GLP-1 agonist as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a GLP-1 agonist as well as a preparation method and application thereof. The GLP-1 agonist has a structure as shown in a formula I, or a pharmaceutically acceptable salt or solvate thereof. The GLP-1 agonist provided by the invention has relatively high activity and bioavailability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a GLP-1 agonist and a preparation method and application thereof. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar levels and caused by absolute or relative insulin deficiency and utilization disorders. The disease is mainly divided into three types: type 1, type 2, and gestational diabetes, of which type 2 diabetes (T2DM) is the most common form, accounting for more than 90% of diabetes cases.

[0003] Due to the current fast-paced lifestyle and overnutrition, most patients with diabetes are obese or sedentary adults, and insulin resistance begins to appear. Although lifestyle changes can effectively control the disease, anti-diabetic drugs are still needed.

[0004] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) act in tandem to regulate insulin secretion in response to glucose intake. Although the incretin effect is significantly diminished (if present at all) in cases of T2DM, GLP-1 retains insulinotropic properties even when the endocrine pancreatic response to GIP is effectively terminated. Therefore, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Drugs targeting the above family of intestinal peptides, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0005] The GLP-1 agonists currently under development have difficulty ensuring both the activity and bioavailability of the drug, resulting in higher dosages that may cause adverse reactions in patients. How to simultaneously improve the activity and bioavailability of the drug is an issue that needs to be addressed urgently. Summary of the invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a GLP-1 agonist and a preparation method and application thereof, wherein the prepared GLP-1 agonist has high activity and bioavailability.

[0007] To achieve the above object, the present invention provides a GLP-1 agonist having a structure as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0008]

[0009] Formula I;

[0010] wherein Ring A and Ring D are each independently selected from substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloalkyl; and at least one of Ring A and Ring D is substituted by one or more SF5;

[0011] The L2 is selected from any of the following structures:

[0012] Wherein, aa represents the connection point with ring D;

[0013] n1 is any integer from 1 to 3;

[0014] L 2A is a single bond or C 1-10 Alkylene;

[0015] R La Selected from H, C 1-6 Alkyl or C(=O)(C 1-6 alkyl);

[0016] R Lb and R Lc Independently selected from H or C 1-6 alkyl;

[0017] R 1 , R 2 and R 3 Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The substituents of the alkyl group are selected from halogen, hydroxyl, C 1-6 One or more of alkoxy groups;

[0018] L 1 Selected from: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- or -S(=O)2;

[0019] Ring B is selected from any of the following structures:

[0020]

[0021] Among them, bb represents L 1 The connection point;

[0022] R 4 , R 5 , R 6 and R 7 Independently selected from: H, halogen or C 1-6 alkyl;

[0023] L 3 is a single bond or C 1-3 Alkylene;

[0024] L4 is a single bond or C 1-5 Alkylene;

[0025] R 8a and R 8b Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted by one or more selected from halogen or C 3-15 The cycloalkyl group is substituted by a substituent; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-15 Cycloalkyl; said C 3-15 The cycloalkyl group may be optionally substituted with one or more substituted or unsubstituted C 1-6 Alkyl substitution;

[0026] R 9 Selected from: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) or (IX-4):

[0027]

[0028] R 9a H or C 1-6 alkyl;

[0029] R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano;

[0030] R 9c , R 9d , R 9e , R 9f and R 9g Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl, C(=O)(C 1-6 Alkyl); the C 1-6 The alkyl group may be optionally substituted with one or more halogen or C 1-6 Alkoxy substitution;

[0031] Ring C is selected from 3 to 12 membered heterocyclic groups, C 3-15 Cycloalkyl or 5-10 membered heteroaryl; wherein the 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10 membered heteroaryl may be optionally substituted by one or more R Ca replace;

[0032] The R Ca Selected from: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or NR c R d ;

[0033] The two R on the same or different ring atoms Ca Together with one or more ring atoms to which they are connected, they can form a 3- to 8-membered cycloalkyl group;

[0034] R c and R d Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) or S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) each may be optionally substituted by one or more independently selected from -OH, halo, C 1-6 The substituents of the alkoxy group are substituted.

[0035] Preferably, the ring A and the ring D are each independently selected from a substituted or unsubstituted 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocyclic group or a C 3~15 cycloalkyl; and at least one of ring A and ring D is substituted with one or more SF5.

[0036] More preferably, the ring A and the ring D are each independently selected from a substituted or unsubstituted 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group. The 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group may be a monocyclic group or a condensed ring group. The condensed ring group may be a condensed ring group formed by condensing two or three rings.

[0037] The 6- to 10-membered aryl group is more preferably a phenyl group.

[0038] The 5- to 10-membered heteroaryl group is more preferably a 5- to 6-membered monocyclic heteroaryl group or a 7- to 10-membered bicyclic heteroaryl group. The heteroatoms of the 5- to 6-membered monocyclic heteroaryl group include any one or more of N, O, and S. The 7- to 10-membered bicyclic heteroaryl group may be a bicyclic heteroaryl group formed by condensing a phenyl group and a monocyclic heteroaryl group, or a bicyclic heteroaryl group formed by condensing two monocyclic heteroaryl groups. The monocyclic heteroaryl group is preferably a 5- to 6-membered monocyclic heteroaryl group. The heteroatoms of the 5- to 6-membered monocyclic heteroaryl group include any one or more of N, O, and S.

[0039] Preferably, at least one of the ring A and the ring D is substituted by 1 to 3 SF5.

[0040] In the present invention, the number of the SF5 substituents includes but is not limited to 1, 2 or 3.

[0041] Preferably, the ring A and ring D are each independently selected from any one of the following structures:

[0042] ;

[0043] Among them, T 1 , T 2 , T 3 , T 4 , T 5 Each independently selected from N, CH or CR QA More preferably, CH or CR QA .

[0044] In some embodiments, T 1 , T 2 , T 4 and T 5 Each may be CH.

[0045] As another non-limiting example, T 1 , T 2 , T 4 and T 5 1-2 (e.g. 1) of them can be CR QA ; and T 1 , T 2 , T 4 and T 5 The remaining ones of each may be CH.

[0046] In some embodiments, T 1 , T 2 , T 4 and T 5 One of them is N; and T 1 , T 2 , T 4and T 5 The remaining are each independently CH or CR QA For example, T 1 , T 2 , T 4 and T 5 The remaining ones of each may be CH.

[0047] Preferably, the R QA Selected from halogen, cyano, hydroxyl, oxo, NR a R b 、C(═O)NR c1 R d1 , substituted or unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl or 3-8 membered cycloalkyl. The 3-12 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl may be a monocyclic or condensed ring group. The condensed ring group may be a condensed ring group formed by condensing two or three rings.

[0048] More preferably, the R QA Selected from F, Cl, Br, cyano, hydroxyl, oxo, NR a R b 、C(═O)NR c1 R d1 , substituted or unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy, 3- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl.

[0049] The oxo group in the present invention refers to a functional group in a molecule containing an oxygen atom connected to a central atom in an organic molecule, wherein the oxygen atom is connected to a carbon atom to form a carbonyl structure.

[0050] Preferably, the R a and R b Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O) (C 1-6 alkyl), C(=O) (C 3-6 Cycloalkyl) or C(=O)O(C 1-6 alkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O) (C 3-6 Cycloalkyl) and C(=O)O(C 1-6alkyl) each may be optionally substituted by one or more independently selected from -OH, halogen, C 1-6 The alkoxy group is substituted by a substituent. The number of the substituent is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1.

[0051] Preferably, R c1 and R d1 Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) or S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) each may be optionally substituted by one or more independently selected from -OH, halo, C 1-6 The alkoxy group is substituted by a substituent. The number of the substituent is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1.

[0052] The C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally substituted with one or more of the following groups: halo, -OH, NR c1 R d1 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 a halogenated alkoxy group or a 3- to 12-membered heterocyclic group; the 3- to 12-membered heterocyclic group may be optionally substituted by one or more of the following substituents: -OH, C 1-6 alkyl, 3- to 12-membered heterocyclic group; the number of the substituents is preferably 1-6, more preferably 1-4.

[0053] The 3-12 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, and 3-8 membered cycloalkyl group may be optionally substituted by one or more of the following groups: 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c1 R d1 , cyano, halogen, C 3-6 Cycloalkyl or 3-12 membered heterocyclic group; the 3-12 membered heterocyclic group may be optionally substituted by one or more of the following substituents: C 1-6 Alkyl or C(=O)C 1-6 The number of the substituents is preferably 1 to 6, more preferably 1 to 4.

[0054] The R c1 , R d1 The scope is the same as described above.

[0055] Or the R QA Selected from -L a -S(O)2-L b -R e ;

[0056] The L a Selected from: single bond, -N(H)-, -N(R c )-or-(CR h R h ) q1 -;

[0057] The L b Selected from: single bond, -O-, -N(H)-, -N(R c )-or-(CR h R h ) q2 -;

[0058] When the L a When selected from a single bond, it means that the L a does not exist, the R QA - S(O)2-L b -R e .

[0059] When the L b When selected from a single bond, it means that the L b does not exist, the R QA For -L a -S(O)2- R e .

[0060] The q 1 and q 2 are independently selected from 1, 2, 3 or 4; when said q 1 and q 2 When q is independently selected from 2, 3 or 4, it means that the corresponding group is repeated 2, 3 or 4 times.1 and q 2 1 or 2 is more preferred.

[0061] The R e Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3- to 8-membered heterocyclic group may be optionally substituted by one or more independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 The number of the substituents of the haloalkoxy group is preferably 1 to 3.

[0062] In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0063] The R h Selected from: H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or two R on the same or different carbon atoms h And connect the two R h One or more carbon atoms together form C 3-6 Cycloalkyl or 4- to 8-membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 The cycloalkyl or 4- to 8-membered heterocyclic group may be optionally substituted by one or more independently selected from halo, cyano, C 1-3 Alkyl, C 1-3Haloalkyl, -OH, C 1-3 Alkoxy or C 1-3 The substituents of the haloalkoxy group are substituted.

[0064] In some embodiments, each occurrence of R h is H. In some embodiments, one occurrence of R h It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halo; and each remaining R h is H. In some embodiments, one occurrence of R h It is C 1-3 alkyl (eg, methyl); and each remaining R h It's H.

[0065] The R c The scope is the same as above;

[0066] And when L a When it is a single bond, -L b -R e Not unsubstituted C 1-3 alkyl.

[0067] In some specific embodiments of the present invention, the R QA Select from any of the following groups:

[0068] ;

[0069] Among them, a is preferably any integer from 1 to 3, which can be 1, 2 or 3, and more preferably 1; b is preferably any integer from 0 to 3, which can be 0, 1, 2 or 3.

[0070] or R QA P(=O)R j R k ;

[0071] Among them, R j and R k Independently selected from the following groups: substituted or unsubstituted C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl; said C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl groups may be optionally substituted with one or more of the following groups: 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, halogen, cyano, C 1-3 Alkyl, C 1-3Haloalkyl, -OH, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, NHC(=O) (C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 cycloalkyl).

[0072] Preferably, the C 1-6 The alkyl group may be optionally replaced by one or more selected from C 1-6 Alkoxy, C 3-6 The substituents of cycloalkyl, halogen, cyano are substituted; the C 3-6 The cycloalkyl group may be optionally substituted with one or more selected from C 1-3 Alkyl or halogen substituents; 6-10 The aryl group may be optionally substituted with one or more selected from C 1-3 The alkyl group is substituted with a substituent.

