um,3*100(Daicel)): Rt:3.494 min, cc: 100%.
Example 50 (S)-5 -(3 - (5 -chloro-6-nitroiso indolin-2 - y1)-3 -oxoprop y1)-5 -c ye loprop ylimidazolidine-2 ,4-dione 50 (s) CI
CI
NH BH3 in T.HF CI Int-1 (s) = NH HN),rNH
02N step1 02N step 2 410, NO2 50a 50b 50 CI
Step 1 5-chloro-6-nitroisoindoline (50b) To a solution of 5-chloro-6-nitroisoindoline-1,3-dione 50a (1 g, 4.42 mmol) in THF (15 mL) was added borane¨tetrahydrofuran (1M, 35 mL) dropwise under N2. The resulting mixture was stirred at 60 C for 24h. The reaction mixture was cooled to ambient temperature and quenched with Me0H (5 mL) until the bubbling ceased. Then 4N HC1 in water (4 mL) was added and the mixture was heated at 80 C for 3 h. After cooled down to RT, 5N KOH was added to adjust pH to 7. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel column (DCM: Me0H(2%NH4OH) = 10: 1) to afford 5-chloro-6-nitroisoindoline 50b (300 mg, 33% yield).
Step 2 (S)-5 -(3 - (5 -chloro-6-nitroiso indolin-2 - y1)-3 -oxoprop y1)-5 -c ye loprop ylimidazolidine-2 ,4-dione 50 To a mixture of 5-chloro-6-nitroisoindoline 50b (10 mg, 0.05m01) in DMF (2 mL) was added triethylamine (18 mg, 0.138 mmol), It-1 (10 mg, 0.047 mmol) and HATU (21mg, 0.055 mmol). The reaction was stirred at r.t for 18h. Water (4 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give the title compound 50 (4 mg, 0.01 mmol, 21% yield).
1H NMR (400 MHz, Methanol-d4): .94 (d, 1H), 7.67 (d, 1H), 4.95 (d, 2H), 4.81 (d, 2H), 2.57 (m, 1H), 2.45 (m, 1H), 2.33 ¨2.14 (m, 2H), 1.34¨ 1.20 (m, 1H), 0.61 (m, 1H), 0.53 ¨0.30 (m, 3H).
LCMS: MS nth (ES!): 393 1M+Hr.

Example 51 (5S)-5 -c yc loprop y1-5 -(3 -(5-(1 -hydro xyethyl) isoindo lin-2- y1)-3 -o xoprop yl) imid azolidine-2,4 -dione 51 HNlH
)r-NH

Boc, Boc, HN
Step 1 Step 2 Br 51a 51b 51c Step 3 Ysi")L
____________ HN)rNH 0N Step 4 ______________________________________________ HNY--1")L OH
I nt-1 ),r-NH
0 51d 0 51 Step 1 Tert-butyl 5-acetylisoindoline-2-carboxylate Sib To a mixture of tert-butyl 5-bromoisoindoline-2-carboxylate 51a (500 mg, 1.68 mmol), tributy1(1-ethoxyvinyl)stannane (726.72 mg, 2.01 mmol) in dioxane (5 mL) was added Pd(PPh3)4 (193.78 mg, 167.69 umol). The reaction was stirred under N2 at 100 C
for 6h. The reaction was cooled to rt, the mixture was diluted with water (50 mL), the mixture was extracted with ethylacetate (20 mL X 3). The organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (hexane:Et0Ac=10:1) to give 51b (105 mg, 401.81 umol, 23.96% yield).
111 NMR (400 MHz, DMSO-d6): 6 7.90-7.84 (m, 2H), 7.35-7.32 (m, 1H), 4.73 (br, 2H), 4.70 (br, 2H), 2.61 (s, 3H), 1.45 (s, 9H).
Step 2 1 -(isoindolin-5 -yl)ethan- 1 -one 51c To a mixture of 51b (50 mg, 191.34 umol) in DCM (3 mL) was added dioxane/HC1 (1N, lmL).
The reaction was stirred at room temperature for 16h. The mixture was concentrated to give crude 51c, the crude product was used to the next step directly without purification.
Step 3 (S)-5 -(3 -(5- acetylisoindolin-2- y1)-3 -oxoprop y1)-5 -cyc loprop ylimidazo lidine-2,4-dione 51d To a solution of 51c (56 mg, 347.39 umol) in DMF (10 mL) was added It-1 (73.72 mg, 347.39 umol) and HATU (198.13 mg, 521.09 umol). The mixture was stirred at room temperature 2h.
Water (30 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2).
The combined organic layers were washed with water (40 mL) and brine (40 mL X 2), dried and concentrated. The crude was purified by prep-HPLC to give 51d (52 mg, 146.32 umol, 42.12%
yield).
1H NMR (400 MHz, CDC13): 6 7.94-7.87 (m, 2H), 7.57 (brs, 1H), 7.42-7.34 (m, 1H), 6.09 (d, 1H), 4.83 (brs, 4H), 2.62 (s, 3H), 2.66-2.62 (m, 1H), 2.47-2.27 (m, 3H), 1.26-1.20 (m, 1H), 0.62-0.59 (m, 1H), 0.48-0.36 (m, 3H).
Step 4 (SS)-5 -c yc loprop y1-5 -(3 -(5-(1 -hydro xyethyl) isoindo lin-2- y1)-3 -o xoprop yl) imid azolidine-2,4 -dione 51 To a mixture of 51d (22 mg, 61.90 umol) in Me0H (3 mL), NaBH4 (11.70 mg, 309.52 umol) was added. The reaction was stirred at room temperature for 4h. The reaction was quenched with water (30 mL), and the mixture was extracted with Et0Ac (20 mL X 3), The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated.
The crude was purified by prep-HPLC to give 51 (7 mg, 19.59 umol, 31.64% yield).
1H NMR (400 MHz, DMSO-d6): 610.51 (brs, 1H), 7.63 (brs, 1H), 7.21-7.12 (m, 3H), 5.06-5.05 (m, 1H), 4.66-4.59 (m, 3H), 4.48 (d, 2H), 2.33-2.26 (m, 1H), 2.18-2.13 (m, 1H), 1.89 (t, 2H), 1.19 (d, 3H), 1.02-0.98 (m, 1H), 0.35-0.19 (m, 3H), 0.01-0.00 (m, 1H).
LCMS: MS nth (ES!): 358.2 [M+Hr.
Example 52 (S)-5 -c ycloprop y1-5 -(3 -(5 -(difluoromethyl) isoindolin-2- y1)-3 -o xoprop yl) imid azolidine-2,4 -dione 52 N

Boc, B,N Boc oc ,N
Step 1 Step 2 Step 3 \ 11 Br 0 51a 52b 52c Boc, HN 0 V
Step 4 Step 5 CHF2 _________________________ * _____________________ HN)r-NH
CHF2 It-1 52d 52e 52 Step 1 Tert-butyl 5-vinylisoindoline-2-carboxylate 52b To a mixture of 51a (1 g, 3.35 mmol), K2CO3 (925.63 mg, 6.71 mmol) and potassium vinyltrifluoroborate (538.88 mg, 4.02 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dppf)C12 (197.54 mg, 335.37 umol). The reaction was stirred under N2 at 80 C for 3h. The reaction mixture was cooled to room temperature and diluted with water (50 mL), extracted with Et0Ac (30 mL X 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by SGC (hexane:Et0Ac=10:1) to give 52b (786 mg, 3.20 mmol, 95.54% yield).
1H NMR (400 MHz, CDC13): 6 7.32-7.15 (m, 3H), 6.71 (dd, 1H), 5.73 (dd, 1H), 5.23 (d, 1H), 4.67 (br, 2H), 5.22 (br, 2H), 1.52 (d, 9H).
Step 2 Tert-butyl 5-formylisoindoline-2-carboxylate 52c To a mixture of 52b (400 mg, 1.63 mmol), NaI04 (697.88 mg, 3.26 mmol) in dioxane (7 mL) and water (4 mL) was added osmium tetroxide (41.45 mg, 163.05 umol). The reaction was stirred at room temperature for 0.5 h and then diluted with water (40 mL). The mixture was extracted with ethylacetate (20 mL X 3), the organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexane:Et0Ac=5:1) to give 52c (98 mg, 396.30 umol, 24.30% yield).
1H NMR (400 MHz, CDC13): 6 10.01 (s, 1H), 7.82-7.76 (m, 2H), 7.44-7.40 (m, 1H), 4.76-7.73 (m, 4H), 1.53 (s, 9H).
Step 3 Tert-butyl 5-(difluoromethyl)isoindoline-2-carboxylate 52d To a mixture of 52c (50 mg, 202.19 umol) and Et0H (930.09 ug, 20.22 umol) in DCM (3 mL) was added DAST (162.96 mg, 1.01 mmol). The reaction was stirred at room temperature for 16h. The reaction was quenched with water (30 mL), and the mixture was extracted with Et0Ac (20 mL X 3). The organic solution was washed with brine, dried over Na2SO4 and concentrated to give crude 52d (52 mg, 193.10 umol, 95.50% yield).
1H NMR (400 MHz, CDC13): 6 7.36-7.19 (m, 3H), 6.57 (t, 1H), 4.65 (br, 2H), 4.61 (br, 2H), 1.45 (s, 9H).
19F NMR (400 MHz, CDC13): 6 -109.86.
Step 4 5 -(difluoromethyl)isoindoline 52e To the mixture of 52d (30 mg, 111.41 umol) in DCM (3 mL) was add HO/dioxane (1N, 1 mL).
The reaction was stirred at room temperature for 16 hours. The mixture was concentrated to give the crude 52e.
Step 5 (S)-5 -c ycloprop y1-5 -(3 -(5 -(difluoromethyl) isoindolin-2- y1)-3 -o xoprop yl) imid azolidine-2,4 -dione 52 To a solution of 52e (35 mg, 206.89 umol) in DMF (3 mL) was added It-1 (43.90 mg, 206.89 umol), TEA (62.81 mg, 620.67 umol) and HATU (94.40 mg, 248.27 umol). The mixture was stirred at room temperature for 2h. Water (30 mL) was added and the mixture was extracted with EA (20 mL X 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried and concentrated. The crude was purified by prep-HPLC to give 52 (5 mg, 13.76 umol, 6.65% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.64 (brs, 0.5H), 7.73 (brs, 0.5H), 7.73-7.70 (m, 1H), 7.58-7.49 (m, 2H), 7.05 (t, 1H), 4.88-4.84 (m, 2H), 4.67-4.65 (m, 2H), 2.50-2.28 (m, 2H), 2.07-1.97 (m, 2H), 1.12-0.85 (m, 1H), 0.46-0.27 (m, 2H), 0.20-0.05 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -108.63.
LCMS: MS nth (ES!): 364.0 1M+Hr.
Example 53 (S)-5 -(3 -(5 -chloro -6-iodo isoindo lin-2- y1)-3 -oxoprop y1)-5 -cyc loprop ylimid azo lidine-2,4-dione 53 H Ny NH 41 I

CI step 1 TI:IfIIIIICI step 2 CI
step 3 CI
NH _____________________________ NH -1' NH

50a 53b 3c 53d step 4 (s) _______________ HN)r-NH
Int-1 Step 1 5- amino -6- chloro isoindo line- 1 ,3-dione 53b To a mixture of 50a (1 g, 4.4 mmol) in Me0H (20 mL) was added ammonia solution (3 mL), 5 H20 (5m1) and Na2S204 (7.6 g, 44 mmol). The reaction was stirred at r.t for 24h. Water (4 mL) was added and the mixture was extracted with Et0Ac (30 mL X 4). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford 53b (0.5 g, 2.5 mmol, yield 56%). The residue was used in next step without further purification.
Step 2 5 - chloro-6 - iodoisoindoline- 1 ,3-dione 53c To a stirred suspension of 53b (0.5 g 2.5 mmol) in 15 mL water was added dropwise at 10 C.
A solution of 0.4 mL concentrated sulfuric acid in 5 mL water. After the mixture was cooled to 5 C, a solution of sodium nitrite (276 mg, 4 mmol) in 5 mL water was added dropwise and the stirring continued at 0 C for 90 mins. A solution of potassium iodide (1.4 g, 8.8 mmol) in 8 mL water was then added dropwise over 40 mins while maintaining the reaction temperature between 0 C and 5 C. The reaction mixture was then warmed to room temperature and subsequently heated at 35 C for 45 mins and then 60 C for 30 mm. Then the mixture was cooled down to room temperature and was extracted with Et0Ac (30 mL X 4). The combined organic layers were dried, filtered and concentrated. The residue was resuspended in 30 mL
DCM, stirred for 10 mins at room temperature and the resulting crystals collected by filtration to yield compound 53c (240 mg, 0.78 mmol, 31% yield).
Step 3 5-chloro-6-iodoisoindoline 53d To a solution of 53c (120mg, 0.38 mmol) in THF (5 mL) was added borane¨tetrahydrofuran (1M, 60 mL) dropwise under N2. The resulting mixture was stirred at 60 C for 24h. The reaction mixture was cooled to ambient temperature and quenched with Me0H (6 mL) until the bubbling ceased. Then 4N HC1 in water (2 mL) was added and the mixture was heated at 80 C for 3 h. Then the mixture was cooled down to room temperature and 5N KOH
was added to adjust pH to 7. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel column (DCM: Me0H(2%NH4OH) = 10: 1) to afford 53d (51 mg, 0.18 mmol 47 % yield).
Step 4 (S)-5 -(3 - (5 -chloro-6-iodoiso indolin-2 - y1)-3 -oxoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4-dione 53 To a mixture of 53d (10 mg, 0.035 mmol) in DMF (2 mL) was added triethylamine (12mg, 0.1 mmol), It-1 (9 mg, 0.042 mmol) and HATU (21 mg, 0.055 mmol). The reaction was stirred at r.t for 18h. Water (3 mL) was added and the mixture was extracted with Et0Ac (20 mL X
2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated.
The residue was purified with prep-HPLC to give title compound 53 (4 mg, 0.008 mmol, 22 %
yield).
1H NMR (400 MHz, Methanol-d4): 6 7.92 (d, 1H), 7.53 (d, 1H), 4.84 (s,2H), 4.71 (s, 2H), 2.61-2.33 (m, 2H), 2.30-2.15 (m, 2H), 1.20-1.30 (m, 1H), 0.68-0.32 (m, 4H).
LCMS: nth (ES!): 474 [M+1-11+
Example 54 (S)-5 -(3 - (5 - amino-6-chloroiso indolin-2 - y1)-3 -oxoprop y1)-5-cyclopropylimidazolidine-2 ,4-dione 54 HN NH S) CI

To a mixture of 50 (10 mg, 0.025 mmol) in Me0H (2 mL) was added ammonia solution (0.3m1), H20 (1m1) and Na2S204 (65mg, 0.375 mmol). The reaction was stirred at r.t for 18h. Water (6 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 54 (6 mg, 0.016 mmol, 64% yield).
1H NMR (400 MHz, Methanol-d4): 6 7.64 (d, 1H), 7.32 (d, 1H), 6.98 (d, 2H), 4.79 (d, 2H), 4.67 (s, 2H), 2.55 (m, 1H), 2.42 (m, 1H), 2.31 ¨2.13 (m, 2H), 1.34 ¨ 1.19 (m, 1H), 0.60 (td, 1H), 0.53 ¨0.30 (m, 3H).

LCMS: MS raiz (ES!): 363 [IVI+Hr.
Example 55 (S)-N-(6-chloro-2-(3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-y0propanoy0isoindolin-5-yl)acetamide 55 JV
0\\
HI\nP) r NH 411. 55 NH

CI
To a mixture of 54 (3 mg, 0.08 mmol) in THE (2 mL) was added acetic anhydride (8mg 0.075 mmol) and triethylamine (18 mg 0.14 mmol). The reaction was stirred at 30 C
for 18h. The mixture was concentrated. The residue was purified with prep-HPLC to give title compound 55 (2.1 mg, 0.005 mmol, 62% yield).
1H NMR (400 MHz, Methanol-d4): 6 7.74 (s, 1H), 7.47 (d, 1H), 4.84 (s, 2H), 4.74 (s, 2H), 2.68-2.33 (m, 2H), 2.30-2.12 (m, 5H), 1.30 ¨ 1.21 (m, 1H), 0.68-0.29 (m, 4H).
LCMS: MS raiz (ES!): 405 [IVI+Hr.
Example 56 (S)-2-(3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-y0propanoy0isoindoline-5-carboxylic acid )r_ N H

The title compound was prepared with similar method as Example 1.
LCMS: MS raiz (ES!): 358 [IVI+Hr.
Example 57 (S)-5-(3-(5-chloro-6-methylisoindolin-2-y0-3-oxopropy1)-5-cyclopropylimidazolidine-2,4-dione 57 CI
H N (s) )r-NH CH3 CI NH step 1 CI s N¨Boc step 2 CI
N¨Boc 53d 57a 57b step 3 CI step 4 N ei CI
NH HNyNH CH3 57c 0 Step 1 tert-butyl 5-chloro-6-iodoisoindoline-2-carboxylate 57a To a mixture of 53d (40 mg, 0.143 mmol) in 5N KOH solution (2 mL) was added di-tert-butyl dicarbonate (100 mg, 0.45 mmol), the reaction was stirred at r.t for 18h. The mixture was cooled to 0 C, then filtered to give 57a (28 mg, 0.09 mmol, 63% yield).
Step 2 tert-butyl 5-chloro-6-methylisoindoline-2-carboxylate 57b To a solution of 57a (20 mg, 0.052 mmol) in DME (3 mL) was added water (2 mL), CH3B(OH)2 (20mg 0.33 mmol), K2CO3 (15 mg 0.1 mmol) and Pd (PPh3)2C12 (3 mg, 0.0052 mmol). The reaction mixture was stirred at 80 C for 18h under N2 atmosphere.
After the reaction was completed, the reaction mixture was quenched and extracted with Et0Ac (20 mL
X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford 57b. The crude product was used without purification for next step.
Step 3 5 -chloro -6-methylisoindo line 57c To a solution of 57b (20 mg, 0.052 mmol) in DCM (3 mL) was added 4N HC1 in 1,4 dioxane(2 mL). After the reaction was complete. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel column (DCM: Me0H(2%NH4OH) = 10: 1) to afford 57c (5 mg, 0. 029 mmol 60 % yield).
Step 4 (S)-5 -(3 - (5-chloro-6-methylisoindo lin-2- y1)-3 -o xoprop y1)-5-c ycloprop ylimid azolidine-2 ,4 -dione 57 To a mixture of 57c (5 mg, 0.029 mmol) in DMF (2 mL) was added Triethylamine (13 mg, 0.1mmol), It-1 (5 mg, 0.022 mmol) and HATU (12 mg, 0.031 mmol). The reaction was stirred at r.t for 18h. Water (3 mL) added and the mixture was extracted with Et0Ac (20 mL X 2).
The combined layer was washed with brine, dried over Na2SO4 and concentrated.
The residue was purified with prep-HPLC to give title compound 57 (3 mg, 0.008 mmol, 36 %
yield).
1H NMR (400 MHz, Methanol-d4): 6 7.36 (d, 1H), 7.28 (d, 1H), 4.83 (s, 2H), 4.71 (d, 2H), 2.63-2.41 (m, 2H), 2.39 (s, 3H), 2.23 (m, 2H), 0.60 (td, 2H), 0.53-0.38 (m, 2H), 0.35 (dt, 1H).
LCMS: nth (ES!): 3621M+Hr.
Example 58 (5S)-5 -c yc loprop y1-5 - (3 - (5,6-dichloro-1 -ethylisoindo lin-2- y1)-3 -o xoprop yl) imid azolidine-2 ,4-dio ne 58 V..r)L0 HN)r-NH CI

CI

Step 1 Step 2 N Step 3 o NH

CI CI CI

20a 58b 58c 58d Step 4 CI Step 5 )""tfrAN
HN)r_NH
NH-3" CI

58e 58 ci Step 1 4,5-dichloro-2-propionylbenzoic acid 58b The mixture of 20a (1.0 g, 4.61 mmol), 2-methylpropanedioic acid (761.85 mg, 6.45 mmol) and pyridine (1 mL) was stirred at 75 C for 3 h. The mixture was diluted with water (2 mL) and concentrated HC1 (2 mL), and the mixture was heated to 140 C and stirred for 2 h. After the reaction mixture was cooled to RT, the mixture was filtered and the cake was dried to give 58b (640 mg, 2.59 mmol, 56.21% yield).

LCMS: MS in/z (ES!): 249.3 [M+Hr.
Step 2 6,7-dichloro-4-ethyl- 1H-b enzo [d] [1,2]oxazin- 1 -o ne 58c 58b (200 mg, 809.47 umol) was added to the solution of KOH (129.45 mg, 2.31 mmol) in H20 .. (1.2 mL), and then hydroxylamine hydrochloride (120.38 mg, 1.73 mmol) was added portion-wise. The reaction was stirred at 30 C overnight. Then the mixture was filtered and the filter cake was dried to give 58c (80 mg, 327.77 umol, 40.49% yield).
11INMR (400 MHz, DMSO-d6): 6 8.40 (s, 1H), 8.31 (s, 1H), 3.01 (q, 2H), 1.24 (t, 3H).
LCMS: MS m/z (ES!): 244.3 [M+Hr.
Step 3 5 ,6-dichloro-3 -ethyliso indolin- 1 -one 58d To a solution of 58c (350 mg, 1.43 mmol) in acetic acid (5 mL) was added Zn (937.69 mg,

14.34 mmol). The mixture was heated to 118 C and stirred overnight. The mixture was filtered and the cake was washed with DCM, the filtrate was concentrated, and the residue was triturated with ether and filtered to give 58d (180 mg, 782.30 umol, 54.55%
yield).
11INMR (400 MHz, DMSO-d6): 6 8.96 (brs, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 4.59-4.56 (m, 1H), 2.01-1.90 (m, 1H), 1.65-1.54 (m, 1H), 0.79 (t, 3H).
LCMS: MS m/z (ES!): 230.4 [M+Hr.
Step 4 5,6-dichloro-1 -ethylisoindo line 58e To a solution of 58d (1.32 g, 5.74 mmol) in THF (10 mL) was added BH3/THF
(793.68 mg, 57.37 mmol, 55 mL). The mixture was heated to 60 C and stirred overnight. The reaction was quenched with Me0H (5 mL) and then 6 M HC1 (adjusted pH to 1-2). The mixture was heated to 80 C for lh and then cooled to RT. The mixture was adjusted pH to 7-8 with aq. NaOH (6N).
Then the mixture was dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (Et0Ac/hexane=1:20-1:1) to afford 58e (630 mg, 2.92 mmol, 50.82% yield).
11INMR (400 MHz, DMSO-d6): 6 7.50 (s, 1H), 7.47 (s, 1H), 4.19-4.16 (m, 1H), 4.03 (s, 2H), 1.80-1.71 (m, 1H), 1.47-1.43 (m, 1H), 0.90 (t, 3H).
.. LCMS: MS m/z (ES!): 216.4 [M+Hr.
Step 5 (5S)-5 -c yc loprop y1-5 - (3 - (5,6-dichloro-1 -ethylisoindo lin-2- y1)-3 -o xoprop yl) imid azolidine-2,4-dione 58 To a solution of 58e (50 mg, 231.37 umol) in DMF (2 mL) was added TEA (0.3 mL), It-1 (53 mg, 249.76 umol) and HATU (100 mg, 263.00 umol). The mixture was stirred at room temperature for 3 h. Water was added, and then the mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give 58 (30 mg, 73.12 umol, 31.60% yield).
11INMR (400 MHz, DMSO-d6): 6 10.58 (br, 1H), 7.79-7.63(m, 3H), 5.27-5.21 (m, 1H), 4.83-4.66 (m, 2H), 2.42-1.72 (m, 6H), 1.16-1.05 (m, 1H), 0.61-0.51 (m, 3H), 0.47-0.29 (m, 3H), 0.16-0.07 (m, 1H).
LCMS: MS nth (ES!): 410.1 [M+Hr.
Example 59 (S)-5 -(3 -(5-bromo-6 - (triflu oro methyl) iso indolin-2 -y1)-3 -o xoprop y1)-c ycloprop ylimidazolidine-2 ,4-dione 59 Br H2N Step 1 Br Step 2 Br Step 3 CFI CFI CF3 Br 40d 59b 590 Oy..*=V

Br Step 4 Br Step 5 NH OIC __ HN NH )r- NH CF3 59d 59e Br Step 1 Methyl 5 -bromo -2-methy1-4- (trifluoromethyl)b enzo ate 59b To a suspension of 40d (500 mg, 2.14 mmol) in CH3CN (20 mL) was added isoamyl nitrite (377 mg, 3.22 mmol) and CuBr2 (960 mg, 4.30 mmol). After the mixture was stirred at 70 C
overnight, the mixture was cooled down to room temperature and poured into ice water (20 mL). Then the mixture was extracted with Et0Ac (50 mL). The organic phase was dried over Na2SO4(,), filtered. The filtrate was concentrated to afford crude 59b (600 mg, 2.02 mmol, 94.20% yield).

