A glp-1 agonist and its preparation method and application

Abstract

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

Description

TECHNICAL FIELD

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

[0002] Diabetes mellitus is a chronic disease marked by hyperglycemia caused by absolute or relative insulin secretion deficiency and utilization disorder. The disease is mainly divided into three types: type 1, type 2 and gestational diabetes, among which type 2 diabetes (T2DM) is the most common form, accounting for more than 90% of diabetes cases.

[0003] Due to factors such as high-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, antidiabetic drugs still need to be taken.

[0004] In healthy individuals, the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) of the intestinal insulinotropic hormone can tandemly regulate the secretory response of insulin to glucose uptake. Although the intestinal insulinotropic effect is significantly weakened (if it exists at all) in cases of T2DM, GLP-1 still retains the property of promoting insulin even if the endocrine pancreas response to GIP is effectively terminated. Therefore, intestinal insulin mimetics and other GLP-1-based therapies can help stimulate insulin production in T2DM patients. Drugs targeting the above-mentioned intestinal peptide family, 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 are difficult to simultaneously ensure the activity and bioavailability of the drug, resulting in a higher dosage of the drug, which may cause adverse reactions in patients. How to simultaneously improve the activity and bioavailability of the drug is a problem that needs to be solved at present. SUMMARY

[0006] Therefore, the technical problem to be solved by the present application is to provide a GLP-1 agonist and a preparation method and application thereof. The prepared GLP-1 agonist has high activity and bioavailability.

[0007] To achieve the above-mentioned purpose, the present application provides a GLP-1 agonist having the structure 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, heterocyclyl or cycloalkyl; and at least one of ring A and ring D is substituted with one or more SF5;

[0011] said L2is selected from any one of the following structures:

[0012] wherein, aa represents the connecting point with ring D;

[0013] n1is any integer from 1 to 3;

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

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

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

[0017] R 1 , R 2 and R 3 are independently selected from: H, substituted or unsubstituted C 1-6 alkyl; the substituent of said C 1-6 alkyl is selected from one or more of halogen, hydroxyl, C 1-6 alkoxy;

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

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

[0020]

[0021] wherein, bb represents the connecting point with L 1 ;

[0022] R 4 , R 5 , R 6 and R 7 are 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 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl; said C 1-6 alkyl can optionally be substituted with one or more substituents selected from halo or C 3-15 cycloalkyl; or R 8a and R 8b together with the carbon atom to which each is attached form a C 3-15 cycloalkyl; said C 3-15 cycloalkyl can optionally be substituted with one or more substituted or unsubstituted C 1-6 alkyl;

[0026] R 9 is selected from the group consisting of 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 is H or C 1-6 alkyl;

[0029] R 9b is 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 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl, C(=O)(C 1-6 alkyl); said C 1-6 alkyl can optionally be substituted with one or more halo or C 1-6 alkoxy;

[0031] cyclic C is selected from 3-12 membered heterocyclyl, C 3-15 cycloalkyl or 5-10 membered heteroaryl; wherein said 3-12 membered heterocyclyl, C 3-15 cycloalkyl or 5-10 membered heteroaryl can optionally be substituted with one or more R Ca substituents;

[0032] said R Ca is selected from: halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or NR c R d ;

[0033] two R Ca groups on the same or different ring atoms, together with the ring atom(s) to which each is attached, can collectively form a 3-8 membered cycloalkyl group;

[0034] said R c and R d are independently selected from the group consisting of 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 said 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) are each optionally substituted with one or more substituents independently selected from -OH, halo, C 1-6 alkoxy.

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

[0036] More preferably, said ring A and ring D are each independently selected from a substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl. Said 6-10 membered aryl, 5-10 membered heteroaryl can be a monocyclic group or a fused ring group. Said fused ring group can be a bicyclic or tricyclic fused ring group.

[0037] Said 6-10 membered aryl is more preferably phenyl.

[0038] The 5-10 membered heteroaryl group is more preferably a 5-6 membered monocyclic heteroaryl group or a 7-10 membered bicyclic heteroaryl group. The heteroatom of the 5-6 membered monocyclic heteroaryl group includes any one or more of N, O, and S. The 7-10 membered bicyclic heteroaryl group can be a bicyclic heteroaryl group formed by the fusion of a phenyl group and a monocyclic heteroaryl group, or a bicyclic heteroaryl group formed by the fusion of two monocyclic heteroaryl groups. The monocyclic heteroaryl group is preferably a 5-6 membered monocyclic heteroaryl group. The heteroatom of the 5-6 membered monocyclic heteroaryl group includes any one or more of N, O, and S.

[0039] Preferably, at least one of rings A and D is replaced by 1 to 3 SF5 molecules.

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

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

[0042] ;

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

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

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

[0046] In some implementations, T 1 T 2 T 4 and T 5 One of them is N; and T 1 T 2 T 4and T 5 each of the remaining ones in T QA is independently CH or CR 1 , T 2 , T 4 and T 5 each of the remaining ones in T

[0047] Preferably, R QA is 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 heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-8 membered cycloalkyl. The 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl can be monocyclic or fused ring group. The fused ring group can be bicyclic or tricyclic fused ring group.

[0048] More preferably, R QA is 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, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl.

[0049] Oxo in the present application refers to a functional group in a molecule containing an oxygen atom attached to a central atom in an organic molecule, the above-mentioned oxygen atom is attached to a carbon atom, forming a carbonyl structure.

[0050] Preferably, R a and R b are independently selected from 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 1-6each of which is optionally substituted with 1 or more substituents independently selected from -OH, halo, C 1-6 The number of said substituents is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1.

[0051] Preferably, R c1 and R d1 are independently selected from the group consisting of 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 said 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) are each optionally substituted with 1 or more substituents independently selected from -OH, halo, C 1-6 alkoxy, the number of said substituents is preferably 1 to 6, more preferably 1 to 3, and even more preferably 1.

[0052] The C 1-6 alkyl, C 1-6 alkoxy can be optionally substituted with one or more of the following: halo, -OH, NR c1 R d1 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or 3- to 12-membered heterocyclyl; said 3- to 12-membered heterocyclyl can be optionally substituted with one or more of the following: -OH, C 1-6 alkyl, 3- to 12-membered heterocyclyl; the number of said substituents is preferably 1 to 6, more preferably 1 to 4.

[0053] The 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 8-membered cycloalkyl can be optionally substituted with one or more of the following: C 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- to 12-membered heterocyclyl; said 3- to 12-membered heterocyclyl can optionally be substituted with one or more C 1-6 alkyl or C(=O)C 1-6 alkyl; preferably 1 to 6, more preferably 1 to 4.

[0054] said R c1 , R d1 are as described before.

[0055] or said R QA is selected from -L a -S(O)2-L b -R e ;

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

[0057] said L b is selected from: a single bond, -O-, -N(H)-, -N(R c )- or -(CR h R h ) q2 -;

[0058] when said L a is selected from a single bond, it is meant that said L a is absent and said R QA is -S(O)2-L b -R e .