[0073] or R j and R k Together with the phosphorus atoms to which they are connected, they form a 5- to 8-membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group may be optionally substituted with one or more selected from C 1-6 The alkyl group is substituted by a substituent; the heteroatom of the 5- to 8-membered heterocyclic group is P or includes one or more of O, S, N and P;

[0074] In some specific embodiments of the present invention, the R j and R k Independently selected from substituted or unsubstituted C 1-3 Alkyl; the C 1-3 The alkyl group may be optionally replaced by one or more selected from C 1-3 Alkoxy, C 3-6 The substituents are substituted with cycloalkyl or halogen.

[0075] The R j and R k Can be the same or different.

[0076] In some specific embodiments of the present invention, the R QA is P(=O)Me2, or said R QA is P(=O)Et2, or the R QA It is P(=O)iPr2.

[0077] Preferably, in the present invention, the GLP-1 agonist structure represented by Formula I contains 1 to 4 QA substituent groups.

[0078] The R QB For SF5.

[0079] Preferably, the ring A and the ring D are each independently selected from a phenyl group or a fused aryl group formed by condensing a five-membered or six-membered heteroaryl group and a phenyl group. The heteroatom of the five-membered or six-membered heteroaryl group is preferably any one or more of N, O, and S. More preferably, the five-membered or six-membered heteroaryl group is selected from a heteroaryl group containing 1 to 3 N atoms. In some specific embodiments of the present invention, the five-membered or six-membered heteroaryl group is selected from an imidazolyl group, a pyrazolyl group, or a triazolyl group.

[0080] Preferably, the ring A and ring D are each independently selected from any one of the following structures:

[0081] ;

[0082] Wherein, m1 is 0, 1 or 2;

[0083] T 6 , T 7 , T 8 Independently selected from CR 10 R 11 or NR 12 ;

[0084] R 10 , R 11 , R 12 Independently selected from halogen, C 1~10 Alkyl or absent; more preferably F, Cl, Br, C 1~6 Alkyl group may not exist.

[0085] The C1-10 alkyl group may be optionally substituted by a substituent selected from halogen, nitro, and amino.

[0086] The R 10 , R 11 , R 12 The absence of this is to satisfy the valence state of the C or N atoms.

[0087] The R QA The scope is the same as described above.

[0088] The R QB For SF5.

[0089] And optionally, the R QA In the R QB The interposition.

[0090] In some specific embodiments of the present invention, the ring A and the ring D are independently selected from substituted or unsubstituted phenyl or benzopyrazolyl.

[0091] Preferably, the L2 is selected from any of the following structures:

[0092] .

[0093] Preferably, the L 1 It is -C(=O)-.

[0094] The ring B is selected from any of the following structures:

[0095]

[0096] Among them, bb represents L 1 connection point.

[0097] R 4 , R 5 , R 6 and R 7 Independently selected from: H, halogen or C 1-6 Alkyl, more preferably H, F, Cl, Br or C 1-3 alkyl.

[0098] L 3 is a single bond or C 1-3 Alkylene.

[0099] L 4 is a single bond or C 1-5 Alkylene.

[0100] Preferably, the R 8a and R 8b Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted by one or more selected from halogen or C 3-15 The cycloalkyl group is substituted by a substituent; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-15 Cycloalkyl; said C 3-15 The cycloalkyl group may be optionally substituted with one or more substituted or unsubstituted C 1-6 Alkyl substitution.

[0101] Preferably, the R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-8 Cycloalkyl; said C 3-8 The cycloalkyl group may be optionally substituted with one or more substituted or unsubstituted C 1-6The number of the substituents is preferably 1 to 2.

[0102] More preferably, the R 8a and R 8b Together with the carbon atoms to which they are attached, they form a substituted or unsubstituted cyclopropyl or cyclobutyl group; the cyclopropyl group and the cyclobutyl group may be optionally substituted or unsubstituted by one or more C 1-6 Alkyl substitution.

[0103] The substituent C 1-6 The alkyl group may be further substituted with one or more of the following secondary substituents:

[0104] Halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The halogenated alkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 alkyl and 3 to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of alkyl and 3 to 12-membered heterocyclic group. c , R d The scope is the same as described above and will not be repeated here.

[0105] Further preferably, the R 8a and R 8b Together with the carbon atoms to which they are attached, they form any of the following groups:

[0106] .

[0107] The R 9 Selected from: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) or (IX-4):

[0108]

[0109] R 9a H or C 1-6 Alkyl; preferably H or C 1-3 alkyl;

[0110] R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; preferably H, C 1-3 Alkyl, C(=O)(C 1-3 Alkyl), S(O)0-2 (C 1-3 alkyl) or cyano;

[0111] R 9c , R 9d , R 9e , R 9f and R 9g Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl, C(=O)(C 1-6 Alkyl); the C 1-6 The alkyl group may be optionally substituted with one or more halogen or C 1-6 Alkoxy substituted; more preferably H, substituted or unsubstituted C 1-3 Alkyl, C(=O)(C 1-3 Alkyl); the C 1-3 The alkyl group may be optionally substituted with one or more halogen or C 1-3 Alkoxy substitution.

[0112] Preferably, the R 9 Has the following structure:

[0113]

[0114] The R 9d Selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted with one or more halogen or C 1-6 Alkoxy substituted; more preferably H, substituted or unsubstituted C 1-3 Alkyl; the C 1-3 The alkyl group may be optionally substituted with one or more halogen or C 1-3 Alkoxy substitution.

[0115] Preferably, L in the ring B 3 -C(R 8a R 8b )-L 4 -R 9 The structure of the part is any of the following:

[0116] .

[0117] Preferably, the GLP-1 agonist of the present invention has a structure shown in Formula I-a or Formula I-b, or a pharmaceutically acceptable salt or solvate thereof:

[0118]

[0119] Wherein, the ring A and the L 2 At least one of the attached phenyl groups is substituted with one or more SF5;

[0120] The ring E is selected from substituted or unsubstituted C3-6 cycloalkyl; more preferably substituted or unsubstituted cyclopropyl or cyclobutyl.

[0121] The R 8c is selected from H, substituted or unsubstituted C 1-6 Alkyl, more preferably H, substituted or unsubstituted C 1-3 Alkyl. 1-6 Alkyl or the C 1-3 Alkyl groups may be optionally substituted with one or more of the following substituents:

[0122] Halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The halogenated alkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 alkyl and 3 to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of alkyl and 3 to 12-membered heterocyclic group. c , R d The scope is the same as described above and will not be repeated here.

[0123] In Formula I-a or Formula I-b, Ring A, Ring C, L 1 , L 2 , R 1 -R 7 , R 9 , R QA The range of m1 and m2 is as described above and will not be repeated here.

[0124] Preferably, the R QA In relation to L 2 The interposition or counterposition of.

[0125] Preferably, the structure of formula I-a or formula I-b Partially selected from the following structures:

[0126] .

[0127] Further preferably, the GLP-1 agonist has a structure as shown in Formula Ⅰ-a-1, or a pharmaceutically acceptable salt or solvate thereof:

[0128]

[0129] R QB For SF5.

[0130] In Formula Ⅰ-a-1, ring C, L 1 , L 2 , R 1 -R 7, R 9 , R QA The range of m1 is as mentioned above, and the ring E and R 8c The scope is as described in general formula Ⅰ-a or Ⅰ-b, which will not be repeated here.

[0131] Preferably, the R QA In relation to L 2 The interposition or counterposition of.

[0132] Preferably, the structure of formula Ⅰ-a-1 Partially selected from the following structures:

[0133] .

[0134] Further preferably, the GLP-1 agonist has a structure as shown in Formula Ⅰ-a-2, or a pharmaceutically acceptable salt or solvate thereof:

[0135]

[0136] R QB For SF5.

[0137] In Formula Ⅰ-a-1, ring C, R 1 -R 7 , R 9 , R QA The range of m1 is as mentioned above, R 8c The scope is as described in general formula Ⅰ-a or Ⅰ-b, which will not be repeated here.

[0138] Further preferably, the GLP-1 agonist has a structure shown in Formula Ⅰ-a-3 or Formula Ⅰ-a-4, or a pharmaceutically acceptable salt or solvate thereof:

[0139]

[0140]

[0141] Wherein, a is any integer from 1 to 3; b is any integer from 0 to 3;

[0142] R j and R k Independently selected from substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C1-3 Alkyl), N(C 1-3 Alkyl)2, NHC(=O) (C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 Cycloalkyl);

[0143] The T1, T2, T3, T4 and T5 are independently selected from NR 12 , O, S or CR 13 R 14 ;

[0144] The R 12 , R 13 and R 14 independently selected from H, halogen, substituted or unsubstituted C 1~6 Alkyl, C 1~6 Alkoxy; the C 1~6 Alkyl, C 1~6 The alkoxy group may be optionally substituted by one or more substituents selected from halogen and cyano.

[0145] Preferably, any one of T1, T2, T3, T4, and T5 is O, and the others are CR 13 R 14 .

[0146] More preferably, T3 is O, and the rest are CR 13 R 14 .

[0147] Preferably, the six-membered ring formed by T1, T2, T3, T4, and T5 has the following structure:

[0148] .

[0149] The R ca is selected from H, halogen, substituted or unsubstituted C 1~6 Alkyl, C 1~6 Alkoxy; the C 1~6 Alkyl, C 1~6 The alkoxy group may be optionally substituted by one or more substituents selected from halogen and cyano.

[0150] More preferably, the R ca is selected from H, halogen, substituted or unsubstituted C 1~3 Alkyl, C 1~3 Alkoxy; the C 1~3Alkyl, C 1~3 The alkoxy group may be optionally substituted by one or more substituents selected from halogen and cyano.

[0151] Further preferably, the R ca is selected from H, F, Cl, Br, substituted or unsubstituted methyl, ethyl, propyl, methoxy, ethoxy or propoxy.

[0152] In formula Ⅰ-a-4, the remaining groups, such as R 1 -R 7 , R QA , R QB The range of m1 is as mentioned above, R 8c The scope is as described in general formula Ⅰ-a or Ⅰ-b, which will not be repeated here.

[0153] R j and R k The preferred range of is the same as described above and will not be repeated here.

[0154] Based on the uncertainty of the drug structure-activity relationship, the present invention introduces the SF5 group into the GLP-1 agonist structure and studies the remaining multiple structural groups. The test results show that:

[0155] When L2 is selected from , Ring B is selected from When the structure is modified, under the premise of introducing SF5, the compound can obtain higher activity and bioavailability at the same time.

[0156] Especially when SF5 is introduced into the A position of ring and the substituent R QA Selected from -L a -S(O)2-L b -R e or P(=O)R j R k hour.

[0157] Further, when both ring A and ring D are phenyl, and the substituent R of ring D is QA Select from any of the following groups:

[0158] or P(=O)Me2, P(=O)Et2, P(=O)iPr2, the compound has the highest activity and bioavailability, and under the condition of halving the dose, a C max (Peak drug concentration).

[0159] Preferably, the GLP-1 agonist has any of the following structures, or a pharmaceutically acceptable salt or solvate thereof:

[0160]

[0161]

[0162] .

[0163] The present invention also provides a salt form of the above-mentioned GLP-1 agonist.

[0164] The salt may be a pharmaceutically acceptable salt or other salts, including but not limited to intermediates that can be used to prepare and / or purify the compound of formula (I) and / or separate the enantiomers of the compound of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compound of formula (I) include trifluoroacetate.

[0165] The present invention also provides a solvate of the above-mentioned GLP-1 agonist. The compound of formula (I) or its salt can be isolated in the form of a solvate, and any such solvate is included in the scope of the present invention. For example, the compound of formula (I) and its salt can exist in a non-solvated form and a solvated form formed with a pharmaceutically acceptable solvent (such as water, ethanol and the like).