111 NMR (400 MHz, CDC13): 6 8.20 (s, 1H), 7.56 (s, 1H), 3.93 (s, 3H), 2.59 (s, 3H).
Step 2 Methyl 5 -bromo-2- (bro momethyl)-4- (trifluoromethyl)benzo ate 59c To a solution of 59b (100 mg, 336.62 umol) in CC14 (3 mL) was added AIBN (1.66 mg, 10.10 umol) and NBS (71.89 mg, 403.95 umol), and the mixture was stirred at 70 C
overnight. The mixture was cooled to room temperature and filtered, the cake was washed with DCM, the filtrate was concentrated in vacuo to give crude 59c (150 mg, 398.97 umol, 118.52% yield).
Step 3 6 -bro mo -5- (triflu oromethyl) iso indolin- 1 -one 59d To a solution of 59c (150 mg, 398.97 umol) in Me0H (1 mL) was added NH3/Me0H
(4 mL), the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (Et0Ac/hexane=1/5) to give 59d (60 mg, 214.25 umol, 53.70% yield).
11INMR (400 MHz, DMSO-d6): 6 9.03 (brs, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 4.44 (s, 2H).
LCMS: MS m/z (ES!): 280.3 1M+Hr.
Step 4 5 -bromo -6- (trifluoromethyl) isoindo line 59e To a solution of 59d (60 mg, 214.25 umol) in THF (2 mL) was added BH3/THF
(29.64 mg, 2.14 mmol, 5 mL), and the mixture was heated to 60 C and stirred overnight.
The reaction was quenched with Me0H (5 mL) and the mixture was adjusted to pH 1-2 with 6M HC1.
The mixture was heated to 80 C and stirred for lh. The reaction was cooled to room temperature and adjusted to pH 7-8 with 6 M NaOH. The mixture was extracted with ethylacetate and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Me0H/DCM=1/20) to afford 59e (20 mg, 75.17 umol, 35.09% yield).
LCMS: MS m/z (ES!): 268.2 1M+H1 .
Step 5 (S)-5 -(3 -(5-bromo-6 - (triflu oro methyl) iso indolin-2 -y1)-3 -o xoprop y1)-c ycloprop ylimidazolidine-2 ,4-dione 59 To a solution of 59e (20 mg, 75.17 umol) in DMF (1.5 mL) was added TEA (0.2 mL), Int-1 (16 mg, 75.40 umol) and HATU (30 mg, 78.90 umol). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EA.
The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give 59 (10 mg, 21.73 umol, 28.90% yield).
11INMR (400 MHz, DMSO-d6): 6 10.62 (brs, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 4.86-4.81 (m, 2H), 4.68-4.63 (m, 2H), 2.41-2.22 (m, 2H), 2.03-1.98 (m, 2H), 1.15-1.07 (m, 1H), 0.50-0.29 (m, 3H), 0.16-0.07 (m, 1H).
19F NMR (400 MHz, CDC13): 6 -60.79.
LCMS: MS raiz (ES!): 462.3 11\4+Hr.
Example 60 5-(3-oxo-3-(5-(trifluoromethyflisoindolin-2-yflpropy1)-5-(pyridin-2-yflimidazolidine-2,4-dione 60 \ /

Step 1 Step 2 Step 3 I I

a 0 60a 0 c 60b 0 HN-1(NH 0 Step 4 0 \ /
\ /

60d 60 CF3 Step 1

15 Tert-butyl 4-oxo-4-(pyridin-2-yl)butanoate 60b To a solution of 1-(pyridin-2-yl)ethanone 60a (24.2 g, 199 mmol) in THF (300 mL) at -70 C
was added LDA (120 mL, 240 mmol) dropwise. After the addition, the reaction mixture was stirred at this temperature for 30 min before tert-butyl 2-bromoacetate (39 g, 199 mmol) was added dropwise. Then the resulting mixture was stirred atroom temperature for 18 hours. The reaction mixture was diluted with aq. NH4C1 (100 mL). The mixture was extracted with Et0Ac (400 mL X 3). The organic layers were combined, washed with brine (400 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography (Et0Ac/hexane = 1/10 to 1/2) to afford 60b (11.0 g, 46.7 mmol, yield: 23.4%).
LCMS: MS m/z (ES!): 236.1[1\4+Hr.
Step 2 Tert-butyl 3 -(2,5 -dio xo -4-(p yridin-2- yl)imidazolidin-4- yl)prop ano ate 60c A mixture of 60b (4.7 g, 20.0 mmol), (NH4)2CO3 (16.3 g, 170 mmol), NaCN (2.45 g, 50.00 mmol), Et0H (25 mL) and H20 (25 mL) was heated in an autoclave at 85 C for 18 hours. The resulting mixture was diluted with water (60 mL). The mixture was extracted with Et0Ac (200 mL X 5). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Et0Ac/hexane = 1/10 to 1/1) to afford 60c (3.0 g, 9.83 mmol, yield:
49.2%).
LCMS: MS m/z (ES!): 306.1[1\4+Hr.
Step 3 3 -(2,5 -dio xo -4-(p yridin-2- yl)imidazolidin-4- yl)propanoic acid 60d To a solution of 60c (1.0 g, 3.28 mmol) in DCM (10 mL) was added HC1/1,4-dioxane (30 mL, 3.0 M). The resulting mixture was stirred at room temperature for 18 hours.
Then the reaction mixture was concentrated under reduced pressure. The residue was washed with Et20 (10 mL), dried in vacuum to afford 60d (800 mg, 3.21 mmol, 98.01% yield).
LCMS: MS m/z (ES!): 248.2 [M-11-.
Step 4 5 -(3 -oxo-3- (5 -(trifluoro methyl) isoindo lin-2- yflprop y1)-5 - (p yridin-2- yl) imid azolidine-2 ,4-dione 60 A mixture of 60d (100 mg, 401.25 umol), 5-(trifluoromethyl)isoindoline 1-1 (89.7 mg, 401um01), Et3N (140 mg, 1.39 mmol), HATU (153 mg, 401um01) and DMF (10 mL) was stirred at room temperature for 18 hours. Then the reaction mixture was purified by prep-HPLC
to afford 60 (30 mg, 71.71 umol, 17.9% yield).
111 NMR (400 MHz, DMSO-d6): 6 10.92 (brs, 1H), 8.59 (d, 1H), 8.16-8.10 (m, 1H), 7.84 (t, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.59-7.51 (m, 2H), 7.37-7.34 (m, 1H), 4.83 (brs, 2H), 4.69 (brs, 2H), 4.43-4.28 (m, 4H).

LCMS: MS raiz (ES!): 419.0 [M+Hr.
Example 61 5-(3 -(5,6-dichloro isoindolin-2- y1)-3 -oxoprop y1)-5 -(p yridin-2 -y1) imid azo lidine-2,4-dione 61 O
HN)i-NH CI

CI
To a solution of 60d (66.87 mg, 268.31 umol) in DMF (6 mL) was added DIEA
(173.06 mg, 1.34 mmol), followed by the addition of 20c (60 mg, 268.31 umol), EDCI (128.59 mg, 670.77 umol) and HOBt (47.13 mg, 348.80 umol). The mixture was stirred for 2 hours and then the mixture was purified by prep-HPLC to afford the tittle compound 61 (8.8 mg, 20.93 umol, 7.80%
yield).
111 NMR (400 MHz, DMSO-d6): 6 10.87 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 7.86 (t, 1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.54 (d, 1H), 7.39-7.37 (m, 1H), 4.74 (brs, 2H), 4.60 (brs, 2H), 2.50-2.39 (m, 2H), 2.33-2.30 (m, 2H).
LCMS: MS raiz (ES!): 419.0 1M-PH1 .
Example 62 5-(1-methy1-1H-imidazol-2-y1)-5-(3-oxo-3-(5-(trifluoromethyflisoindolin-2-yflpropyflimidazolidine-2,4-dione 62 ON
N

Step 1 N-yc Step 2 N Step 3 _____________________ /

62a 62b 62c HWANH HN-1.NH 0 Step 4 Step 5 0 0 0 0 OH N-' N¨

N
62d 62e 62 C F3 Step 1 1 -(1 -methyl- 1H-imid azol-2- yl)ethan- 1 -one 62b To a solution of 1-methyl-1H-imidazole 62a (39 g, 475.01 mmol) in THF (350 mL) at -70 C
was added n-BuLi (356 mL, 1.6N, 570.01 mmol) dropwise. After the addition, the resulting mixture was allowed to warm to 0 C and stirred at this temperature for 30 mm, and then the reaction was re-cooled to -70 C. Ethyl acetate (104.63 g, 1.19 mol) was added dropwise at -70 C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with aq. NH4C1 (100 mL). The whole mixture was extracted with Et0Ac (400 mL
X 3). The organic layers were combined, washed with brine (400 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Et0Ac/hexane = 1/10 to 1/2) to afford 62b (26 g, 209.44 mmol, 44.09%
yield).
111 NMR (400 MHz, CDC13): 6 7.14 (s, 1H), 7.04 (s, 1H), 4.00 (d, 3H), 2.66 (d, 3H).
Step 2 Tert-butyl 4 -(1 -methyl- 1H-imid azol-2- y1)-4-o xobutano ate 62c A solution of LDA (77.3 mL, 2N, 154.66 mmol) in THF (200 mL) was cooled to -78 C. A
solution of 62b (16.0 g, 128.89 mmol) was added dropwise, then the resulting mixture was warmed to 0 C and stirred for 30 mm. The reaction mixture was re-cooled to -78 C and tert-butyl 2-bromoacetate (25.14 g, 128.89 mmol) was added slowly. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4C1 aq.(150 mL), the whole mixture was extracted with Et0Ac (150 mL X 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Et0Ac/hexane = 1/8 to 1/1) to afford 62c (13 g, 54.56 mmol, 42.33% yield).

111 NMR (400 MHz, CDC13): 6 7.15-7.13 (m, 1H), 7.06 (s, 1H), 4.01-3.99 (m, 3H), 3.44-3.38 (m, 2H), 2.67-2.61 (m, 2H), 1.46-1.43 (m, 9H).
Step 3 Tert-butyl 3 -(4-(1 -methyl-1H-imidazol-2 - y1)-2 ,5 -dio xo imidazolidin-4-yflprop ano ate 62d A mixture of 62c (4.0 g, 16.79 mmol), (NH4)2CO3 (13.70 g, 142.69 mmol), NaCN
(2.23 g, 41.97 mmol), Et0H (25 mL) and H20 (25 mL) was added to sealed vessel and heated to 85 C
reacted for 18 hours. The reaction mixture was diluted with water (100 mL).
The whole mixture was extracted with n-BuOH (100 mL X 3). The combined organic layers were washed with brine (50 mL), concentrated under reduced pressure. The residue was purified by column chromatography (DCM/Me0H= 100/1 to 10/1) to afford 62d (700 mg, 2.27 mmol, 13.52%
yield).
LCMS: miz (ES!): 309.4 1M+H1 .
Step 4 3 -(4 -(1-methy1-1H-imid azol-2- y1)-2,5 -dioxoimid azo lidin-4 - yflprop ano ic acid 62e To a solution 62d (700 mg, 2.27 mmol) in dioxane (20 mL) was added HO/dioxane (20 mL, 6N, 120 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to afford crude 62e (700 mg, 2.78 mmol).
LCMS: miz (ES!): 253.1 1M+H1 .
Step 5 5 -(1 -methy1-1H-imidazol-2- y1)-5 -(3 -o xo -3 -(5 -(trifluoro methyl) iso indolin-2 -yl)propyl) imidazolidine-2 ,4-dione 62 The mixture of 62e (100 mg, 396.47 umol) and 5-(trifluoromethyl)isoindoline 1-1 (89 mg, 396.47 umol) in DMF (5 mL) was added HATU (150mg, 396.47 umol) and Et3N (160 mg, 1.59 mmol), the reaction was stirred at room temperature for 18 hours. The reaction mixture was purified by prep-HPLC to afford 62 (30 mg, 71.20 umol, 17.96% yield).
111 NMR (400 MHz, DMSO-d6): 6 8.59-8.57 (m, 1H), 7.77 (s, 1H), 7.68-7.65 (m, 1H), 7.60-7.58 (m, 1H), 7.19 (s, 1H), 6.85 (s, 1H), 4.86-4.85 (m, 2H), 4.71 (br, 2H), 3.55 (s, 3H), 2.61-2.54 (m, 2H), 2.50-2.38 (m, 2H).
LCMS: MS miz (ES!): 422.4 1M+H1 .
Examples 62-1 and 62-2 (S)-5-(1-methy1-1H-imidazol-2-y1)-5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-y1)propyl)imidazolidine-2,4-dione 62-1 (R)-5-(1-methy1-1H-imidazol-2-y1)-5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-y1)propyl)imidazolidine-2,4-dione 62-2 01"'l7_ 0 N N -="-\

62 (200 mg) was separated by SFC to give two single enantiomers (62 mg and 63 mg).
Enantiomer (shorter retention time):
111 NMR (400 MHz, DMSO-d6) 6 11.22 (s, 1H), 8.58 (d, 1H), 7.76 (s, 1H), 7.66 (d, 1H), 7.58 (dd, 1H), 7.19 (s, 1H), 6.85 (t, 1H), 4.86-4.84 (m, 2H), 4.71 (brs, 2H), 3.54 (s, 3H), 2.62-2.53 (m, 2H), 2.49-2.39 (m, 2H).
LCMS: m/z (ES!): 422.1 11\4+Hr.
ChirHPLC (CO2/Et0H/DEA 60/40/0.04 2.8m1/min OZ,5um,4.6*250(Daicel)): Rt:3.326 mm, ee:94.58%.
Enantiomer (longer retention time):
111 NMR (400 MHz, DMSO-d6) 6 11.23 (s, 1H), 8.59 (d, 1H), 7.76 (s, 1H), 7.66 (d, 1H), 7.59 (dd, 1H), 7.20 (s, 1H), 6.86 (s, 1H), 4.86-4.84 (d, 2H), 4.71 (brs, 2H), 3.55 (s, 3H), 2.61-2.53 (m, 2H), 2.49-2.42 (m, 2H).
LCMS: m/z (ES!): 422.1 11\4+Hr.
ChirHPLC (CO2/Et0H/DEA 60/40/0.04 2.8m1/min OZ,5um,4.6*250(Daicel)): Rt:4.538 mm, ee:100%.
Example 63 5-(methoxymethyl)-5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yflpropyflimidazolidine-2,4-dione 63 HN)r-NH CF3 _____________________________________________________ ) HO) Step 1 Step 2 Step 3 r 63a 63b 63c Step 4 0 CF3 HN)i-NH CF3 63d 0 63 Step 1 Methyl 5-methoxy-4-oxopentanoate 63b To a solution of iodosylbenzene (16.82 g, 76.45 mmol) in DCM (700 mL) at 0 C
was added pent-4-ynoic acid 63a (5 g, 50.97 mmol), boron trifluoride etherate (14.47 g, 101.94 mmol) was added dropwise. The reaction was stirred at r.t for lh. The resulting precipitate was separated by filtration and the solid was dried. Me0H (20 mL) was added, the reaction was stirred at r.t for 18h. The solution was concentrated and the residue was purified by silica gel chromatography (hexane:Et0Ac=10:1) to give 63b (3.6 g, 44.10% yield).
1H NMR (400 MHz, CDC13): 6 4.07 (s, 2H), 3.68 (s, 3H), 3.43 (s, 3H), 2.77-2.75 (m, 2H), 2.67-2.64 (m, 2H).
Step 2 5-methoxy-4-oxopentanoic acid 63c To a solution of 63b (500 mg, 3.12 mmol) in Water (10 mL) and THF (10 mL) was added LiOH (149 mg, 6.24 mmol). The reaction was stirred at r.t for 2h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The organic solution was washed with brine, dried over Na2SO4 and concentrated to give crude 63c (260 mg, 56.99% yield). The crude product was used directly in next step.
Step 3 5 -metho xy- 1 - (5 - (triflu oro methyl) isoindo lin-2- yl)pentane- 1 ,4-dio ne 63d To a solution of 63c (260 mg, 1.78 mmol) and 5-(trifluoromethyl)isoindoline 1-1 (333 mg, 1.49 mmol, HC1) in DMF (20 mL) was added triethylamine (720 mg, 7.12 mmol) and HATU

(812mg, 2.13 mmol). The reaction was stirred at r.t for 2h. Water (40 mL) was added and the mixture was extracted with Et0Ac (30 mL X 2), the organic solution was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexane: Et0Ac=2:1) to give 63d (320 mg, 96.10% yield).
LCMS: raiz (ES!): 316.1 [M+Hr.

Step 4 -(metho xymethyl)-5 -(3-o xo -3 -(5 -(triflu oro methyl)isoindo lin-2- yl)prop yl) imidazolidine-2 ,4-dione 63 To a solution of 63d (200 mg, 634.34 umol) in Et0H (5 mL) was added to a solution of 5 Ammonium carbonate (488 mg, 5.07 mmol) in water (5 mL). Then Sodium cyanide (78 mg, 1.59 mmol) was added. The reaction was stirred at 80 C for 18h in the sealed vessel. The solution was cooled to r.t. Water (50 mL) was added and the mixture was extracted with Et0Ac (40 mL X 2). The organic solution was washed with brine, dried over Na2SO4 and concentrated.
The residue was purified by prep-HPLC to give 63 (140 mg, 57.27% yield).
111 NMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 4.88-4.85 (m, 2H), 4.68 (br, 2H), 3.51 (d, 1H), 3.35 (d, 1H), 3.25 (s, 3H), 2.43-2.34 (m, 1H), 2.27-2.18 (m, 1H), 1.89-1.75 (m, 2H).
LCMS: m/z (ES!): 386.1 lIVI+Hr.
Examples 63-1 and 63-2 (S)-5 -(methoxymethyl)-5 -(3 -oxo-3 -(5 -(trifluoromethyl) isoindolin-2-yl)prop yl)imid azo lidine-2,4-dione 63-1 (R)-5 -(metho xymethyl)-5 -(3 -oxo-3 -(5-(trifluoromethyl) isoindo lin-2-yl)prop yl)imid azolidine-2,4 -dione 63-2 HNn y H N"--)L NH CF3 NH CF3 63 was seperated by SFC to give the title single enantiomer compounds (42 mg and 55 mg).
Enantiomer (shorter retention time):
111 NMR (400 MHz, DMSO-d6): 6 10.59 (br, 1H), 7.89 (d, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (d, 1H), 4.88-4.85 (m, 2H), 4.68 (br, 2H), 3.50 (d, J= 9.6 Hz, 1H), 3.35 (d, 1H), 3.25 (s, 3H), 2.42-2.32 (m, 1H), 2.26-2.17 (m, 1H), 1.89-1.76 (m, 2H).
LCMS: m/z (ES!): 386.1 [1\4+Hr ChirHPLC (Et0H/DEA 5%_40% 1.5m1/min IC, 3um 3.0*100(Daicel)): Rt:4.084 mm, cc: 100%.
Enantiomer (longer retention time):

111 NMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (d, 1H), 4.88-4.85 (m, 2H), 4.68 (br, 2H), 3.50 (d, 1H), 3.35 (d, 1H), 3.25 (s, 3H), 2.43-2.32 (m, 1H), 2.27-2.17 (m, 1H), 1.88-1.76 (m, 2H).
LCMS: raiz (ES!): 386.11M+Hr.
ChirHPLC (Et0H/DEA 5%_40% 1.5m1/min IC, 3um 3.0*100(Daicel)): Rt:4.766 min, ee:100%.
Example 64 5-(1 -methylc ycloprop y1)-5 -(3 -oxo-3 -(5-(triflu oromethyl) iso indolin-2 -yl)propyl)imidazolidine-2,4-dione 64 j3 )c Step 1 Step 2 0 Step 3 >i __________________________________ >1)(0 ___________ HNy.NH
0 64a 64b 064c HN = CF3 0 j)L
OH
HN Step 4 NH HNyNH 4100 CF3 64d 0 Step 1 Tert-butyl 4-(1 -methylc yc loprop y1)-4-o xobu tano ate 64b The solution of LDA (1.31 g, 12.23 mmol) in THF (5 mL) was colded to -78 C and stirred for min under N2 atmosphere. Then the solution of 1-(1-methylcyclopropyl)ethanone 64a (1.0 g, 10.19 mmol) in THF (3 mL) was added dropwise before the reaction mixture was warmed to 20 C for 30 min. Then the mixture was re-cooded to -78 C before the solution of tert-butyl 2-bromoacetate (1.99 g, 10.19 mmol) in THF (2 mL) was added dropwise. The mixture was 20 stirred at room temperature overnight. The reaction was quenched by saturated NH4C1 and then extracted with ethylacetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Et0Ac/hexane=1/10) to afford 64b (1.6 g, 7.54 mmol, 73.97%
yield).
Step 2 Tert-butyl 3 -(4- (1 -methylc ycloprop y1)-2 ,5-dioxoimidazolidin-4- yl)prop ano ate 64c To a solution of 64b (1.7 g, 8.01 mmol) in Me0H (25 mL) was added (NH4)2CO3 (4.16 g, 43.24 mmol), H20 (25 mL) and NaCN (1.06 g, 20.02 mmol). The reaction mixture was stirred at 80 C in a seal tube overnight and then cooled to RT. Water was added, the mixture was extracted with ethylacetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with Et0Ac/hexane=1/5, filtered and dried to give 64c (880 mg, 3.28 mmol, 40.96% yield).
11INMR (400 MHz, CDC13): 6 8.31 (brs, 1H), 6.01 (brs, 1H), 2.32-2.24 (m, 2H), 2.18-2.07 (m, 2H), 1.44 (s, 9H), 1.21 (s, 3H), 0.76-0.70 (m, 1H), 0.61-0.55 (m, 1H), 0.41-0.28 (m, 2H).
Step 3 3 -(4- (1 -methylc yclopropy1)-2,5-dioxoimidazolidin-4- yl)propanoic acid 64d To a solution of 64c (880 mg, 3.28 mmol) in Me0H (10 mL) was added HC1/Dioxane (16 mL, 6N), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ether, filtered and dried to give 64d (630 mg, 2.97 mmol, 90.52% yield). The product was directly used for the next reaction.
Step 4 5 -(1 -methylc ycloprop y1)-5 -(3 -oxo-3 - (5- (trifluoromethyl) iso indolin-2 -yl)prop yl) imidazolidine-2 ,4-dione 64 To a solution of 5-(trifluoromethyl)isoindoline 1-1 (90 mg, 480.87 umol) in DMF (10 mL) was added TEA (0.3 mL), 64d (100 mg, 471.25 umol) and HATU (197.10 mg, 518.37 umol).
The mixture was stirred at room temperature for 2h. Water was added, and the mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC
to give 64 (130 mg, 340.90 umol, 72.34% yield).
11INMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 4.86 (brs, 2H), 4.70 (brs, 2H), 2.42-2.20 (m, 2H), 2.07-1.94 (m, 2H), 1.15 (s, 3H), 0.65-0.58 (m, 1H), 0.50-0.44 (m, 1H), 0.29-0.18 (m, 2H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.55.
LCMS: MS m/z (ES!): 396.4 [M+Hr.