[0059] when said L b is selected from a single bond, it is meant that said L b is absent and said R QA is -L a -S(O)2-R e .

[0060] said q 1 and q 2 are independently selected from 1, 2, 3 or 4; when said q 1 and q 2 are independently selected from 2, 3 or 4, it is meant that the corresponding group is repeated 2, 3 or 4 times. Said q1 and q 2 More preferably, n is 1 or 2.

[0061] said R e is selected from H, C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 8-membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkyl, C 3-6 alkyl, C 1-3 alkyl, C 1-3 haloalkyl, -OH, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, C 1-3 alkyl, C 1-3 alkyl, C

[0062] In some embodiments, R e is C 1-6 alkyl or C 1-6 haloalkyl, each of which is optionally substituted with one to three substituents each independently selected from 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 alkyl, C 1-3 alkyl, C e haloalkyl. In some embodiments, R 1-6 is C e alkyl. For example, R 1-3 may be C h alkyl, such as methyl or ethyl.

[0063] said R 1-6 is selected from H, halo, C 3-6 alkyl, C h cycloalkyl; or two R h on the same or different carbon atoms, together with the carbon atom(s) to which they are attached, form a C 3-6 cycloalkyl or 4- to 8-membered heterocyclyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl or 4- to 8-membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, C 1-3 alkyl, C 1-3haloalkyl, -OH, C 1-3 alkoxy or C 1-3 haloalkoxy substituted.

[0064] In some embodiments, each occurrence of R h is H. In some embodiments, each occurrence of R h 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, each occurrence of R h is C 1-3 alkyl (e.g., methyl); and each remaining R h is H.

[0065] said R c are as previously described;

[0066] and when L a is a single bond, -L b -R e is not unsubstituted C 1-3 alkyl.

[0067] In some embodiments of the application, said R QA is selected from any of the following groups:

[0068] ;

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

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

[0071] wherein R j and R k are independently selected from the following groups: substituted or unsubstituted C 1-6 alkyl, C 3-6 cycloalkyl or C 6-10 aryl; which C 1-6 alkyl, C 3-6 cycloalkyl or C 6-10 aryl can optionally be substituted with one or more of the following groups: C 1-6 alkoxy, C 1-6 haloalkoxy, 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, said C 1-6 alkyl is optionally substituted with one or more substituents selected from C 1-6 alkoxy, C 3-6 cycloalkyl, halogen, cyano; said C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from C 1-3 alkyl or halogen; said C 6-10 aryl is optionally substituted with one or more substituents selected from C 1-3 alkyl.

[0073] or R j and R k together with the phosphorus atom to which each is attached form a 5-8 membered heterocyclyl, which is optionally substituted with one or more substituents selected from C 1-6 alkyl; the heteroatom of the 5-8 membered heterocyclyl is P or includes one or more of O, S, N and P;

[0074] In some embodiments of the application, said R j and R k are independently selected from substituted or unsubstituted C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with one or more substituents selected from C 1-3 alkoxy, C 3-6 cycloalkyl or halogen.

[0075] Said R j and R k may be the same or different.

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

[0077] In preferred embodiments of the application, the GLP-1 agonist of Formula I has from 1 to 4 QA substituents.

[0078] R QB is SF5.

[0079] In preferred embodiments, each of ring A and ring D is independently selected from phenyl or from a five- or six-membered heteroaryl and a phenyl fused to form a fused aryl. The heteroatoms of the five- or six-membered heteroaryl are preferably any one or more of N, O, or S. More preferably, the five- or six-membered heteroaryl is selected from a heteroaryl having from 1 to 3 N atoms. In some embodiments of the application, the five- or six-membered heteroaryl is selected from imidazolyl, pyrazolyl, or triazolyl.

[0080] In preferred embodiments, each of ring A and ring D is 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 is independently selected from CR 10 R 11 or NR 12 ;

[0084] R 10 , R 11 , R 12 is independently selected from halogen, C 1~10 alkyl, or null; more preferably F, Cl, Br, C 1~6 alkyl, or null.

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

[0086] R 10 , R 11 , R 12 is null in order to satisfy the valency of the C or N atom.

[0087] R QA is as previously described.

[0088] R QB is SF5.

[0089] and optionally, R QA is in the meta position relative to R QB .

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

[0091] In preferred embodiments of the present application, L2is selected from any one of the following structures:

[0092] .

[0093] In preferred embodiments of the present application, L 1 is -C(=O)-.

[0094] Ring B is selected from any one of the following structures:

[0095]

[0096] wherein bb represents the point of attachment to L 1 .

[0097] R 4 , R 5 , R 6 and R 7 are 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, R 8a and R 8b are independently selected from H, substituted or unsubstituted C 1-6 alkyl; the C 1-6 alkyl can optionally be substituted with one or more substituents selected from halogen or C 3-15 cycloalkyl; or R 8a and R 8b together with the carbon atom to which each is attached form a C 3-15 cycloalkyl; the C 3-15 cycloalkyl can optionally be substituted with one or more substituted or unsubstituted C 1-6 alkyl.

[0101] Preferably, R 8a and R 8b together with the carbon atom to which each is attached form a C 3-8 cycloalkyl; the C 3-8 cycloalkyl can optionally be substituted with one or more substituted or unsubstituted C 1-6alkyl groups. The number of said substituents is preferably 1 to 2.

[0102] More preferably, said R 8a and R 8b together with the carbon atom to which each is attached form a substituted or unsubstituted cyclopropyl or cyclobutyl group; said cyclopropyl and said cyclobutyl group can optionally be substituted with one or more substituted or unsubstituted C 1-6 alkyl groups.

[0103] said substituents C 1-6 alkyl groups can be further substituted with one or more secondary substituents selected from the group consisting of:

[0104] halo, -OH, NR c R d , C 1-6 alkoxy, C 1-6 haloalkoxy and 3- to 12-membered heterocyclyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of -OH, C 1-6 alkyl and 3- to 12-membered heterocyclyl. Said R c , R d are in the range as described before and will not be repeated here.

[0105] Further preferably, said R 8a and R 8b together with the carbon atom to which each is attached form any of the following groups:

[0106] .

[0107] said R 9 is selected from the group consisting of 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 is H or C 1-6 alkyl; preferably H or C 1-3 alkyl;

[0110] R 9b is 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 are independently selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl, C(=O)(C 1-6 alkyl); said C 1-6 alkyl is optionally substituted with one or more halogen or C 1-6 alkoxy; more preferably H, substituted or unsubstituted C 1-3 alkyl, C(=O)(C 1-3 alkyl); said C 1-3 alkyl is optionally substituted with one or more halogen or C 1-3 alkoxy.

[0112] Preferably, said R 9 has the following structure:

[0113]

[0114] said R 9d is selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more halogen or C 1-6 alkoxy; more preferably H, substituted or unsubstituted C 1-3 alkyl; said C 1-3 alkyl is optionally substituted with one or more halogen or C 1-3 alkoxy.

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

[0116] .