[0166] The present invention provides a method for preparing the above-mentioned GLP-1 agonist, comprising the following steps:

[0167] Using the intermediate represented by formula A and the intermediate represented by formula B as raw materials, an amination reaction is carried out to obtain the intermediate represented by formula C;

[0168] Using the intermediate represented by formula C as a raw material, a GLP-1 agonist represented by formula I is prepared;

[0169]

[0170] Among them, ring A, R 1 -R 3 The scope is as described above;

[0171] Pg is an amino protecting group.

[0172] Preferably, the Pg is a carbamate protecting group, including but not limited to Boc.

[0173] Optionally, the solvent for the amination reaction of the intermediate represented by formula A and the intermediate represented by formula B is a polar aprotic solvent, including but not limited to DMSO.

[0174] The present invention has no particular limitation on the source of the intermediate represented by formula A, and it can be commercially available or prepared according to methods well known to those skilled in the art. Preferably, it can be prepared according to the following method:

[0175] The intermediate represented by formula A-1 and the intermediate represented by formula A-2 are subjected to condensation reaction to obtain the intermediate represented by formula A-3;

[0176] The intermediate represented by formula A-3 reacts with the intermediate represented by formula A-4 to obtain the intermediate represented by formula A;

[0177]

[0178] Pg is as described above.

[0179] In formula A-1, formula A-2, formula A-3, and formula A-4, ring A, R 1 -R 3 The range is as mentioned above.

[0180] Alternatively, the intermediate of formula A-1 and the intermediate of formula A-2 are subjected to condensation reaction by treating with HCl gas in DCM at room temperature, followed by treating with Py-HCl in EtOH under reflux.

[0181] Optionally, the intermediate represented by formula A-3 and the intermediate represented by formula A-4 are reacted, and the solvent is selected from polar aprotic solvents, including but not limited to THF; optionally, the reaction is carried out under the action of an alkaline compound, and the alkaline compound can be sodium hydroxide, sodium carbonate aqueous solution, etc.

[0182] The present invention has no particular limitation on the method for preparing the GLP-1 agonist of formula I using the intermediate of formula C as a raw material, and can be a method disclosed in the art. Preferably, the reaction process is as follows:

[0183] .

[0184] Optionally, the compound I4 is treated with an acidic compound, and then the secondary amino group is protected to obtain compound I5. The acidic compound includes but is not limited to MeSO3H and the like. The solvent for the reaction is preferably THF, and the reaction temperature is preferably 50-70°C, more preferably 60°C. Boc2O can be used to protect the secondary amino group.

[0185] Optionally, the protecting group of compound I5 is removed to obtain compound I6. The present invention has no particular limitation on the method for removing the amino protecting group, which may be a method well known to those skilled in the art, and is optionally carried out under acidic conditions, including but not limited to HCl solution, and the solvent includes but is not limited to 1,4-dioxane.

[0186] Alternatively, I6 is coupled with I7 or I8 under standard amide bond forming conditions to obtain compound I9 or I10. The forming conditions include but are not limited to the presence of a carboxyl activator such as HATU, or in a polar aprotic solvent, such as but not limited to DMF.

[0187] Compound I9 or I10 is then coupled with compound I11, wherein ring D is as defined for formula I and X is a halide (e.g., -Br or -I) or a pseudohalide (e.g., -OTf) (e.g., under typical Ullman coupling conditions known in the art) to afford compound I12 or I13, which is a compound of formula I.

[0188] As a non-limiting example, CuI, K2CO3 and The coupling was carried out in NMP in the presence of .

[0189] The coupling temperature is preferably 120-140°C, more preferably 130°C.

[0190] The present invention also provides a GLP-1 agonist composition, comprising the above-mentioned GLP-1 agonist and a pharmaceutically acceptable excipient.

[0191] The present invention provides the use of the above-mentioned GLP-1 agonist or the above-mentioned GLP-1 agonist composition in the preparation of a drug for preventing, treating and / or alleviating diabetes.

[0192] The above-mentioned diabetes includes, but is not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain caused by the use of other medications, gout, excessive sugar addiction, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, blood restenosis after cannula angioplasty, intermittent claudication, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

[0193] Preferably, the above-mentioned diabetes is type 2 diabetes or obesity.

[0194] The present invention also provides a method for preventing, treating and / or alleviating diabetes, which comprises administering to the patient a therapeutically effective amount of a GLP-1 agonist of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0195] The GLP-1 agonist or the GLP-1 agonist composition provided by the present invention can also be used in combination with other drugs for treating diabetes.

[0196] definition

[0197] When values ​​are described as ranges, it should be understood that such disclosure includes disclosure of all possible sub-ranges within such ranges, as well as specific values ​​falling within such ranges, whether or not a specific value or a specific sub-range is explicitly stated.

[0198] As used herein, the term "halo" or "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl (sometimes referred to herein as "chloro" or "chloros"), -Br (sometimes referred to herein as "bromo" or "bromos"), and -I (sometimes referred to herein as "iodo" or "iodos").

[0199] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical having one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl and hexyl.

[0200] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring containing the indicated number of carbon atoms. 3-6 "Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon having three to six ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3. [1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and the like. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are connected via only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane and the like.

[0201] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic ring system), with 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N or S (e.g., carbon atoms and 1 to 3, 1 to 6 or 1 to 9 heteroatoms of N, O or S in the case of a monocyclic, bicyclic or tricyclic ring, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. Heterocyclyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 1 .0]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[ [2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane and the like.

[0202] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., a C6 monocyclic, C10 bicyclic, or C14 tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0203] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic radical having the indicated number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms); wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolyl, e.g., tetrahydroquinolyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophenyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b] Pyridyl, quinazolinyl, quinolyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc.

[0204] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl and iodomethyl.

[0205] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is located on the oxygen atom. 1-6 "Alkoxy" refers to an -O-(C1-6 alkyl) group, wherein the group is on the oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group is on the oxygen atom.

[0206] As used herein, “ ” indicates the optional presence of single or double bonds where valency permits.

[0207] As used herein, “ ” indicates the point of attachment to the parent molecule.

[0208] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise stated, a compound identified herein as one particular tautomeric form by name or structure is intended to encompass the other tautomeric forms.

[0209] As used herein, the term "tautomer" refers to compounds whose structures differ significantly by arrangement of atoms, but which readily and rapidly equilibrate, and it is understood that the compounds provided herein may be depicted as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compound does not exclude any tautomer.

[0210] As used herein, the term "GLP-1R" or "GLP-1R receptor" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0211] As used herein, the term "GLP-1 related disease" is intended to include, but is not limited to, all those diseases, disorders, or conditions in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms, and / or progression of the disease, disorder, or condition.

[0212] As used herein, the term "GLP-1 agonist or "GLP-1RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RA enhances glucose-dependent insulin secretion; inhibits inappropriate increases in glucagon levels in the fasting and postprandial states; and slows gastric emptying.

[0213] The term "pharmaceutically acceptable" as used herein indicates that the compound or its salt or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the patient being treated therewith.

[0214] As used herein, the term "effective amount" or "effective dose" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity to alleviate one or more symptoms of the disease or condition being treated to a certain extent, and may include curing the disease. "Cure" means eliminating the symptoms of active disease. The results include alleviating and / or relieving the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including a compound as disclosed herein required to significantly reduce the symptoms of the disease clinically. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" of a compound provided herein refers to the amount of the compound that is effective as a monotherapy or combination therapy.

[0215] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating substance. In some embodiments, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0216] The term "pharmaceutical composition" refers to a mixture of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof, and other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners. Pharmaceutical compositions facilitate administration of the compound to an organism. There are a variety of techniques for administering a compound in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0217] In the context of treating a disease, disorder or condition, the terms "treat," "treating," or "treatment" are intended to include alleviating or eliminating the disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or slowing the progression, spread, or worsening of the disease, disorder or condition, or one or more symptoms thereof.

[0218] The term "preventing" as used herein is the complete or partial prevention of the onset, recurrence or spread of a disease or condition as described herein, or symptoms thereof.

[0219] As used herein, the terms "subject," "patient," or "individual" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans.

[0220] In some embodiments, the patient is a human.

[0221] In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0222] The terms "therapeutic regimen" and "dosing schedule" are used interchangeably to refer to the dosages and timing of administration of the various therapeutic agents in the combinations of the invention.

[0223] The term "pharmaceutical combination" as used herein refers to a medical therapy obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0224] The term "combination therapy" as used herein refers to a dosing regimen of two different therapeutically active agents (ie, components of the combination or combination partners) wherein the therapeutically active agents are administered together or separately in a manner prescribed by a healthcare practitioner or according to a regulatory regime as defined herein.

[0225] As used herein, the term "modulate" means to regulate or adjust (eg, increase or decrease), and may include, for example, agonism, partial agonism, or antagonism.

[0226] Compared with the prior art, the present invention provides a GLP-1 agonist having a structure shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof. The present invention provides the above-mentioned GLP-1 agonist having high activity and bioavailability. DETAILED DESCRIPTION

[0227] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0228] All raw materials of the present invention have no particular limitation on their sources, and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0229] Analytical methods, materials and instruments

[0230] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer at 400 MHz or 600 MHz. Spectra are given as δ values ​​in ppm, and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet), coupling constant (Hz), integral value. High resolution mass spectra (HRMS) were collected using a Bruker SolariX XR.

[0231] Abbreviations used in the following examples and elsewhere herein are:

[0232] Boc2O Boc anhydride

[0233] DCM Dichloromethane

[0234] DIPEA N,N-Diisopropylethylamine

[0235] DMF N,N-Dimethylformamide

[0236] DMSO Dimethyl sulfoxide

[0237] EA Ethyl acetate

[0238] eq equivalent

[0239] Et Ethyl

[0240] HATU O-(7-azabenzotriazole)-N,N,N`,N`-tetramethyluronium hexafluorophosphate

[0241] HCl

[0242] iPr Isopropyl

[0243] Me Methyl

[0244] MeOH Methanol

[0245] m / z mass-to-nuclear ratio

[0246] NMP N-Methylpyrrolidone

[0247] NMR Nuclear Magnetic Resonance

[0248] PE Petroleum Ether

[0249] ppm parts per million

[0250] tBu tert-butyl

[0251] TEA Triethylamine

[0252] THF Tetrahydrofuran

[0253] The overall reaction equation for the following examples is as follows:

[0254]

[0255] Example 1

[0256] Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY101)

[0257]

[0258] Step 1: (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0259]

[0260] 4-Fluoro-3,5-dimethylphenylhydrazine hydrochloride (5.0 g, 26.23 mmol, 1 eq), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (6.14 g, 26.23 mmol, 1 eq), pyridine hydrochloride (303 mg, 2.623 mmol, 0.1 eq) and ethanol (100 mL) were added to a 250 mL single-necked bottle. o C for 2 hours. The reaction system was cooled to room temperature and concentrated to remove ethanol. A 2N aqueous sodium hydroxide solution was added to the residue to pH 9-10, and a yellow solid was precipitated, filtered, and dried to obtain a pale yellow crude product. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA=10 / 1-8 / 1-6 / 1-4 / 1) to obtain (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (8g, yield 81.5%), a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ: 7.23 (d, J= 6.4Hz, 2H), 5.20 (br. s, 2H), 5.01-5.12 (m,1H), 4.02-4.16 (m, 1H), 2.98-3.07 (m, 1H), 2.42-2.46 (m, 2H), 2.25 (d, J = 2.0Hz, 6H), 1.43 (s, 9H), 1.24-1.26 (m, 3H).