Examples 64 -1 and 64-2 (R)-5-(1-methylcyclopropy1)-5-(3-oxo-3-(5-(trifluoromethyflisoindolin-2-yl)propyflimidazolidine-2,4-dione 64-1 (S)-5 -(1-methylcyclopropy1)-5-(3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yl)propyl)imidazolidine-2,4-dione 64-2 Od; 0 )r-NH CF 3 )i-NH = CF3 64 (70 mg) was separated by SFC (DAICELCHIRALCELOIG) to give two enantiomers (22 mg and 18 mg).
Enantiomer (shorter retention time):
11INMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 4.87-4.85 (m, 2H), 4.70 (brs, 2H), 2.40-2.19 (m, 2H), 2.08-1.94 (m, 2H), 1.15 (s, 3H), 0.65-0.58 (m, 1H), 0.50-0.44 (m, 1H), 0.30-0.17 (m, 2H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.56.
LCMS: MS m/z (ES!): 396.4 1M+H1 .
Chiral HPLC (CO2/Me0H/DEA 5%-40% 1.5m1/min IG,3um,3*100(Daicel)): Rt: 5.027 min, cc: 100%.
Enantiomer (longer retention time):
11INMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 4.86 (brs, 2H), 4.70 (brs, 2H), 2.41-2.20 (m, 2H), 2.04-1.93 (m, 2H), 1.15 (s, 3H), 0.63-0.60 (m, 1H), 0.47 (br, 1H), 0.29-0.17 (m, 2H).
19FNMR (376.5 MHz, DMSO-d6): 6 -60.56.
LCMS: MS m/z (ES!): 396.4 1M+H1 .
Chiral HPLC (CO2/Me0H/DEA 5%-40% 1.5m1/min IG,3um,3*100(Daicel)): Rt: 5.892 min, cc: 100%.
Example 65 5-(2-((benzyloxy)methyl)-3-oxo-3-(5-(trifluoromethyl)isoindolin-2-yflpropy1)-5-cyclopropylimidazolidine-2,4-dione 65 HNyNhl v)X-I
0 Step 1 AT Step 2 HN
OBn 0 CF3 ________________________ CF3 42e 65a SI 65 Step 1 2 -((benzylo xy)methyl)-4 -cyc loprop yl- 1 - (5 - (trifluoromethyl) iso indolin-2- yl)b utane- 1,4-dio ne 5 65a To a solution of 42e (200 mg, 762.48 umol) and 5-(trifluoromethyl)isoindoline 1-1 (120 mg, 638.66 umol) in DMF (10 mL), triethylamine (232 mg, 2.29 mmol) and HATU
(347.90 mg, 914.98 umol) were added. The reaction was stirred at room temperature for 2h.
Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2), the organic solution was 10 washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC
to give 65a (200 mg, 60.80% yield).
LCMS: m/z (ES!): 432.1 [M+Hr.
Step 2 5 -(2- ((b enz ylo xy)methyl)-3 -oxo-3 - (5- (triflu oromethyl)iso indolin-2 -yflprop y1)-5 -15 cyclopropylimidazolidine-2,4-dione 65 To a solution of 65a (200 mg, 463.56 umol) in Et0H (2 mL), ammonium carbonate (356.35 mg, 3.71 mmol), NaCN (61.47 mg, 1.16 mmol) and water (2 mL) were added. The reaction was stirred at 80 C for 18h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2), the organic solution was washed with brine, dried over Na2SO4 and 20 concentrated. The residue was purified by prep-HPLC to give 65 (85 mg, 36.56% yield).
111 NMR (400 MHz, DMSO-d6): 6 10.68 (brs, 1H), 7.78-7.66 (m, 3H), 7.61-7.53 (m, 1H), 7.23 (br, 5H), 5.03-4.64 (m, 4H), 4.45 (s, 2H), 3.55-3.42 (m, 2H), 2.99-2.91 (m, 1H), 2.33-2.23 (m, 1H), 1.86-1.82 (m, 1H), 1.08-0.99 (m, 1H), 0.44-0.24 (m, 3H), 0.04-0.01 (m, 1H).
LCMS: m/z (ES!): 502.2 [M+Hr.
Example 66 (5 S)-5 -c ycloprop y1-5 - (3 - (5 ,6-dichloro-1 -methylisoindo lin-2- y1)-3 -o xoprop yl) imidazolidine-2 ,4-dione 66 N H CI

Step 1 Step 2 CI Step 3 oI _____________________________________________________________________ NH

CI CI CI

20a 66b 66c 66d Step 4 CI Step 5 NH ____ . HNH 40 CI

66e 66 CI
Step 1 2-acetyl-4,5-dichlorobenzoic acid 66b To a mixture of 5,6-dichloroisobenzofuran-1,3-dione 20a (5g, 23.04 mmol) and 3,3-dihydroxypropanoic acid (3.67 g, 34.56 mmol) in pyridine (5 mL) was stirred at 75 C for 2h.
Water (16 mL) and conc. HC1 (16 mL) were added, the reaction was stirred at 130 C for 30min.
The mixture was cooled to r.t, then filtered to give 66b (2.1 g, 39.11%
yield).
LCMS: MS rah (ES!): 230.9 1M-H1-.
Step 2 6,7 -dichloro-4-methyl- 1H-b enzo [d][1,21oxazin- 1 -o ne 66c To a solution of 66b (2.1 g, 9.01 mmol) in water (12 mL) was added KOH (1.52 g, 27.03 mmol).
Then hydroxylamine hydrochloride (1.25 g, 18.02 mmol) was slowly added to the solution.
The reaction was stirred at room temperature for 18h. The solution was cooled to 0 C, the resulting precipitate was filtered. The solid was dried to give 66c (1.2 g, 57.89% yield).
LCMS: MS rah (ES!): 230.1 1M+Hr.
Step 3 5 ,6 -dichloro-3 -methyliso indolin- 1 -o ne 66d To a solution of 66c (3 g, 13.04 mmol) in acetic acid (20 mL) was added Zn (10 g, 153.85 mmol). The reaction was stirred at 115 C for 24h. The mixture was cooled to room temperature and filtered, the cake was washed with DCM, and the filtrate was concentrated.
The residue was purified by trituration (hexane: Et0Ac=4:1) to give 66d (2 g, 70.98%
yield).
LCMS: MS nth (ES!): 216.1 [M+Hr.
Step 4 5 ,6-dichloro-1 -methylisoindo line 66e To a solution of 66d (2 g, 9.26 mmol) in THF (10 mL) was added borane-tetrahydrofuran complex (629.44 mg, 37.03 mmol, 20 mL). The reaction was stirred at 60 C for 18h. Me0H
(2 mL) was added dropwise and HC1 (6M, 2mL) was added, the reaction was stirred at 80 C
for 2h. Then NaOH (5M) was added to adjust the mixture to pH=7, the solution was dried and concentrated. The residue was purified by was added (DCM:Me0H=20:1) to give 66e (900 mg, 4.45 mmol, 48.11% yield).
111 NMR (400 MHz, DMSO-d6): 6 7.62 (s, 2H), 4.63-4.58 (m, 1H), 4.31-4.19 (m, 2H), 1.46 (d, J= 6.8 Hz, 3H).
LCMS: nth (ES!): 202.1 [M+Hr.
Step 5 (5 S)-5 -c ycloprop y1-5 - (3 - (5 ,6-dichloro-1 -methylisoindo lin-2- y1)-3 -o xoprop yl) imidazolidine-2,4-dione 66 To a solution of 66e (1 g, 4.95 mmol) and Int-1 (1.16 g, 5.44 mmol) in DMF (50 mL), triethylamine (1.50 g, 14.85 mmol) and HATU (2.26 g, 5.94 mmol) were added.
The reaction was stirred at room temperature for 2h. Water (100 mL) was added and the mixture was extracted with Et0Ac (100 mL X 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatagraphy (DCM: Me0H=50:1) to give 66 (900 mg, 46% yield).
LCMS: MS nth (ES!): 396 [M+Hr 111 NMR (400 MHz, Methanol-d4) 6 7.40 (d, 2H), 5.14 (q, 1H), 4.71 (d, 2H), 2.56-2.23 (m, 2H), 2.22-2.01 (m, 2H), 1.39 (t, 3H), 1.13 (m, 1H), 0.48 ¨0.17 (m, 4H).
Examples 66-1 and 66-2 (S)-5 -c yc loprop y1-5 -(3 - ((S) - 5 ,6 -dichloro -1 -methylisoindo lin-2-y1)-3 -oxoprop yl)imidazolidine-2,4-dione 66-1 (S)-5 -c yc loprop y1-5 -(3 - ((R) - 5 ,6-dichlor o-1 -methylisoindo lin-2 -y1)-3 -oxoprop yl)imidazolidine-2,4-dione 66-2 FdNI),r NH HNN
CI yNH * I CI

CI C

Racemate 66 (900 mg) was seperated by SFC to give to give two isomers (340 mg and 320 mg separately).
Isomer with longer retention time:
111 NMR (400 MHz, DMSO-d6): 6 10.62 (s, 1H), 7.78-7.65 (m, 3H), 5.20 -5.10 (m, 1H), 4.81-4.71 (m, 2H), 2.49-2.18 (m, 2H), 2.03-1.97(m, 2H), 1.44-1.39 (m, 3H), 1.15-1.07 (m, 1H), 0.49-0.29 (m, 3H), 0.15-0.08 (m, 1H).
LCMS: nth (ES!): 396.0 1M+H1 .
ChirHPLC(CO2/Me0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:3.001 min, ee 97.10%.
Isomer with shorter retention time:
111 NMR (400 MHz, DMSO-d6): 6 10.64 (br, 1H), 7.80-7.65 (m, 3H), 5.25-5.10 (m, 1H), 4.81-4.71 (m, 2H), 2.51-2.23 (m, 2H), 2.10-1.93 (m, 2H), 1.43-1.38 (m, 3H), 1.15-1.05 (m, 1H), 0.49-0.29 (m, 3H), 0.14-0.06 (m, 1H).
LCMS: nth (ES!): 396.0 1M+H1 .
ChirHPLC (CO2/Me0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:1.689 min, ee:100%.
Examples 67-1, 67-2, 68-1, 68-2 (S)-5 -(3 -((R)-8 -chloro-9-fluoro-1 -methyl-1,2 ,4,5 -tetrahydro-3H-b enzo [di azepin-3 - y1)-3 -oxoprop y1)-5-cyclopropylimidazolidine-2,4-dione 67-1 (S)- 5 -(3 -((S)-8-chloro-9-fluoro-l-methy1-1,2,4 ,5-tetrahydro-3H-benzo [di azepin-3 -y1)-3 -oxoprop y1)-5-cyclopropylimidazolidine-2,4-dione 67-2 (S)-5 -(3 -((S)-8-chloro-7 -fluoro-l-methyl-1,2,4 ,5-tetrahydro-3H-benzo [di azepin-3 -y1)-3 -oxopropy1)-5-cyclopropylimidazolidine-2,4-dione 68-1 (S)-5 -(3 -((R)-8 -chloro-7 -fluoro-1 -methyl-1,2 ,4,5 -tetrahydro-3H-b enzo [di azepin-3 - y1)-3 -oxoprop y1)-5-cyclopropylimidazolidine-2,4-dione 68-2 N N
HN CI HN-------r CI
yNH )r...NH

H H
NN CI HN)r...NH CI
)r-N

F F
CI CF3 Step 1 CI CF3 CI CF3 Step 2 CI CI

37b 68b 67b 67c 68c N N
HN V. HN F N
CI
)r-NH )7...NH CI HN NH . CI
)7--Step 3 0 67 SFC 0 67-2 F 0 67-1 )r-NH HN)rNH CI Fdr-r-----N CI
0 68 F )7...NH

Step 1 Mixture of 1-(8-chloro-9-fluoro-1-methy1-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-y1)-2,2,2-trifluoro ethan-1 -one 67b & 1-(8-chloro-7-fluoro-l-methy1-1,2,4,5-tetrahydro-benzo [d] azepin-3 - y1)-2,2,2-trifluoro ethan-1 -one 68b To a solution of 37b (2 g, 6.86 mmol) in 1,2-dichloroethane (12 mL), trifluoromethanesulfonic acid (10.29 g, 68.56 mmol) and Selectfluor (4.86 g, 13.71 mmol) were added.
The reaction was stirred at 75 C for 18h. Water (50 mL) was added and the mixture was extracted with DCM
(20 mL X 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatagraphy (hexane:
Et0Ac = 20: 1) to give the mixture of 67b & 68b (800 mg, 37.68% yield).
LCMS: MS mh (ES!): 310.0 [M+Hr.
Step 2 Mixture of 8-chloro-9-fluoro-l-methy1-2,3,4,5-tetrahydro-1H-benzo[d]azepine 67c & 1-(8-chloro-9-fluoro-l-methy1-1,2,4,5-tetrahydro-3H-benzo [d]azepin-3 - y1)-2,2,2-trifluoro ethan-1 -one 68c To a solution of 67b & 68b (800 mg, 2.58 mmol) in Me0H (18 mL) was added a solution of NaOH (207 mg, 5.17 mmol) in water (5 mL). The reaction was stirred at room temperature for 2h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X
3), the combined layers was washed with brine, dried over Na2SO4 and concentrated to give the mixture of 67c & 68c (550 mg, 2.57 mmol, 99.64% yield). The crude solid was used to next step directly.
Step 3 Mixture of (5S)-5-(3 -(8-chloro-9-fluoro-1-methyl- 1,2,4,5 -tetrahydro-3H-benzo [di azep in-3 -y1)-3 -o xoprop y1)-5 -c ycloprop ylimid azolidine-2,4 -dio ne 67 & (SS)-5 -(3 -(8-chloro-7-flu oro -1-methyl-1 ,2,4,5 -tetrahydro -3H-b enzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 68 To a solution of 67c & 68c (500 mg, 2.34 mmol) and 34(45)-4-cyclopropy1-2,5-dioxo-imidazolidin-4-yllpropanoic acid It-1 (601 mg, 2.83 mmol) in DMF (20 mL), triethylamine (710.34 mg, 7.02 mmol) and HATU (1.07 g, 2.81 mmol) were added. The reaction was stirred at room temperature for 2h. The reaction was diluted with water (50 mL) and the mixture was extracted with Et0Ac (50 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the mixture of 67 & 68 (700 mg, 73.35% yield).
(S)-5 -(3 -((R)-8 -chloro-9 -fluoro-1 -methyl-1,2 ,4,5 -tetrahydro-3H-b enzo [di azepin-3 - y1)-3 -oxopropy1)-5-cyclopropylimidazolidine-2,4-dione 67-1 & (S)-5 -(3-((S)-8-chloro -9-fluoro-1 -methyl-1 ,2,4,5 -tetrahydro -3H-b enzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 67-2 (S)- 5 -(3 -((S)-8-chloro-7 -flu oro -1 -methyl- 1,2,4 ,5-tetrahydro-3H-benzo [di azepin-3 -y1)-3 -o xoprop y1)-5 -cyc loprop ylimid azo lidine-2,4-dione 68-1 & (S)-5 -(3 -((R)-8 -chloro-7 -fluoro-1-methyl-1 ,2,4,5 -tetrahydro -3H-b enzo [di azepin-3 - y1)-3 -o xoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 68-2 Mixture of 67 & 68 was separated by SFC (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel)) to give four isomers.
Isomer (peak 1, Rt: 4.729 min):
111 NMR (400 MHz, DMSO-d6): 6 10.59 (d, 1H), 7.70 (d, 1H), 7.33 (t, 1H), 7.02 (t, 1H), 3.91-3.48 (m, 4H), 3.33-3.30 (m, 1H), 3.28-3.07 (m, 1H), 2.94-2.82 (m, 1H), 2.40-2.15 (m, 2H), 1.97-1.73 (m, 2H), 1.15 (dd, 3H), 1.08-0.99 (m, 1H), 0.43-0.25 (m, 3H), 0.10-0.03 (m, 1H).

LCMS: m/z (ES!): 408.1[1\4+Hr.
ChirHPLC 1 (Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): peak 1, Rt:
4.729 min.
ChirHPLC 2 (CO2/Et0H/DEA 60/40/0.04 2.8m1/min AD,5um,4.6*250(Daicel)):
Rt:2.736 min, ee:100%.
Isomer (peak 2, Rt: 5.284 min):
1H NMR (400 MHz, DMSO-d6): 6 10.59 (d, 1H), 7.71 (d, 1H), 7.33 (t, 1H),7.02 (t, 1H), 3.89-3.47 (m, 4H), 3.31-3.06 (m, 2H), 2.91-2.82 (m, 1H), 2.36-2.00 (m, 2H), 1.95-1.78 (m, 2H), 1.15 (dd, 3H), 1.08-1.00 (m, 1H), 0.46-0.25 (m, 3H), 0.11-0.04 (m, 1H).
LCMS: m/z (ES!): 408.1[1\4+Hr.
ChirHPLC 1 (Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): peak 2, Rt:
5.284 min.
ChirHPLC 2 (CO2/Et0H/DEA 60/40/0.04 2.8m1/min AD,5um,4.6*250(Daicel)):
Rt:5.410 min, ee:99.42%.
Isomer (peak 3, Rt: 5.970 min):
1H NMR (400 MHz, DMSO-d6): 6 10.60 (d, 1H), 7.70 (d, 1H), 7.34 (dd, 1H), 7.23 (t, 1H), 3.65-3.38 (m, 4H), 3.22-2.80 (m, 3H), 2.41-2.21 (m, 2H), 1.93-1.75 (m, 2H), 1.20 (dd, 3H), 1.10-1.01 (m, 1H), 0.46-0.26 (m, 3H), 0.11-0.05 (m, 1H).
LCMS: m/z (ES!): 408.1[1\4+Hr.
Chiral HPLC 1 (Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): peak 3, Rt:
5.970 min.
Chiral HPLC 2 (CO2/Et0H/DEA 60/40/0.04 2.8m1/min AD,5um,4.6*250(Daicel)): Rt:
3.801 min, ee:100%.
Isomer (peak 4, Rt: 6.442 min):
1H NMR (400 MHz, DMSO-d6): 6 10.60 (s, 1H), 7.72 (d, 1H), 7.34 (t, 1H), 7.23 (dd, 1H), 3.66-3.38 (m, 4H), 3.23-2.80 (m, 3H), 2.45-2.16 (m, 2H), 1.93-1.78 (m, 2H), 1.20 (dd, 3H), 1.09-1.00 (m, 1H), 0.48-0.26 (m, 3H), 0.12-0.05 (m, 1H).
LCMS: m/z (ES!): 408.1[1\4+Hr.
ChirHPLC 1 (Me0H/DEA 5%_40% 1.5m1/min IA, 3um 3.0*100(Daicel)): peak 4, Rt:
6.442 min.
ChirHPLC 2 (CO2/Et0H/DEA 60/40/0.04 2.8m1/min AD,5um,4.6*250(Daicel)): Rt:
8.117 min, ee:100%.

Example 69 (5S)-5 -c yc loprop y1-5 - (3 -(5,6-dichloro-1-methylisoindolin-2- y1-3 ,3 -d2)-3-oxopropyl)imidazolidine-2,4-dione 69 CI
(s) HN)r-NH
CI
D D

CI CI CI
NH Step 1 NH Step 2 (s) ________________________________________________ HN),r-NH
CI CI CI

66d 69e 69 Step 1 5 ,6-dichloro-1 -methylisoindo line-3 ,3 -d2 69e To a solution of 66d (500 mg, 2.314 mmol) in THF (4 mL), borane-d3-THF complex solution (1M, 15 mL) was added. The reaction was stirred at 60 C for 18h. Me0H (2 mL) was added dropwise followed by HC1 (6M, 2 mL), the reaction was stirred at 80 C for 2h.
Then NaOH
(5M) was added to adjust the mixture to pH=7, the solution was dried and concentrated. The residue was purified by silica gel chromatagraphy (DCM:Me0H=20:1) to give 69e (320 mg, 1.5 mmol, 65% yield).
LCMS: nth (ES!): 204 [M+Hr.
Step 2 (5S)-5 -c yc loprop y1-5 - (3 -(5,6-dichloro-1-methylisoindolin-2- y1-3 ,3 -d2)-3-oxopropyl)imidazolidine-2,4-dione 69 To a mixture of 69e (20 mg, 0.094 mmol) in DMF (2 mL), triethylamine (40 mg, 0.28 mmol), It-1 (23 mg, 0.108 mmol) and HATU (57 mg, 0.13 mmol) were added. The reaction was stirred at room temperature for 18h. Water (3 mL) was added and the mixture was extracted with Et0Ac (20 mL X 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 69 (22 mg, 0.055mo1, 50 % yield).
111 NMR (400 MHz, Methanol-d4): 7.39 (s, 2H), 5.14 (q, 1H), 2.58 ¨2.22 (m, 2H), 2.20-2.02 (m, 3H), 0.49 (tt, 1H), 0.41-0.18 (m, 4H).
LCMS: nth (ES!): 39811M+Hr.