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

[0118]

[0119] wherein at least one of said ring A and said L 2 connected phenyl is substituted with one or more SF5;

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

[0121] said R 8c is selected from H, substituted or unsubstituted C 1-6 alkyl, more preferably H, substituted or unsubstituted C 1-3 alkyl. Said C 1-6 alkyl or said C 1-3 alkyl can be optionally substituted with one or more of the following substituents:

[0122] halo, -OH, NR c R d , C 1-6 alkoxy, C 1-6 haloalkoxy and 3-12 membered heterocyclyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of -OH, C 1-6 alkyl and 3-12 membered heterocyclyl. Said R c , R d are in the same range as described before, which is not 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 , m1 are in the same range as described before, which is not repeated here.

[0124] Preferably, said R QA is in meta or para position relative to L 2 .

[0125] Preferably, said moiety in the structure of formula I-a or formula I-b is selected from the following structures:

[0126] .

[0127] Further preferably, said GLP-1 agonist has the structure of formula I-a-1, or a pharmaceutically acceptable salt or solvate thereof:

[0128]

[0129] R QB is SF5.

[0130] In formula I-a-1, ring C, L 1 , L 2 , R 1 -R 7 ​R 9 R QA m1 is as previously described, and R 8c is as described for Formula I-a or I-b, which is not repeated here.

[0131] Preferably, R QA is in the meta or para position relative to L 2 .

[0132] Preferably, R in the structure of Formula I-a-1 is selected from the following structures:

[0133] .

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

[0135]

[0136] R QB is SF5.

[0137] In Formula I-a-1, ring C, R 1 R 7 , R 9 , R QA , m1 is as previously described, and R 8c is as described for Formula I-a or I-b, which is not repeated here.

[0138] Further preferably, the GLP-1 agonist has the structure of 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; and b is any integer from 0 to 3;

[0142] R j and R k are independently selected from substituted or unsubstituted C 1-6 alkyl; which C 1-6 alkyl can optionally be substituted with one or more of C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, -OH, NH2, NH(C1-3 alkyl), N(C(=O) (C 1-3 alkyl), 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] said T1, T2, T3, T4, T5are independently selected from NR 12 , O, S or CR 13 R 14 ;

[0144] said R 12 , R 13 and R 14 are independently selected from H, halogen, substituted or non-substituted C 1~6 alkyl, C 1~6 alkoxy; said C 1~6 alkyl, C 1~6 alkoxy can be optionally substituted with one or more substituents selected from halogen, cyano.

[0145] Preferably, any one of said T1, T2, T3, T4, T5is O, and the rest are CR 13 R 14 .

[0146] Further preferably, said T3is O, and the rest are CR 13 R 14 .

[0147] Preferably, said T1, T2, T3, T4, T5form a six-membered ring having the following structure:

[0148] .

[0149] said R ca is selected from H, halogen, substituted or non-substituted C 1~6 alkyl, C 1~6 alkoxy; said C 1~6 alkyl, C 1~6 alkoxy can be optionally substituted with one or more substituents selected from halogen, cyano.

[0150] More preferably, said R ca is selected from H, halogen, substituted or non-substituted C 1~3 alkyl, C 1~3 alkoxy; said C 1~3Alkyl, C 1~3 The alkoxy group may optionally be substituted by one or more substituents selected from halogens or cyano groups.

[0151] More preferably, the R ca 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 described above, R 8c The scope is as described in general formula I-a or I-b, and will not be repeated here.

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

[0154] Due to the uncertainty of the structure-activity relationship of drugs, this invention introduces an SF5 group into the structure of the GLP-1 agonist and studies several other structural groups. The experimental results show that:

[0155] When L2 is selected Ring B is selected from When constructing the compound, by introducing SF5, the compound can simultaneously achieve high activity and bioavailability.

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

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

[0158] When P(=O)Me2, P(=O)Et2, or P(=O)iPr2 is used, the compound exhibits the highest activity and bioavailability. Under conditions of halving the dosage, C values ​​comparable to or even higher than those of existing compounds can be obtained. 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 application also provides a salt form of the GLP-1 agonist described above.

[0164] The salt can be a pharmaceutically acceptable salt or other salt, including but not limited to an intermediate useful for preparing and / or purifying the compound of Formula (I) and / or isolating an enantiomer of the compound of Formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compound of Formula (I) include trifluoroacetate.

[0165] The present application also provides a solvate of the GLP-1 agonist described above. The compound of Formula (I) or salt thereof can be isolated in the form of a solvate, and any such solvate is included within the scope of the present application. For example, the compound of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

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

[0167] using an intermediate of Formula A and an intermediate of Formula B as raw materials, performing an amination reaction to obtain an intermediate of Formula C;

[0168] using the intermediate of Formula C as a raw material, preparing the GLP-1 agonist of Formula I;

[0169]

[0170] wherein, ring A, R 1 -R 3 are in the range described above;

[0171] Pg is an amino protecting group.

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

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

[0174] The source of the intermediate of Formula A is not particularly limited in the present application, and can be commercially available or prepared according to methods well known to those skilled in the art, preferably 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 and the intermediate represented by Formula A-4 are subjected to reaction 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, the ring A, R 1 -R 3 The range of R is as described above.

[0180] Optionally, the condensation reaction of the intermediate represented by Formula A-1 and the intermediate represented by Formula A-2 is treated with HCl gas in DCM at room temperature, followed by treatment with Py-HCl in EtOH under reflux.

[0181] Optionally, the reaction of the intermediate represented by Formula A-3 and the intermediate represented by Formula A-4 is carried out in a solvent selected from polar aprotic solvents, including but not limited to THF; optionally, the reaction is carried out in the presence of a basic compound, which can be sodium hydroxide, aqueous sodium carbonate or the like.

[0182] The method for preparing the GLP-1 agonist represented by Formula I from the intermediate represented by Formula C is not particularly limited in the present application, and can be a method known 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 temperature for the reaction is preferably 50-70°C, more preferably 60°C. The secondary amino group can be protected by Boc2O.

[0185] Optionally, the protecting group of compound I5 is removed to obtain compound I6. The method for removing the amino protecting group is not particularly limited in the present application, and can be a method known to those skilled in the art. Optionally, the removal is carried out under acidic conditions, which include but are not limited to HCl solution, and the solvent includes but is not limited to 1,4-dioxane.

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

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

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

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

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

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

[0192] The aforementioned diabetes includes, but is not limited to, type 1 diabetes, type 2 diabetes, early onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), youth-onset autoimmune diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain induced by use of other agents, gout, excessive sugar craving, 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, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic kidney failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, bipolar disorder / severe depression, skin and connective tissue disorders, foot ulcer, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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, impaired cognition, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

[0193] Preferably, the aforementioned diabetes is type 2 diabetes or obesity.

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

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

[0196] Definitions

[0197] Where values are described as ranges, it is to be understood that the disclosure is along the entire range of values and any particular value within the overall range of values, whether the particular value is expressly identified or not.