[0261] Step 2: (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0262]

[0263] To a 100 mL three-necked flask, add (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.0 g, 8.01 mmol, 1 eq), saturated aqueous sodium carbonate solution (10.9 mL) and THF (60 mL), and cool to 0 o C, add 2,2,2-trichloroethyl chloroformate (4.4mL, 32.04mmol, 4eq) dropwise. Then slowly warm to room temperature and stir overnight. Add 20mL of water to the reaction system and extract with EA (30mL*3). The organic phase is washed with saturated brine (30mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA=10 / 1-8 / 1) to obtain (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (4.3g, yield 97.7%), a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 7.10-7.08 (m,2H), 6.98-6.40 (br. s, 1H), 5.38-5.14 (m, 1H), 4.91-4.65 (m, 2H), 4.52-4.19(m, 1H), 3.20-2.96 (m, 1H), 2.83-2.66 (m, 2H), 2.26 (s, 6H), 1.49 (s, 9H), 1.33 (d, J = 5.3Hz, 3H).

[0264] Step 3: (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0265]

[0266] To a 250 mL single-necked bottle, add (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.8 g, 5.09 mmol, 1.0 eq), aminoacetaldehyde dimethyl acetal (803 mg, 7.64 mmol, 1.5 eq), DIPEA (890 uL, 5.09 mmol, 1.0 eq) and DMSO (60 mL). Then, under argon protection, heat at 100 °C. o C for 1 hour. The reaction system was cooled to room temperature, poured into 100 mL of ice water, and then extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. PE / EA (20 / 1, 40 mL) was added to the crude product, stirred for 10 minutes, filtered, and dried to obtain (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.4 g, yield 83.3%), an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.18 (d, J = 6.4Hz, 2H), 6.40 (br. s, 1H), 5.12-5.01 (m, 1H), 4.30 (t, J = 5.3Hz, 1H), 4.27-4.05 (m,1H), 3.24 (s, 6H), 3.18-2.99 (m, 3H), 2.63-2.55 (m, 2H), 2.23 (d, J = 2.2Hz,6H), 1.42 (s, 9H), 1.25-1.17 (m, 3H).

[0267] Step 4: (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0268]

[0269] To a 100 mL single-necked bottle, (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.8 g, 5.538 mmol, 1.0 eq) and THF (30 mL) were added, followed by methanesulfonic acid (0.29 mL, 4.430 mmol, 0.8 eq). The resulting mixture was heated at an external temperature of 60 °C. o C and stirred for 2 hours. Cool to room temperature, add potassium phosphate (1.18g, 5.538mmol, 1.0eq) in water (12mL) and Boc2O (483.4mg, 2.215mmol, 0.4eq), and then stir at room temperature overnight. Add 10mL of water to the reaction system and extract with EA (10mL*3). Wash the organic phase with saturated brine (10mL*3), dry over anhydrous sodium sulfate, filter, and spin dry to obtain a light yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA=3 / 1-2 / 1-1 / 1) to give (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.4 g, yield 97.9%) as a yellow solid. 1H NMR(400 MHz, Chloroform-d) δ 9.98 (br. s, 1H), 7.04 (d, J = 6.2Hz, 2H), 6.34 (d,J = 2.7Hz, 1H), 6.12 (br. s, 1H), 5.38-5.14 (m, 1H), 4.54-4.24 (m, 1H), 3.10 (br. s, 1H), 2.85-2.70 (m, 2H), 2.21 (d, J = 2.1Hz, 6H), 1.48 (s, 9H), 1.26-1.24 (m, 3H).

[0270] Step 5: (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0271]

[0272] To a 50 mL single-necked bottle, add (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (600 mg, 1.359 mmol, 1.0 eq) and DCM (4 mL), and then add 4N HCl(g) / 1,4-dioxane solution (3.4 mL, 13.6 mmol, 10 eq) dropwise under an ice-water bath. After the addition is complete, the reaction system is slowly heated to room temperature and stirred overnight. The residue was concentrated and dried in vacuo to give (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (473 mg, yield 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (br. s, 1H), 9.98 (br. s, 1H), 9.33 (br. s,1H), 7.09 (d, J =6.2Hz, 2H), 6.62 (d, J = 2.4Hz, 1H), 6.51 (d, J = 2.4Hz, 1H), 4.53-4.48 (m,1H), 3.61-3.56 (m, 1H), 3.34-3.24 (m, 1H), 3.06-2.96 (m, 2H), 2.20 (d, J =2.2Hz, 6H), 1.29 (d, J = 6.6Hz, 3H).

[0273] Step 6: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)- 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0274]

[0275] To a 25 mL single-necked bottle was added (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (184 mg, 0.487 mmol, 1.0 eq), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (210.4 mg, 0.511 mmol, 1.05 eq) and HATU (203.7 mg, 0.536 mmol, DIPEA (424uL, 2.435mmol, 5eq) was added to a DMF (4mL) solution of 1.1eq). The mixture was then stirred at room temperature overnight under argon protection. 5mL of water was added to the reaction system and extracted with EA (10mL*4). The organic phase was washed with saturated brine (5mL*6), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1-100 / 1) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (330 mg, yield 92.2%) as a light yellow solid.

[0276] Step 7: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)- 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0277]

[0278] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (180 mg, 0.245 mmol, 1.0 eq), 4-bromophenylsulfur pentafluoride (104 mg, 0.367 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.098 mmol, 0.4 eq) and potassium carbonate (67.7 mg, 0.49 mmol, 2.0 eq) were dispersed in anhydrous NMP (2 mL), and then CuI (9.3 mg, 0.049 mmol, 0.2 eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 1 hour. Cool to room temperature, add 5 mL of water, and extract with EA (10 mL*6). The organic phase is washed with saturated brine (10 mL*6), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1) to obtain 135 mg of a yellow solid.

[0279] 135 mg of the yellow solid was dispersed in 2.48 mL of anhydrous ethanol and then heated at 80 o C for 5 minutes, then at 40 o C for 1 hour, and finally stirred at room temperature overnight. The white precipitate was collected by filtration and dried in vacuo to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (77 mg, yield 33.5%). 1 H NMR (400 MHz, DMSO-d6, 80 oC) δ 11.57 (br. s, 1H), 7.92 (br. s, 4H), 7.52 (s, 1H), 7.42 (d, J = 8.5Hz, 1H), 7.32 (s, 1H), 7.26 (dd, J = 8.6,1.7Hz, 1H), 7.14 (d, J = 6.3Hz, 2H), 6.91 (br. s, 1H), 6.85 (br. s, 1H), 5.55(br. s, 1H), 4.47 (br. s, 1H), 3.81-3.58 (m, 2H), 3.57 (br. s, 1H), 3.04-2.96(m, 2H), 2.94-2.85 (m, 1H), 2.21 (d, J = 2.2Hz, 6H), 1.81-1.50 (m, 7H), 1.48-1.36 (m, 3H), 1.31-1.27 (m, 3H), 1.23-1.12 (m, 6H). HRMS: m / z 959.31029 (M+Na) +

[0280] Example 2: Synthesis of 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY102)

[0281]

[0282] Step 8: 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0283]

[0284] To a solution of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (203 mg, 0.453 mmol, 1.0 eq), (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid (189 mg, 0.476 mmol, 1.05 eq) and HATU (189.5 mg, 0.498 mmol, 1.1 eq) in DMF (4 mL) was added DIPEA (395 uL, 4% dextrin) and 1% dextrin. 2.265mmol, 5eq). The mixture was then stirred at room temperature overnight under argon protection. 5mL of water was added to the reaction system and extracted with EA (10mL*4). The organic phase was washed with saturated brine (10mL*3), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-50 / 1-40 / 1) to give 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (245 mg, yield 75%) as a light yellow solid.

[0285] Step 9: 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0286]

[0287] 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (140 mg, 0.194 mmol, 1.0 eq), 4-bromophenylsulfur pentafluoride (82.4 mg, 0.291 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.0776 mmol, 0.4eq) and potassium carbonate (53.6mg, 0.388mmol, 2.0eq) were dispersed in anhydrous NMP (1.5mL), and then CuI (7.4mg, 0.0388mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1 hour. Cool to room temperature, add 5 mL of water, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1) to give 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (45 mg, yield 25.1%) as a light yellow solid. 1 H NMR (600 MHz, DMSO-d6, 60 oC) δ 11.86(br. s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.07-7.82 (br. s, 4H), 7.47-7.37 (m,1H), 7.30 (br. s, 1H), 7.17-6.99 (m, 3H), 6.72 (dd, J = 7.4, 1.9Hz, 1H), 6.43(br. s, 1H), 5.70 (br. s, 1H), 4.09 (br. s, 1H), 3.72 (m, 2H), 3.41 (br. s,1H), 2.92 (m, 1H), 2.83-2.71 (m, 2H), 2.20 (s, 6H), 1.78-1.40 (m, 7H), 1.36-1.24 (m, 7H), 1.20 (s, 3H). HRMS: m / z 945.29425 (M+Na) + .

[0288] Example 3: Synthesis of 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY103)

[0289]

[0290] Step 10: 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0291]

[0292] To a solution of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (236 mg, 0.625 mmol, 1.0 eq), (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid (260.6 mg, 0.656 mmol, 1.05 eq) and HATU (261 mg, 0.6875 mmol, 1.1 eq) in DMF (5 mL) was added DIPEA (544 uL, 4% dextrin) and 1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (236 mg, 0.625 mmol, 1.0 eq), (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid (260.6 mg, 0.656 mmol, 1.05 eq). 3.125mmol, 5eq). Then the mixture was stirred at room temperature overnight under argon protection. 10mL of water was added to the reaction system and extracted with a mixed solvent of DCM / MeOH (20 / 1, 10mL*4). The organic phase was washed with saturated brine (10mL*3), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1-40 / 1) to give 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (340 mg, yield 75.5%) as a light yellow solid.

[0293] Step 11: 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0294]

[0295] 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (290 mg, 0.402 mmol, 1.0 eq), 4-bromophenylsulfur pentafluoride (170.8 mg, 0.603 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (23 mg, 0.161 mmol, 0.4eq) and potassium carbonate (111 mg, 0.804 mmol, 2.0eq) were dispersed in anhydrous NMP (3 mL), and then CuI (15 mg, 0.0804 mmol, 0.2eq) was added. The reaction system was incubated at 130 °C under argon protection. o C for 1 hour. Cool to room temperature, add 5 mL of water, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1-80 / 1) to give 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (178 mg, yield 48%) as a light yellow solid. 1 H NMR (600 MHz, DMSO-d6, 60 oC) δ11.85 (br. s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.10-7.70 (m, 4H), 7.43 (br. s,1H), 7.30 (br. s, 1H), 7.19-6.92 (m, 3H), 6.72 (dd, J = 7.4, 1.9Hz, 1H), 6.43(br. s, 1H), 5.70 (br. s, 1H), 4.09 (br. s, 1H), 3.77-3.66 (m, 2H), 3.45-3.45(m, 1H), 2.93 (t, 1H), 2.84-2.71 (m, 2H), 2.19 (d, J = 8.6Hz, 6H), 1.78-1.59(m, 4H), 1.59-1.39 (m, 3H), 1.38-1.23 (m, 7H), 1.20 (s, 3H). HRMS: m / z959.29493 (M+Na) + .

[0296] Example 4: Synthesis of (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY104)

[0297]

[0298] Step 12: (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0299]

[0300] To a solution of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (236 mg, 0.625 mmol, 1.0 eq), 3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-7-(tetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid (242.4 mg, 0.656 mmol, 1.05 eq) and HATU (261 mg, 0.6875 mmol, 1.1 eq) in DMF (5 mL) in a 25 mL single-necked bottle was added DIPEA (544 uL, 3.125 mmol, 5 eq). The mixture was then stirred at room temperature overnight under argon protection. 10 mL of water was added to the reaction system and extracted with a mixed solvent of DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH = 100 / 1-80 / 1-60 / 1-40 / 1) to give (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (330 mg, yield 76.3%) as a light yellow solid.