Examples 69-1 and 69-2 (S)-5-cyclopropy1-5-(3-((S)-5,6-dichloro-1-methylisoindolin-2-y1-3,3-d2)-3-oxopropyl)imidazolidine-2,4-dione 69-1:
(S)-5-cyclopropy1-5-(3-((R)-5,6-dichloro-1-methylisoindolin-2-y1-3,3- d2)-3 -oxopropyl)imidazolidine-2,4-dione 69-2:
(S) N
(s) HNTh N H H N N H
4s) C I (R) CI

CI CI

69 (85mg) was separartecl by SFC to give two diastereomers (15mg, 16mg).
Diastereomer (shorter retention time):
1HNMR (400 MHz, DMSO-d6): 6 10.66-10.63 (m, 1H), 7.80-7.65 (m, 3H), 5.25-5.10 (m, 1H), 2.40-2.22 (m, 2H), 2.09-1.93 (m, 2H), 1.40 (dd, 3H), 1.15-1.06 (m, 1H), 0.49-0.29 (m, 3H), 0.14-0.07 (m, 1H).
LCMS: MS miz (ES!): 398.0 1M+H1 .
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt:
1.581 min, de: 100%.
Diastereomer (longer retention time):
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.79-7.65 (m, 3H), 5.22-5.10 (m, 1H), 2.44-2.36 (m, 1H), 2.26-2.17 (m, 1H), 2.03-1.96 (m, 2H), 1.40 (dd, 3H), 1.15-1.07 (m, 1H), 0.48-0.29 (m, 3H), 0.14-0.08 (m, 1H).
LCMS: miz (ES!): 398.0 1M+H1 .
ChirHPLC (CO2/Me0H/DEA 60/40/0.04 1.8m1/min IA, 3um 3*100(Daicel)): Rt: 3.053 mm, de:99.38%.
Example 70 (SS)-5 -cyclopropy1-5-(3-(5,6-dichloro-1-methylisoindolin-2-y1)-2-methyl-3 -oxopropyl)imidazolidine-2,4-dione ()L
HNHN C I

To a mixture of 66e (10 mg, 0.049 mmol) in DMF (2 mL), triethylamine (20 mg, 0.15 mmol), Int-2A (9 mg, 0.042 mmol) and HATU (22.8 mg, 0.06 mmol) were added. The reaction was stirred at room temperature for 18h. Water (3 mL) added and the mixture was extracted with Et0Ac (20 mL X 2). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 70 (6 mg, 0.014 mmol, 33 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.26 (t, J = 3.3 Hz, 2H), 4.99 (q, 1H), 4.52 (d, 2H), 2.21 (m, 1H), 1.76 (m, 2H), 1.29 (dd, 3H), 0.97 (dd, 4H), 0.37 ¨0.05 (m, 4H).
LCMS: nth (ES!): 411 [M+Hr.
Example 71 (5S)-5 -(3 - (5-chloro -1-methy1-6- (trifluoromethyl) is oindolin-2- y1-3 ,3 -d2)-3-o xoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4-dione 71 HN (s) N
)i¨NH CI
D D

NH NH
step 1 CI
CI CI step 2 D D
0 71b 0 41f 71 Step 1 5 -chloro -1 -methyl-6 - (triflu oromethyl)iso indoline-3 ,3 -d2 71b Small scale To a solution of 41f (50 mg, 0.2 mmol) in THF (2 mL) was added Borane-d3-THF
complex solution (6 mmol, 6 mL). The reaction was stirred at 60 C for 18h. Me0H (2 mL) was added dropwise followed by HC1 (6M, 2mL). The reaction was stirred at 80 C for 2h.
Then NaOH
(5M) was added to adjust the mixture to pH=7, the solution was dried and concentrated. The residue was purified by silica gel chromatagraphy (DCM:Me0H=20:1) to give 71b (39 mg, 0.147 mmol, 70% yield).
Large scale To a solution 6-chloro-3-methy1-5-(trifluoromethyl)isoindolin-1-one 41f (800 mg, 3.20 mmol) in THF (10 ml) was added BD3 (1M in THF, 64 ml, 64 mmol). After addition, the reaction was stirred at 60 C (in a sealed tube) for 10 hours. It was quenched with Me0H (10 ml), followed by HC1 (6 M, 20 ml). It then was stirred at 80 C for 8 hours. 2 N
NaOH was added to adjust pH to 7 and extracted with Et0Ac, 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 % Me0H
in DCM, to get the desired product 71b which is used for next step.
LCMS: MS miz (ES!): 238.1 [M+Hr.
Step 2 (5 S)-5 -(3 - (5-chloro -1-methy1-6- (trifluoromethyl) is oindolin-2- y1-3 ,3 -d2)-3-o xoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 71 Small scale To a mixture of 71b (20 mg, 0.084 mmol) in DMF (2 mL) was added triethylamine (40 mg, 0.28 mmol), It-1 (23 mg, 0.108 mmol) and HATU (57 mg, 0.13 mmol). The reaction was stirred at r.t for 18h. Water (3 mL) was added and the mixture was extracted with Et0Ac (20 mL X 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give title compound 71 (24 mg, 0.055 mol, 51 % yield).
Large scale To a solution of (S)-3-(4-cyclopropy1-2,5-dioxoimidazolidin-4-yl)propanoic acid It-1 (680 .. mg, 3.2 mmol) in DMF (10 ml) was added EDCI (920 mg, 4.8 mmol) and HATU
(1.83 g, 4.8 mmol). After stirring for 10 minutes, the isoindoline 71b collected from the previous step was added. The reaction was stirred at ambient temperature for 3 hours. LCMS
showed that the reaction was completed. It was directly purified on a reverse phase HPLC to get the desired product 71 (1.10 g, 79.6% yield over two steps).
111 NMR (400 MHz, CD30D,): 7.76 (s, 1 H), 7.63-7.60 (m, 1 H), 5.57-5.53 (m, 1 H), 2.59-2.40 (m, 2 H), 2.28-2.19 (m, 2 H), 1.56-1.50 (m, 3 H), 1.28-1.21 (m, 1 H), 0.62-0.58 (m, 1 H), 0.49-0.41 (m, 3 H).
LCMS: MS miz (ES!): 432 [M+Hr.
Examples 71-1 and 71-2 (S)-5-(3 -((R)-5 -chloro -1 -methyl-6 - (triflu oro methypiso indolin-2 - y1-3 ,3 -d2)-3-oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 71-1 (S)-5-(3 -((S)-5 -chloro-1 -methyl-6-(triflu oromethyl)isoindo lin-2 - y1-3 ,3 -d2)-3 -oxoprop y1)-5 -cyclopropylimidazolidine-2,4-dione 71-2 ()LN
HN HN
CI CI

71 (1.10 g) was separarted by SFC to give two diastereomers (325mg and 415mg separately).
Enantiomers (shorter retention time):
1H NMR (500 MHz, DMSO-d6) 6 10.63 (s, 1H), 7.89 (d, 1H), 7.75 (t, 2H), 5.30 ¨
5.16 (m, 1H),4.23 (d, 1H), 2.37 ¨ 2.27 (m, 2H), 1.99 (dq, 2H), 1.53 (s, 1H), 1.43 (dd, 3H), 1.11 (td, 1H), 0.49 ¨0.30 (m, 3H), 0.11 (dt, 1H).
LCMS: MS m/z (ES!): 432.3 [1\4+Hr ChirHPLC (1% DEA in Et0H/hexane 60/40, 1.0 mL/min, 35 C, CHIRALPAK 1G, 150*4.6mm, Sum): Rt: 4.594 min, de:100%.
Enantiomers (longer retention time):
1H NMR (500 MHz, DMSO-d6) 6 10.53 (s, 1H), 7.89 (d, 1H), 7.80 ¨ 7.66 (m, 2H), 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), 1.44 (dd, 3H), 1.11 (td, 1H), 0.50 ¨ 0.29 (m, 3H), 0.16 ¨ 0.08 (m, 1H).
LCMS: MS m/z (ES!): 432.3 lIVI+Hl+
ChirHPLC (1% DEA in Et0H/hexane 60/40, 1.0 mL/min, 35 C, CHIRALPAK 1G, 150*4.6mm, Sum): Rt: 10.931 min, de:100%.
Example 72 (S)-5 -cycloprop y1-5 -(3 -o xo -3-(5 -(2,2,2 -triflu oro ethyl)isoindo lin-2-yl)prop yl)imid azolidine-2,4-dione 72 (\)N
HN)r-NH

Boo, Boc, HN
N r.
Step 1 Step 2 HCI
Br 3 51a 72b 72c Step 3 HN),r 72 r.NH
It-1 0 ¨.3 Step 1 Tert-butyl 5-(2,2,2-trifluoroethyl)isoindoline-2-carboxylate 72b To a mixture of 51a (500.00 mg, 1.68 mmol) and 1,1,1-trifluoro-2-iodoethane (1.76 g, 8.38 mmol) in DMSO (3 mL) was added copper (1.07 g, 16.77 mmol). The reaction was stirred at 120 C for 40h. The reaction was cooled to rt, and water (100 mL) was added.
The mixture was extracted with Et0Ac (30 mL X 2), and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude was purified by prep-HPLC to give 72b (33 mg, 109.52 umol, 6.53% yield).
1H NMR (400 MHz, CDC13): 6 7.21-7.15 (m, 3H), 4.69-4.65 (m, 4H), 3.37 (q, 2H), 1.52 (s, 9H).
19FNMR (400 MHz, CDC13): 6 -66.03.
Step 2 5-(2,2,2-trifluoroethyflisoindoline hydrochloride 72c The mixture of 72b (23 mg, 76.41 umol) in DCM (3 mL) was add HO/dioxane (1N, 1 mL).
The reaction was stirred at room temperature for 16 hours. The mixture was concentrated to give 72c as crude which was used to the next step.
Step 3 (S)-5 -c yc loprop y1-5 -(3 - (5- (diflu oro methyl) isoindolin-2- y1)-3 -o xoprop yl) imid azo lidine-2,4-dione 72 To a solution of 72c (23 mg, 206.89 umol) in DMF (3 mL) was added It-1 (23mg, 109.35 umol), TEA (30 mg, 298.23 umol) and HATU (45 mg, 119.29 umol). The mixture was stirred at room temperature 2h. Water (30 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried and concentrated. The crude was purified by prep-HPLC to give 72 (13 mg, 32.88 umol, 33.08% yield).

1H NMR (400 MHz, CDC13): 6 10.62 (brs, 1H), 7.74 (s, 1H), 7.37-7.27 (m, 3H), 4.80 (br, 2H), 4.62 (br, 2H), 3.67 (q, 2H), 2.47-2.40 (m, 1H), 2.30-2.26 (m, 1H), 2.01 (t, 2H), 1.13-1.09 (m, 1H), 0.47-0.31 (m, 3H), 0.13-0.10 (m, 1H).
19F NMR (400 MHz, CDC13): 6 -64.44.
LCMS: MS nth (ES!): 396.1 11\4+Hr.
Example 73 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(1-methyl-1H-imidazol-2-yflimidazolidine-2,4-dione 73 1\1 N.-- 0 HNNH

The title compound was prepared with similar method as Examples 40 and 62.
1H NMR (400 MHz, DMSO-d6): 6 8.57 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.19 (d, 1H), 6.84 (d, 1H), 4.85-4.81 (m, 2H), 4.71-4.67 (m, 2H), 3.54 (s, 3H), 2.59-2.54 (m, 2H), 2.45-2.38 (m, 2H).
LCMS: MS nth (ES!): 455.9 11\4+Hr.
Examples 73-1 and 73-2 (S)-5 -(3 -(5 -chloro-6-(trifluoromethyl)isoindolin-2-y1)-3 -oxoprop y1)-5 -(1 -methyl-1H-imidazol-2-yl)imidazolidine-2,4-dione 73-1 & (R)-5-(3-(5-chloro-6-(trifluoromethypisoindolin-2-y1)-3-oxopropy1)-5-(1-methyl-1H-imidazol-2-y1)imidazolidine-2,4-dione 73-2 0 Ny 0 HN),r-NH = HN)r-NH CF3 = CF3 0 73_1 CI 0 73_2 CI
73 (24 mg) was chirally separated by SFC to afford two enantiomers (5.0 mg, 5.0 mg).
Enantiomer (shorter retention time):
1H NMR (400 MHz, DMSO-d6): 6 11.16 (br, 1H), 8.57 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.19 (s, 1H), 6.84 (s, 1H), 4.85-4.81 (m, 2H), 4.71-4.67 (m, 2H), 3.54 (s, 3H), 2.59-2.54 (m, 2H), 2.45-2.38 (m, 2H).

LCMS: MS mh (ES!): 456.1 [M+Hr.
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 2.8ml/min OD,5um,4.6*250(Daicel)): Rt:
2.823 min, ee: 100%.
Enantiomer (longer retention time):
111 NMR (400 MHz, DMSO-d6): 6 11.18 (br, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.20 (s, 1H), 6.85 (s, 1H), 4.85-4.81 (m, 2H), 4.71-4.67 (m, 2H), 3.54 (s, 3H), 2.59-2.54 (m, 2H), 2.45-2.38 (m, 2H).
LCMS: MS nth (ES!): 456.0 [M+Hr.
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 2.8ml/min OD,5um,4.6*250(Daicel)): Rt:
3.878 min, ee: 96.48%.
Example 74 (S)-5-cyclopropy1-5-(3-(5-(difluoromethyl)-6-fluoroisoindolin-2-y1)-3-oxopropyl)imidazolidine-2,4-dione 74 o V
Hr\()(N
)õr NH 40 CHF2 o F OH _____ Step 1 Br OH Step 2 Br 0 Step 3 Br o Br F F F
74a 74b 74c 74d Step 4 ,... Br / Step 5 Br i& NH ____ Step 6 Br = N
Boc Step 7 3.- ..-NH
F F
F
74e 74f 74g / Step 8 (:) Step 9 F2HC Step 10 N¨Boc __________________________________ N¨Boc __________ N Boc __ ..-F F F
74h 74i 74j F2HC i& Step 11 NH ______________________ .- HNC)N

F

74k 74 Step 1 5-Bromo-4-fluoro-2-methylbenzoic acid 74b To a solution of 4-fluoro-2-methylbenzoic acid 74a (10 g, 64.88 mmol) in H2504 (50 mL) was added NBS (11.6 g, 65.18 mmol) in portions at 0 C. The reaction mixture was stirred at 0-5 C
for 2 his. The resulting mixture was poured into ice-water. The solid was collected by filtration and dried in vacuum to give 74b (14 g, 60.08 mmol, 92.60% yield).
111 NMR (400 MHz, DMSO-d6): 6 8.07 (d, 1H), 7.39 (d, 1H), 2.51 (s, 3H).
Step 2 Methyl 5-bromo-4-fluoro-2-methylbenzoate 74c To a solution of 74b (15 g, 64.37 mmol) in Me0H (150 mL) at 0 C was added SOC12 (22.97 g, 193.10 mmol, 14 mL) slowly. The reaction mixture was heated to 80 C for 2 hr. Then the mixture was cooled to room temperature and concentrated in vacuum. The residue was diluted with aq NH4C1 and extracted with Et0Ac. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to afford crude 74c (15.2 g, 61.52 mmol, 95.58% yield).
111 NMR (400 MHz, DMSO-d6): 6 8.02 (d, 1H), 7.37 (d, 1H), 3.78 (s, 3H), 2.45 (s, 3H).
Step 3 Methyl 5-bromo-2-(bromomethyl)-4-fluorobenzoate 74d To a solution of 74c (15.2 g, 61.52 mmol) in CC14 (250 mL) was added NBS
(13.14 g, 73.83 mmol) and AIBN (1.01 g, 6.15 mmol). The reaction mixture was stirred at 80 C
overnight.
Then the mixture was cooled down to room temperature and filtered. The cake was washed with CC14, the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatagraphy (Et0Ac: hexane=1:20) to afford 74d (19 g, 58.29 mmol, 94.74%
yield).
111 NMR (400 MHz, DMSO-d6): 6 8.16 (d, 1H), 7.71 (d, 1H), 4.98 (s, 2H), 3.88 (s, 3H).
Step 4 6-bromo-5 -fluoroiso indo lin- 1 -one 74e The solution of 74d (4.6 g, 14.11 mmol) in NH3/Me0H (40 mL, 7N) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, the residue was purified by silica gel chromatagraphy (MeOH: DCM=1:50) to give 74e (3.0 g, 13.04 mmol, 92.41% yield).
LCMS: MS m/z (ES!): 230.3 1M+Hr.
Step 5 5-bromo-6-fluoroisoindoline 74f To a solution of 74e (3.0 g, 13.04 mmol) in THF (20 mL) was added BH3/THF (1N
in THF, 90 mmol, 90 mL), and the mixture was heated to 65 C overnight. The reaction was quenched with methanol (5 mL) and 6M HC1 to adjust pH to 2. The mixture was heated to 80 C for 2 h, and cooled to RT. The mixture was adjusted to pH 7-8 with 6M NaOH, and was extracted with ethyl acetate (3x). The combined organic phases was dried over anhydrous Na2SO4, and concentrated in vacuum. The crude mixture was purified by silica gel chromatagraphy (MeOH: DCM=1:20) to afford 74f (350 mg, 1.62 mmol, 12.42% yield).
1H NMR (400 MHz, DMSO-d6): 6 7.62 (d, 1H), 7.33 (d, 1H), 4.14-4.10 (m, 4H).
LCMS: MS m/z (ES!): 216.2 1M+Hr.
Step 6 Tert-butyl 5-bromo-6-fluoroisoindoline-2-carboxylate 74g To a solution of 74f (350 mg, 1.62 mmol) in DCM (5 mL) was added TEA (492 mg, 4.86 mmol) and Boc20 (425 mg, 1.94 mmol), the mixture was stirred at room temperature for 4 h.
The reaction mixture was concentrated in vacuum. The crude mixture was purified by silica gel chromatagraphy (Et0Ac:hexane=1:20) to afford 74g (580 mg, 1.83 mmol, 113.24% yield).
1H NMR (400 MHz, DMSO-d6): 6 7.71-7.67 (m, 1H), 7.40-7.35 (m, 1H), 4.55-4.52 (m, 4H), 1.47-1.44 (m, 9H).
LCMS: MS m/z (ES!): 316.2 1M+Hr.
Step 7 Tert-butyl 5-fluoro-6-vinylisoindoline-2-carboxylate 74h To a solution of 74g (580 mg, 1.83 mmol) in 1,4-dioxane (20 mL) and H20 (3 mL) was added potassium trifluoro(vinyl)borate (270 mg, 2.02 mmol), Pd(dppf)C12 (150 mg, 183.45 umol) and K2CO3 (760 mg, 5.50 mmol), the reaction was replaced with N2 for three times. The mixture was stirred at 100 C overnight. Water was added and the reaction mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude mixture was purified by silica gel chromatagraphy (Et0Ac:hexane=1:20) to afford 74h (400 mg, 1.52 mmol, 82.81% yield).
1H NMR (400 MHz, DMSO-d6): 6 7.63-7.58 (m, 1H), 7.22-7.17 (m, 1H), 6.82 (dd, 1H), 5.89 (dd, 1H), 5.41 (d, 1H), 4.58-4.52 (m, 4H), 1.45 (s, 9H).
LCMS: MS m/z (ES!): 208.0 [M-tBu+Hr.
Step 8 Tert-butyl 5-fluoro-6-formylisoindoline-2-carboxylate 74i To solution of 74h (400 mg, 1.52 mmol) in 1,4-dioxane (8 mL) was added NaI04 (650 mg, 3.04 mmol) and H20 (2 mL), and the mixture was stirred at RT. Then 0s04 (39 mg, 151.91 umol) was added. The reaction mixture was stirred at room temperature for 3 h.
Saturated sodium bicarbonate was added, and then the reaction mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude mixture was purified by silica gel chromatagraphy (Et0Ac:hexane=1:20) to give 74i (180 mg, 678.53 umol, 44.67%
yield).
1H NMR (400 MHz, DMSO-d6): 6 10.20 (s, 1H), 7.81-7.76 (m, 1H), 7.44-7.39 (m, 1H), 4.67-4.58 (m, 4H), 1.45 (s, 9H).
LCMS: MS m/z (ES!): 210.4 [M-tBu+Hr.
Step 9 Tert-butyl 5-(difluoromethyl)-6-fluoroisoindoline-2-carboxylate 74j To a solution of 74i (180 mg, 678.53 umol) in DCM (5 mL) was added Et0H (3.1 mg, 67.85 umol), then DAST (547 mg, 3.39 mmol) was added dropwise at RT. The mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude mixture was purified by silica gel chromatagraphy (Et0Ac:hexane=1:20) to afford 74j (180 mg, 626.57 umol, 92.34%
yield).

1H NMR (400 MHz, DMSO-d6): 6 7.62-7.58 (m, 1H), 7.40-7.33 (m, 1H), 7.20 (t, 1H), 4.64-4.57 (m, 4H), 1.45 (s, 9H).
LCMS: MS in/z (ES!): 232.4 [M-tBu+Hr.
Step 10 5 -(difluoromethyl)-6-fluoroiso indoline 74k To a solution of 74j (180 mg, 626.57 umol) in the flask was added HC1 in1,4-dioxane (4N, 10 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuum to give 74k (110 mg, 587.73 umol, 93.80% yield).
LCMS: MS nth (ES!): 188.1 [M+Hr.
Step 11 (S)-5 -c yc loprop y1-5 -(3 -(5-(diflu oro methyl)-6-fluoroiso indo lin-2- y1)-oxopropylnmidazolidine-2,4-dione 74 To a solution of 74k (110 mg, 587.73 umol) in DMF (5 mL) was added TEA (0.4 mL), (S)-3-(4-c ycloprop y1-2 ,5 -dio xo imidazo lidin-4- yl)prop ano ic acid Int-1 (125 mg, 587.73 umol) and HATU (246 mg, 646.50 umol). The mixture was stirred at room temperature for 2 h. Water was added and reaction mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give 74 (24 mg, 62.93 umol, 10.71% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.51 (brs, 1H), 7.62 (s, 1H), 7.51 (d, 1H), 7.28 (dd, 1H), 7.09 (t, 1H), 4.73-4.68 (m, 2H), 4.55-4.50 (m, 2H), 2.33-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.91-1.86 (m, 2H), 1.08-0.96 (m, 1H), 0.38-0.17 (m, 3H), 0.03-0.00 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -112.85, --120.80.
LCMS: MS nth (ES!): 382.4 [M+Hr.
Exampe 75 5 -(3 -(5 -chloro-6-(triflu oro methyl) iso indolin-2 - y1)-3 -o xoprop y1)-5 -(5 -methyli so xazol-3 -yl)imid azo lidine-2,4-dione 75 bN 0 0.......)L
N
HN),rNH 40 CI