[0198] As used herein, the term "halogenated" 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-chain or branched monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having one to six carbon atoms. Non-limiting examples of alkyl groups 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. For example, "C 3-6 "Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon having three to six cyclic carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may contain multiple fused and / or bridging rings. Non-limiting examples of fused / bridging 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 similar groups. Cycloalkyl also includes spirocyclic (e.g., spirobicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, 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 similar groups.

[0201] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring system (e.g., a 3- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system) containing the indicated number of ring atoms, 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, the heteroatoms selected from O, N, or S (e.g., carbon atoms, and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms, respectively, in the case of monocyclic, bicyclic, or tricyclic rings), wherein 0, 1, 2, or 3 atoms of each ring can be substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl groups can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl groups include: 2-azabicyclo[l. l.0]butane, 2-azabicyclo[2. l.0]pentane, 2-azabicyclo[l. l. l]pentane, 3-azabicyclo[3. l.0]hexane, 5-azabicyclo[2. l. l]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4. l.0]heptane, 7-azabicyclo[2.2. l]heptane, 6-azabicyclo[3. l. l]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2. l]octane, 2-oxabicyclo[l. l.0]butane, 2-oxabicyclo[2. l.0]pentane, 2-oxabicyclo[l. l. l]pentane, 3-oxabicyclo[3. l.0]hexane, 5-oxabicyclo[2. l. l]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4. l.0]heptane, 7-oxabicyclo[2.2. l]heptane, 6-oxabicyclo[3. l. l]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2. l]octane, and the like. Heterocyclyl groups also include spiro rings (e.g., spiro bicyclic rings in which two rings are connected via only one atom).Non-limiting examples of spirocyclic heterocyclyl groups 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-oxa-9-azaspiro[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 in which at least one ring in the system is aromatic (e.g., a C6monocyclic, C10bicyclic, or C14tricyclic 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 group 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 ring containing a heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. A heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothiophenyl, benzoxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][l,4]dioxine, benzo[d][l,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][l,4]oxathiine, isoindoline, and the like.

[0204] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms have been replaced with 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 on the oxygen atom. For example, C 1-6 As used herein, the term "alkoxy" refers to an -O-(C1-6alkyl) group, wherein the group is on the oxygen atom. Examples of alkoxy groups 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, "n" indicates a single or double bond as valence allows. As used herein, "n" indicates a single or double bond as valence allows.

[0207] As used herein, "n" indicates a single or double bond as valence allows. As used herein, "n" indicates a single or double bond as valence allows.

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

[0209] As used herein, the term "tautomer" refers to a compound whose structure differs significantly from that of another, but which is readily and rapidly equilibrating, and it is understood that the compounds provided herein can be depicted as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present application, and the naming of a compound does not exclude any tautomer.

[0210] The term "GLP-1R" or "GLP-1R receptor" as used herein 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] The term "GLP-1 related disease" as used herein 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] The term "GLP-1 agonist" or "GLP-1 RA" as used herein refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in the fasting and postprandial state; and slow gastric emptying.

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

[0214] The term "effective amount" or "effective dose" or "pharmaceutically effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a chemical entity to relieve to some extent one or more of the symptoms of the disease or condition from which the subject is treated, and can include curing the disease. By "cure" is meant the elimination of symptoms of active disease. The result includes alleviation and / or remission of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein, which is required to eliminate clinically significant adverse effects of a disease. An 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 when used as a monotherapy or in a 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, vehicle, solvent, or encapsulating material. In some embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a drug formulation and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, 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) or a pharmaceutically acceptable salt or solvate thereof as described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickeners. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist and include, but are not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0217] The term "treat," "treating," or "treatment" in the context of treating a disease, disorder, or condition is intended to include alleviating or abrogating one or more symptoms of the disorder, disease, or condition or symptoms associated with the disorder, disease, or condition; or to exasperate, slow or stop the progression, spread or worsening of the disease, disorder, or condition or one or more symptoms thereof.

[0218] The term "prevent," as used herein, is to prevent the onset, recurrence, or spread of a disease or condition, or symptoms thereof, completely or partially.

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

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

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

[0222] The terms “treatment regimen” and “administration procedure” are used interchangeably to refer to the dosage and timing of the various therapeutic agents administered in the combination of the present invention.

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

[0224] As used herein, the term "combination therapy" refers to a regimen of administration of two different therapeutic agents (i.e., components or combinations thereof), wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or by a regulatory body as defined herein.

[0225] As used herein, the term “regulation” refers to control or adjustment (e.g., increase or decrease) and may include, for example, activating, partially activating or antagonizing effects.

[0226] Compared with existing technologies, the present invention provides a GLP-1 agonist having the structure shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof. The present invention provides a GLP-1 agonist with high activity and bioavailability. Detailed Implementation

[0227] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0228] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0229] Analytical methods, materials and instruments

[0230] Reagents and solvents were used as received from commercial vendors unless otherwise noted. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer at 400 MHz or 600 MHz. Spectra are given in delta (δ) values with the solvent as the internal standard. The following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet, coupling constants are in Hz, and integrations are given between parentheses. High resolution mass spectrometry (HRMS) was collected using a Bruker SolariX XR.

[0231] The 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-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0241] HCl hydrochloric acid

[0242] iPr isopropyl

[0243] Me methyl

[0244] MeOH methanol

[0245] m / z mass to charge ratio

[0246] NMP N-methyl pyrrolidone

[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 scheme 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)-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

[0259]

[0260] Into a 250 mL single necked flask was added 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). Then the reaction was heated to 85 °C for 2 hours. The reaction was cooled to room temperature and the ethanol was removed by concentration. 2N sodium hydroxide aqueous solution was added to the residue until pH 9-10, a yellow solid was precipitated, filtered and dried to get a light 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 get (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 (8 g, yield 81.5%) as a light yellow solid. o C was reacted for 2 hours. The reaction was cooled to room temperature and the ethanol was removed by concentration. 2N sodium hydroxide aqueous solution was added to the residue until pH 9-10, a yellow solid was precipitated, filtered and dried to get a light 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 get (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 (8 g, yield 81.5%) as a light 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] Into a 100 mL three-necked flask, was placed (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 the temperature was lowered to 0 °C. Then chloroformic acid-2,2,2-trichloroethyl ester (4.4 mL, 32.04 mmol, 4 eq) was added dropwise. Then the temperature was slowly raised to room temperature and stirred overnight. To the reaction system was added 20 mL water, and extracted with EA (30 mL*3). The organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA = 10 / 1-8 / 1) to give (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 (4.3 g, yield 97.7%) as a light yellow solid. o C, dropwise chloroformic acid-2,2,2-trichloroethyl ester (4.4 mL, 32.04 mmol,4 eq). Then slowly raise to room temperature and stir overnight. To the reaction system was added 20 mL water, and extracted with EA (30 mL*3). The organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil. The crude product was purified by column (silica gel, 200-300 mesh, PE / EA = 10 / 1-8 / 1) to give (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 (4.3 g, yield 97.7%) as 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)-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

[0265]