[0301] Step 13: (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0302]

[0303] (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (250 mg, 0.361 mmol, 1.0 eq), 4-bromophenylsulfur pentafluoride (153 mg, 0.541 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (20.5 mg, 0.144 mmol, 0.4eq) and potassium carbonate (100mg, 0.722mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (14mg, 0.0722mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1 hour. Cool to room temperature, add 5 mL of water, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1-100 / 1-80 / 1) to give (S)-3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(4-(pentafluorothio)phenyl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (94 mg, yield 29.1%) as a light yellow solid. 1 H NMR (600 MHz, DMSO-d 6, 60 oC) δ 11.86 (br. s,1H), 8.15 (d, J = 7.3Hz, 1H), 8.07-7.74 (m, 4H), 7.43 (br. s, 1H), 7.31 (br.s, 1H), 7.12 (br. s, 2H), 7.03 (br. s, 1H), 6.73 (dd, J = 7.4, 1.9 Hz, 1H), 6.44 (br. s, 1H), 5.71 (d, J = 9.8Hz, 1H), 4.09 (br. s, 1H), 3.97 (dd, J =11.1, 4.2Hz, 2H), 3.46 (t, J = 11.5Hz, 2H), 3.40 (br. HRMS: m / z 895.28171 (M+H) + .

[0304] Example 5: Synthesis of 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY105)

[0305]

[0306] Step 14: 4-(Pentafluorothio)phenylhydrazine

[0307]

[0308] Concentrated sulfuric acid (4.5 mL) and sodium nitrite (1.10 g, 15.96 mmol, 1.06 eq) were added to a 100 mL three-necked flask. The white slurry obtained above was then cooled to 5-10 o C, add 4-(pentafluorothio)aniline (3.3 g, 15 mmol, 1.0 eq) in glacial acetic acid (16.8 mL) dropwise, control the drop rate, and keep the internal temperature no higher than 10 o C. After the addition is complete, oC for 30 minutes, then heated to 60 o C, and continue stirring for 1 hour. The reaction system is cooled to 5 o C, add a solution of tin dichloride dihydrate (13.9 g, 61.5 mmol, 4.1 eq) in concentrated hydrochloric acid (10 mL) dropwise. Heat is released during the addition, and the internal temperature is controlled not to exceed 10 o C. A white viscous solid appeared in the reaction system. After stirring for half an hour in an ice-water bath, the mixture was filtered and the filter cake was transferred in batches to a mixture of 28% ammonia water (56 mL) and crushed ice (14 g). The white suspension was stirred at room temperature for half an hour, filtered with diatomaceous earth, and the filter cake was washed thoroughly with ether. The filtrate was separated into layers, the aqueous phase was extracted with ether (50 mL*4), the ether phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, and dried to obtain a yellow oily substance, which solidified after being left overnight to obtain 4-(pentafluorothio)phenylhydrazine (2.5 g, yield 70.8%) as a yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.8Hz, 2H), 6.79 (d, J = 8.7Hz, 2H), 5.49 (br. s, 1H), 3.58 (br. s, 2H).

[0309] Step 15: (S)-tert-butyl 3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0310]

[0311] 4-(Pentafluorothio)phenylhydrazine (2.96 g, 12.64 mmol, 1.0 eq), (2S)-3-cyano-2-methyl-4-ketopiperidine-1-carboxylic acid tert-butyl ester (3.02 g, 12.64 mmol, 1.0 eq), pyridine hydrochloride (146 mg, 1.26 mmol, 0.1 eq) and toluene (60 mL) were added to a 250 mL single-necked bottle equipped with a condenser. oC for 2 hours. Cool to room temperature, pour the reaction solution into water (30 mL), adjust the pH to 9-10 with 1 mol / L sodium hydroxide aqueous solution. Extract with ethyl acetate (30 mL*3). Combine the organic phases, wash with saturated brine (30 mL*3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 6.5 g of yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA=10 / 1-8 / 1-6 / 1) to obtain (S)-3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.62 g, yield 97.9%), light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.8Hz, 2H), 7.84 (d, J = 8.8Hz, 2H), 5.55 (br. s, 2H), 5.03-5.16 (m, 1H), 4.24-4.00(m, 1H), 3.16-2.96 (m, 1H), 2.55-2.46 (m, 2H), 1.43 (s, 9H), 1.25 (d, J =6.6Hz, 3H).

[0312] Step 16: (S)-tert-butyl 4-methyl-2-(4-(pentafluorothio)phenyl)-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0313]

[0314] To a 50 mL two-necked bottle, add (S)-3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.0 g, 2.2 mmol, 1.0 eq), saturated aqueous sodium carbonate solution (3.3 mL) and THF (20 mL), then cool to 0 oC, add 2,2,2-trichloroethyl chloroformate (1.2mL, 8.8mmol, 4eq) dropwise. After the addition is completed, slowly warm to room temperature and stir overnight. Add 2,2,2-trichloroethyl chloroformate (0.3mL, 1eq) and continue the reaction for 1 hour. Add 10mL of water to the reaction system and extract with EA (10mL*3). Wash the organic phase with saturated brine (10mL*3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA=20 / 1-15 / 1-10 / 1) to give (S)-4-methyl-2-(4-(pentafluorothio)phenyl)-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.16 g, yield 84%) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.6Hz, 2H), 7.64 (d, J = 8.6Hz, 2H), 5.25 (br. s, 1H), 4.98-4.66 (m, 2H), 4.47-4.30 (br.s, 1H), 3.22-2.97 (m, 1H), 2.82-2.67 (m, 2H), 1.48 (s, 9H), 1.36 (br. s, 3H).

[0315] Step 17: (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0316]

[0317] To a 100 mL single-necked bottle, add (S)-4-methyl-2-(4-(pentafluorothio)phenyl)-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.16 g, 1.842 mmol, 1.0 eq), aminoacetaldehyde dimethyl acetal (290.4 mg, 2.762 mmol, 1.5 eq), DIPEA (321 uL, 1.842 mmol, 1.0 eq) and DMSO (20 mL). Then, under argon protection, the temperature was 110 °C. oC for 2 hours. The reaction system was cooled to room temperature, poured into 20 mL of ice water, and then extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA = 10 / 1-5 / 1-3 / 1-2 / 1) to obtain (S)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.92 g, yield 85.2%), a white foamy solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 8.7Hz, 2H), 7.63 (d, J =8.7Hz, 2H), 7.63 (br. s, 1H), 5.74 (br. s, 1H), 5.13 (q, J = 6.8Hz, 1H), 4.30(t, J = 4.9Hz, 1H), 4.26-4.16 (m, 1H), 3.46-3.25 (m, 2H), 3.33 (s, 6H), 3.21-3.09 (m, 1H), 2.77-2.62 (m, 2H), 1.53-1.23 (m, 12H).

[0318] Step 18: (S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0319]

[0320] To a 50 mL single-necked bottle, (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.92 g, 1.571 mmol, 1.0 eq) and THF (10 mL) were added, and then methanesulfonic acid (82 uL, 1.257 mmol, 0.8 eq) was added at room temperature. The resulting mixture was heated at an external temperature of 60 °C. oC and stirred for 2 hours. Cool to room temperature, add potassium phosphate (333.5 mg, 1.571 mmol, 1.0 eq) in water (4 mL) and Boc2O (137 mg, 0.628 mmol, 0.4 eq), and then stir at room temperature overnight. Add 5 mL of water to the reaction system and extract with EA (10 mL*3). Wash the organic phase with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, filter, and spin dry to obtain a white solid. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA = 5 / 1-3 / 1-2 / 1-1 / 1) to give (S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (660 mg, yield 80.6%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.40 (br. s, 1H), 7.78 (d, J = 8.7Hz, 2H), 7.51 (d, J =8.7Hz, 2H), 6.42 (br. s, 1H), 6.19 (br. s, 1H), 5.41-5.14 (m, 1H), 4.58-4.26(m,1H), 3.22-3.00 (br. s, 1H), 2.80 (br. s, 2H), 1.49 (s, 9H), 1.27 (d, J =6.6Hz, 3H).

[0321] Step 19: (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0322]

[0323] Add (S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (700 mg, 1.342 mmol, 1.0 eq) and DCM (10 mL) to a 50 mL single-necked bottle, and then add 4N HCl(g) / 1,4-dioxane solution (3.35 mL, 13.4 mmol, 10 eq) dropwise under an ice-water bath. After the addition is complete, the reaction system is slowly heated to room temperature and stirred for 2 hours. The residue was concentrated and dried to give (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (620 mg, yield 100%) as a white solid.

[0324] Step 20: 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0325]

[0326] To a solution of (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (620 mg, 1.34 mmol, 1.0 eq), (R)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid (585.8 mg, 1.474 mmol, 1.1 eq) and HATU (611.4 mg, 1.608 mmol, 1.2 eq) in DMF (10 mL) was added DIPEA (1.17 mL, 5% dextrin) and 4-(4-(pentafluorothio)phenyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (620 mg, 1.34 mmol, 1.0 eq). 6.70mmol, 5eq). The mixture was then stirred at room temperature overnight under argon protection. 20mL of water was added to the reaction system and extracted with a mixed solvent of DCM / MeOH (20 / 1, 20mL*4). The organic phase was washed with saturated brine (10mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-100 / 1-80 / 1-60 / 1) to give 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (760 mg, yield 71%) as a yellow solid.

[0327] Step 21: 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0328]

[0329] 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.1873 mmol, 1.0 eq), 5-bromo-4-fluoro-1-methyl-2H-indazole (64.4 mg, 0.2810 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (10.7 mg, 0.0749mmol, 0.4eq) and potassium carbonate (51.8mg, 0.375mmol, 2.0eq) were dispersed in anhydrous NMP (2mL), and then CuI (7.1mg, 0.0375mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 3 hours. Cool to room temperature, add 10 mL of water, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1-60 / 1) to give 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4, 3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (12 mg, yield 6.7%) as a light yellow solid. 1H NMR(600 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.11-8.00 (m, 2H), 7.80-7.53 (m, 4H), 7.31 (s, 1H), 7.09-6.97 (m, 2H), 6.72(dd, J = 7.5, 1.9Hz, 1H), 6.45 (s, 1H), 5.73 (br. s, 1H), 4.10 (s, 4H), 3.77-3.60 (m, 2H), 3.42 (br. s, 1H), 2.94 (s, 1H), 2.79 (br. s, 2H), 1.78-1.63 (m,4H), 1.59-1.23 (m, 10H), 1.21 (s, 3H). HRMS: m / z 949.30366 (M+H) + .

[0330] Example 6: Synthesis of 3-(1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY106)

[0331]

[0332] Step 22: 3-(1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0333]

[0334] 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (280 mg, 0.35 mmol, 1.0 eq), 1-bromo-4-(cyclopropylsulfonyl)benzene (137 mg, 0.525 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol, 0.4eq) and potassium carbonate (96.7mg, 0.7mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (13.3mg, 0.07mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1.5 hours. Cool to room temperature, add 10 mL of water, and extract with DCM (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 3-(1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (120 mg, yield 34.9%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.11-7.58 (m, 8H), 7.53 (br. s,1H), 7.30 (s, 1H), 7.12 (br. s, 1H), 6.72 (dd, J = 7.4, 1.9Hz, 1H), 6.44 (s,1H), 5.71 (br. s, 1H), 4.10 (br. s, 1H), 3.72 (dd, J = 9.4, 2.3Hz, 2H), 3.42(br. s, 1H), 2.94 (tt, J = 12.4, 3.6Hz, 1H), 2.87-2.73 (m, 3H), 1.87-1.40 (m,7H), 1.40-0.97 (m, 14H). HRMS: m / z 981.28444 (M+H) + .