N Step 1 )..3) __________________________ "' 0 0 _______ Ol< Step 2 0 HNCNNH I

75a 75b 75c ti 0N 0 , N 0 Step 3 0 Step 4 0,.......)( OH N
HN),r..-N1H
HI\l,NFI

75d 75 Step 1 Tert-butyl 445 -methyliso xazol-3 - y1)-4 -oxobutano ate 75b 5 To a solution of 1-(5-methylisoxazol-3-y0ethan-1-one 75a (3.00 g, 23.99 mmol) in THF (10 mL) was added NaHMDS (4.40 g, 23.99 mmol) dropwise at -70 C. The resulting mxiture was stirred at this temperature for 30 mm before tert-butyl 2-bromoacetate (4.68 g, 23.99 mmol) was added dropwsie. After addition, the reaction mixture was stirred at -20 C
for 1.0 hour, then warmed to room temperature for 18 hours. The resulting mixture was cooled to 0 C, quenched 10 with aq. NaHCO3 (20 mL). The whole mixture was extracted with Et0Ac (30 mL x 4). The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Et0Ac/hexane= 1/20 to 1/4) to afford 75b (400 mg, 1.67 mmol, 6.97% yield).
LCMS: MS rah (ES!): 240.5 [M+Hr.
15 Step 2 Tert-butyl 3 -(4- (5-methyliso xazol-3 - y1)-2 ,5 -dio xo imidazolidin-4-yl)prop ano ate 75c To the solution of 75b (350 mg, 1.46 mmol) in H20 (5 mL) and Me0H (5 mL) was added (NH4)2CO3 (1.12 g, 11.70 mmol) and NaCN (176 mg, 3.66 mmol). The reaction was stirred at 85 C overnight. The mixture was concentrated and the residue was extracted with Et0Ac. The organic solution was dried and concentrated. The residue was slurred with Et20 to give 75c (180 mg, 581.93 umol, 39.78% yield).
LCMS: MS raiz (ES!): 332.1 1M+Nar.
Step 3 3 -(4 - (5-methyliso xazol-3 - y1)-2 ,5-dio xo imidazo lidin-4 - yl)propanoic acid 75d The mixture of 75c (30 mg, 96.99 umol) in HC1/1,4-dixoane (2 mL, 4N) was stirred at room temperature for lh. The mixture was oncentrated to give crude 75d (20 mg, 78.99 umol, 81.44%
yield).
LCMS: MS raiz (ES!): 254.0 1M+H1 .
Step 4 5 -(3 -(5 -chloro-6- (triflu oro methyl) iso indolin-2 - y1)-3 -o xoprop y1)-5 -(5 -methyli so xazol-3 -yl)imidazolidine-2,4-dione 75 To the solution of 5-chloro-6-(trifluoromethyl)isoindoline 40h (17.50 mg, 78.99 umol) in DMF
(2 mL) was added HATU (33 mg, 86.88 umol), Et3N (24 mg, 236.96 umol) and 75d (20 mg, 78.99 umol). The mixture was stirred at room temperature for lh. The reaction mixture was purified by prep-HPLC to give 75 (2.5 mg, 5.47 umol, 6.93% yield).
1H NMR (400 MHz, CDC13): 6 8.45 (br, 1H), 7.62 (br, 1H), 7.48 (br, 1H), 7.00 (br, 1H), 6.20 (brs, 1H), 4.80 (br, 4H), 2.60-2.45 (m, 4H), 2.42 (s, 3H).
LCMS: MS raiz (ES!): 457.0 1M+H1 .
Example 76 (S)-5 -c ycloprop y1-5 -(3 -(5 - (methylamino)-6-(trifluoromethyl) iso indolin-2 - y1)-3 -oxopropyl)imidazolidine-2,4-dione 76 N
HN' )r-NH 41fr CF3 76 NHMe Br Br Step 1 Step 2 1\1 NH __________________________ . N¨Boc _____ CF3= N¨Boc 59e 76a 76b H Ii Step 3 1\1 Step 4 NH ____ HN)i-NH CF3 76c 76 NHMe Step 1 Tert-butyl 5 -bromo-6-(trifluoromethyl)isoindoline-2-carboxylate 76a To a solution of 59e (920 mg, 3.46 mmol) in THF (20 mL) was added TEA (1.8 mL) and Boc20 (906 mg, 4.15 mmol). The mixture was stirred at room temperature for 4h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1/20) to afford 76a (810 mg, 2.21 mmol, 63.97% yield).
LCMS: MS raiz (ES!): 311.9 lIVI+H--tBur.
Step 2 Tert-butyl 5 -(methylamino)-6-(trifluoromethyl)isoindoline-2-carboxylate 76b To a solution of 76a (100 mg, 273.09 umol) in 1,4-dioxane (5 mL) was added MeNH2/THF
(1N in THF, 0.5 mL, 0.5 mmol), Pd2(dba)3 (25 mg, 27.31 umol), Cs2CO3 (267 mg, 819.28 umol) and XantPhos (32 mg, 54.62 umol). The reaction was stirred at 90 C in a sealed tube under N2 overnight. Water was added and the mixture was extracted with Et0Ac.
The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give 76b (45 mg, 142.26 umol, 52.09% yield).
11INMR (400 MHz, DMSO-d6): 6 7.38 (d, 1H), 6.69 (s, 1H), 5.59 (d, 1H), 4.56-4.52 (m, 2H), 4.48-4.45 (m, 2H), 2.75 (t, 3H), 1.45 (s, 9H).
LCMS: MS raiz (ES!): 358.1 lIVI+H+CH3C1\11 .

Step 3 N-methyl-6-(trifluoromethyl) iso indolin-5 -amine 76c The solution of 76b (45 mg, 142.26 umol) of HC1/1,4-dioxane (5 mL, 1N) was stirred at room temperature for 3h. The reaction mixture was concentrated in vacuo to give 76c (30 mg, 138.76 umol, 97.54% yield).
LCMS: MS nth (ES!): 217.1 1M+1-11 .
Step 4 (S)-5 -c ycloprop y1-5 -(3 -(5 -(methylamino)-6-(trifluoromethyl) iso indolin-2 -y1)-3 -oxopropyl)imidazolidine-2,4-dione 76 To a solution of 76c (30 mg, 138.76 umol) in DMF (2 mL) was successively added TEA (0.1 mL), It-1 (30 mg, 138.76 umol) and HATU (58 mg, 152.63 umol). The mixture was stirred at room temperature for 2h. Water was added and the mixture was extracted with Et0Ac. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by prep-HPLC to give 76 (10 mg, 24.37 umol, 17.56% yield).
1H NMR (400 MHz, DMSO-d6): 6 10.64 (s, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 6.72 (s, 1H), 5.61 (d, 1H), 4.76 (brs, 1H), 4.67 (brs, 1H), 4.59 (brs, 1H), 4.51 (brs, 1H), 2.77 (d, 3H), 2.44-2.21 (m, 2H), 2.05-1.96 (m, 2H), 1.14-1.09 (m, 1H), 0.50-0.29 (m, 3H), 0.16-0.12 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -61.20.
LCMS: MS nth (ES!): 411.2 1M+H1 .
Example 77 5 -(3 -(5-chloro-6-(trifluoromethyl) isoindo lin-2- y1)-3 -o xoprop y1)-5 -(1-methyl- 1H-p yrazol-3 -yl)imid azo lidine-2,4-dione 77 HN)r-NH CF3 isL) 0 CStep 1 / N Step 2 NN Ste C)(y<
0 _________________________________________ 0 FIN)r- NH

77a 77b 77c 0 N) Step 3 Step 4 OH NH FIN)rNH

77d 77 CI
Step 1 Tert-butyl 4-(1 -methyl- 1H-p yrazol-3 - y1)-4-o xobu tano ate 77b To the solution of 1-methyl-1H-pyrazole-3-carbaldehyde 77a(3.87 g, 35.11 mmol) in THF (10 mL) was added P(Bu)3 (5.4 g, 42.13 mmol), and the reaction mixture was heated at 50 C for 5min, tert-butyl prop-2-enoate (4.5 g, 35.11 mmol) was added and the mixture is stirred at 80 C
for 3h. More tert-butyl prop-2-enoate (4.5 g, 35.11 mmol) was added and this process was repeated until no elution is observerd by TLC. The mixture was purified by silica gel chromatagraphy (hexane/Et0Ac=10/1) to give 77b (1.2 g, 5.04 mmol, 14.34%
yield).
LCMS: MS raiz (ES!): 183.1 1M+1-tBur.
Step 2 Tert-butyl 3 -(4- (1 -methyl- 1H-p yrazol-3 - y1)-2,5-dioxoimid azo lidin-4 -yl)prop ano ate 77c To the solution of 77b (300 mg, 1.26 mmol) in H20 (2 mL) and Me0H (2 mL) was added NaCN (155 mg, 3.15 mmol) and (NH4)2CO3 (967 mg, 10.07 mmol). The reaction was stirred at 85 C overnight. LCMS showed the product produced. Water was added and the mixture was extracted with Et0Ac (10 mL x 2), the combined organic layers were concentrated to give crude 77c (100 mg, 324.33 umol, 25.76% yield).
111 NMR (400 MHz, DMSO-d6): 6 10.74 (s, 1H), 8.35 (s, 1H), 7.65 (d, 1H), 6.18 (d, 1H), 3.81 (s, 3H), 2.23-2.19 (m, 4H), 1.39 (s, 9H).
LCMS: MS raiz (ES!): 309.1 1M+Hr.
Step 3 3 -(4- (1 -methyl- 1H-p yrazol-3 - y1)-2,5 -dioxoimid azo lidin-4 -yl)prop anoic acid 77d The mixture of 77c (110 mg, 356.76 umol) in H0/1,4-dioxane (2 mL, 2N) was stirred at room temperature for lh. LCMS showed that the product formed. The mixture was concentrated to give 77d (100 mg, 396.47 umol, 111.13% yield).
LCMS: MS raiz (ES!): 253.1 [M+Hr.
Step 4 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y0-3-oxopropy1)-5-(1-methyl-1H-pyrazol-3-y1)imidazolidine-2,4-dione 77 To the solution of 40h (20 mg, 79.29 umol) in DMF (2 mL) was added HOBT (12.85 mg, 95.15 umol), EDCI (19 mg, 95.15 umol) and 77d (17.57 mg, 79.29 umol). The reaction was stirred atroom temperature overnight. LCMS showed that the product formed.
The mixture was purified by prep-HPLC to give 77 (0.88 mg, 1.93 umol, 2.43%
yield).
111 NMR (400 MHz, CDC13): 6 7.63-7.58 (m, 2H), 7.46-7.40 (m, 1H), 7.33 (d, 1H), 6.35-6.31 (m, 2H), 4.80-4.77 (m, 4H), 3.86 (s, 3H), 2.61-2.44 (m, 4H).
19F NMR (376.5 MHz, CDC13): 6 -62.45.
LCMS: MS raiz (ES!): 456.4 [M+Hr.
Example 78 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y0-3-oxopropy1)-5-(5-methyl-1H-pyrazol-3-y1)imidazolidine-2,4-dione 78 HNIN j 0 HN

Step 1 THPN \ Step 2 THPN I Step 3 THPY \ Step 4 THPN 0 ( N \ N

COOH COOH 0 \ 0 0 78a 78b 78c 78d 78e THPN 0 E iNj 0 HNNJ 0 Step 5 Step 6 Step 7 HN)r-NIH HN2r- 78g NH HN2r- 78 NH CF3 0 78f CI

Step 1 -methyl- 1 - (tetrahydro-2H-p yran-2- y1)- 1H-p yrazole-3 -carboxylic acid 78b To a solution of 5-methyl-1H-pyrazole-3-carboxylic acid 78a (1 g, 7.94 mmol) and 3,4-dihydro-2H-pyran (1.33 g, 15.88 mmol) in THF (20 mL) was added PTSA (71 mg, 0.4 mmol).
5 The resulting mixture was stirred at r.t for 18 h. The solution was concentrated, the residue was purified by silica gel column chromatography (eluting with DCM/Me0H = 50/1) to afford the tittle compound 78b (907 mg, 4.32 mmol, 54.41% yield).
111 NMR (400 MHz, CDC13): 6 6.63 (s, 1H), 5.37 (d, 1H), 4.04-4.01 (m, 1H), 3.69-3.63 (m, 1H), 2.50-2.41 (m, 1H), 2.38 (s, 3H), 2.14-2.11 (m, 1H), 2.01-1.98 (m, 1H), 1.75-1.55 (m, 4H).
Step 2 N-methoxy-N,5 -dimethyl- 1 - (tetrahydro -2H-p yran- 2 - y1)- 1H-p yrazo le-3 -carboxamide 78c To a solution of 78b (907 mg, 4.32 mmol) in DCM (15 mL) was added TEA (2.1 mL, 15.12 mmol), the solution was cooled to 0 C. Then HOBt (642 mg, 4.75 mmol) and EDCI
(1 g, 5.18 mmol) were added, the reaction mixture was stirred at 0 C for 30min. N,0-dimethylhydroxylamine hydrochloride (505 mg, 5.18 mmol) was added. The reaction was stirred at r.t for 18h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL x 2), the organic solution was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 1/1) to afford the tittle compound 78c (810 mg, 3.2 mmol, 74.11% yield).
Step 3 1-(5 -methyl- 1 - (tetrahydro-2H-p yran-2- y1)- 1H-p yrazol-3 - yl)ethan- 1 -one 78d To a solution of 78c (810 mg, 3.2 mmol) in THF (15 mL) was added MeMgC1 (3N, 3.2 mL, 9.6 mmmol). The reaction mixture was stirred at 0 C for 1 h. The reaction was quenched with aqueous NH4C1 (20 mL), extracted with Et0Ac (20 mL x 2), the organic solution was washed with brine, dried over anhydrous Na2SO4 and concentrated, the residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 4/1) to afford the tittle compound 78d (450 mg, 2.16 mmol, 67.5% yield).

111 NMR (400 MHz, CDC13): 6 6.54 (d, 1H), 5.34 (dd, 1H), 4.04-4.00 (m, 1H), 3.70-3.64 (m, 1H), 2.56 (s, 3H), 2.52-1.45 (m, 1H), 2.36 (s, 3H), 2.18-2.12 (m, 1H), 2.01-1.96 (m, 1H), 1.75-1.61 (m, 3H).
Step 4 Tert-butyl 4-(5 -methyl- 1 - (tetrahydro-2H-p yran-2-y1)- 1H-p yrazol-3 - y1)-4-o xobu tano ate 78e To a solution of 78d (200 mg, 0.96 mmol) in THF (3 mL) was added NaHMDS (2 N, 0.55 mL, 1.1 mmoL) dropwise at -78 C. After lh, tert-butyl bromoacetate (0.146 mL, 1 mmoL) was added to the solution dropwise. The reaction was stirred at r.t for 18h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL x 2). The combined organic layeres were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with hexane/Et0Ac =
10/1) to afford the tittle compound 78e (180 mg, 0.87 mmol, 90.58% yield).
111 NMR (400 MHz, CDC13): 6 6.55 (s, 1H), 5.34 (dd, 1H), 4.02-3.99 (m, 1H), 3.69-3.63 (m, 1H), 3.38-3.22 (m, 2H), 2.67-2.56 (m, 2H), 2.51-2.44 (m, 1H), 2.35 (s, 3H), 2.19-2.14 (m, 1H), 1.99-1.95 (m, 1H), 1.73-1.65 (m, 3H), 1.43 (s, 9H).
Step 5 Tert-butyl 3 -(4 - (5-methyl- 1 - (tetrahydro-2H-p yran-2- y1)- 1H-p yrazol-3 -y1)-2,5 -dioxoimid azo lidin-4 -yl)prop ano ate 78f To a solution of 78e (2 g, 6.21 mmol) in Et0H (30 mL) and water (30 mL) was added (NH4)2CO3 (4.77 g, 49.69 mmol) and NaCN (760.73 mg, 15.53 mmol). The reaction was done in sealed tube and stirred at 90 C for 18h. The mixture was poured to water (100 mL) and extracted with Et0Ac (50 mL x 3), the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with hexane to afford the tittle compound 78f (2.2 g, 5.61 mmol, 90.37% yield).
LCMS: MS m/z (ES!): 393.2 1M+Hr.
Step 6 3 -(4-(5 -methyl-1H-p yrazol-3 - y1)-2,5 -dioxoimid azolidin-4 -yl)prop anoic acid 78g A solution of 78f (500 mg, 1.28 mmol) in H0/1,4-dioxane (4N, 10 mL) was stirred at r.t for 18h. The solution was concentrated to afford the tittle compound 78g (350 g, 1.21 mmol, 94.53%
yield).
111 NMR (400 MHz, DMSO-d6): 6 10.82 (s, 1H), 8.42 (s, 1H), 6.04 (s, 1H), 2.25-2.18 (m, 7H).
Step 7 5 -(3 -(5-chloro-6-(trifluoromethyl) isoindo lin-2- y1)-3 -o xoprop y1)-5 -(5-methyl- 1H-p yrazol-3 -yl)imid azo lidine-2,4-dione 78 To a solution of 78g (50 mg, 0.17 mmol) in DMF (5 mL) was added TEA (0.12 mL, 0.85 mmol) and 5-chloro-6-(trifluoromethyl)isoindoline 40h (44 mg, 0.17 mmol), then HATU
(65 mg, 0.17 mmol) was added. The reaction was stirred at r.t for 2h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the tittle compound 78 (18 mg, 0.04 mmol, 23.53% yield).
111 NMR (400 MHz, DMSO-d6): 6 12.50 (brs, 1H), 10.71 (brs, 1H), 8.35 (s, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 5.96 (s, 1H), 4.81 (d, 2H), 4.67 (d, 2H), 2.50-2.29 (m, 4H), 2.20 (s, 3H).
LCMS: MS raiz (ES!): 456.1 [M+Hr.
Example 79 5 -(3 -(5-chloro -6-(trifluoromethyl) isoindolin-2- yl) -3 -oxoprop y1)-5 -(p yrimidin-2-yl)imid azo lidine-2,4-dione 79 NN o HN)rNH CI

0 NN N A\I 0 Step 1 Step 2 0 HN/NH
(:)<

79a 79b 79c (m N A\I 0 0 Step 3 0 Step 4 OH ___ HN )r-NH
HN/NH CI

79d 79 Step 1 Tert-butyl 4-oxo-4-(pyrimidin-2-yl)butanoate 79b To the solution of 1-(pyrimidin-2-yl)ethan- 1-one 79a (3 g, 24.57 mmol) in THF
(100 mL) was added DMPU (4.15 g, 32.43 mmol) and LiHMDS (5.39 g, 29.48 mmol) at 0 C, the reaction was stirred at this temperature for 30 min. Then tert-butyl 2-bromoacetate (4.79 g, 24.57 mmol) was added at 0 C, and the reaction was stirred for 3h. The reaction mixture was quenched by water and concentrated. The residue was purified by silica gel chromatography (Et0Ac/hexane = 1/20) to give 79b (500 mg, 8.61% yield).
LCMS: MS rah (ES!): 237.1 [M+Hr.
Step 2 Tert-butyl 3 -(2,5 -dioxo-4 -(p yrimidin-2 - yl)imid azolidin-4 - yl)prop ano ate 79c To the solution of 79b (100 mg, 423.25 umol) in H20 (1 mL) and Me0H (1 mL) was added NaCN (56.12 mg, 1.06 mmol) and (NH4)2CO3 (325.06 mg, 3.39 mmol). The reaction was stirred at 85 C overnight. The mixture was concentrated and extracted with Et0Ac. The organic solution was dried and concentrated; the residue was slurred with Et20 to give crude 79c (25 mg, 19.28% yield) for next step as is.
LCMS: MS rah (ES!): 305.0 [M-Ht.
Step 3 3 -(2,5-dioxo-4-(pyrimidin-2- yl)imidazolidin-4- yl)propanoic acid 79d The solution of 79c (25 mg, 81.62 umol) in 4N HO/dixoane (2 mL) was stirred at room temperature for lh. LCMS showed that the product was produced and the mixture was concentrated to give 79d (16 mg, 78.35% yield) for next step as it is.
LCMS: MS raiz (ES!): 251.0 [M+Hr.
Step 4 5 -(3 - (5-chloro -6- (trifluoromethyl) isoindolin-2- y1)-3 -oxoprop y1)-5 -(p yrimidin-2-yl)imidazolidine-2,4-dione 79 To the solution of 79d (16 mg, 0.0634 mmol) in THF (5 mL) was added HATU
(231.63 mg, 609.19 umol), DIEA (62.38 mg, 487.35 umol) and 5-chloro-6-(trifluoromethyl)isoindoline 40h (14 mg, 0.063 mmol). The reaction was stirred at room temperature overnight.
The mixture was concentrated and the residue was purified by prep-HPLC to give 79 (2.13 mg, yield 7.34%).
1H NMR (400 MHz, CDC13): 6 8.80 (brs, 1H), 8.79 (brs, 1H), 8.15 (brs, 1H), 7.60 (d, 1H), 7.60 (d, 1H), 7.32 (br, 1H), 6.46 (brs, 1H), 4.84-4.75 (m, 4H), 2.85-2.78 (m, 2H), 2.56 (br, 2H).
LCMS: MS raiz (ES!): 454.1 [M+Hr.
Example 80 (S)-5 -cyc loprop y1-5 - (3 -(5 ,6-dichloro isoindo lin-2- yl- 1,1,3,3 -d4)-3 -o xoprop yl) imidazolidine-2,4-dione 80 0 \7' D D
HN (s)NH

CI

V
0).L
OH
0 (S)NH
D D HN D D
CI CI
HN Bal/THF, 60 jc HNJC

0 epInt-1 HNNH
CI then HCI, 80C CI 0 0 D D st 2 CI
Step1 20b 80a 80 CI
Step 1 ,6 -dichloro isoindoline- 1,1 ,3 ,3 -c/4 80a To a solution of 4,5-dichlorophthalimide 20b (500 mg, 2.3 mmol) in THF (15 mL) was added BD3¨tetrahydrofuran (1M, 20 mL) dropwise under N2. The resulting mixture was stirred at 60 C for 24h. The reaction mixture was cooled to ambient temperature and quenched with 5 Me0H (6 ml) until the bubbling ceased. Then 4N HC1 in water (20 ml) was added and the mixture was heated at 80 C for 1 h. After cooled down to room temperature and 5N KOH was added to adjust pH to 7. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel column (DCM: Me0H(2%NH4OH) = 10: 1) to afford 5,6-dichloroisoindoline-1,1,3,3-d480a (300 mg, 70% yield).
Step 2 (S)-5 -cycloprop y1-5 - (3 - (5 ,6 -dichloro isoindo lin-2- yl- 1,1,3 ,3 -d4)-3-oxoprop yl)imid azolidine-2,4-dione 80 To a mixture of 5,6-dichloroisoindoline-1,1,3,3-d4 80a (35 mg, 0.19 mmol) in DMF (4 mL) was added triethylamine (72 mg, 0.56 mmol), It-1 (40 mg, 0.16mmol) and HATU
(98.8 mg, 0.23 mmol). The reaction was stirred at r.t for 18h. Water (5 mL) was added and the mixture was extracted with Et0Ac (40 mL x 3). The combined layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give the title compound (30 mg, 40 % yield).
111 NMR (400 MHz, Methanol-d4): 6 7.54 (d, 2H), 2.56 (ddd, 2H), 2.32-2.13 (m, 2H), 1.34-1.19 (m, 1H), 0.60 (td, 2H), 0.53-0.30 (m, 2H).
LCMS: MS m/z (ES!): 386 [M+Hr.
Example 81 5 -(3 -(5 -chloro-6- (triflu oro methyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 -(2-methylo xazol-4 -yl)imidazolidine-2,4-dione 81 ro No HNyNH CF3 0 COOH Step \ /
1 Nr...N) µN-0 Step Step 3 81a 81b 81c 81d Step 4 0 (:),< Step 5, Step 6 HN HN)r-HN N H NH 1,(NH CF3 81e 81f CI
Step 1 N-methoxy-N,2-dimethylo xazole-4-c arbo xamide 81b To a solution of 2-methyloxazole-4-carboxylic acid 81a (500 mg, 3.94 mmol) in DCM (15 mL) was added TEA (1.9 mL, 13.79 mmol), the solution was cooled to 0 C. Then HOBt (585 mg, 4.33 mmol) and EDCI (906 mg, 4.73 mmol) were added. The reaction mixture was stirred at 0 C for 30min. N,O-Dimethylhydroxylamine hydrochloride (460 mg, 4.73 mmol) was added.
The reaction was stirred at r.t for 18h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 1/1) to afford the tittle compound 81b (600 mg, 3.53 mmol, 89.58% yield).
111 NMR (400 MHz, CDC13): 6 8.07 (s, 1H), 3.74 (s, 3H), 3.37 (s, 3H), 2.51 (s, 3H).
Step 2 1 -(2 -methylo xazol-4- yl)ethan- 1 -one 81c To a solution of 81b (200 mg, 1.18 mmol) in THF (20 mL) was added MeMgC1 (3N, 1.18 mL, 3.52 mmmol). The reaction mixture was stirred at 0 C for 1 h. The reaction was diluted with aqueue NH4C1 (30 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 4/1) to afford the tittle compound 81c (100 mg, 0.59 mmol, 49.86% yield).
111 NMR (400 MHz, CDC13): 6 8.10 (s, 1H), 2.51 (s, 6H).
Step 3 Tert-butyl 4-(2-methyloxazol-4-y1)-4-oxobutanoate 81d To a solution of 81c (1.25 g, 10 mmol) in THF (100 mL) was added dropwise NaHMDS (2 N, 5.5 mL,11 mmoL) at -78 C. After lh, tert-Butyl bromoacetate (1.46 mL, 10 mmoL) was added to the solution dropwise. The reaction was stirred at r.t for 18h. Water (200 mL) was added and the mixture was extracted with Et0Ac (100 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 10/1) to afford the tittle compound 81d (680 mg, 2.85 mmol, 28.45% yield).
Step 4 Tert-butyl 3 - (4- (2-methylo xazol-4- y1)-2,5 -dioxoimidazolidin-4- yl)prop ano ate 81e To a solution of 81d (700 mg, 2.93 mmol) in Et0H (10 mL) and water (10 mL) was added (NH4)2CO3 (2.25 g, 23.43 mmol) and NaCN (359 mg, 7.33 mmol). The reaction was sealed in a vessel and stirred at 90 C for 18h. The mixture was poured to Water (100 mL) and extracted with Et0Ac (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by reversed phase column chromatography to afford the tittle compound 81e (180 mg, 0.58 mmol, 19.88%
yield).
LCMS: MS mh (ES!): 254.5 [M-tBu+Hr.
Step 5 3 -(4- (2-methylo xazol-4- y1)-2 ,5 -dioxoimid azo lidin-4 - yflprop anoic acid 81f A solution of 81e (60 mg, 0.19 mmol) in H0/1,4-dioxane (4N, 4 mL) was stirred at r.t for 4h.
The solution was concentrated to afford the tittle compound 81f (55 mg, 0.19 mmol, 100%
yield).
Step 6 5 -(3 -(5 -chloro-6- (triflu oro methyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 -(2-methylo xazol-4 -yl)imidazolidine-2,4-dione 81 To a solution of 81f (55 mg, 0.19 mmol) in DMF (5 mL) was added TEA (0.12 mL, 0.85 mmol) and 5-chloro-6-(trifluoromethyl)isoindoline 40h (44 mg, 0.17 mmol), then HATU
(65 mg, 0.17 mmol) was added. The reaction was stirred at r.t for 2h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the tittle compound 81 (20 mg, 0.044 mmol, 23.08% yield).
111 NMR (400 MHz, DMSO-d6): M0.88 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.90 (d, 3.2 Hz, 1H), 7.76 (d, 1H), 4.84 (d, 2H), 4.68 (d, 2H), 2.39 (s, 3H), 2.36-2.23 (m, 4H).
LCMS: MS raiz (ES!): 457.1 [1\4+Hr Example 82 5-(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(1-ethy1-1H-imidazol-2-yl)imidazolidine-2,4-dione 82 HN)r-NH CF3 CI
/=\