[0266] Into a 250 mL single necked flask, was placed (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 (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 the reaction was stirred at 100 °C for 1 h under argon protection. The reaction was poured into 100 mL ice water, 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 give a yellow solid. To the crude product was added PE / EA (20 / 1, 40 mL), stirred for 10 min, then filtered and dried to give (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 (2.4 g, 83.3% yield) as a white solid. o C was stirred at 100 °C for 1 h under argon protection. The reaction was poured into 100 mL ice water, 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 give a yellow solid. To the crude product was added PE / EA (20 / 1, 40 mL), stirred for 10 min, then filtered and dried to give (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 (2.4 g, 83.3% yield) as a 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)-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

[0268]

[0269] To a 100 mL single necked flask was added (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), then methanesulfonic acid (0.29 mL, 4.430 mmol, 0.8 eq) was added. The resulting mixture was stirred at 60 °C for 2 hours. Cooled to room temperature, a solution of potassium phosphate (1.18 g, 5.538 mmol, 1.0 eq) in water (12 mL) and Boc20 (483.4 mg, 2.215 mmol, 0.4 eq) was added, then stirred at room temperature overnight. 10 mL water was added to the reaction system, extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give 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. o C stirred for 2 hours. Cooled to room temperature, a solution of potassium phosphate (1.18 g, 5.538 mmol, 1.0 eq) in water (12 mL) and Boc20 (483.4 mg, 2.215 mmol, 0.4 eq) was added, then stirred at room temperature overnight. 10 mL water was added to the reaction system, extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give 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 = 6.2 Hz, 2H), 6.34 (d, J = 2.7 Hz, 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 = 2.1 Hz, 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 flask was added (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 (600 mg, 1.359 mmol, 1.0 eq) and DCM (4 mL), then 4N HCl(g) / 1,4-dioxane solution (3.4 mL, 13.6 mmol, 10 eq) was added dropwise under ice water bath. After the addition was completed, the reaction system was slowly raised to room temperature and stirred overnight. Concentration, vacuum drying 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 = 6.2 Hz, 2H), 6.62 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 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 = 2.2 Hz, 6H), 1.29 (d, J = 6.6 Hz, 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 neck flask containing (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, 1.1 eq) in DMF (4 mL) was added DIPEA (424 uL, 2.435 mmol, 5 eq). The mixture was then stirred at room temperature under argon overnight. To the reaction was added 5 mL water and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (5 mL*6), dried over anhydrous sodium sulfate and rotary evaporated to give the 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, 92.2% yield), 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]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (180 mg, 0.245 mmol, 1.0 eq), 4-bromophenylsulfonium 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), followed by the addition of CuI (9.3 mg, 0.049 mmol, 0.2 eq). The reaction system was incubated at 130 °C under argon protection. o React at C for 1 hour. Cool to room temperature, add 5 mL of water, and extract with EA (10 mL * 6). Wash the organic phase with saturated brine (10 mL * 6), dry to anhydrous sodium sulfate, and evaporate to dryness to obtain a black oily substance. Purify the crude product by column chromatography (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 at 80 °C... o C. Stir for 5 minutes, then at 40°C. o Stir at C for 1 hour, then stir overnight at room temperature. Filter and collect the white precipitate, then dry under vacuum 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]pyridin-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 = 8.5 Hz, 1H), 7.32 (s, 1H), 7.26 (dd, J = 8.6, 1.7 Hz, 1H), 7.14 (d, J = 6.3 Hz, 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 = 2.2 Hz, 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 25 mL single neck flask containing (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, 2.265 mmol, 5 eq). The mixture was then stirred at room temperature under argon protection overnight. To the reaction was added 5 mL water and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate and rotary evaporated to get the 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 get 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)indolizidin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (245 mg, yield 75%) as a 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-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine-5-carbonyl)indolizidin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0286]

[0287] (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.0776 mmol, 0.4 eq) and potassium carbonate (53.6 mg, 0.388 mmol, 2.0 eq) were dispersed into anhydrous NMP (1.5 mL), then CuI (7.4 mg, 0.0388 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated to get black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1) to get 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 (45 mg, yield 25.1%), light yellow solid. o Creacted for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated to get black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1-120 / 1) to get 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 (45 mg, yield 25.1%), light yellow solid. 1 H NMR (600 MHz, DMSO-d6, 60 oC) δ 11.86 (br. s, 1H), 8.14 (d, J = 7.3 Hz, 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, 1.9 Hz, 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 25 mL single neck flask containing (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, 3.125 mmol, 5 eq). The mixture was then stirred at room temperature under argon overnight. To the reaction was added 10 mL water and extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate and concentrated to give the 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)indolizidin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (340 mg, 75.5% yield), 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-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine-5-carbonyl)indolizidin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0294]

[0295] (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (23 mg, 0.161 mmol, 0.4 eq) and potassium carbonate (111 mg, 0.804 mmol, 2.0 eq) were dispersed into anhydrous NMP (3 mL), then CuI (15 mg, 0.0804 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated to get 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 get 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 (178 mg, yield 48%), light yellow solid. o Creacted for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated to get 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 get 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 (178 mg, yield 48%), light yellow solid. 1 H NMR (600 MHz, DMSO-d6, 60 oC) δ 11.85 (br. s, 1H), 8.14 (d, J = 7.3 Hz, 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, 1.9 Hz, 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 = 8.6 Hz, 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 / z 959.29493 (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 25 mL single neck flask containing (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) was added DIPEA (544 uL, 3.125 mmol, 5 eq). The mixture was then stirred at room temperature under argon protection overnight. To the reaction system was added 10 mL water and extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate and rotary evaporated to get the 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 get (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)indolizidin-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)indolizidin-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, 0.4 eq) and potassium carbonate (100 mg, 0.722 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (14 mg, 0.0722 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated 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 obtain (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%), light yellow solid. o Creacted for 1 hour. After cooling to room temperature, 5 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, and rotary evaporated 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 obtain (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%), light yellow solid. 1 H NMR (600 MHz, DMSO-d 6, 60 oC) δ 11.86 (br. s, 1H), 8.15 (d, J = 7.3 Hz, 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 = 9.8 Hz, 1H), 4.09 (br. s, 1H), 3.97 (dd, J = 11.1, 4.2 Hz, 2H), 3.46 (t, J = 11.5 Hz, 2H), 3.40 (br. s, 1H), 2.86-2.68 (m, 3H), 2.20 (s, 6H), 1.79-1.72 (m, 2H), 1.70-1.60 (m, 4H), 1.44 (br. s, 1H), 1.35-1.28 (m, 4H). 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] Into a 100 mL three-necked flask, concentrated sulfuric acid (4.5 mL) and sodium nitrite (1.10 g, 15.96 mmol, 1.06 eq) were added successively. The white slurry obtained above was then cooled to 5-10 o C, dropwise added a solution of 4-(pentafluorothio)phenylamine (3.3 g, 15 mmol, 1.0 eq) in glacial acetic acid (16.8 mL) at a rate to keep the internal temperature below 10 o C. After the addition was completed, the reaction mixture was stirred at 24-26 oC for 30 minutes, then heated to 60 o C, continue stirring for 1 hour. The reaction system is cooled to 5 o C, dropwise add tin dichloride dihydrate (13.9 g, 61.5 mmol, 4.1 eq) in concentrated hydrochloric acid (10 mL). Exothermic during dropwise addition, control the internal temperature not more than 10 o C. White sticky solid appears in the reaction system. After stirring in an ice water bath for half an hour, filter, and transfer the filter cake to a mixture of 28% ammonia water (56 mL) and crushed ice (14 g) in batches. After stirring at room temperature for half an hour, filter with diatomite, and wash the filter cake with ether. Separate the filtrate, extract the aqueous phase with ether (50 mL*4), wash the ether phase with saturated brine (50 mL*3), dry over anhydrous sodium sulfate, and rotary evaporate to obtain yellow oil, which solidifies after standing overnight, to obtain 4-(pentafluorothio)phenylhydrazine (2.5 g, yield 70.8%), 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)-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