[0335] Example 7: Synthesis of 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY107)

[0336]

[0337] Step 23: 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0338]

[0339] 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (280 mg, 0.35 mmol, 1.0 eq), 1-bromo-4-((methylsulfonyl)methyl)benzene (131 mg, 0.525 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol, 0.4eq) and potassium carbonate (96.7mg, 0.7mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (13.3mg, 0.07mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 3 hours. Cool to room temperature, add 10 mL of water, extract with DCM (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 3-(1-(7-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (88 mg, yield 26%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.03 (d, J = 8.5Hz, 2H), 7.87-7.45 (m, 6H), 7.39 (br. s, 1H), 7.30 (s, 1H), 7.05 (br. s, 1H),6.72 (dd, J = 7.3, 1.9 Hz, 1H), 6.44 (s, 1H), 5.71 (br. s, 1H), 4.50 (s, 2H),4.10-4.05 (br. s, 1H), 3.84-3.59 (m, 2H), 3.42 (br. s, HRMS: m / z 969.28454 (M+H) + .

[0340] Example 8: Synthesis of 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY108)

[0341]

[0342] Step 24: 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0343]

[0344] To a solution of (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (750 mg, 1.638 mmol, 1.0 eq), (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indolizine-2-carboxylic acid (716 mg, 1.802 mmol, 1.1 eq) and HATU (747.4 mg, 1.966 mmol, 1.2 eq) in DMF (10 mL) was added DIPEA (1.43 mL, 5% dextrin) and 4-(4-(pentafluorothio)phenyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (750 mg, 1.638 mmol, 1.0 eq). 8.19mmol, 5eq). Then the mixture was stirred at room temperature overnight under argon protection. 10mL of water was added to the reaction system and extracted with EA (20mL*5). The organic phase was washed with saturated brine (20mL*5), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1) to give 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.0 g, yield 76.3%) as a light yellow solid.

[0345] Step 25: 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0346]

[0347] 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.125 mmol, 1.0 eq), 5-bromo-4-fluoro-1-methyl-2H-indazole (31.5 mg, 0.137 mmol, 1.1 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (26.7 mg, 0.1875mmol, 1.5eq) and potassium carbonate (34.6mg, 0.250mmol, 2.0eq) were dispersed in anhydrous NMP (2mL), and then CuI (35.7mg, 0.1875mmol, 1.5eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1 hour. Cool to room temperature, add 5 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*3). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (19 mg, yield 16%) as a light yellow solid. 1H NMR(600 MHz, DMSO-d6) δ 11.86 (br. s, 1H), 8.24 (br. s, 1H), 8.14 (d, J = 7.3Hz,1H), 8.05 (d, J = 8.6Hz, 2H), 7.72-7.44 (m, 4H), 7.30 (br. s, 1H), 7.09-7.03(m, 2H), 6.72 (dd, J = 7.3, 1.9Hz, 1H), 6.45 (s, 1H), 5.73 (br. s, 1H), 4.11(s, 4H), 3.72 (d, J = 8.7Hz, 2H), 3.42 (br. s, 1H), HRMS: m / z 971.28452 (M+Na) + .

[0348] Example 9: Synthesis of 3-(1-(2-((S)-3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY109)

[0349]

[0350] Step 26: 3-(1-(2-((S)-3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0351]

[0352] 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.375 mmol, 1.0 eq), 1-bromo-4-(cyclopropylsulfonyl)benzene (146.7 mg, 0.562 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21.3 mg, 0.150mmol, 0.4eq) and potassium carbonate (103.5mg, 0.749mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (14.3mg, 0.075mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1.5 hours. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a brown solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1-60 / 1) to give 3-(1-(2-((S)-3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (270 mg, yield 73.4%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.07-7.40 (m, 9H), 7.30 (s, 1H), 7.12 (br. s, 1H), 6.72 (dd, J = 7.4, 1.9Hz,1H), 6.44 (s, 1H), 5.74 (br. s, 1H), 4.10 (br. s, 1H), 3.83-3.61 (m, 2H), 3.47-3.35 (m, 1H), , 2.94 (td, J = 10.7, 9.1, 6.1Hz, 1H), 2.87-2.76 (m, 3H),1.80-1.40 (m, 7H), 1.36-1.23 (m, 7H), 1.20 (s, 3H), 1.15-1.12 (m, 2H), 1.07-1.02 (m, 2H). HRMS: m / z 981.28282 (M+H) + .

[0353] Example 10: Synthesis of 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY110)

[0354]

[0355] Step 27: 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0356]

[0357] 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.375 mmol, 1.0 eq), 1-bromo-4-((methylsulfonyl)methyl)benzene (140 mg, 0.562 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21.3 mg, 0.150mmol, 0.4eq) and potassium carbonate (103.5mg, 0.749mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (14.3mg, 0.075mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 3 hours. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a brown solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1-60 / 1) to give 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (124 mg, yield 34.1%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s, 1H), 8.14 (d, J = 7.3Hz, 1H), 8.03 (d, J = 8.6Hz, 2H), 7.89-7.19 (m, 8H), 7.05 (br. s, 1H), 6.72 (dd, J =7.3, 1.9Hz, 1H), 6.44 (s, 1H), 5.73 (br. s, 1H), 4.50 (s, 2H), 4.10 (br. s,1H), 3.89-3.66 (m, 2H), 3.52-3.34 (m, 1H), 3.00-2.86 (m, 4H), 2.79 (br. s,2H), 1.86-1.63 (m, 4H), 1.59-1.41 (m, 3H), 1.36-1.23 (m, 7H), 1.21 (s, 3H).HRMS: m / z 991.26793 (M+Na) + .

[0358] Example 11: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY111)

[0359]

[0360] Step 28: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0361]

[0362] To a 50 mL single-necked bottle was added (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (760 mg crude, 1.534 mmol, 1.0 eq), 5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid (694.3 mg, 1.687 mmol, 1.1 eq) and HATU (700 mg, 1.841 mmol, DIPEA (1.33 mL, 7.67 mmol, 5 eq) was added to a DMF (10 mL) solution of 1.2 eq). The mixture was then stirred at room temperature overnight under argon protection. 10 mL of water was added to the reaction system and extracted with EA (20 mL*5). The organic phase was washed with saturated brine (20 mL*5), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1-40 / 1) to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1.1 g, yield 88%) as a light yellow solid.

[0363] Step 29: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0364]

[0365] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.368 mmol, 1.0 eq), 5-bromo-4-fluoro-1-methyl-2H-indazole (126.5 mg, 0.552 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.147 mmol, 0.4 eq) and potassium carbonate (101.8 mg, 0.736 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), and then CuI (14 mg, 0.074 mmol, 0.2 eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 3 hours. Cool to room temperature, add 10mL of water, and extract with a mixed solvent of DCM / MeOH (20 / 1, 10mL*4). The organic phase was washed with saturated brine (10mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to obtain 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo- =Then the product was prepared from 2-(4-(pentafluorothio)phenyl)-2-(4-((4-(pentafluorothio)phenyl)-2-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (45 mg, yield 12.7%), off-white solid. 1H NMR (600 MHz, DMSO-d6) δ 11.62 (br. s,1H), 8.23 ​​(br. s, 1H), 8.06 (d, J = 8.9Hz, 2H), 7.85-7.34 (m, 5H), 7.40 (s,1H), 7.26 (d, J = 8.5Hz, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 5.69 (br. s, 1H), 4.40 (br. s, 1H), 4.10 (s, 3H), 3.85-3.64 (m, 2H), 3.63 (br. s, 1H), 3.04(td, J = 10.7, 8.8, 6.1Hz, 1H), 2.95 (br. s, 2H), 1.88-1.38 (m, 10H), 1.34-1.23 (m, 5H), 1.19 (s, 4H). HRMS: m / z 985.30114 (M+Na) + .

[0366] Example 12: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY112)

[0367]

[0368] Step 30: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0369]

[0370] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.368 mmol, 1.0 eq), 1-bromo-4-(cyclopropylsulfonyl)benzene (144 mg, 0.552 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.147 mmol, 0.4 eq) and potassium carbonate (101.8 mg, 0.736 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), and then CuI (14 mg, 0.074 mmol, 0.2 eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 1.5 hours. Cool to room temperature, add 10 mL of water, and extract with a mixed solvent of DCM / MeOH (20 / 1, 10 mL*4). The organic phase is washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a brown-yellow solid. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to obtain 230 mg of a light yellow solid.

[0371] Disperse 230 mg of the crude product into 4 mL of anhydrous ethanol and then o C for 5 minutes, 40 o C for 1 hour, and finally stirred at room temperature overnight. The white solid was collected by filtration and dried in vacuo to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (145 mg, yield 39.6%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 11.60 (br. s, 1H), 8.22-7.84 (m, 6H), 7.65 (br. s,2H), 7.52 (br. s, 2H), 7.41 (d, J = 8.5Hz, 1H), 7.26 (d, J = 8.5Hz, 1H), 7.10(br. s, 1H), 6.92 (br. s, 1H), 5.71 (br. s, 1H), 4.40 (br. s, 1H), 3.75-3.70(m, 2H), 3.62 (br. s, 1H), 3.06-3.02 (m, 1H), 2.99-2.77 (m, 3H) 1.84-1.66 (m,4H), 1.60 (dd, J = 14.6, 6.6Hz, 2H), 1.53 (t, J = 12.8Hz, 1H), 1.40 (br. s,3H), 1.28-1.25 (m, 4H), 1.19 (s, 3H), 1.13 (br. s, 3H), 1.10-1.00 (m, 3H).HRMS: m / z 1017.28195 (M+Na) + .

[0372] Example 13: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY113)

[0373]

[0374] Step 31: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0375]

[0376] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.368 mmol, 1.0 eq), 1-bromo-4-((methylsulfonyl)methyl)benzene (137.6 mg, 0.552 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.147 mmol, 0.4 eq) and potassium carbonate (101.8 mg, 0.736 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), and then CuI (14 mg, 0.074 mmol, 0.2 eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 1.5 hours. Cool to room temperature, add 10 mL of water, and extract with EA (10 mL*4). The organic phase is washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a brown-yellow color. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to obtain 200 mg of light yellow solid.

[0377] Disperse 200 mg of the crude product in 3.5 mL of anhydrous ethanol and then o C for 5 minutes, 40 o C for 1 hour, and finally stirred at room temperature overnight. The white solid was collected by filtration and dried in vacuo to give 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (109 mg, yield 30.1%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 11.61 (br. s, 1H), 8.05 (d, J = 8.6Hz, 2H), 7.83-7.59 (m, 4H), 7.53 (br. s, 3H), 7.41 (d, J = 8.7Hz, 2H), 7.26 (d, J =8.5Hz, 1H), 7.04 (br. s, 1H), 6.92 (br. s, 1H), 5.66 (br. s, 1H), 4.49 (s,2H), 4.40 (br. s, 1H), 3.77-3.70 (m, 2H), 3.63 (br. s, 1H), 3.04 (tt, J =12.4, 3.6Hz, 1H), 2.99-2.85 (m, 5H), 1.87-1.66 (m, 4H), 1.62 (dd, J = 12.3,8.4Hz, 2H), 1.54 (t, J = 13.0 Hz, 1H), 1.49-1.33 (m, 3H), 1.29-1.25 (m, 4H),1.23-1.10 (m, 5H). HRMS: m / z 1005.28174 (M+Na) + .

[0378] Example 14: Synthesis of (S)-3-(1-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY114)

[0379]

[0380] Step 32: (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0381]

[0382] To a solution of compound (S)-1-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (750 mg, 1.638 mmol, 1.0 eq), 3-(1-(4-oxo-4,5-dihydro-1H-imidazol-2-yl)cyclopropyl-7-(tetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid (665.6 mg, 1.802 mmol, 1.1 eq) and HATU (747.4 mg, 1.966 mmol, 1.2 eq) in DMF (10 mL) was added DIPEA (1.43 mL, 8.19 mmol, 1.0 eq). 5eq). The mixture was then stirred at room temperature overnight under argon protection. 10 mL of water was added to the reaction system and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*6), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH= 125 / 1-100 / 1-80 / 1) to give (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (0.9 g, yield 71.4%) as a light yellow solid.