Step 1 N(yjHro Step 2 CHO HNyNH

82a 82b 0 82c /=\ /=\
N N
n NN,/ o 0 Step 3 OH __ Step 4 HNy-NH
HN)rNH 44I CF3 82d 82 CI
Step 1 Tert-butyl 4-(1-ethy1-1H-imidazol-2-y1)-4-oxobutanoate 82b To a solution of 1-ethyl-1H-imidazole-2-carbaldehyde 82a (500 mg, 4.03 mmol) in THE (6 mL) was added tributylphosphine (0.82 mL, 3.843 mmol), the solution was stirred at 50 C for 5min. Then tert-butyl acrylate (468 mg, 3.66 mmol) was added. The reaction was stirred at 80 C
for 18h. The solution was concentrated. The residue was purified by silica gel chromatography (eluting with hexane/Et0Ac = 10/1) to afford the tittle compound 82b (84 mg, 0.33 mmol, 8.27%
yield).

1H NMR (400 MHz, CDC13): V.14 (d, 1H), 7.08 (d, 1H), 4.43 (q, 2H), 3.41 (t, 2H), 2.63 (t, 2H), 1.43 (s, 9H), 1.41 (t, 3H).
Step 2 Tert-butyl 3 -(4 -(1-ethy1-1H-imidazol-2 -y1)-2 ,5 -dioxo imidazolidin-4-yflprop ano ate 82c To a solution of 82b (1.7 g, 6.66 mmol) in Et0H (30 mL) and water (30 mL) was added (NH4)2CO3 (5.12 g, 53.3 mmol) and NaCN (816 mg, 16.66 mmol). The reaction was sealed in a vessel and stirred at 90 C for 18h. The mixture was poured to water (100 mL) and extracted with 1-butanol (50 mL x 8). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash reversed phase column chromatography to .. afford the tittle compound 82c (220 mg, 0.68 mmol, 10.26% yield).
LCMS: MS m/z (ES!): 323.5 [M+Hr.
Step 3 3 -(4 -(1-ethyl- 1H-imidazol-2 -y1)-2,5 -dio xo imidazolidin-4- yflprop ano ic acid 82d A solution of 82c (50 mg, 0.16 mmol) in H0/1,4-dioxane (4N, 4 mL) was stirred at r.t for 4h.
.. The solution was concentrated to afford the tittle compound 82d (45 mg, 0.16 mmol, 100%
yield), which was used directly for next step reaction.
Step 4 5 -(3 -(5 -chloro-6-(triflu oro methyl) iso indolin-2 - y1)-3 -oxoprop y1)-5 -(1 -ethyl- 1H-imid azol-2-yl)imidazolidine-2,4-dione 82 To a solution of 82d (45 mg, 0.16 mmol) in DMF (5 mL) was added TEA (0.09 mL, 0.85 mmol) and 5-chloro-6-(trifluoromethyl)isoindoline 40h (32 mg, 0.12 mmol), then HOBt (22 mg, 0.16 mmol) and EDCI (31 mg, 0.16 mmol) were added. The reaction was stirred at r.t for 18h. The mixture was purified by prep-HPLC to afford the tittle compound 82 (2.8 mg, 0.006 mmol, 3.75% yield).
.. 1H NMR (400 MHz, Methanol-d4): 6 7.78 (d, 1H), 7.67 (s, 1H), 7.62 (d, 1H), 7.46 (s, 1H), 4.93-4.90 (m, 2H), 4.79-4.77 (m, 4H), 4.43 (q, 2H), 2.81-2.60 (m, 4H), 1.53 (t, 7.2 Hz, 3H).
LCMS: MS m/z (ES!): 470.1 [M+Hr.

Examples 83-1 & 83-2 (S)-5 -(3 -(5-chloro -6-(trifluoromethyl) isoindo lin-2-y1)-3 -o xoprop y1)-5 -(thiazol-2-yl)imidazolidine-2,4-dione 83-1 &
(R)-5 -(3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2-y1)-3 -o xoprop y1)-5 -(thiazol-2 -yl)imidazolidine-2,4-dione 83-2 /-=\
Nr¨\, N S 0 00r? ssS;jL N
MI 1 um (R) 2.rNH 11, CF3 NH CF3 J1,0H Step 1 SFC
*
HN HN4tNH (s) (R) N
HN, _NH
CF3 )r-NH c3 CF3 43d 83 CI 83-1 CI 83-2 CI
Step 1 (S)-5 -(3 -(5-chloro -6-(trifluoromethyl) isoindo lin-2-y1)-3 -o xoprop y1)-5 -(thiazol-2-yl)imidazolidine-2,4-dione 83-1 & (R)-5-(3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2- y1)-3 -oxoprop y1)-5 -(thiazol-2- yl) imidazolidine-2 ,4 -dio ne 83-2 A mixture of 43d (102 mg, 400 umol), 40h (103 mg, 400 umol), HATU (152 mg, 400 umol) and Et3N (161 mg, 1.60 mmol) in DMF (4 mL) was stirred at room temperature for 18 hours.
Then the reaction mixture was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10 um OBD 19*250 mm, Mobile Phase A: 0.1% NH4OH in water, Mobile Phase B: CH3CN, Flow: 20 mL/min, Column temp: RT) to afford racemic mixture 83 (60 mg), which was separated by SFC to afford two enantiomers (18 mg, 39.23 umol, 9.82%
yield, and 20 mg, 43.59 umol, 10.9% yield, separately).
enantiomer with shorter retention time:
1H NMR (400 MHz, DMSO-d6): 6 11.10 (br, 1H), 8.83 (br, 1H), 7.91-7.85 (m, 2H), 7.81-7.74 (m, 2H), 4.83-4.78 (m, 2H), 4.69-4.66 (m, 2H), 2.44-2.33 (m, 4H).
HPLC: 99.985% @ 254 nm, 99.985% @ 214 nm.
Chiral HPLC ((CO2/Et0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): Rt:
2.119 min, cc: 100%.

LCMS: MS m/z (ES!): 459.0 [IVI+HIt enantiomer with longer retention time:
111 NMR (400 MHz, DMSO-d6): 6 11.10 (br, 1H), 8.83 (br, 1H), 7.91-7.85 (m, 2H), 7.81-7.74 (m, 2H), 4.83-4.78 (m, 2H), 4.69-4.66 (m, 2H), 2.44-2.33 (m, 4H).
HPLC: 99.078% @ 254 nm, 99.403% @ 214 nm.
Chiral HPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): Rt:
5.782 min;
ee: 100%.
LCMS: MS m/z (ES!): 459.0 [M+Hr.
Examples 84-1 and 84-2 (R)-5 -(3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione 84-1 (S)-5 -(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione 84-2 HN
m rNH CF3 y NH CF3 04:1N1 0 0 CNC' 0 HN
HN -NH ,IrNH afr CF3- HN)r-NI-1 CF3 HN)r-NI-1 CF3 60d 84 CI 84-1 CI 84-2 CI
Step 1 (R)-5 -(3-(5-chloro-6-(trifluoromethyflisoindolin-2-y1)-3-oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione 84-1 & (S)-5 -(3-(5-chloro-6-(trifluoromethyl)isoindolin-2-y1)-3 -oxopropy1)-5-(pyridin-2-yl)imidazolidine-2,4-dione 84-2 A mixture of 60d (114 mg, 399 umol), 40h (78 mg, 302 umol), HATU (152 mg, 399 umol), TEA (162 mg, 1.60 mmol) and DMF (4.0 mL) was stirred at room temperature for 18 hours.
The reaction mixture was purified by Prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10 urn OBD 19*250 mm, Mobile Phase A: 0.1% NH4OH in water, Mobile Phase B:

CH3CN, Flow: 20 mL/min, Column temp: RT) to afford racemic mixture 84 (60 mg), which was separated by SFC to afford two enantiomers (15 mg, 33.13 umol, 8.30%
yield, and 15 mg, 33.13 umol, 8.30% yield).
enantiomer with shorter retention time:
111 NMR (400 MHz, DMSO-d6): 6 10.87 (brs, 1H), 8.62 (dd, 1H), 8.51 (s, 1H), 7.91-7.84 (m, 2H), 7.76 (d, 1H), 7.54 (d, 1H), 7.41-7.37 (m, 1H), 4.83-4.80 (m, 2H), 4.69-4.66 (m, 2H), 2.51-2.41 (m, 2H), 2.36-2.30 (m, 2H).
LCMS: MS m/z (ES!): 453.0 1M+H1 .
Chrial HPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): RT, 1.852;
Purity: 100%.
enantiomer with longer retention time:
111 NMR (400 MHz, DMSO-d6): 6 10.88 (brs, 1H), 8.62 (dd, 1H), 8.53 (s, 1H), 7.91-7.85 (m, 2H), 7.76 (d, 1H), 7.54 (d, 1H), 7.41-7.37 (m, 1H), 4.83-4.80 (m, 2H), 4.69-4.66 (m, 2H), 2.51-2.44 (m, 2H), 2.36-2.30 (m, 2H).
LCMS: MS m/z (ES!): 453.1 1M+H1 .
Chrial HPLC (CO2/Et0H/DEA 60/40/0.04 1.8m1/min IG,3um,3*100(Daicel)): RT, 2.713;
Purity: 99.32%.
Examples 85-1 and 85-2 (R)-5 -(3-(5 -chloro -6-(trifluoromethyl) iso indolin-2 -y1)-3 -oxoprop y1)-5 -(p yrazin-2-yl)imidazolidine-2 ,4-dione 85-1 & (S)-5 -(3 -(5 -chloro-6-(trifluoro methyl) isoindo lin-2- y1)-3 -o xoprop y1)-5 -(p yrazin-2-yl)imidazolidine-2,4-dione 85-2 (R) N
HN HN
410 CI 2(-NH 410 CI

Step 1 Step 2 Step 3 k 0 0 OH
N
N
N N

85a 85b 85c 85d Step 4 HN SFC )r- HN)r HN
NH )r.-NH 0 CI -NH CI 1100 CI

Step 1 tert-butyl 4-oxo-4-(thiazol-2-yffbutanoate 85b To a solution of 1-(pyrazin-2-yl)ethan-1-one 85a (12.0 g, 98.3 mmol) in THF
(200 mL) at -70 C
was added NaHMDs (49.2 mL, 98.3 mmol, 2.0 M in THF) dropwise. The resulting mxiture was stirred at this temperature for 30 mm before tert-butyl 2-bromoacetate (19.2 g, 98.3 mmol) was added drop-wsie. After addition, the reaction mixture was stirred at -20 C
for 1.0 hour, then warmed to room temperature and stirred for 18 hours. The resulting mixture was cooled to 0 C, then quenched with aq. NaHCO3 (200 mL). The mixture was extracted with Et0Ac (300 mL x 4). The organic layers were combined, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Et0Ac/hexane = 1/20 to 1/4) to afford 85b (13.5 g, 57.14 mmol, 58.2% yield).
LCMS: MS rah (ES!): 237.1[1\4+Hr.
Step 2 tert-butyl 3 - (2 ,5 -dioxo-4- (p yrazin-2- yl)imidazolidin-4-yl)propanoate 85c A mixture of 85b (13.0 g, 55.0 mmol), (NH4)2CO3 (44.9 g, 468 mmol) and NaCN
(11.7 g, 220 mmol) in Et0H (60 mL) and H20 (60 mL) was heated to 120 C in an autocalve and stirred for 18 hours. The resulting mixture was diluted with water (100 mL). The mixture was extracted with Et0Ac (200 mL x 3) and n-BuOH (200 mL x 3). The combined organic layers were washed with brine (200 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Me0H/DCM = 1/100 to 1/30) to afford 85c (3.0 g, 9.79 mmol, 17.80% yield).
LCMS: MS rah (ES!): 307.1[1\4+Hr.

Step 3 3 -(2,5 -dio xo -4-(p yrazin-2 - yl)imidazo lidin-4 - yl)prop ano ic acid 85d To a solution of 85c (900 mg, 2.94 mmol) in DCM (30 mL) was added HC1/1,4-dioxane (30 mL, 4.0 M) drop wise. The reaction mixture was stirred room temperature for 18 hours. The resulting mixture was filtered in vacuum. The filter cake was collected, dried in vacuum to afford 85d (600 mg, 2.40 mmol, 81.62% yield).
LCMS: MS nth (ES!): 249.01M-H1-.
Step 4 (R)-5 -(3-(5 -chloro -6-(trifluoromethyl) iso indolin-2 -y1)-3 -oxoprop y1)-5 -(p yrazin-2-yl)imidazolidine-2,4-dione 85-1 & (S)-5 -(3 -(5 -chloro-6-(trifluoro methyl) isoindo lin-2- y1)-3 -o xoprop y1)-5 -(p yrazin-2-yl)imidazolidine-2,4-dione 85-2 A mixture of 85d (130 mg, 519.56 umol), 40h (134 mg, 519.56 umol), TEA (157.72 mg, 1.56 mmol) and HATU (198 mg, 519.56 umol) in DMF (5 mL) was stirred at room temperature for 18 hours. The resulting mixture was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10 um OBD 19*250 mm, Mobile Phase A: 0.1% NH4OH in water, Mobile Phase B: CH3CN, Flow: 20 mL/min, Column temp: RT) to afford racemic mixture 85 (about 50 mg), which was further separated by SFC to afford two enantiomers (16 mg, 35.26 umol, 6.79%
yield, and 15 mg, 33.05 umol, 6.36% yield).
enantiomer with shorter retention time:
111 NMR (400 MHz, DMSO-d6): 6 11.05 (brs, 1H), 8.83 (d, 1H), 8.73-8.71 (m, 1H), 8.67 (d, 1H), 8.65 (br, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 4.84-4.80 (m, 2H), 4.69-4.65 (m, 2H), 2.49-2.46 (m, 2H), 2.37-2.33 (m, 2H).
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 2.8m1/min AY,5um,4.6*250(Daicel)): Rt:
2.652min, cc: 100%.
LCMS: MS nth (ES!): 454.1 1M+H1t enantiomer with longer retention time:

111 NMR (400 MHz, DMSO-d6): 6 11.01 (br, 1H), 8.82 (d, 1H), 8.72-8.70 (m, 1H), 8.67 (d, 1H), 8.57 (brs, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 4.84-4.80 (m, 2H), 4.69-4.65 (m, 2H), 2.49-2.46 (m, 2H), 2.37-2.33 (m, 2H).
Chiral HPLC (CO2/Me0H/DEA 60/40/0.04 2.8m1/min AY,5um,4.6*250(Daicel)): Rt:
4.485;
ee: 99.43%.
LCMS: MS raiz (ES!): 454.1 [M+Hr.
Examples 86-1, 86-2, 86-3 and 86-4 (S)-5 -((S)-3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2-34)-2-(hydroxymethyl)-3 -oxoprop y1)-5 -cyc loprop ylimid azo lidine-2,4-dione 86-1 &
(S)-54(R)-3 -(5-chloro-6-(triflu oromethyl) isoindo lin-2-34)-2-(hydroxymethyl)-3 -o xoprop y1)--cyc loprop ylimid azo lidine-2,4-dione 86-2 &
(R)-5 -((S)-3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2- y1)-2-(hydroxymethyl)-3 -oxoprop y1)-5 -cyc loprop ylimid azo lidine-2,4-dione 86-3 &
(R)-5 -((R)-3 -(5-chloro-6-(triflu oro methyl) isoindo lin-2-34)-2-(hydroxymethyl)-3 -o xoprop y1)--c yc loprop ylimidazolidine-2 ,4 -dio ne 86-4 o0 rNH 411 CI y-NH

)7OH
HN NH CI HN)r,NH ,-o V. o 7.
HNL
so NH - N HNILL
. CI rNH 0 I/ CI
.Ayyt 0 0 OH N
Step 1 Step 2 r cõ CF3 86b-1 86b-2 40 0 cõ
_ N 04, 0 t65e 86a HNI 1 HN2r NH NH -,,o II CI 0 . CI

86b-3 86h-4 ck.2:.....,_ .J.LV.
HN/ 7 7 " =

,---(-)LN
step 3 HI\li.....XILN Step 4 N
2rNH --,0 . CI HN - r,..NH __ . CI
HN'..H.........tit' 2r-NH -.,0H = CI 0 27.-NH
OH * CI
so cõ=so CF3 86b-1 86-1 86b-2 86-2 cD__. C1/4 k y so r 'N
HN1 1 Step 5 HN .' Step 6 N NH 7,0 ii cõ
HNIH CI _,.. 1 )r-NH _,.. HNI iNH's. OH t crN ,...OH * CI 0 e0 ii CI * 1 86h-4 86-3 86h-4 86-4 Step 1 2-((benzyloxy)methyl)-1-(5-chloro-6-(trifluoromethyl)isoindolin-2-34)-4-cyclopropylbutane-1,4-dione 86a To a solution of 2-((benzyloxy)methyl)-4-cyclopropy1-4-oxobutanoic acid 65e (350 mg, 1.33 mmol) and 5-chloro-6-(trifluoromethyl)isoindoline 40h (310 mg, 1.20 mmol) in DMF (10 mL) was added TEA (675 mg, 6.67 mmol) and HATU (609 mg, 1.60 mmol). The reaction was stirred at r.t for 2h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL X 2), The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 86a (400 mg, 858.57 umol, 64.34% yield).
LCMS: rah (ES!): 466.1 [M+Hr.
Step 2 Four isomers of 5-(2-((benzyloxy)methyl)-3-(5-chloro-6-(trifluoromethyl)isoindolin-2-34)-3 -oxopropy1)-5-cyclopropylimidazolidine-2,4-dione 86b To a solution of 86a (600 mg, 1.29 mmol) in Et0H (20 mL) was added ammonium carbonate (991 mg, 10.32 mmol), NaCN (158 mg, 3.23 mmol) and water (20 mL). The reaction was stirred at 90 C for 18h. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash reversed phase column chromatography to give 86b (370 mg), which was further seperated by SFC to give four isomers (127 mg, 118 mg, 55 mg and 48 mg).
isomers 1 (1st peak from SFC):
1H NMR (400 MHz, DMSO-d6): 6 10.66 (s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.25-7.22 (m, 5H), 5.01-4.62 (m, 4H), 4.44 (s, 2H), 3.54-3.43 (m, 2H), 2.96-2.90 (m, 1H), 2.28-2.21 (m, 1H), 1.84-1.81 (m, 1H), 1.06-1.00 (m, 1H), 0.42-0.23 (m, 3H), 0.02-0.01 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.88.
Chiral HPLC: Rt: 3.12 min, cc: 100%.
LCMS: miz (ES!): 536.1 lIVI+Hr.
isomers 2 (2nd peak from SFC):
1H NMR (400 MHz, DMSO-d6): 6 10.66 (s, 1H), 7.91 (d, 1H), 7.77 (d, 1H), 7.71 (d, 1H), 7.25-7.22 (m, 5H), 5.01-4.62 (m, 4H), 4.44 (s, 2H), 3.54-3.43 (m, 2H), 2.96-2.90 (m, 1H), 2.29-2.21 (m, 1H), 1.85-1.81 (m, 1H), 1.06-1.00 (m, 1H), 0.42-0.23 (m, 3H), 0.03-0.01 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.87.
Chiral HPLC: Rt: 3.34 min, cc: 100%.
LCMS: miz (ES!): 536.1 lIVI+Hr.
isomers 3 (3th peak from SFC):
1H NMR (400 MHz, DMSO-d6): 6 10.52 (s, 1H), 7.91 (s, 1H), 7.77-7.75 (s, 2H), 7.25-7.20 (m, 5H), 5.00-4.54 (m, 4H), 4.44 (s, 2H), 3.55-3.47 (m, 2H), 3.16-3.09 (m, 1H), 2.31-2.25 (m, 1H), 1.73-1.70 (m, 1H), 1.06-1.01 (m, 1H), 0.43-0.26 (m, 3H), 0.13-0.06 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.85.
Chiral HPLC: Rt: 4.25 min, cc: 100%.