[0310]

[0311] Into a 250 mL single-neck flask equipped with a condenser, add 4-(pentafluorothio)phenylhydrazine (2.96 g, 12.64 mmol, 1.0 eq), (2S)-3-cyano-2-methyl-4-oxopiperidine-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). Then heat to 90 oThe reaction was allowed to react for 2 hours. After cooling to room temperature, the reaction solution was poured into water (30 mL) and the pH was adjusted to 9-10 with 1 mol / L aqueous sodium hydroxide solution. Extraction was performed with ethyl acetate (30 mL*3). The organic phase was combined, washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6.5 g of a yellow solid. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA = 10 / 1-8 / 1-6 / 1) to obtain (S)-tert-butyl 3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.62 g, yield 97.9%), a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 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 = 6.6 Hz, 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] Into a 50 mL two-necked flask was added (S)-tert-butyl 3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.0 g, 2.2 mmol, 1.0 eq), saturated aqueous sodium carbonate solution (3.3 mL) and THF (20 mL), and then cooled to 0 °C. After the addition of sodium borohydride (0.2 g, 5.4 mmol, 2.5 eq), the reaction was allowed to react for 2 hours. After cooling to room temperature, the reaction solution was poured into water (30 mL) and the pH was adjusted to 9-10 with 1 mol / L aqueous sodium hydroxide solution. Extraction was performed with ethyl acetate (30 mL*3). The organic phase was combined, washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6.5 g of a yellow solid. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA = 10 / 1-8 / 1-6 / 1) to obtain (S)-tert-butyl 3-amino-4-methyl-2-(4-(pentafluorothio)phenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.62 g, yield 97.9%), a light yellow solid. oC, drop chloroformic acid-2,2,2-trichloroethyl ester (1.2 mL, 8.8 mmol, 4 eq). After the end of the addition, slowly rise to room temperature and stir overnight. Supplement chloroformic acid-2,2,2-trichloroethyl ester (0.3 mL, 1 eq), then continue to react for 1 hour. Add 10 mL of water to the reaction system, extract with EA (10 mL*3). The organic phase is washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The crude product is purified by column (silica gel, 200-300 mesh, PE / EA=20 / 1-15 / 1-10 / 1) to obtain (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 (1.16 g, yield 84%), 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] Into a 100 mL single-necked flask, add (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 (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, 110 oThe reaction was allowed to react for 2 hours. The reaction system was reduced 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%), 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] Into a 50 mL single-necked flask was added (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, 1.571 mmol, 1.0 eq) and THF (10 mL), then methanesulfonic acid (82 uL, 1.257 mmol, 0.8 eq) was added at room temperature. The resulting mixture was heated to 60 °C for 2 hours. The reaction was allowed to react for 2 hours. The reaction system was reduced 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%), white foamy solid. oC Stir for 2 hours. Cool to room temperature, add potassium phosphate (333.5 mg, 1.571 mmol, 1.0 eq) in water (4 mL) and Boc20 (137 mg, 0.628 mmol, 0.4 eq), then stir at room temperature overnight. Add 5 mL water to the reaction system, extract with EA (10 mL*3). Wash the organic phase with saturated brine (10 mL*3), dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain a white solid. Purify the crude product by column chromatography (silica gel, 200-300 mesh, PE / EA = 5 / 1-3 / 1-2 / 1-1 / 1) to obtain (S)-tert-butyl 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-carboxylate (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 = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 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 = 6.6 Hz, 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] To a 50 mL single necked flask was added (S)-4-methyl-3-(2-oxo-2,3-dihydro-lH- imidazol-l-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), then 4N HC1(g) / 1,4-dioxane solution (3.35 mL, 13.4 mmol, 10 eq) was added dropwise under ice water bath. After the addition was completed, the reaction system was slowly warmed to room temperature and stirred for 2 hours. Concentration and drying gave (S)-l-(4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride (620 mg, yield 100%) as a white solid.

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

[0325]