[0383] Step 33: (S)-3-(1-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0384]

[0385] (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (200 mg, 0.2588 mmol, 1.0 eq), 5-bromo-4-fluoro-1-methyl-2H-indazole (89 mg, 0.3882 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (14.7 mg, 0.1035 mmol, 0.4eq) and potassium carbonate (71.5mg, 0.5176mmol, 2.0eq) were dispersed in anhydrous NMP (2mL), and then CuI (10mg, 0.052mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 4 hours. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1-60 / 1), and then purified by preparative plate to give (S)-3-(1-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, yield 12.6%) as a light yellow solid. 1H NMR(600 MHz, DMSO-d6) δ 11.87 (br. s, 2H), 8.23 ​​(s, 1H), 8.15 (d, J = 7.3Hz,1H), 8.11-8.00 (m, 2H), 7.83-7.41 (m, 4H), 7.30 (s, 1H), 7.14-6.91 (m, 2H),6.85-6.56 (m, 1H), 6.45 (s, 1H), 5.72 (br. s, 1H), 4.10 (s, 4H), 4.02-3.94(m, 2H), 3.48-3.44 (m, 3H), 2.91-2.66 (m, 3H), 1.82-1.59 (m, 5H), 1.53-1.20(m, 6H). HRMS: m / z 921.27131 (M+H) + .

[0386] Example 15: Synthesis of (S)-3-(1-(2-(3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY115)

[0387]

[0388] Step 34: (S)-3-(1-(2-(3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0389]

[0390] (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (280 mg, 0.362 mmol, 1.0 eq), 1-bromo-4-(cyclopropylsulfonyl)benzene (142 mg, 0.543 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.145 mmol, 0.4eq) and potassium carbonate (100 mg, 0.725 mmol, 2.0eq) were dispersed in anhydrous NMP (3 mL), and then CuI (14 mg, 0.0725 mmol, 0.2eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 1.5 hours. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*5), dry over anhydrous sodium sulfate, and spin dry to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give (S)-3-(1-(2-(3-(3-(4-(cyclopropylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (230 mg, yield 66.6%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s,1H), 8.16 (d, J = 7.3Hz, 1H), 8.10-7.45 (m, 9H), 7.30 (s, 1H), 7.12 (br. s,1H), 6.74 (dd, J = 7.3, 1.9Hz, 1H), 6.45 (s, 1H), 5.74 (br. s, 1H), 4.11 (br.s, 1H), 3.98 (dd, J = 11.3, 4.2Hz, 2H), 3.52-3.35 (m, 3H), 2.88-2.72 (m, 4H),1.82-1.58 (m, 6H), 1.44 (br. s, 1H), 1.35-1.22 (m, 4H), 1.15-1.14 (m, 2H), 1.07-1.02 (m, 2H). HRMS: m / z 975.23659 (M+Na) + .

[0391] Example 16: Synthesis of (S)-3-(1-(2-(4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY116)

[0392]

[0393] Step 35: (S)-3-(1-(2-(4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0394]

[0395] (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (280 mg, 0.362 mmol, 1.0 eq), 1-bromo-4-((methylsulfonyl)methyl)benzene (135.4 mg, 0.543 mmol, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.145 mmol, 0.4eq) and potassium carbonate (100mg, 0.725mmol, 2.0eq) were dispersed in anhydrous NMP (3mL), and then CuI (14mg, 0.0725mmol, 0.2eq) was added. The reaction system was heated at 130°C under argon protection. o C for 3 hours. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, extract with EA (10 mL*4). Wash the organic phase with saturated brine (10 mL*4), dry over anhydrous sodium sulfate, and spin dry to obtain a crude product. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give (S)-3-(1-(2-(4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (104 mg, yield 30.5%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.86 (br. s,1H),8.15 (d, J = 7.3Hz, 1H), 8.03 (d, J = 8.6Hz, 2H), 7.84-7.35 (m, 7H), 7.30 (s,1H), 7.05 (br. s, 1H), 6.73 (dd, J = 7.3, 1.9Hz, 1H), 6.45 (s, 1H), 5.73 (br.s, 1H), 4.50 (br. s, 2H), 4.10 (br. s, 1H), 3.98 (dd, J = 10.5, 4.2Hz, 2H),3.56-3.37 (m, 3H), 2.91 (s, 3H), 2.85-2.69 (m, 3H), 1.80-1.74 (m, 2H), 1.73-1.55 (m, 4H), 1.44 (br. s, 1H), 1.36-1.23 (m, 4H). HRMS: m / z 941.25370 (M+H) + .

[0396] Example 17: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY117)

[0397]

[0398] Step 36: (4-Bromophenyl)diethylphosphine oxide

[0399]

[0400] 4-iodobromobenzene (1.0 g, 3.535 mmol, 1 eq), diethylphosphine oxide (412.5 mg, 3.888 mmol, 1.1 eq), Xantphos (204.5 mg, 0.3535 mmol, 0.1 eq), Pd2(dba)3 (161.8 mg, 0.177 mmol, 0.05 eq) and 1,4-dioxane (20 mL) were added to a 100 mL single-necked bottle. After replacing the argon atmosphere three times, TEA (983 uL, 7.070 mmol, 2 eq) was added. Then, the mixture was stirred at an external temperature of 60 °C for 2 h. o C overnight. The reaction system was cooled to room temperature, concentrated to remove 1,4-dioxane, 10 mL of water was added to the residue, and extracted with EtOAc (10 mL*3). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and spin-dried to obtain a brown oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA / MeOH = 1 / 1 / 0-1 / 2 / 0-1 / 2 / 0.1-1 / 4 / 0.1) to obtain (4-bromophenyl) diethyl phosphine oxide (640 mg, yield 69.3%) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 8.4, 2.2Hz, 2H), 7.56 (dd, J = 10.2, 8.3Hz, 2H), 1.99 (ddd, J = 15.1, 12.7, 7.6Hz, 2H), 1.85 (ddd, J = 15.1, 9.7, 7.6Hz, 2H), 1.11 (dt, J = 17.0, 7.6Hz, 6H).

[0401] Step 37: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0402]

[0403] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.184 mmol, 1 eq), (4-bromophenyl)diethylphosphine oxide (53 mg, 0.202 mmol, 1.1 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (39.3 mg, 0.276mmol, 1.5eq) and potassium carbonate (51mg, 0.368mmol, 2eq) were dispersed in anhydrous NMP (5mL), and then CuI (52.6mg, 0.276mmol, 1.5eq) was added. The reaction system was heated at 130°C under argon protection. o C for 1 hour. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*3). The organic phase is washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1-80 / 1-60 / 1-40 / 1) to obtain a yellow solid.

[0404] The obtained yellow solid was slurried with ether / hexane (1v / 5v, 5mL), filtered, and dried in vacuo to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (101 mg, yield 55.1%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ11.63 (s, 1H),8.04 (d, J = 8.6Hz, 2H), 7.97-7.75 (m, 4H), 7.65 (br. s, 2H), 7.56-7.44 (m,2H), 7.41 (d, J = 8.5Hz, 1H), 7.26 (d, J = 8.5Hz, 1H), 7.07 (br. s, 1H), 6.93(br. s, 1H), 5.66 (br. s, 1H), 4.40 (br. s, 1H), 3.77-3.69 (m, 2H), 3.67-3.57(br. s, 1H), 3.04 (tt, J = 12.6, 3.7Hz, 1H), 2.99-2.91 (m, 2H), 2.12-1.81 (m,4H), 1.77-1.34 (m, 10H), 1.31-1.25 (m, 4H), 1.22-1.08 (m, 5H), 0.96 (dt, J =15.9, 7.6Hz, 6H). HRMS: m / z 995.34501 (M+H) + .

[0405] Example 18: Synthesis of (S)-3-(1-(2-(3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY118)

[0406]

[0407] Step 38: (S)-3-(1-(2-(3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0408]

[0409] (S)-3-(1-(2-(4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (140 mg, 0.1812 mmol, 1 eq), (4-bromophenyl)diethylphosphine oxide (52 mg, 0.1993 mmol, 1.1 eq), (1S, 2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (39 mg, 0.2718 mmol, 1.5 eq) and potassium carbonate (50 mg, 0.1812 mmol, 1.5 eq) were added. 0.3624mmol, 2eq) was dispersed in anhydrous NMP (5mL), and then CuI (52mg, 0.2718mmol, 1.5eq) was added. The reaction system was heated at 130°C under Ar protection. o C for 1 hour. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*3). The organic phase is washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1-40 / 1) to obtain a yellow crude product. The resulting yellow crude product was then purified by preparative plate to give (S)-3-(1-(2-(3-(3-(4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-(tetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (40 mg, yield 23.2%) as a light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.15 (d, J = 7.3Hz, 1H), 8.02(d, J = 8.6Hz, 2H), 7.96-7.70 (m, 4H), 7.63 (br. s, 2H), 7.47 (br. s, 1H),7.30 (s, 1H), 7.07 (br. s, 1H), 6.73 (dd, J = 7.3, 1.9Hz, 1H), 6.44 (s, 1H),5.73 (br. s, 1H), 4.10 (br. s, 1H), 3.97 (dd, J = 10.6, 4.3Hz, 2H), 3.50-3.39(m, 3H), 2.87-2.67 (m, 3H), 2.00-1.82 (m, 4H), 1.81-1.73 (m, 2H), 1.72-1.58(m, 4H), 1.44 (br. s, 1H), 1.36-1.22 (m, 4H), 0.96 (dt, J = 16.1, 7.5Hz, 6H).HRMS: m / z 975.28130 (M+Na) + .

[0410] Example 19: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (FY119)

[0411]

[0412] Step 39: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0413]

[0414] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (150 mg, 0.184 mmol, 1 eq), (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (58.8 mg, 0.202 mmol, 1.1 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (39.3 mg, 0.276 mmol, 1.5 eq) and potassium carbonate (51 mg, 0.368 mmol, 2 eq) were dispersed in anhydrous NMP (5 mL), and then CuI (52.6 mg, 0.276 mmol, 1.5 eq) was added. The reaction system was heated at 130 °C under argon protection. o C for 1 hour. Cool to room temperature, add 10 mL of saturated sodium carbonate aqueous solution, and extract with EA (10 mL*3). The organic phase is washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and spin-dried to obtain a black oil. The crude product is purified by column (silica gel, 200-300 mesh, DCM / MeOH=80 / 1-60 / 1-40 / 1) to obtain 140 mg of yellow solid.

[0415] Disperse 140 mg of the crude product in 2.4 mL of anhydrous ethanol and then o C for 5 minutes, 40 o C for 1 hour, and finally stirred at room temperature overnight. The white solid was collected by filtration and dried in vacuo to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (117 mg, yield 62%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ11.61(br. s, 1H), 8.04 (d, J = 8.6Hz,2H), 7.74-7.59 (m, 3H), 7.52(br. s, 1H), 7.40(d, J = 8.7Hz, 2H), 7.25 (d, J =8.6Hz, 1H), 7.05-6.91 (m, 4H), 5.65(br. s, 1H), 4.39 (br. s, 1H), 3.72-3.73(m, 2H), 3.62 (br. s, 1H), 3.03(t, J = 12.4Hz, 1H), 2.94 (br. s, 2H), 2.75(br. s, 3H), 1.91-1.86(m, 4H), 1.75-1.50 (m, 7H), 1.44-1.35 (m, 2H), 1.31-1.12 (m, 10H), 1.01 (dt, J = 15.9, 7.5Hz, 6H). HRMS: m / z 1046.35484 (M+Na) + .