LCMS: rniz (ES!): 536.1 [1\4+Hr.
isomers 4 (4th peak from SFC):
1H NMR (400 MHz, DMSO-d6): 6 10.52 (s, 1H), 7.91 (s, 1H), 7.77-7.75 (m, 2H), 7.25-7.20 (m, 5H), 5.00-4.54 (m, 4H), 4.44 (s, 2H), 3.55-3.47 (m, 2H), 3.16-3.09 (m, 1H), 2.31-2.25 (m, 1H), 1.73-1.70 (m, 1H), 1.06-1.01 (m, 1H), 0.43-0.26 (m, 3H), 0.13-0.06 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.85 nm.
Chiral HPLC: Rt: 4.60 min, ee: 98.76%.
LCMS: rniz (ES!): 536.1 11\4+Hr.
Step 3 (S)-5 -((S)-3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2- y1)-2-(hydroxymethyl)-3 -oxoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4 -dio ne 86-1 To a solution of isomers 1 from step 2 (120 mg, 0.22 mmol) in Et0Ac (60 mL) was added PdC12 (60 mg). Then the reaction was stirred at room temperature under H2 atmosphere for 2h.
The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash reversed phase column chromatography to give the compound 86-1(74 mg, 74.75%).
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 5.04-4.97 (m, 2H), 4.89-4.83 (m, 1H), 4.77-4.60 (m, 2H), 3.51-3.36 (m, 2H), 2.77-2.70 (m, 1H), 2.20-2.13 (m, 1H), 1.80-1.74 (m, 1H), 1.05-0.98 (m, 1H), 0.42-0.22 (m, 3H), 0.04--0.029 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.84 nm.
Chiral HPLC: Rt: 3.29 min, cc: 100%.
LCMS: rn/z (ES!): 446.1 11\4+Hr.
Step 4 (S)-54(R)-3 -(5-chloro-6-(triflu oromethyl) isoindo lin-2- y1)-2-(hydroxymethyl)-3 -o xoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4 -dio ne 86-2 To a solution of isomers 2 from step 2 (110 mg, 0.21 mmol) in Et0Ac (50 mL) was added PdC12 (50 mg). Then the reaction was stirred at room temperature under H2 atmosphere for 2h.
The mixture was filtered and the filtrate was concentrated. The residue was purified by flash reversed phase column chromatography to give the compound 86-2(65 mg, 71.04%).
1H NMR (400 MHz, DMSO-d6): 6 10.63 (s, 1H), 7.90(d, 1H), 7.77 (s, 1H), 7.66 d, 1H), 5.04-4.97 (m, 2H), 4.89-4.82 (m, 1H), 4.77-4.60 (m, 2H), 3.51-3.36 (m, 2H), 2.76-2.70 (m, 1H), 2.20-2.13 (m, 1H), 1.80-1.75 (m, 1H), 1.05-0.98 (m, 1H), 0.43-0.23 (m, 3H), 0.04--0.031 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.84 nm.
Chiral HPLC: Rt: 4.66 min, cc: 100%.
LCMS: raiz (ES!): 446.1 11\4+Hr.
Step 5 (R)-5 -((S)-3 -(5 -chloro-6-(trifluoromethyl) isoindo lin-2- y1)-2-(hydroxymethyl)-3 -oxoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4 -dio ne 86-3 To a solution of isomers 3 from step 2 (50 mg, 0.093 mmol) in Et0Ac (25 mL) was added PdC12 (25 mg). Then the reaction was stirred at room temperature under H2 atmosphere for 2h, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash reversed phase column chromatography to give the compound 86-3(37 mg, 89.16%).
1H NMR (400 MHz, DMSO-d6): 6 10.50 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 5.04-4.97 (m, 2H), 4.87-4.80 (m, 1H), 4.74-4.67 (m, 1H), 4.60-4.53 (m, 1H), 3.51-3.34 (m, 2H), 2.96-2.89 (m, 1H), 2.25-2.19 (m, 1H), 1.67-1.63 (m, 1H), 1.07-1.00 (m, 1H), 0.43-0.25 (m, 3H), 0.11-0.05 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.84.
Chiral HPLC: Rt: 5.73 min, cc: 97.83%.
LCMS: raiz (ES!): 446.1 11\4+Hr.
Step 5 (R)-5 -((R)-3 -(5-chloro-6-(triflu oro methyl) isoindo lin-2- y1)-2-(hydroxymethyl)-3 -o xoprop y1)-5 -c yc loprop ylimidazolidine-2 ,4 -dio ne 86-4 To a solution of isomers 4 from step 2 (45 mg, 0.084 mmol) in Et0Ac (25 mL) was added PdC12 (25 mg). Then the reaction was stirred atroom temperature under H2 atmosphere for 2h, the mixture was filtered and the filtrate was concentrated. The residue was purified by flash reversed phase column chromatography to give the compound 86-4(37 mg, 89.16%).
1H NMR (400 MHz, DMSO-d6): 6 10.50 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 5.05-4.97 (m, 2H), 4.87-4.81 (m, 1H), 4.75-4.68 (m, 1H), 4.60-4.53 (m, 1H), 3.51-3.40 (m, 2H), 2.96-2.89 (m, 1H), 2.25-2.20 (m, 1H), 1.67-1.63 (m, 1H), 1.07-1.00 (m, 1H), 0.43-0.24 (m, 3H), 0.11-0.05 (m, 1H).
19F NMR (376.5 MHz, DMSO-d6): 6 -60.83.
Chiral HPLC: Rt: 7.07 mm, cc: 97.16%.
LCMS: raiz (ESI): 446.1 1M+1-11 .
The following compounds were prepared using the similar methods as Examples 1-86.
Ex# Structure and chemical name 1H NMR and mass spectra 10 oV 1H NMR (400 MHz, CD30D): 6 7.25-7.23 HN/ N = 0HCF2 (m, 1H), 7.04-7.01 (m, 1H), 7.02-6.98 (m, N H

1H), 4.77-4.73 (m, 2H), 4.65-4.62 (m, 2 H), (S)-5 -c ycloprop y1-5 -(3-(5 - 2.46-2.41 (m, 2H), 2.37-2.33 (m, 1H), 2.14-(difluoromethoxy)isoindolin-2- 2.10 (m, 2H), 1.17-1.15 (m, 1H), 0.50-0.47 y1)-3 -o xoprop yl) imidazolidine- (m, 1H), 0.34-0.30 (m, 2H), 0.27-0.22 (m, 2,4-dione 1H).
LC-MS: MS m/z (ESI): 1M+Hr. 380.2 11 0 V 0 1H NMR (400 MHz, CD30D): 6 7.22-1.16 HNL
(m, 4H), 4.78-4.73 (m, 2H), 4.67-4.62 (m, 2 NH
0 11 H), 2.46-2.44 (m, 1H), 2.37-2.34 (m, 1 H), (S)-5 -c yc loprop y1-5 -(3 - 2.14-2.10 (m, 2H), 1.16-1.12 (m, 1H), 0.51-(isoindolin-2-y1)-3- 0.47 (m, 1H), 0.34-0.30 (m, 2H), 0.27-0.23 oxopropyl)imidazolidine-2,4- (m, 1H).
dione LC-MS: MS m/z (ESI): 1M+H1 . 314.2 12 1H NMR (400 MHz, CD30D): 6 8.41-8.37 (m, 1H), 7.81-7.78 (m, 1H), 7.34-7.31 (m, \
o 12 1H), 4.72-4.68 (m, 2H), 3.57-3.55 (m, 2 H), (S)-5-cyclopropy1-5-(3 -(5,7- 2.46-2.42 (m, 1H), 2.36-2.34 (m, 1H), 2.14-dihydro-6H-pyrro1o[3,4- 2.12 (m, 2H), 1.16-1.14 (m, 1H), 0.50-0.47 b]pyridin-6-y1)-3- (m, 1H), 0.33-0.30 (m, 2H), 0.27-0.23 (m, oxopropyl)imidazolidine-2,4- 1H).
dione LC-MS: MS m/z (ESI): [M+Hr. 315.2 13 a V (D.L 1H NMR (400 MHz, CD30D): 6 8.74-8.72 HN/ q/
2r-NH 13 / (m, 1H), 8.67-8.63 (m, 1H), 7.90-7.87 (m, 1H), 5.04-5.01 (m, 2H), 4.88-4.85 (m, 2 H), (S)-5-cyclopropy1-5-(3 -(1,3- 2.47-2.45 (m, 1H), 2.39-2.35 (m, 1 H), 2.18-dihydro-2H-pyrro1o[3,4- 2.11 (m, 2H), 1.15-1.13 (m, 1H), 0.50-0.48 c]pyridin-2-y1)-3- (m, 1H), 0.33-0.30 (m, 2H), 0.27-0.23 (m, oxopropyl)imidazolidine-2,4- 1H).
dione LC-MS: MS m/z (ESI): [M+Hr. 315.2 14 o V 1H NMR (400 MHz, CD30D): 6 7.36-7.28 HN H LN
)7,-N
= (m, 4H), 5.28 (q, 1H), 4.89-4.84 (m, 2H), o 14 2.57-2.43 (m, 2H), 2.25-2.22 (m, 2H), 1.50 (S)-5-cyclopropy1-5-(3 -((R)-1- (d, 3H), 1.40-1.37 (m, 2H), 1.28-1.26 (m, methylisoindolin-2-y1)-3- 1H), 0.50-0.48 (m, 1H), 0.34-0.32 (m, 2 H), oxopropyl)imidazolidine-2,4- 0.27-0.23 (m, 1H).
dione LC-MS: MS m/z (ESI): [M+Hr. 328.2 15 0 V 0 1H NMR (400 MHz, CD30D): 6 7.35-7.28 =-=-:-.(0=\)LN
HN
)r-NH 410k (m, 4H), 5.28 (q, 1H), 4.89-4.85 (m, 2H), o 15 2.57-2.43 (m, 2H), 2.25-2.21 (m, 2H), 1.50 (S)-5-cyclopropy1-5-(3 -((S)-1- (d, 3H), 1.39-1.34 (m, 2H), 1.28-1.22 (m, methylisoindolin-2-y1)-3- 1H), 0.50-0.44 (m, 1H), 0.34-0.30 (m, 2 H), oxopropyl)imidazolidine-2,4- 0.27-0.23 (m, 1H).
dione LC-MS: MS m/z (ESI): [M+Hr. 328.2

16 o y 0 1H NMR (400 MHz, CD30D): 6 7.25-7.22 HNN
NH (m, 1H), 7.08-7.06 (m, 1H), 6.96-6.92 (m, y.
O 16 1H), 4.85-4.81 (m, 2H), 4.69-4.66 (m, 2 H), (S)-5 -c yc loprop y1-5 -(3 -(4- 2.47-2.42 (m, 1H), 2.36-2.34 (m, 1H), 2.12-fluoroisoindolin-2-y1)-3- 2.09 (m, 2H), 1.17-1.14 (m, 1H), 0.50-00.47 oxopropyllimidazolidine-2,4- (m, 1H), 0.33-0.31 (m, 2H), 0.27-0.23 (m, dione 1H).
LC-MS: MS m/z (ESI): 1M+Hr. 332.2

17 o V 1H NMR (400 MHz, CD30D): 6 7.38 ¨7.27 FdNN
)r-NH = F (m, 1H), 7.16 ¨ 6.96 (m, 2H), 4.72 (d, 2H), 3.37 (s, 2H), 2.60 ¨2.54 (m, 1H), 2.48 ¨ 2.42 (S)-5-cyclopropy1-543 (m, 1H), 2.33 ¨ 2.11 (m, 2H), 1.25 (tt, 1H), fluoroisoindolin-2-y1)-3- 0.69 ¨ 0.53 (m, 1H), 0.53 ¨ 0.37 (m, 2H), oxopropyllimidazolidine-2,4- 0.37 ¨ 0.23 (m, 1H).
dione LC-MS: MS m/z (ESI): 1M+Hr. 332.2

18 0 V 0 1H NMR(400 MHz, CD30D): 7.34-7.30 (m, HN
2H), 7.20-7.17 (m, 2H), 5.50 (d, 1 H), 5.32 L
),r-NH (d, 1H), 2.46-2.02 (m, 6H), 1.42-1.30 (m, 0 18 2H), 1.19-1.16 (m, 1H), 0.54-0.51 (m, 1H), (SS)-5 -cycloprop y1-5 -(3 -o xo -3- 0.44-0.27 (m, 3H).
(1,2,3,4 -tetrahydro- 1,4 - LC-MS: MS m/z (ESI): 1M+Hr. 340.2;
epiminonaphthalen-9-yl)propyllimidazolidine-2,4-dione

19 0 V 1H NMR (400 MHz, CD30D) 6 7.27 (dt, )r-NH F 2H), 4.85 (s, 2H), 4.72 (s, 2H), 2.58-2.53 (m, 0 19 1H), 2.45 ¨ 2.41 (m, 1H), 2.29 ¨ 2.18 (m, (S)-5-cyclopropy1-543 2H), 1.32 ¨ 1.18 (m, 1H), 0.64 ¨0.58 (m, difluoroisoindolin-2-y1)-3- 1H), 0.52 ¨ 0.23 (m, 3H).
oxopropyllimidazolidine-2,4- LC-MS: MS m/z (ESI): 1M+H1t 350.2 dione 21 0 V 1H NMR (500 MHz, DMSO-d6) 6 10.07 (br, HNtNH 21 CI 1H), 7.74 (d, 1H), 7.14-7.06 (m, 3H), 3.56-3.33 (m, 4H), 3.12-3.03 (m, 1H), 2.98-2.70 (S)-5-(3 -((R)-8-chloro -1 -methyl-(m, 2H), 2.41-2.12 (m, 2H), 1.83-1.72 (m, 1,2,4,5 -tetrahydro-3H-b enzold] azep y1)-3 oxopropy1)-5- 2H), 1.11 (m, 3H), 0.98-0.96 (m, 1H), 0.40-cyclopropylimidazolidine-2,4- 0.20 (m, 3H), 0.05--0.06 (m, 1H).
dione LCMS: MS m/z (ESI): 390.1 [M+Hr.
22 o Mixture of two diastereomers 1H NMR (400 MHz, CD30D): 7.08-6.98 (m, 0 1H), 6.90-6.70 (m, 2H), 3.66-3.58 (m, 2H), Mixture of two diastereomers 3.48-3.35 (m, 2H), 3.18-3.11 (m, 1 H), 3.04-(5 S)-5 -cycloprop y1-5 -(3 -(8- 2.94 (m, 1H), 2.87-2.73 (m, 1H), 2.41-2.18 flu oro -1-methyl- 1,2,4,5 - (m, 2H), 1.98-1.85 (m, 2H), 1.37-1.28 (m, tetrahydro-3H-benzo [d] azep in-3 - 3H), 1.11-1.02 (m, 1H), 0.48-0.42 (m, 1H), y1)-3-oxopropyflimidazolidine-0.38-0.15 (m, 3H).
2,4-dione MS m/z (ESI): [M+Hr. 374.2 23 o V 1H NMR (400 MHz, CD30D): 7.18-7.16 (m, HN CI 1H), 7.01-6.99 (m, 2H), 3.63-3.58 (m, 2H), o 23 3.16-3.14 (m, 1H), 3.10-3.07 (m, 1 H), 2.98-(S)-5 -(3 -(7-chloro-1,2 ,4,5 - 2.94 (m, 1H), 2.91-2.87 (m, 1H), 2.39-2.36 tetrahydro-3H-benzo [d] azep in-3 - (m, 1H), 2.29-2.26 (m, 1H), 1.97-1.90 (m, y1)-3-oxopropy1)-5- 2H), 1.10-1.06 (m, 2H), 0.46-0.44 (m, 1H), cyclopropylimidazolidine-2,4- 0.33-0.18 (m, 4H).
dione LC-MS: MS m/z (ESI): [M+Hr. 376.2 MS m/z (ESI): [M+Hr. 344.2 HN2r- 24NH OMe (S)-5-cyclopropy1-5-(3 -(5-methoxyisoindolin-2-y1)-3-oxopropyflimidazolidine-2,4-dione OMe 1H NMR (400 MHz, CD30D): 6 7.29-7.25 HNrNH 25 irk (m, 1H), 7.0-6.89 (m, 2H), 3.62-3.58 (m, 2H), 3.67 (s, 3H), 3.16-3.14 (m, 1H), 3.10-(S)-5-cyclopropy1-5-(3 -(6-3.08 (m, 1H), 2.98-2.96 (m, 1H), 2.90-2.88 metho xy- 1,2 ,4,5 -tetrahydro-3 H -(m, 1H), 2.38-2.35 (m, 1H), 2.28-2.25 (m, benzo[d]azepin-3-y1)-3-oxopropyl)imidazolidine-2,4- 1H), 1.95-1.91 (m, 2H), 1.10-1.05 (m, 2H), dione 0.45-0.42 (m, 1H), 0.33-0.18 (m, 4H).
LC-MS: MS m/z (ESI): [M+Hr. 372.2 26 0., V lic) 1H NMR (400 MHz, CD30D) 6 7.40 (t, 1H), 7.21 (dt, 1H), 7.15 ¨ 7.02 (m, 2H), 3.81 -H
\_- 26 0 3.70 (m, 3H), 3.15 (dt, 2H), 2.60 ¨ 2.49 (m, (S)-5-cyclopropy1-5-(3-(1,1- 1H), 2.49 ¨ 2.35 (m, 1H), 2.24 ¨ 2.03 (m, dimethy1-1,2,4,5-tetrahydro-3H- 3H), 1.44 ¨ 1.27 (m, 6H), 1.27 ¨ 1.12 (m, benzo[d1azepin-3-y1)-3- 1H), 0.65 ¨ 0.57 (m, 1H), 0.49 ¨ 0.21 (m, oxopropyl)imidazolidine-2,4- 3H).
dione LC-MS: MS m/z (ESI): [M+Hr. 370.2 27&28 o V 3 1H NMR (500 MHz, DMSO-d6) 6 10.61 (d, HN NH F 1H), 7.72 (d, 1H), 7.16 (td, 1H), 6.98 ¨
6.92 r 27 (m, 2H), 3.68 ¨ 3.49 (m, 2H), 3.23 ¨2.74 (S)- 5 -cyclopropy1-5-(3-((R)-8- (m, 4H), 2.41-2.36 (m, 1H), 2.27-2.20 (m, fluoro-1-methyl-1,2,4,5- 1H), 1.95-1.90 (m, 2H), 1.21 (dd, 4H), 1.09 tetrahydro-3H-benzo[d]azepin-3- _ 1.01 (m, 1H), 0.94 ¨0.80 (m, 1H), 0.47 ¨
y1)-3-oxopropyl)imidazolidine- 0.28 (m, 2H), 0.09 (dd, 1H).
2,4-dione Enantiomer 1 with shorter retention o _IV time: HPLC: 99.560% @ 214 nm N
yNH F
Chiral HPLC: Rt: 13.049 min, ee: 92.3%.

LC-MS: MS m/z (ESI): [M+Hr. 374.2 (S)-5 -cyclopropy1-5-(3-((S)-8-Enantiomer 2 with longer retention time fluoro-l-methyl-1,2,4,5-HPLC: 100.000% @ 214 nm tetrahydro-3H-benzo[d]azepin-3-Chiral HPLC: Rt: 13.070 min, cc: 89.4%.
y1)-3-oxopropyl)imidazolidine-LC-MS: MS m/z (ESI): [M+Hr. 374.2 2,4-dione 39 o y 0 1H NMR (400 MHz, CD30D) 6 7.78 ¨ 7.64 HNLN
OM 1H), 7.36 (t, 1H), 4.91 (s, 2H), 4.80 (d, rNH CF3 39 2H), 2.57 (m, 1H), 2.45 (m, 1H), 2.24 (m, (S)-5 -cyclopropy1-5-(3-(5-fluoro- 2H), 1.26 (m, 1H), 0.68 ¨0.52 (m, 1H), 6-(trifluoromethyl)isoindolin-2- 0.54 ¨ 0.28 (m, 3H).
19F NMR (376.5 MHz, CD30D) 6 -77.44, -62.82 y1)-3-oxopropyflimidazolidine- LCMS: MS m/z (ESI): 400.0 1M+Hl+
2,4-dione 46 o 1H NMR (400 MHz, CD30D): 6 7.67 (s, NH N 4. CI 1H), 7.51 (s, 1H), 2.49-2.42 (m, 1H), 2.36-D D

2.30 (m, 1H), 2.18-2.06 (m, 2H), 1.30-1.10 (S)-5-(3-(5-chloro-6- (m, 1H), 0.52-0.47 (m, 1H), 0.39-0.24 (m, (trifluoromethyl)isoindolin-2-yl- 3H).
1,1,3,3-d4)-3-oxopropy1)-5-LC-MS: MS m/z (ESI): 1M+Hr. 420.2 cyclopropylimidazolidine-2,4-dione 47 o V._ 1 1H NMR (400 MHz, CD30D): 6 7.36 (s, Hkr-13) N CI 1H), 6.89 (s, 1H), 4.83 (s, 2H), 2.41-2.33 (m, )r-NH

4H), 2.29-2.21 (m, 1H), 2.09-1.99 (m, 2H), (S)-5-cyclopropy1-5-(3-(5',6'-1.13-1.08 (m, 1H), 0.81-0.78 (m, 2H), 0.50-dich1orospirolcyc1opropane-1,1'-0.44 (m, 1H), 0.37-0.31 (m, 3H).
isoindolin1-2'-y1)-3-LC-MS: MS m/z (ESI): 1M+Hl+ 408.1.
oxopropyl)imidazolidine-2,4-dione The following compounds can be prepared using the similar methods as Examples 1-86.
Structure O
HN)r-NH CF3 Dv HNNH
OMe CF3 t HNN

2r-NH
0 V. o F
N
rNH

IL F
HN
)r..NH
=

HN.L
rNH = CHF2 CI
N-N

HNrNH CF3 CI
BIOLOGICAL ASSAYS
The present disclosure will be further described with reference to the following test examples, but the examples should not be considered as limiting the scope of the disclosure.
Test Example 1. In vitro fluorescence assay of ADAMTS-4 or ADAMTS-5 activity A FRET (fluorescence resonance energy transfer) peptide was cleaved by recombinant ADAMTS-4 or ADAMTS-5 proteins into two separate fragments resulting in an increase of fluorescence signal which was quantified. The peptide was 5-FAM-TEGEARGSVILLK(5-TAMRA)K-NH2, customized from ANASPEC. ADAMTS-4 recombinant protein (catalog #
4307-AD) and ADAMTS-5 recombinant protein (catalog # 2198-AD) were purchased from R&D Systems.
An assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM CaCl2, 0.1%
CHAPS and 5 % Glycerol was prepared. A volume of 2.5 jai of compound in the assay buffer was dispensed to a 384-well plate, and 2.5 jai of ADAMTS-4 or ADAMTS-5 protein (final concentration in the reaction was 10 nM) was added. The compounds and proteins were pre-incubated at room temperature for 15 minutes. Then, 5 jai of substrate was added to each well.
The final substrate concentrations for ADAMTS-4 and ADAMTS-5 were 15 iaM and 8 iaM, respectively. The fluorescence signal in each well was determined, after incubation at 37 C for 3 hours, on a TECAN plate reader (Excitation, 490 nm; Emission, 520 nm).
Data Analysis:
The data was inputted into GraphPad Prism, and the IC5() values were calculated using function "log (inhibitor) vs. response -- Variable slope (four parameters)".
(See Table 1) Table 1. The IC50 values of the exemplified compounds in FRET-peptide enzymatic assays.
Example No. ADAMTS-4 (IC50, ADAMTS-5 nM) (IC50, nM)