[0326] To a 50 mL single neck flask containing (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, 6.70 mmol, 5 eq). The mixture was then stirred at room temperature under argon overnight. To the reaction was added 20 mL water and extracted with mixed solvent DCM / MeOH (20 / 1, 20 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and rotary evaporated to give the 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 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] (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (10.7 mg, 0.0749 mmol, 0.4 eq) and potassium carbonate (51.8 mg, 0.375 mmol, 2.0 eq) were dispersed into anhydrous NMP (2 mL), then CuI (7.1 mg, 0.0375 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 3 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to get 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 get 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%), yellowish solid. o Creacted for 3 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to get 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 get 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%), yellowish solid. 1H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 7.3 Hz, 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, 1.9 Hz, 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] (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, 0.4 eq) and potassium carbonate (96.7 mg, 0.7 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (13.3 mg, 0.07 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with DCM (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated 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-(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%), light yellow solid. o Creacted for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with DCM (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated 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-(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%), 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] (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, 0.4 eq) and potassium carbonate (96.7 mg, 0.7 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (13.3 mg, 0.07 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 3 hours. After cooling to room temperature, 10 mL of water was added, and extracted with DCM (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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%), light yellow solid. o Creacted for 3 hours. After cooling to room temperature, 10 mL of water was added, and extracted with DCM (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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%), light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 8.5 Hz, 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, 1H), 2.96-2.91 (m, 4H), 2.79 (br. s, 2H), 1.76-1.60 (m, 4H), 1.59-1.41 (m, 3H), 1.31-1.26 (m, 7H), 1.20 (s, 3H). 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 50 mL single neck flask containing (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, 8.19 mmol, 5 eq). The mixture was then stirred at room temperature under argon overnight. To the reaction was added 10 mL water and extracted with EA (20 mL*5). The organic phase was washed with saturated brine (20 mL*5), dried over anhydrous sodium sulfate and concentrated to give the 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 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] (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (26.7 mg, 0.1875 mmol, 1.5 eq) and potassium carbonate (34.6 mg, 0.250 mmol, 2.0 eq) were dispersed in anhydrous NMP (2 mL), then CuI (35.7 mg, 0.1875 mmol, 1.5 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1 hour. After cooling to room temperature, 5 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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%), light yellow solid. o Creacted for 1 hour. After cooling to room temperature, 5 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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%), light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.86 (br. s, 1H), 8.24 (br. s, 1H), 8.14 (d, J = 7.3 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.72-7.44 (m, 4H), 7.30 (br. s, 1H), 7.09-7.03 (m, 2H), 6.72 (dd, J = 7.3, 1.9 Hz, 1H), 6.45 (s, 1H), 5.73 (br. s, 1H), 4.11 (s, 4H), 3.72 (d, J = 8.7 Hz, 2H), 3.42 (br. s, 1H), 2.99-2.88 (m, 1H), 2.87-2.69 (m, 2H), 1.85-1.60 (m, 4H), 1.59-1.42 (m, 3H), 1.40-1.24 (m, 7H), 1.20 (s, 3H). 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] (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, 0.150 mmol, 0.4 eq) and potassium carbonate (103.5 mg, 0.749 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (14.3 mg, 0.075 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 1.5 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to obtain a brown-yellow 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 obtain 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%), light yellow solid. o Creacted for 1.5 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to obtain a brown-yellow 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 obtain 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%), 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] (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, 0.150 mmol, 0.4 eq) and potassium carbonate (103.5 mg, 0.749 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (14.3 mg, 0.075 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 3 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column chromatography (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%), light yellow solid. o Creacted for 3 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column chromatography (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%), 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 neck flask containing (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, 1.2 eq) in DMF (10 mL) was added DIPEA (1.33 mL, 7.67 mmol, 5 eq). The mixture was then stirred at room temperature under argon overnight. To the reaction was added 10 mL water and extracted with EA (20 mL*5). The organic phase was washed with saturated brine (20 mL*5), dried over anhydrous sodium sulfate and rotary evaporated to give the 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, 88% yield), 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] (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-pyrrolo[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), then CuI (14 mg, 0.074 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 3 hours. After cooling to room temperature, 10 mL of water was added and extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and rotary evaporated to give 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-((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-pyrrolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol- 5(4H)-one (45 mg, yield 12.7%), white solid. o Creacted for 3 hours. After cooling to room temperature, 10 mL of water was added and extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and rotary evaporated to give 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-((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-pyrrolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol- 5(4H)-one (45 mg, yield 12.7%), 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] (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), then CuI (14 mg, 0.074 mmol, 0.2 eq) was added. The reaction system was stirred at 130 °C under argon protection for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH = 150 / 1-120 / 1-100 / 1-80 / 1) to give 230 mg of a light yellow solid. o C. The reaction was stirred at 130 °C for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH = 150 / 1-120 / 1-100 / 1-80 / 1) to give 230 mg of a light yellow solid.

[0371] The 230 mg of crude product was dispersed in 4 mL of anhydrous ethanol, then stirred at 80 °C for 5 minutes, 40 °C for 1 hour, and finally stirred at room temperature overnight. The white solid was collected by filtration and dried under vacuum 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%), white solid. o C. The reaction was stirred at 130 °C for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH = 150 / 1-120 / 1-100 / 1-80 / 1) to give 230 mg of a light yellow solid. o C. The reaction was stirred at 130 °C for 1.5 hours. After cooling to room temperature, 10 mL of water was added, and it was extracted with mixed solvent DCM / MeOH (20 / 1, 10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give a brown-yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH = 150 / 1-120 / 1-100 / 1-80 / 1) to give 230 mg of a light yellow 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] To a solution of 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) in anhydrous NMP (3 mL) was added CuI (14 mg, 0.074 mmol, 0.2 eq). The reaction was stirred at 130 °C for 24 h under argon. The reaction was cooled to room temperature and 10 mL of water was added. The mixture was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and concentrated to give a brown yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 200 mg of a yellow solid. o C for 1.5 h. After cooling to room temperature, 10 mL of water was added and the mixture was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and concentrated to give a brown yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 200 mg of a yellow solid.

[0377] The 200 mg of crude product was dispersed in 3.5 mL of anhydrous ethanol, then stirred at 80 °C for 5 min, 40 °C for 1 h and finally at room temperature overnight. The white solid was collected by filtration and dried under vacuum 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. o C for 1.5 h. After cooling to room temperature, 10 mL of water was added and the mixture was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and concentrated to give a brown yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 200 mg of a yellow solid. o C for 1.5 h. After cooling to room temperature, 10 mL of water was added and the mixture was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate and concentrated to give a brown yellow solid. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=150 / 1-120 / 1-100 / 1-80 / 1) to give 200 mg of a yellow 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 50 mL single neck flask containing 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)indolizin- 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, 5 eq). The mixture was then stirred at room temperature under argon protection overnight. To the reaction system was added 10 mL water, extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*6), dried over anhydrous sodium sulfate, rotary evaporated to give 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%), 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, 0.4 eq) and potassium carbonate (71.5 mg, 0.5176 mmol, 2.0 eq) were dispersed in anhydrous NMP (2 mL), then CuI (10 mg, 0.052 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 4 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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), 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%), yellowish solid. o C was reacted for 4 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give 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), 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%), yellowish solid. 1H NMR (600 MHz, DMSO-d6) δ 11.87 (br. s, 2H), 8.23 (s, 1H), 8.15 (d, J = 7.3 Hz, 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, 0.4 eq) and potassium carbonate (100 mg, 0.725 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (14 mg, 0.0725 mmol, 0.2 eq) was added. The reaction system was heated to 130 °C under argon protection. After 1.5 hours, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*5), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the 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 obtain (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%), light yellow solid. o Creacted for 1.5 hours. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*5), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the 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 obtain (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%), light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (br. s, 1H), 8.16 (d, J = 7.3 Hz, 1H), 8.10-7.45 (m, 9H), 7.30 (s, 1H), 7.12 (br. s, 1H), 6.74 (dd, J = 7.3, 1.9 Hz, 1H), 6.45 (s, 1H), 5.74 (br. s, 1H), 4.11 (br. s, 1H), 3.98 (dd, J = 11.3, 4.2 Hz, 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, 0.4 eq) and potassium carbonate (100 mg, 0.725 mmol, 2.0 eq) were dispersed in anhydrous NMP (3 mL), then CuI (14 mg, 0.0725 mmol, 0.2 eq) was added. The reaction system was protected by argon and heated to 130 °C for 3 hours. It was cooled to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the 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 obtain (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%), light yellow solid. o Creacted for 3 hours. It was cooled to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and it was extracted with EA (10 mL*4). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to obtain the 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 obtain (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%), light yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.86 (br. s, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.84-7.35 (m, 7H), 7.30 (s, 1H), 7.05 (br. s, 1H), 6.73 (dd, J = 7.3, 1.9 Hz, 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, 4.2 Hz, 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] Add 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) to a 100 mL single-necked flask. After purging with argon three times, add TEA (983 μL, 7.070 mmol, 2 eq). Then heat to 60 °C. o The reaction was carried out overnight at C. The reaction system was cooled to room temperature, and 1,4-dioxane was concentrated to remove it. 10 mL of water was added to the residue, and the mixture was extracted with EtOAc (10 mL * 3). The organic phase was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a brown oil. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA / MeOH = 1 / 1 / 0-1 / 2 / 0-1 / 2 / 0.1-1 / 4 / 0.1) to give (4-bromophenyl)diethylphosphine oxide (640 mg, yield 69.3%), a pale 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]pyridin-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, 0.276 mg (1.5 eq) and potassium carbonate (51 mg, 0.368 mmol, 2 eq) were dispersed in anhydrous NMP (5 mL), followed by the addition of CuI (52.6 mg, 0.276 mmol, 1.5 eq). The reaction system was incubated at 130 °C under argon protection. o React at C for 1 hour. Cool to room temperature, add 10 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 to anhydrous sodium sulfate, and evaporate to dryness to obtain a black oily substance. Purify the crude product by column chromatography (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 resulting yellow solid was slurried with diethyl ether / n-hexane (1v / 5v, 5mL), filtered, and dried under vacuum 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]pyridin-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%), a pale yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.97-7.75 (m, 4H), 7.65 (br. s, 2H), 7.56-7.44 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 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, 3.7 Hz, 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, 7.6 Hz, 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, 0.3624 mmol, 2 eq) were dispersed in anhydrous NMP (5 mL), then CuI (52 mg, 0.2718 mmol, 1.5 eq) was added. The reaction system was heated to 130 °C under Ar protection. After 1 hour, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1-40 / 1) to give yellow crude. Then the obtained yellow crude was 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%), light yellow solid. o Creacted for 1 hour. After cooling to room temperature, 10 mL of saturated aqueous sodium carbonate solution was added, and extracted with EA (10 mL*3). The organic phase was washed with saturated brine (10 mL*4), dried over anhydrous sodium sulfate, and rotary evaporated to give black oil. The crude product was purified by column (silica gel, 200-300 mesh, DCM / MeOH=100 / 1-80 / 1-60 / 1-40 / 1) to give yellow crude. Then the obtained yellow crude was 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%), 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]pyridin-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), followed by the addition of CuI (52.6 mg, 0.276 mmol, 1.5 eq). The reaction system was incubated at 130 °C under argon protection. o React at C for 1 hour. Cool to room temperature, add 10 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 to anhydrous sodium sulfate, and evaporate to dryness to obtain a black oily substance. Purify the crude product by column chromatography (silica gel, 200-300 mesh, DCM / MeOH = 80 / 1-60 / 1-40 / 1) to obtain 140 mg of a yellow solid.