[0416] Example 20: h-GLP-1 activity assay

[0417] Step 1) Cell treatment and plating. HEK293 cells expressing GLP-1R receptors in good growth state were taken, digested with 0.25% Trypsin-EDTA, counted by trypan blue staining, collected, and cell density was adjusted with detection diluent. 100 µL / well was added to a 96-well plate, and the number of cells was 5×10 4 / well; place the above 96-well plate in a 37 °C, 5% CO2 incubator and incubate overnight.

[0418] Step 2) Sample addition. Discard the culture medium in the 96-well plate with Human GLP-1R (Luc) HEK293 Reporter Cells, and add the agonist sample to be tested, Tirzepatide dilution, and DMSO dilution to the corresponding 96-well plate, i.e., add 80 µL / well dilution to the sample test wells, and repeat 2 wells. Add the same volume of test dilution to the blank wells.

[0419] Step 3) Incubate. Place the cell plate in a 37 °C, 5% CO2 incubator for approximately 3 hours.

[0420] Step 4) Reading. Remove the cell plate, equilibrate to room temperature, add 80 µL of an equal volume of ONE-Glo™ Luciferase solution, and shake on a microshaker for 2 minutes to lyse the cells. Mix each well by pipetting (20 to 25 times) and transfer 110 μL to the corresponding white opaque 96-well microplate. Read the RLU value of the plate using a microplate chemiluminometer.

[0421] Step 5) Data processing. Tirzepatide was used as a positive control, and 1000 nM Tirzepatide was set as 100% response. The data were analyzed using GraphPad Prism7 software, with sample concentration as the horizontal axis and RLU value as the vertical axis. The four-parameter dose-effect curve was fitted, and the EC of the sample was calculated. 50 The values ​​are presented in Table 1.

[0422] As shown in Table 1, the compounds exhibited potent h-GLP-1 agonist activity ("A" means > 0 nM and ≤ 20 nM; "B" means > 20 nM and ≤ 200 nM; "C" means > 200 nM).

[0423] Table 1 Compound numbers and corresponding chemical structures and EC 50 value

[0424] Example 21: Pharmacokinetic testing of compounds

[0425] The compound of the present invention is formulated in 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM glycine-NaOH pH 10 and administered via oral gavage (PO) at a dose of 5 mg per kg body weight in fasted SD rats. Plasma samples are collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. Compound concentration is determined by LC-MS, and pharmacokinetic parameters are calculated using a non-compartmental analysis model by WinNonlin 8.2. The PK parameters of representative compounds are listed in Table 2.

[0426]

[0427] Control compound

[0428] Table 2 PK parameters of compounds

[0429]

[0430] The data in Table 1 and Table 2 show that the compounds provided by the present invention have both high activity and bioavailability and still meet the peak concentration requirements of the drug at a lower dosage.

[0431] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A GLP-1 agonist having a structure as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof: Formula I; in, Ring A and Ring D are each independently selected from substituted or unsubstituted aryl, heteroaryl, heterocyclyl or cycloalkyl; and at least one of Ring A and Ring D is substituted by one or more SF5; The L2 is selected from any of the following structures: Wherein, aa represents the connection point with ring D; n1 is any integer from 1 to 3; L 2A is a single bond or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl or C(=O)(C 1-6 alkyl); R Lb and R Lc Independently selected from H or C 1-6 alkyl; R 1 , R 2 and R 3 Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The substituents of the alkyl group are selected from halogen, hydroxyl, C 1-6 One or more of alkoxy groups; L 1 Selected from: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- or -S(=O)2; Ring B is selected from any of the following structures: Among them, bb represents L 1 The connection point; R 4 , R 5 , R 6 and R 7 Independently selected from: H, halogen or C 1-6 alkyl; L 3 is a single bond or C 1-3 Alkylene; L 4 is a single bond or C 1-5 Alkylene; R 8a and R 8b Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted by one or more selected from halogen or C 3-15 The cycloalkyl group is substituted by a substituent; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-15 Cycloalkyl; said C 3-15 The cycloalkyl group may be optionally substituted with one or more substituted or unsubstituted C 1-6 Alkyl substitution; R 9 Selected from: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) or (IX-4): R 9a H or C 1-6 alkyl; R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g Independently selected from: H, substituted or unsubstituted C 1-6 Alkyl, C(=O)(C 1-6 Alkyl); the C 1-6 The alkyl group may be optionally substituted with one or more halogen or C 1-6 Alkoxy substitution; Ring C is selected from 3 to 12 membered heterocyclic groups, C 3-15 Cycloalkyl or 5-10 membered heteroaryl; wherein the 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10 membered heteroaryl may be optionally substituted by one or more R Ca replace; The R Ca Selected from: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or NR c R d ; The two R on the same or different ring atoms Ca Together with one or more ring atoms to which they are connected, they can form a 3- to 8-membered cycloalkyl group; R c and R d Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) or S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) each may be optionally substituted by one or more independently selected from -OH, halo, C 1-6 The substituents of the alkoxy group are substituted.

2. The GLP-1 agonist according to claim 1, characterized in that The ring A and the ring D are each independently selected from a substituted or unsubstituted 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 3- to 12-membered heterocyclic group or a C 3~15 cycloalkyl; and at least one of ring A and ring D is substituted with one or more SF5.

3. The GLP-1 agonist according to claim 2, characterized in that The ring A and ring D are each independently selected from any one of the following structures: ； Among them, T 1 , T 2 , T 3 , T 4 , T 5 Each independently selected from N, CH or CR QA ; R QA Selected from halogen, cyano, hydroxyl, oxo, NR a R b 、C(═O) NR c1 R d1 , substituted or unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, 3- to 8-membered cycloalkyl group; or R QA Selected from -L a -S(O)2-L b -R e ; L a Selected from: single bond, -N(H)-, -N(R c1 )-or-(CR h R h ) q1 -; L b Selected from: single bond, -O-, -N(H)-, -N(R c1 )-or-(CR h R h ) q2 -; q 1 and q 2 Independently selected from 1, 2, 3 or 4; R e Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3 to 8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3- to 8-membered heterocyclic group may be optionally substituted by one or more independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 Substitution of haloalkoxy substituents; R a and R b Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O) (C 1-6 alkyl), C(=O) (C 3-6 Cycloalkyl) or C(=O)O(C 1-6 alkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O) (C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl) and C(=O)O(C 1-6 alkyl) each may be optionally substituted by one or more independently selected from -OH, halogen, C 1-6 Substitution of alkoxy groups; R c1 and R d1 Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) or S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) each may be optionally substituted by one or more independently selected from -OH, halo, C 1-6 Substitution of alkoxy groups; R h Selected from: H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or two R on the same or different carbon atoms h And connect the two R h One or more carbon atoms together form C 3-6 Cycloalkyl or 4- to 8-membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 The cycloalkyl or 4- to 8-membered heterocyclic group may be optionally substituted by one or more independently selected from halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy or C 1-3 Substitution of haloalkoxy substituents; And when L a When it is a single bond, -L b -R e Not unsubstituted C 1-3 alkyl; or R QA P(=O)R j R k ; Among them, R j and R k Independently selected from the following groups: substituted or unsubstituted C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl; said C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl groups may be optionally substituted with one or more of the following groups: 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, NHC(=O) (C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 Cycloalkyl); or R j and R k Together with the phosphorus atoms to which they are connected, they form a 5- to 8-membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group may be optionally substituted with one or more selected from C 1-6 The alkyl group is substituted by a substituent; the heteroatom of the 5- to 8-membered heterocyclic group is P or includes one or more of O, S, N and P; The R QB For SF5.

4. The GLP-1 agonist according to claim 3, characterized in that The ring A and ring D are each independently selected from any one of the following structures: ； Wherein, m1 is 0, 1 or 2; T 6 , T 7 , T 8 Independently selected from CR 10 R 11 or NR 12 ; R 10 , R 11 , R 12 independently selected from halogen, C 1~10 The alkyl group may be absent; the C1~10 alkyl group may be optionally substituted by a substituent selected from halogen, nitro, and amino.

5. The GLP-1 agonist according to claim 1, characterized in that The L2 is selected from any of the following structures: 。 6. The GLP-1 agonist according to claim 1, characterized in that The L 1 It is -C(=O)-.

7. The GLP-1 agonist according to claim 1, characterized in that The R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-8 Cycloalkyl; said C 3-8 The cycloalkyl group may be optionally substituted with one or more substituted or unsubstituted C 1-6 Alkyl substitution.

8. The GLP-1 agonist according to claim 7, characterized in that The R 8a and R 8b Together with the carbon atoms to which they are attached, they form a substituted or unsubstituted cyclopropyl or cyclobutyl group; the cyclopropyl group and the cyclobutyl group may be optionally substituted or unsubstituted by one or more C 1-6 Alkyl substitution.

9. The GLP-1 agonist according to claim 1, characterized in that The R 9 Has the following structure: The R 9d Selected from: H, substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted with one or more halogen or C 1-6 Alkoxy substitution.

10. The GLP-1 agonist according to any one of claims 1 to 9, characterized in that The GLP-1 agonist has a structure shown in Formula I-a or Formula I-b, or a pharmaceutically acceptable salt or solvate thereof: Wherein, the ring A and the L 2 At least one of the attached phenyl groups is substituted with one or more SF5; The ring E is selected from substituted or unsubstituted C 3-6 Cycloalkyl; The R 8c is selected from H, substituted or unsubstituted C 1-6 alkyl.

11. The GLP-1 agonist according to any one of claims 1 to 10, characterized in that The GLP-1 agonist has a structure shown in Formula Ⅰ-a-1, or a pharmaceutically acceptable salt or solvate thereof: R QB For SF5.

12. The GLP-1 agonist according to any one of claims 1 to 11, characterized in that The GLP-1 agonist has the structure shown in Formula Ⅰ-a-2, or a pharmaceutically acceptable salt or solvate thereof: R QB For SF5.

13. The GLP-1 agonist according to any one of claims 1 to 12, characterized in that The GLP-1 agonist has a structure shown in Formula Ⅰ-a-3 or Formula Ⅰ-a-4, or a pharmaceutically acceptable salt or solvate thereof: Wherein, a is any integer from 1 to 3; b is any integer from 0 to 3; R j and R k Independently selected from substituted or unsubstituted C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2, NHC(=O) (C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 Cycloalkyl); The T1, T2, T3, T4 and T5 are independently selected from NR 12 , O, S or CR 13 R 14 ; The R 12 , R 13 and R 14 independently selected from H, halogen, substituted or unsubstituted C 1~6 Alkyl, C 1~6 Alkoxy; the C 1~6 Alkyl, C 1~6 The alkoxy group may be optionally substituted by one or more substituents selected from halogen and cyano.

14. The GLP-1 agonist according to claim 1, characterized in that The GLP-1 agonist has any of the following structures, or a pharmaceutically acceptable salt or solvate thereof: 。 15. The method for preparing the GLP-1 agonist according to any one of claims 1 to 14, comprising the following steps: Using the intermediate represented by formula A and the intermediate represented by formula B as raw materials, an amination reaction is carried out to obtain the intermediate represented by formula C; Using the intermediate represented by formula C as a raw material, a GLP-1 agonist represented by formula I is prepared; Among them, ring A, R 1 -R 3 The range is as described in any one of claims 1 to 14; Pg is an amino protecting group.

16. A GLP-1 agonist composition, comprising the GLP-1 agonist according to any one of claims 1 to 14, and a pharmaceutically acceptable excipient.

17. Use of the GLP-1 agonist according to any one of claims 1 to 14 or the GLP-1 agonist composition according to claim 16 in the preparation of a drug for preventing, treating and / or alleviating diabetes.

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