20 22 37

21 20 16

22 51 61 compound with shorter retention time 8 9 in 29-1 and 29-2 compound with longer retention time 12 9 in 30-1 and 30-2 compound with shorter retention time 12 7.1 in 32 and 33 compound with longer retention time 3 7 in 34-2-A and 34-2-B

compound with longer retention time 52 98 in 37-1 and 37-2 compound with shorter retention time 8 12 in 37-1 and 37-2 compound with longer retention time 330 110 in 38-1 and 38-2 compound with shorter retention time 120 42 in 38-1 and 38-2 compound with shorter retention time 50 27 in 41-1 and 41-2 compound with shorter retention time 10 11 in 49-2a and 49-2b compound with longer retention time 44 38 in 62-1 and 62-2 compound with longer retention time 280 280 in 64-1 and 64-2 compound with a retention time of 21 37 4.729 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with a retention time of 170 250 5.284 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with a retention time of 93 104 6.442 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with a retention time of 7 5 5.970 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with shorter retention time 24 18 in 69-1 and 69-2 compound with shorter retention time 18 31 in 71-1 and 71-2 compound with longer retention time 4300 4900 in 71-1 and 71-2 compound with shorter retention time 54 25 in 73-1 and 73-2 compound with longer retention time 61 34 in 83-1 and 83-2 compound with longer retention time 74 32 in 84-1 and 84-2 compound with longer retention time 100 39 in 85-1 and 85-2 compound with shortest retention time 16 15 in 86-1, 86-2, 86-3 and 86-4 Conclusion: The compounds of the present disclosure have a significant inhibition effect on the enzymatic activity of ADAMTS-4 and ADAMTS-5.
Test Example 2. In vitro ELISA (enzyme-linked immunosorbent assay) of ADAMTS-5 activity In this assay, the enzymatic activity of recombinant ADAMTS-5 protein (catalog #
2198-AD, R&D Systems) was assayed with a protein substrate, the aggrecan IGD
protein. The aggrecan IGD protein is a polypeptide connecting human aggrecan globular domains 1 and 2 (T331 ¨ G458) expressed in E. Coli with a C-terminal His-tag (catalog#
30411000, BIOTEZ).
The enzymatic product ARGSVIL-peptide was detected using an ELISA kit from BioTEZ
(catalog# 30510111).
An assay buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM CaCl2, 0.1%
CHAPS and 5 % Glycerol was prepared. Recombinant ADAMTS-5 protein was diluted to 0.3 nM in the assay buffer. Ten jai of buffer and 10 jai of compound solution was transferred to each well of a 96-well plate and incubated at room temperature for 15 minutes.
Substrate aggrecan-IGD was diluted to 100 nM with the assay buffer and 20 jai was added to each well.
The plate was incubated at 37 C for 45 minutes. After incubation, the newly generated epitope ARGSVIL-peptides were measured using the Aggrecanase Activity ELISA Assay Kit following the manufacturer's instructions. Then, 100 jai of stop solution was added and the absorbance of each well was read at 450 nM, using 620 nM as reference on a TECAN plate reader.
Data Analysis:
A standard curve of the ELISA assay was generated in GraphPad Prism using Sigmoidal 4PL function and the corresponding peptide concentrations were calculataed based on the standard curve. The IC50 values were calculated using function "log (inhibitor) vs.
response -- Variable slope (four parameters)". (See Table 2).
Table 2. The IC50 values of the exemplified compounds from the Aggrecan-IGD
enzymatic assay.
Example No. ADAMTS-5 (IC50, nM) compound with shorter retention time in 29-1 and 29-2 compound with shorter retention time in 32 and 33 compound with longer retention time in 34-2-A and 34-2-B

compound with longer retention time in 38-1 and 38-2 compound with shorter retention time in 38-1 and 38-2 compound with shorter retention time in 41-1 and 41-2 compound with shorter retention time in 49-2a and 49-2b compound with longer retention time in 62-1 and 62-2 compound with a retention time of 4.729 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with a retention time of 6.442 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with a retention time of 5.970 mm in 67-1, 67-2, 68-1 and 68-2 (Me0H/DEA 5%_40% 1.5ml/min IA, 3um 3.0*100(Daicel) compound with shorter retention time in 69-1 and 69-2 compound with shorter retention time in 71-1 and 71-2 compound with shorter retention time in 73-1 and 73-2 compound with longer retention time in 84-1 and 84-2 compound with longer retention time in 85-1 and 85-2 Conclusion: The compounds of the present disclosure have a significant inhibition effect on the enzymatic activity of ADAMTS-5.

Test Example 3. Mouse Explant Assay In this assay, fresh mouse femoral head cartilage was treated with IL-la protein (Sigma-Aldrich, catalog# 12778) in culture media, which induces the cartilage catabolism. Then, the GAGs attached to the cleaved aggrecan fragments (released in the media) and the GAGs 10 attached to the intact aggrecan were measured by dimethylmethylene blue dye in the Glycosaminoglycans Assay Kit (Chondrex, catalog# 6022).
Femoral head cartilage samples were isolated from mice (25 days old, male, C57BL/6, from Charles River Lab) and put into 2.0 ml tubes filled-up with media (DMEM, 10% FBS, 4 mM Glutamine, penicillin-streptomycin, 20 mM HEPES). Two hundred pl of media without 15 FBS was added to each well of a 48-well plate, and one piece of cartilage was transferred to a well in the plate. Then the media was aspirated, and compounds and IL-la protein were added to the plate in a total volume of 400 pl of fresh media without FBS. The final concentration of IL-la was 1 ng/ml. The plate was incubated at 37 C for 72 hours in a humidified incubator with 5% CO2 supply.
20 The supernatant was transferred to a 1.5 ml tube and kept at -20 C. Each cartilage sample was tranferred to another 1.5 ml tube containing 400 plof freshly made papain solution.
The papain solution contained 125 pg/ml papain (Sigma-Aldrich, catalog#
P3125), 0.1 M
sodium acetate (Sigma-Aldrich, catalog# S7899), pH 5.5 and 5 mM EDTA and 5 mM
L-cysteine-HC1 (Sigma-Aldrich, catalog# C7880). The cartilage samples were kept rocking in a 25 60 C water bath for 24 hours.
The lysates were vortexed for 10 seconds and spinned at 10,000 rpm for 2 minutes.
Both the supernatant and the lysate samples were diluted with PBS and mixed with 100 pl of dye from the Glycosaminoglycans Assay Kit. The optical density from each well was determined with a TECAN plate reader set to a wavelength of 525 nm.
30 Data Analysis:
The concentrations of GAGs in the supernatant and lysates were determined based on the standard curve with a dose range of chondroitin sulfate provided in the kit. The percentage [GAG]supernatant of GAG release was calculated as the following: GAG% =( [GAG]supernatant + [GAG]lysate) x 100%.
The test compound effect was expressed as the percent of inhibition using the following formula:
Inhibition ____________________ % =(1h GAG%(Compound+ILla)¨ GAG%(Vehicle)) x 100%
GAG%(Vehicle+IL1c)¨ GAG%(Vehicle) The inhibition data of selected exemplified compounds at 2 iaM and 20 iaM
concentrations were listed in Table 3.
Table 3. The IC50 values of the exemplified compounds from the mouse explant assay.
Example No. Inhibition % at 2 It M Inhibition % at 20 P. M

compound with shorter retention time in 29-1 and 29-2 compound with shorter retention time in 32 and 33 compound with longer retention time in 34-2-A and 34-2-B

compound with shorter retention time in 41-1 and 41-2 compound with longer retention time in 62-1 and 62-2 compound with shorter retention time in 69-1 and 69-2 compound with shorter retention time in 71-1 and 71-2 compound with shorter retention time in 73-1 and 73-2 The foregoing embodiments and examples are provided for illustration only and are not intended to limit the scope of the disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on the present disclosure, and such changes and modifications may be made without departure from the spirit and scope of the present disclosure. All literature cited are incorporated herein by reference in their entireties without admission of them as prior art.

Claims (25)

PCT/US2021/016364What is claimed is:

1. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R2a R2b R4a 0 R4b 0 Ri HN R3b \\G2 0 R5a R5b G4¨G3 ( I ) wherein:
G1, G2, G3 and G4 are each identical or different, and each is independently N
or CR6, provided that no more than two of them are N;
R1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, hydroxyalkyl, SO2R11a, NRllaRllb, C(=0)0Rila, C(=0)NRilaR1113, NHC(=o)Rlla, NHC(=0)0R1la, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2a, R213, R3a and x -.-s3b are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with .. one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, NR12aRl2b, C(=0)ORl2a, C(=0)NR12aRl2b, NHC(=o)R12a, NHC(=0)01V2a, OR12a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R2a, R3a and R3b together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
R4a, R413, R5a and x -.-s5b are each identical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R3, 4a, ¨41R5a and R5b together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R13a, SO2NR13aRl3b, NR13aRl3b, C(=0)0R13a, C(=0)NR13aRl3b, NHC(=o)R13a, NHC(=0)0R13a, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2Rl4a, SO2NR14aRl4b, NR14aRl4b, C(=0)0R14a, C(=0)NR14aRl4b, NHC(=o)R14a, NHC(=0)0R14a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Rlla, Rl2a, Rl3a, and Rl4a are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, alkoxy, alkyl, aryl and cycloalkyl;
R11b, R12b, R13b, R14b are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl and alkoxy;
n is 1 or 2; and m is 1 or 2.

2. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
G1, G2, G3 and G4 are each identical or different, and each is independently N
or CR6, provided that no more than two of them are N;
R1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, hydroxyalkyl, SO2R11a, NR1laR1 lb, C(=0)0R1la, C(=0)NR1laR1113, NHC(=o)R1 NHC(=0)0R1la, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2a, R213, R3a and x -.-s3b are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, NR12aRl2b, C(=0)ORl2a, C(=0)NR12aRl2b, NHC(=o)R12a, NHC(=0)ORl2a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R2a, R3a and R36 together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
R4a, R4b, R5a and x -.-s5b are each identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two of R4a, R5a and R5b together with the carbon atom to which they are attached form cycloalkyl or heterocyclyl;
each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, so2R13a, so2NR13aR1313, NR13aRl3b, C(=0)ORl3a, C(=0)NR13aRl3b, NHC(=o)R13a, NHC(=0)01V3a, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, SO2R14a, SO2NR14aRl4b, NR14aRl4b, C(=O)ORl4a, C(=0)NR14aRl4b, NHC(=o)R14a, NHC(=0)0R14a, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Rlla, Rl2a, Rl3a, and R14a are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, alkoxy, alkyl and cycloalkyl;
Rllb, Rl2b, R131, Rl4b are each independently selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl and alkoxy;
n is 1 or 2; and m is 1 or 2.

3. The compound of claim 1 or 2, having a structure of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R2a R2b R4a 0 R4b 0.4 HN R3b1, R3a \\G2 R5a R5b G4¨G3 11 ) wherein G1, G2, G3, G4, R1, R2a to R5a, R2b tO R5b, n and m are each as defined in claim 1 or 2.

4. The compound of any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein G1 and G2 are each identical or different, and each is independently N or CR6; and G3 and G4 are each CR6; wherein R6 is as defined in claims 1 to 3.

5. The compound of any one of claims 1 to 4, having a structure of formula (III) or (Ina), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

R2a R2b R4a 0 R4b R2a R2b R4a 0 R1 R4b HN eio 6\
R3b (R61 17 R3b 0 R5a R5b 0 R5a R 5b ( ) ( IIIa ) wherein:
s is 0, 1 or 2; and R1, R2a to R5a, R26 to R5b, R6, n and m are each as defined in claims 1 to 4.

6. The compound of any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Ri is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl and heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of alkyl and alkoxy; preferably Ri is selected from the group consisting of C1-6 alkyl, 3 to 8-member cycloalkyl and 5 to 10-member heteroaryl, wherein the C1-6 alkyl, 3 to 8-member cycloalkyl and 5 to 10-member heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of C1-6 alkyl and Ci_6 alkoxy.

7. The compound of any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Ri is cycloalkyl or heteroaryl, optionally substituted by alkyl;
preferably Ri is cycloalkyl, more preferably cyclopropyl.

8. The compound of any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2a and R2b are both hydrogen.

9. The compound of any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a structure of formula (IV) or (IVa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

R4a R4a 0 R4b R4b 0 0 cl 0 N
HN HN
R3b R6 )r¨NH R3b R6 0 R5a R5b 0 R5 a R5b ( IV ) ( IVa ) wherein:
R4a, R5a, R3b to R5b, n and m are each as defined in claim 1 to 8.

10. The compound of any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3a and R3b are identical or different, and each is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and hydroxyalkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and alkoxy; preferably, R3a and R3b are identical or different, and each is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 hydroxyalkyl, wherein the C1-6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1_6 alkoxy.

11. The compound of any one of claims 1 and 3 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R4a, R41), R5a and R5b are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1_6 alkyl; or R5a and R5b together with the carbon atom to which they are attached form 3 to 8-member cycloalkyl, R4a and R4b are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1-6 alkyl; or R4a and tc together with the carbon atom to which they are attached form 3 to 8-member cycloalkyl, R5a and R5b are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and C1-6 alkyl.

12. The compound of any one of claims 1 and 3 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R4a, R413, R5a and R5b are each dentical or different, and each is independently selected from the group consisting of hydrogen, deuterium, halogen and alkyl; preferably R4a, K-413, R5a and R5b are each dentical or different, and each is independently selected from the group consisting of hydrogen, halogen and alkyl.

13. The compound of any one of claims 1 to 4, 6 to 8, and 10 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically k4a R4b acceptable salt, solvate or prodrug thereof, wherein R5a R5b G4G3 is selected from the Raa R4b R4a R4b (R6), s s R5a R5a 5b N
5b group consisting of R
R4a R4a R4a N (R6)s N
R5a , and R5a ; preferably R5a or R4a *(N
(R6)s R5a =
s is 0, 1 or 2; and R4a, R4b, R5 a, R5b and K-rs 6 are as defined in claims 1 to 4, 6 to 8, and 10 to 12.

14. The compound of any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a structure of formula (V) , or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
R4a 0 Ri 0 HN
R3b 11 R6 R5a ( V ) wherein:
Ri is selected from the group consisting of cycloalkyl and heteroaryl, wherein the cycloalkyl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy and hydroxyalkyl; and R313, K R5a and R6 are each as defined in claim 1 to 13.

15. The compound of any one of claims 1 to 14, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and C(=0)0R13a; R13a is as defined in claim 1; preferably, R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano and C(=0)0R13a; and Ri3a is hydrogen or C1_6 alkyl.

16. The compound of any one of claims 1 to 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein each R6 is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano.

17. The compound of any one of claims 1 to 16, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is selected from the group consisting of:

0 '7.
O V 0 ? 0 0 ---(N
--(N
N HNINFI HN \.NH
HNCL
)7.-NH 4410f 1 CF3 g 2 * 11 O CI 0 3 * CN
, , 0(17.o 0 V O .
HN 0, V
NH 0 jj Mo.j.LN
HN \,NH N
>7/N
ll V- a / HNINH r.
0 4 . OCF3, cji 5 , 0 6 -. 3 , HN
=
0 CF3 )1=--.THLN Oy().L
)L7LN N
HN _.-NH
HNNFI
....NH

, , O V 0 v -N H1\1) N V
-L
HNC) NH 41 OCHF2 y NH 41 HNI) y-NH
O 10 0 11 , 0 12 , O V 0 0 V 0 0 v 0 */)N N
)7 HNI\R/ HN HN'------,-NH i N yNH . YNH
¨/
0 13 , 0 14 , 0 15 , O v 0 0 7 0 F 0,y1õ).LO
N
1-11\1 N HN''....:()LN
NH 11, HN NH

)r- * F yNH
O 16 , 17 , 0_\/=,. I ..
N HNN

HNLIC) NH F )7.-NH CI

F , CI 0 21 , , 0 V 0_\/ I
HNLN N N
HN/---r --' )i F HN)rNH CI -NH )i-NH 41. OMe O 22 , 0 23 =

, 0 24 , OMe ri - :
N N
HNLC) HN N HN H
0)r-NH

, o V 0 0 V 0 N N
HN'-----ri)LN F HNNH HN nN,NH 110, y NH

O 28 0 , 29 29-1 CFHNNzNH E.: N
HN,NH .. N H
H 11 CF3 HN 40 )(NH =
0 I.

29-2 , 0 30 30-1 04µy)k CF3 40 CF3 (:) CHL
N
HNN,NHo ._L N
0 HN)rNH

0 )r-NH 0 30-2 , 0 31-1 O V 0 o V 0 0 V 0 HNN HN N N
Y--r-L HN------( NH :).
),r..NH afr CF3 ),(NH
= CF3 )4,--- = C F3 OyDL 0>s,' 0 y.y.i:"..*Z
µ
(Ryl. l''N N
N HN)r.NH (s) HN)r-NH = CI HN)r-NH
0 = CI = CI

CI , 34-1 CI 34-2 CI , , O V 0 0 V 0 0 v 0 CI
HN N ,---"-N HN (s) N 140) y-NH II CI HN)r-NH = afr CI yeNH OMe OL v o ))CL
o V
CI 0,....)k CI
N (s) N el N
HNy-NH HN)rNH OMe HN)r-NH CI
OMe O , 0 36-1 , 0 37 CI , o V 0 y"...AN
o V 0 CI I, N CI
HNH N cl HN
NH
HN)r...NH CI
o a 0 CI
37-1 37-2 , 0 38 o V 0 CI p, 7 H .-N H HN N CI
HN)7-NH
N)r-NH CI CI 411 CF3 O 38-1 , o 38-2 F
, , O V 0 v 0 HNI'"---NHN
)r - CI
.sss.
HNI----r yNH CF3 HN)(NH N CF3 0 CI CI , 41-1 , , HN)L NH 0 -a \.. N
y NH CI
HN N 400 NI_ 1 .,;.---= ith 41-2 42 a oF3 , , , O .7')L
0 V o o V o D
D
(s) N )HN
HN)r_NH F
HN'..-1AN rp3 HN P CI
_.
O D
44 , 0 45 0 46 CF3 , , 0 )\/H

0,.......)..L 0 N N
HN (s) CI HN)i- NH N

7.--NH 41 a HN)rNH .

, ' , r , N
(:)..\ v ./ = II
Od rN
N HN NH =
HN/ 1 HN NH ),i 41 p Y -NH 41 CF3 - 3 = CF3 49-1 49-2 49-2a 4.
0>_..*=.)7 CI, N
HNNH (s) N OV
fi * CF3 HN)r...NH NO2 OH

49-2h 50 CI 0 51 ' HN
0sy % ,:rõ)1 \./ 1 = (s) N
(s) N
N .1.-NH HN
= I )7.--NH CI
.
HNr-r -)r...NH 40 CHF2 0 52 53 CI 54 NH2 , v 0 Oy...i.L
(s) N 0 0 V 0 C....YAC) 0 CI
(s) N
HN)r_NH )¨ -()LN HN),r-NH
II NH HN)r-NH 0 CH3 55 CI , 0 56 OH 57 NH

HN N N '------1-"A HNI---1").. N
)r...NH CI . CF3 \ i 0 0 59 60 *
58 CI Br , CF3 , NI-17._,e NH
0 "'" NI

N --1 , H Ny N H CI `----JN1¨ * Lp ¨
*

0 61 CF3 , CI , 62 62-1 , HN-1( 0 ...,....z.NF.:. \

N1'----- 0 L........2¨

* HN)r-NH N .
HN\...._NH N

, , \

C CD...s---N Ci.._. N
HN1 1 HN),i-NH NH 40 CF3 N

HN NH)r- 4. CF3 0 63-2 , 0 64 64-1 O N
0...?) L

HN'yr4i 40 c HN'.----(jLN CF3 FIN.---()(N
)7...NH II CF3 0 0 )r..-NH CI

64-2 65 66 CI , O_\(..y.).Lo 04 C) .=.).
N
HN
),r...NH , ii CI HN)r_NH CI \)LN F

HN)(NH CI
CI CI

O V
-- ---µ F F
HN H CI FIN\,,NH CI HN)r...NH CI -N
0 67-2 , 0 68-1 F , 0 v 0 = - = z-)( HNr"--1H N - CI HN NIH N
CI HN CI N D D

, 9 , _ 0,..s...( ---, N (s) N
N
HNI'N
yNH
(R) CI HN \_,..NH

69-1 69-2 70 CI , , , D

_ ,----).L. N N
HN (s) N HN HI\h .).'L
)r... CI

NH CI if_NH

, CI

, , , /-=\ /-=\
N , N---- 0 c).....11 0..N..:).L 0 N' N N
N HN)T¨NH

CI , , 0;ILT\N---- o 0,yr...}Lo t (DµN 0 N o,......).L
HN N N
NH HN eH
400 CF3 HN)r-NH . CHF2 41 CI

CI 9 F CF3 , , CiN 0 HNJ
, \

HN'------()LN C21..___)..
yNH 40 N

yNH 41 CF3 "NyNH 41 CF3 / 77 , , CI 78 CI , D
0.L D N, HN _________________________ NH N 0 0.___.)...L
N
D
HN N
)r...NH 08 HNyNH

CF

CI , CI , /=\ /

N, S 0 N , S 0 0 )..L
N 04.,, HN)rNH N N
(s) 410' CF3 HN)r NH
41 CF3 FIN)r NH . CF3 5 CI 9 ci , 83-1 CI , /=\
N µ S 0 Nr 0 CN 0 N 0 R N 0).L
N 0,,õ), R) N
HNNH * CF3 HN CF3 )r-NH HN 4 )rNH
* * CF3 83-2 CI 84 CI 84-1 CI , , , N N

0 0.,..,.).L 0 N
NH * CF3 NH N
s7N HN HN
HN)7_, a )7..-NH 40 CI

CI , CF3 86-1 CF3 , , N o v 0 o v 0 .......)-N N
HoN,------(N HN,r_NH (:)H HN-------() CI )r-NH CI
)r-NH 100 a OH

o 85-2 CF3 , 86-1 CF3 86-2 C F3 , 0....
0.......).... 0.µ, 0 HN 0,W
N
)r...NH --..... ' * CI FIN)r NH N
OH
OH afr CI HN
0 )7.-- NH * CF3 0,..IN

HN)r, NH * CF3 H)r OMe CF3 HN N\_..- NH
4Ik 0 , o , o , \
N¨N

V' 0 0.__...?. 0 HC) O
(:).._...............LL
N F
HN)r-NH N
HIN).\-N
HN)r NH
th O 4i CHF2 1,--1\11-1 0 CI , and CI ,

18. A process of preparing the compound of formula (I) according to claim 1 or 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising a step of:
R4a R2a R2b R4b R2a R2b R4a 0 RI 0 R1 R4b OH
HN + G1 __ i. N
HN
/3b R ) ) / \\G2 R R3b \\O2 7....õ-NH 3a r,=1\TH R3a 17 R5a R5b G4 /
0 0 R5a G4 G3 R5b ( IA ) ( IR ) ( I) reacting a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof with a compound of formula (IB) or a salt thereof to obtain the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
wherein:
G1, G2, G3, G4, R1, R2a to R5a, R2b to R5b, n and m are each as defined in claim 1 or 2.

19. A pharmaceutical composition comprising a compound of any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof thereof, and a pharmaceutically acceptable carrier.

20. A method of inhibiting ADAMTS-5 and/or ADAMTS-4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 19.

21. A method of preventing or treating an inflammatory condition or disease involving degradation of cartilage, and/or disruption of cartilage homeostasis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 19.

22. A method of preventing or treating arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 19.

23. The method of claim 22, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthrosis and hypertropic arthritis.

24. Use of a compound of any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manuafacture of a medicament for the treatment of a disease or condition related to ADAMTS-5 and/or ADAMTS-4 activities.

25. The use of claim 24, wherein the disease or disorder is arthritis, preferably rheumatoid arthritis, psoriatic arthritis, osteoarthritis, or hypertropic arthritis.