[0415] Disperse 140 mg of the crude product in 2.4 mL of anhydrous ethanol, then at 80 °C... o C. Stir for 5 minutes, 40 o Stir at C for 1 hour, then stir overnight at room temperature. Filter and collect the white solid, then dry under vacuum 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%), a white solid. 1H NMR (600 MHz, DMSO-d6) δ 11.61 (br. s, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.74-7.59 (m, 3H), 7.52 (br. s, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.6 Hz, 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 = 12.4 Hz, 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, 7.5 Hz, 6H). HRMS: m / z 1046.35484 (M+Na) + .

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

[0417] Step 1) Cell treatment and plating. Take well-grown HEK293 cells expressing GLP-1R receptor, after digestion with 0.25% Trypsin-EDTA, count with trypan blue staining, collect cells, adjust the cell density with detection diluent, add 100 μL / well into a 96-well plate, the number of cells is 5 x 10 4 / well; place the above 96-well plate in a 37 °C, 5% CO2 incubator overnight.

[0418] Step 2) Sample addition. Discard the culture medium in the 96-well plate of Human GLP-1R (Luc) HEK293 Reporter Cell cells, add the agonist sample to be detected and Tirzepatide (Chinese name: Tizpatide) diluent and DMSO diluent into the corresponding 96-well plate, i.e. 80 μL / well of diluent is added to the sample detection well, 2 replicate wells. The blank well is added with the same volume of detection diluent.

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

[0420] Step 4) Readout. The cell plate was removed and equilibrated to room temperature, and 80 μΐ^of an equal volume of ONE-Glo™ Luciferase solution was added, and the cells were lysed by shaking on a microplate shaker for 2 minutes. The contents were mixed (20 to 25 pipetting strokes) per well by pipette and 110 μΐ^was transferred to a corresponding white opaque 96-well microplate. The plates were read for RLU values using a microplate chemiluminescence reader.

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

[0422] As shown in Table 1, the compounds presented effective h-GLP-1 agonistic 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 structure formulas and EC 50 values

[0424]

[0425] Example 21: Pharmacokinetic testing of compounds

[0426] The compounds of the present application were formulated in 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100 mM 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 were collected at 0.25 hour, 0.5 hour, 1 hour, 2 hour, 4 hour, 6 hour, 8 hour, and 24 hour post-dose. Compound concentrations were determined by LC-MS, and pharmacokinetic parameters were calculated by WinNonlin 8.2 using a non-compartmental analysis model. The PK parameters of representative compounds are listed in Table 2.

[0427]

[0428] Control compounds

[0429] Table 2. PK parameters of the compounds

[0430]

[0431] The data in Table 1 and Table 2 show that the compounds provided by the present application have both high activity and bioavailability, and at a lower dosage, still meet the peak concentration requirements of drugs.

[0432] The above examples are only used to help understand the method of the present application and its core idea. It should be noted that for those skilled in the art, without departing from the principles of the present application, the present application can be improved and modified in several ways, and these improvements and modifications also fall within the scope of protection of the claims of the present application.

Claims

1. A GLP-1 agonist having a structure shown in formula I-a-2, or a pharmaceutically acceptable salt thereof: formula I-a-2; wherein, the a is 1; the b is any integer from 0 to 3. The GLP-1 agonist has any one of the following structures, or a pharmaceutically acceptable salt thereof: R 9 selected from the group consisting of (IX-2): The R 9d For H; Ring C is ; The R Ca selected from: C 1-6 straight-chain alkyl.

2. The GLP-1 agonist of claim 1, wherein, said R QA is selected from the group consisting of ； The GLP-1 agonist has any one of the following structures, or a pharmaceutically acceptable salt thereof: 6.A method for preparing the GLP-1 agonist according to any one of claims 1 to 5, comprising the following steps:

3. The GLP-1 agonist of claim 1, wherein, The R QA .

4. A GLP-1 agonist characterized in that, aminoating an intermediate shown in formula A and an intermediate shown in formula B to obtain an intermediate shown in formula C; 。 5. The GLP-1 agonist of claim 4, wherein, preparing the GLP-1 agonist shown in formula I from the intermediate shown in formula C; 。 Pg is an amino protecting group. 7.A GLP-1 agonist composition comprising the GLP-1 agonist according to any one of claims 1 to 5, and a pharmaceutically acceptable excipient. 8.Use of the GLP-1 agonist according to any one of claims 1 to 5 or the GLP-1 agonist composition according to claim 7 in the preparation of a drug for preventing, treating and / or alleviating diabetes. ; R 1 -R 3 、R QB as in any one of claims 1 to 3; ​ ​ ​

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